REVIEW

Aging and the Male Reproductive System

Jean-Marc Kaufman,1 Bruno Lapauw,1 Ahmed Mahmoud,1 Guy T’Sjoen,1
and Ilpo Tapani Huhtaniemi2,3

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1
Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium; 2Department of Surgery and
Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN,
United Kingdom; and 3Department of Physiology, Institute of Biomedicine, University of Turku, 20520 Turku,
Finland
ORCiD numbers: 0000-0002-1400-6812 (J.-M. Kaufman); 0000-0002-1584-4965 (B. Lapauw);
0000-0001-6200-5817 (A. Mahmoud); 0000-0003-0457-9673 (G. T’Sjoen);
0000-0001-9092-7886 (I. T. Huhtaniemi).

ABSTRACT This narrative review presents an overview of current knowledge on fertility and reproductive hormone changes in aging
men, the factors driving and modulating these changes, their clinical consequences, and the benefits and risks of testosterone (T)
therapy. Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show a mild total T
decline, an SHBG increase, a steeper free T decline, and a moderate LH increase with important contribution of comorbidities (e.g.,
obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and are partly responsive to T therapy.
The relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on
body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily
with estradiol and SHBG. Cognitive decline is not consistently linked to low T and is not improved by T therapy. Although limited
evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive
symptoms, and vitality in elderly patients with low T. Suboptimal T (and/or DHT) has been associated with increased risk of stroke,
but not of ischemic heart disease, whereas an association with mortality probably reflects that low T is a marker of poor health.
Globally, neither severity of clinical consequences attributable to low T nor the nature and magnitude of beneficial treatment effects
justify the concept of some broadly applied “T replacement therapy” in older men with low T. Moreover, long-term safety of T
therapy is not established. (Endocrine Reviews 40: 906 – 972, 2019)

A part from the physiological cessation of ovarian

ISSN Print: 0163-769X
ISSN Online: 1945-7189
Printed: in USA
Copyright © 2019
Endocrine Society
Received: 16 July 2018
Accepted: 27 December 2018
First Published Online:
19 March 2019
function at menopause, the clinically most
important and best characterized aging-related changes
in the endocrine system concern pancreatic and thyroid
function. Other endocrine systems, for example, adrenal
function and GH/IGF- secretion, also undergo changes
upon aging, caused either directly by chronological aging
or indirectly by aging-associated changes in general
health, body composition, physical activity, and life-
style. Function of the hypothalamic–pituitary–testicular
(HPT) axis is not an exception, and the extent, clinical
significance, and treatment options of its age-related
deterioration are currently a topical and controversial
issue.
Testosterone (T) is the major anabolic hormone in
men as well as a key player in maintaining normal
reproductive and sexual function. The population mean
of serum T levels declines with aging as a consequence
of the aging process per se and/or lifestyle changes and
comorbidities, although the changes in serum T vary
greatly among individuals. Clinical changes with aging,
which also occur at a variable pace among individual
men, are in several aspects reminiscent of signs and
symptoms of hypogonadism in younger men (). It is
therefore not surprising that possible links between
these hormonal and clinical changes have been the
subject of investigation and speculation. Indeed, a causal
relationship would in turn hold the appealing promise

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 REVIEW

ESSENTIAL POINTS
· In aging men there is a mild to moderate decline of gamete quality and fertility, which is accompanied by a relative
increase of the risk of adverse offspring outcome, but absolute risk remains low
· Hormonal changes in aging men are individually variable, with mean levels in the population showing a mild
decline of total testosterone (T), an increase of SHBG, a more pronounced decline of free T, and a moderate
increase of LH
· Comorbidities and, in particular, the increased prevalence of obesity play an important contributory role in the hormonal
changes in aging men: hypogonadism related to comorbidities tends to be of the secondary type, whereas changes related
to aging appear to be primarily testicular
· Among the most consistent associations with low T in elderly men are the occurrence of sexual symptoms and lower
hematocrit, and both seem at least partly responsive to T therapy
· The association of low T with mortality most likely reflects reverse causality, with low T a marker of poorer health

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status
· Overall, neither the severity of clinical adverse effects attributable to low T, nor the nature and magnitude of beneficial
treatment effects justify the concept of a broadly applied T replacement therapy in older men with low T
· Long-term (cardiovascular and prostate) safety of T therapy has not been established

of possible beneficial antiaging effects of T “re-
placement” therapy. In fact, the appeal of such ten-
tative benefits of T therapy has been such that it has
translated during the last two decades into an
exploding increase of T use by middle-aged and elderly
men. This trend, which is particularly alarming in the
United States (, ), has apparently not been dis-
couraged by major knowledge gaps as to the benefit/
risk profile of T therapy in these men (), and it is not
in line with the much more cautious and restrictive
recommendations by scientific societies (, ) and the
US Food and Drug Administration (FDA) () on
indications for T prescriptions. An apparent decline in
T prescriptions seen since  (, ) may be linked to
the warning by the FDA and the voluntary cessation
by drug companies of direct-to-consumer marketing
of T products.
The decline of androgen levels in elderly men and
its clinical and therapeutic implications were ex-
tensively reviewed in this journal in  (). As to
clinical implications, the conclusion was then nu-
anced, acknowledging that the hormonal changes
might play a contributory role in part of the clinical
alterations that accompany aging in some men, but
concluding that for many clinical signs and symp-
toms reminiscent of the clinical picture in young
hypogonadal men, the data remained inconclusive as
to the causal role of age-related decline of androgen
levels. The conclusion was frankly negative as to the
place of T therapy outside established pronounced
symptomatic hypogonadism, because of lack of data
from randomized controlled trials (RCTs) on hard
clinical endpoints and because the scale of performed
RCTs would clearly not allow for establishing clinical
benefit and, even less so, long-term safety.
An updated review of the evidence seems timely for
several reasons. First, a substantial amount of new data
has become available. Whereas observational data
available for the  review () were mostly from
retrospective and cross-sectional studies, since then
prospectively obtained data are now available from
several large cohorts. Also, significantly contributing
new data from RCTs have become available. Second,
changes in gonadal function in aging men and their
potential clinical consequences are of increasing clinical
relevancy, not only because of demographics with an
increasing number and proportion of elderly men in
the population, but even more so because the assertive
generation of aging baby boomers has high expecta-
tions as to quality of life and functional fitness in all
domains, encompassing cognitive, physical, and sexual
function. Moreover, there is the reality of the wide-
spread misuse of, and publicity for, T therapy in the
management of physical performance. Finally, reports
suggesting increased cardiovascular (CV) risk associ-
ated with T therapy (, ) and the FDA March 
safety announcement () have generated discussion
and controversy. The FDA announced that manu-
facturers are required to change labeling of T products
to add information on possible increased risk of
heart attack and stroke in patients taking T and to
clarify that prescription of T products is approved only
for therapy in men with low T due to certain condi-
tions, that is, due to disorders of the testicles, pituitary
gland, or brain that cause hypogonadism. Moreover,
the FDA states explicitly that, “The benefit and safety of
these medications have not been established for the
treatment of low testosterone levels due to aging, even
if a man’s symptoms seem related to low testosterone”.
This narrative review presents an updated overview
of the state of knowledge on changes in testicular
function in aging men, the clinical consequences, and
the benefits and risks of T therapy. We focus primarily
on human data and largely on studies published since

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REVIEW
the  review. For clinical data, we gave as much
priority as possible to studies with stronger design; for
example, for evaluation of efficacy of T therapy we
Spermatogenesis and Reproductive Capacity in
Aging Men
Parenthood is increasingly postponed, especially in
developed countries. Advanced age of childbearing
has been related to sociodemographic factors ().
Data from the United States indicated that mean
paternal age has increased on average by . years
during the past  years ( to ) from . to
. years of age (). Advanced paternal age is most
commonly (but not universally) defined as . years
of age ().
Age-related changes in spermatogenesis
A recent systematic review and meta-analysis evalu-
ated semen data from almost , men extracted
from  studies (). The results indicated a consistent
age-dependent decline in semen quality. Age was
associated with small to moderate declines in semen
volume, total sperm count per ejaculate, percentage
motility, progressive motility, and normal morphol-
ogy. Sperm concentration did not decline with
increasing age. A significant increase in sperm DNA
fragmentation has also been observed. Overall,
declined progressive motility and increased DNA
fragmentation were the most conspicuous age-
related changes. Some studies have reported age
thresholds for the onset of decline in sperm quality,
with the earliest decline starting from the age of 
to  years (, ).
The observed small decline in total sperm count
with age in the meta-analysis discussed above () is
corroborated by the results of a cross-sectional study
of testicular volume (mostly representing sper-
matogenic tissue) and inhibin B (a marker of Sertoli
cell function and spermatogenesis) in elderly
community-dwelling men  to  years of age ().
The study indicated that the mean testicular volume
in men . years of age is % smaller than in -
to -year-old men. This difference in testicular
volume is accompanied by an almost twofold
elevation of serum FSH levels. Serum inhibin B
was slightly but significantly lower in the elderly
men by %, resulting in a marked decrease in the
inhibin B/FSH ratio. The latter findings together
with the reduced testicular volume are consistent
with the concept that in elderly men Sertoli cell
mass is reduced (), with a compensatory in-
crease of FSH stimulation allowing for global
Sertoli cell function (and spermatogenesis) to
remain relatively stable. Another study also
reported a modest decrease of testicular size from
908 Kaufman et al Aging and the Male Reproductive System
retained only RCTs. Thus, albeit comprehensive, this
review does not intend to exhaustively cover all aspects
of the topic.
an average maximum of . cm  between  and
 years of age to  cm  between  and  years
of age (), again in line with the relatively well-
preserved spermatogenic function of the aged
testis. Histomorphometric studies on testes of
men between young adulthood and old age de-
tected clear age-related changes, albeit with large
individual variation (, ). The most common
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feature of an aging testis is a mosaic of seminif-
erous tubular lesions ranging from complete
spermatogenesis to complete sclerosis of the
seminiferous epithelium. The changes include
narrowing of tubular diameter, thickening of basal
membrane with arrested spermatogenesis and fi-
brosis, and reduction of number of Sertoli and
spermatogenic cells, with vacuolization of the
former and multinucleation of the latter. How-
ever, spermatozoa are observed even in testes of
the oldest men. Thickening and herniation of the
basal membrane with dilatation of seminiferous
tubules can also be observed (–), as well as
increased fibrosis and weight of tunica albuginea
().
Age-related changes in fertilizing capacity
Several studies indicate that increasing male age is
significantly associated with rising time to spontane-
ous pregnancy and declining fertility rate [reviewed in
()]. For example, a study of  planned preg-
nancies indicated that, compared with men , years
of age, the ORs, adjusted for maternal age, for con-
ception in # months were ., ., and . in
men aged  to ,  to , and $ years, re-
spectively (). The oldest reported age at biologically
confirmed parenthood is . years (). There have
been reports of fatherhood at an older age, but these
were not confirmed with the now available tools to
biologically establish paternity.
Data from a prospective study of almost ,
pregnant women () indicated that pregnancies fa-
thered by a man aged $ years had almost twice the
risk of ending in a fetal loss compared with preg-
nancies with younger fathers [hazard ratio (HR),
.]. The paternal age effect tended to be stronger for
late fetal death. There are also a few studies suggesting
that male age may play a negative role in the success of
intrauterine insemination cycles [reviewed in ()].
Conflicting results are reported on the effect of pa-
ternal age on the outcome of in vitro fertilization
(IVF) with or without intracytoplasmic sperm in-
jection (ICSI) [reviewed in (, , )]. A recent
study by Wu et al. () revealed that there were no
Endocrine Reviews, August 2019, 40(4):906–972

differences in the implantation and pregnancy rates in
conventional IVF cycles between the different pa-
ternal age groups when maternal age was , and 
to  years. However, implantation and pregnancy
rates decreased with paternal age in the - to -year-
old maternal age group. Ma et al. () recently
reported a lower OR of live birth and a higher risk of
abortion in the paternal age group of $ years in
IVF/ICSI cycles. Wu et al. () found that increased
paternal age negatively influences the number of high-
quality embryos, but it has no effect on pregnancy
outcomes in couples undergoing IVF/ICSI cycles.
Paternal age did not affect ongoing pregnancy rates in
the first IVF/ICSI cycles as reported by Meijerink et al.
(), but live births were not taken into account. Few
data are available on the outcome of testicular sperm
extraction in advanced paternal age. One study
found that paternal age as an independent factor did
not affect embryo quality and pregnancy outcomes
of IVF/ICSI using testicular spermatozoa (). In
summary, the bulk of evidence supports, although
not unequivocally, a decline in male fertility with
increasing age in both unassisted and assisted
reproduction.
Pathophysiologic mechanisms underlying changes
in reproductive capacity
Several local urogenital and systemic changes oc-
curring with advancing age [see Table  (, , ,
, –)] can contribute to decreased coital
frequency, decreased semen quality and impaired
sperm genetic integrity and reproductive capacity,
increased fetal loss, and adverse health outcomes in
the offspring.
Offspring health
Although older paternal age does not appear to pose
an independent risk of adverse perinatal outcomes, in
pregnancies achieved either with or without assisted
reproductive technology (), negative effects on
physical and mental health in later life have been
reported as summarized below [Table  (, , –)].
The age-related (epi)genetic and genomic changes that
occur in the male germ line have been recently
reviewed (). The authors documented an increase in
congenital birth defects and neurologic disorders and a
statistically significant increase in -year offspring
mortality.
Reviews of studies on mental health indicate a
tripling of the risk of schizophrenia and autistic
spectrum disorders in children of fathers . years
of age compared with fathers aged  to  years
(), a % increased risk of bipolar disease for
children whose fathers were . years of age at their
birth compared with children of younger fathers
(), as well as lower intelligence and learning
abilities with older paternal age. Fathers , of age
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REVIEW
and . years of age sired offspring with lesser mean
intelligence scores (). Relative risks (RRs) are high
for an adverse health outcome in the offspring (RR,
. to .), but absolute risks remain small. For
example, for a father . years of age, the RR for
achondroplasia in the offspring is . with an ab-
solute risk of  out of  [for details, see Ram-
asamy et al. ()]. Counseling regarding the risks of
advanced paternal age should still be conducted with
all couples. Sperm cryopreservation is a possible
option. No current guidelines recommend the
routine use of preimplantation genetic diagnosis/
screening based on advanced paternal age alone ().
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Conclusion
Unlike the situation in the female, the decline in
gamete quality and fertility in the male is only mild
to moderate and gradual, possibly starting at the age
of  to  years. This decline is accompanied by an
increase in the RRs of adverse outcomes affecting
physical and mental health of the offspring. The
absolute risks, however, remain small, precluding a
screening strategy or dissuading fatherhood at a
particular age (). Counseling concerning these effects
is, however, recommended (, , ). Semen cryopres-
ervation at a young age is a possible option, but there are
currently no studies reporting on the outcome. The effect
of treatments aiming at improving male fertility, for “Unlike for total serum T, the
example, varicocele correction () and therapy with findings on free T are quite
antioxidants (), are largely unexplored in men . uniform, with all reporting an
age-related decline….”
years of age.
Sex Steroids in Aging
Influence of aging on blood concentrations
Testosterone
Most studies report a slow aging-related decline in
the circulating concentration of T, starting during
the third to fourth decade of life and continuing
gradually until extreme longevity (). The decline is
not only due to chronological aging, but it is also
strongly influenced by the concomitant weight gain
and other common aging-associated comorbidities
(Fig. ). Longitudinal studies report annualized
decreases of T with a range of .% to .% (–).
Cross-sectional studies showed somewhat smaller
changes (, ). Cohort and secular effects, labo-
ratory drift, and stability of samples upon storage
may explain the difference. One clear confounder is
the expanding epidemic of obesity, which is bound
to differently affect T levels at the two ends of an
observation period, with effects of weight gain
augmenting the apparent age effect. The European
Male Aging Study (EMAS) found the cross-sectional
decline of T in men between  and  years of age
to be .% per year (), and the longitudinally
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Table 1. Factors That May Contribute to Decreased
Reproductive Capacity in Advanced Paternal Age
Hormonal and metabolic changes, for example, decreased T
(see text in this review)
Testicular changes, decreased testicular volume
Body weight increase
Decreased physical activity and lean muscle mass
Decreased bulk and strength of pelvic floor muscles
Systemic disease (e.g., CVD, hypertension, malignancies)
Urogenital disease (including infections, prostatic disease,
varicocele)
Therapy (for prostatic disease, hypertension, hypogonadism,
malignancy)
Erectile and ejaculatory dysfunction, decreased libido, and
coital frequency
Cumulative effects of lifelong exposures to toxins and
pollutants
Excessive generation of reactive oxygen species (DNA
damage)
Genetic changes (e.g., mutations, aneuploidy)
Epigenetic changes (DNA methylation, histone modifications,
and miRNA expression)
assessed decline during a .-year follow-up was
.% per year (). The annualized decline of
testicular steroidogenesis appears to accelerate with
advancing age, as an annualized % decline of T and
.% of DHT was recently reported in men between
 and  years of age (). Another study in men 
to  years of age (mean,  years of age) at baseline
reported an annualized .% T decline during 
years ().
The decreasing trend of T can be found in
random community-dwelling populations, but when
men in exceptionally good health are studied, some
(, ), but not all (), cross-sectional studies have
found no significant age-related decline of T. Also,
several older studies were unable to document the
predominant finding of aging-related decline in
serum total T (). In the absence of convincing
longitudinal data, the effect of aging alone on T
remains open. Interestingly, recent cross-sectional
and longitudinal studies from Japan, Korea, and
China (–) reported either no aging-related
change or increases in T, which persisted after ad-
justment for usual confounders, thus suggesting
ethnic differences in this phenomenon. In conclu-
sion, the majority of studies show a slight gradual
decline in total T levels in men upon aging. The
disparate findings may have multiple explanations,
910 Kaufman et al Aging and the Male Reproductive System
including ethnicity, cohort selection, and analytical
factors. Importantly, however, T concentration in
most aging men remains within the range of young
men, and the levels infrequently drop to the clearly
hypogonadal range.
Unlike for total serum T, the findings on free T
are quite uniform, with all reporting an age-related
decline, usually of the order of .% to .% per
annum [e.g., see ()]. This is explained by the
constant finding of an aging-related increase of
SHBG by ~% per year, which results in a decline of
free T. However, in real life, the increase of SHBG
can be counterbalanced by an opposite trend caused
by obesity and other health problems (see below).
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Therefore, the real impact of T changes has to be
assessed on the basis of increased SHBG due to aging
and the concomitant decrease caused by comor-
bidities. As a representative example of longitudinal
changes, in the EMAS the annual longitudinal de-
crease of total T was .%, the increase of SHBG
was .%, and calculated free T decreased by .%
per year (). The levels of bioavailable, that is,
non–SHBG-bound T (the sum of free T and
albumin-bound T), decline in parallel with free T
upon aging (, ). The mechanisms of aging- and
obesity-dependent changes in SHBG are discussed
below.
Active T metabolites
Besides T, aging-related changes also occur in
concentrations of its two active metabolites, that is,
DHT and estradiol (E). Although well-validated
immunoassay methods are able to reliably monitor
male serum T levels (see below), only the results of
newer mass spectrometry (MS)–based measure-
ments of DHT and E can be considered reliable (,
). DHT levels are ~- to -fold lower than those
of T, and there is high correlation (r 5 .) between
concentrations of the two androgens (). One study
has established the reference range (mean 6  SD)
of DHT for healthy men  to  years of age as .
to . nmol/L (). Handelsman et al. () ob-
served in a large population-based sample (n .
,) that DHT levels change minimally before
the age of  years but decrease gradually thereafter
from a mean of . to . nmol/L in men . years
of age (i.e., by ~.% per year). However, it is ap-
parent that circulating concentrations of DHT are a
poor indicator of action of this hormone, whose
action in target tissues (e.g., prostate) is largely
independent of serum levels but is determined by
in situ conversion of T to DHT (). Also, the
concentration of a weak androgen and substrate
of T production, androstenedione, decreases with
aging ().
Data on aging-related changes in E are in-
consistent [reviewed in ()] due at least in part to
poor accuracy of the immunoassays used in older
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Table 2. Adverse Health Outcomes in the Offspring in Advanced Paternal Age

Disorder RR (or Other) Reference
Reviewed in (9, 11, 39–43) .
Craniosynostotic diseases Abbreviation: NA, not available.

Apert syndrome 9.5 (11)

Crouzon syndrome 8 (11)

Pfeiffer syndrome 6 (11)

Affected growth/connective tissues

Achondroplasia 7.8 (11)

Thanatophoric dysplasia NA (strong evidence) (41)

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Osteogenesis imperfecta NA (strong evidence) (41)

Syndactyly NA (strong evidence) (41)

Cleft palate NA (medium evidence) (41)

Multiple endocrine neoplasia syndromes (MEN2A and MEN2B) NA (42)

Neurofibromatosis I 3.7 (11)

Marfan syndrome NA (strong evidence) (41)

Down syndrome 1.37 (11)

Klinefelter syndrome 1.6 (11)

Retinoblastoma 3 (11)

Brain tumors 1.69 (11)

Childhood leukemia 1.14 (11)

Non-Hodgkin lymphoma 1.51 (40)

Breast cancer 1.6 (11)

Increased 5-y mortality 1.65 (HR) (43)

Epilepsy 1.3 (11)

Bipolar disease 1.37 (40)

Schizophrenia 2.9 (39)

Autistic spectrum disorders 3.45 (HR) (39)

Lower intelligence NA (40)

Lower learning abilities 1.70 (OR) (40)

studies. By MS, the concentrations of E are,
according to Handelsman et al. (), relatively stable,
showing a minor .% annual decrease. Hsu et al.
() found in a -year follow-up study in a group of
apparently healthy men, from the baseline age of 
years a % annual increase of E and a % decrease
in estrone. In a very recent .-year longitudinal
study on -year-old men E levels remained stable
(). Jasuja et al. () reported age-related increases
between  to  and 1 years in both E (.% per
year) and estrone (.% per year), and that the
changes were only partly explained by body mass
index (BMI), diabetes status, and comorbidities.
Thus, several studies have found E levels to increase
during aging, unlike the age-related decreasing
trends of T and DHT. A higher conversion rate of T
to E (in adipose tissue) and increased SHBG levels
in aged men may explain the E findings. However,
calculated free E and non–SHBG-bound E still
show an age-dependent decrease (, ).

doi: 10.1210/er.2018-00178 https://academic.oup.com/edrv 911

REVIEW

Adrenal androgens immunoassays documented longitudinal annual

The adrenal gland also produces androgens and
their precursor steroids, most notably dehydro-
epiandrosterone (DHEA) and its sulfate conjugate
(DHEAS). Their production and secretion clearly
decrease with aging in both sexes. This decrease is
functionally significant in women, but because of
their weak androgenic activity, their overall contri-
bution to male androgens is of lesser importance.
Several earlier studies have monitored the aging-
related changes in adrenal androgen production in
men [e.g., see (, , )]. Earlier studies using
decreasing trends of .% for DHEA, .% to .% for
DHEAS, and .% for androstanediol glucuronide
(, , ). Some discrepant findings, demon-
strating no age-related changes in adrenal andro-
gens, are most likely due to regression to the mean
[reviewed in ()]. The concentration of circulating
T in castrated men is ~% of that in intact men,
which apparently represents the contribution of
adrenal androgens to serum T ().
A comprehensive study of Labrie et al. ()
showed a dramatic decline (% to %) in the

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Figure 1. Relationship between age, BMI, total and free T, LH, and SHBG of 3220 men aged 40 to 79 y, from the EMAS. The cohort was
stratified according to BMI into men who are nonobese (BMI ,25 kg/m2), overweight (BMI of 25 to 30 kg/m2), and obese (BMI .30 kg/
m2). The graphs present mean (with 95% CI in shaded area and vertical lines) levels of total and free T, LH, and SHBG. (a) Total T
concentration decreases in men who are overweight/obese compared with nonobese men at all ages. (b) Free T, similar to total T, is
reduced in men who are overweight/obese compared with nonobese men at all ages. (c) LH increases with age, but is not associated
with BMI, and it was not significantly different among the three BMI groups at the median age of 60 y. LH was higher in nonobese
patients aged .70 y compared with the overweight and obese groups, owing to a negative age interaction. (d) SHBG increases with age.
For total T and SHBG, the age trends in the three BMI categories were similar, indicating lack of interaction between BMI and age. The
free T vs age trend in the group with obesity was less steep than in the other two groups, indicating an interaction between BMI and age.
Male reference ranges are as follows: T, 288 to 1009 ng/dL (10 to 35 nmol/L); free T, 7.2 to 20.2 ng/dL (250 to 700 pmol/L); LH, 1.5 to 8.0
IU/L; SHBG, 13 to 62 nmol/L. [Reproduced with permission from Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis
disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol
Metab 2008;93(7):2737–2745.]

912 Kaufman et al Aging and the Male Reproductive System Endocrine Reviews, August 2019, 40(4):906–972

circulating levels of several adrenal androgens [DHEA,
DHEAS, -androstene-b,b-diol (-diol), -diol-
sulfate, -diol-fatty acid esters, and androstenedione]
in a cross-sectional study between the ages of  to 
years. Most of the decline took place before the age of
 years. Solvent extraction and chromatography were
used to improve specificity of the immunoassay
measurements. It was calculated that the adrenals
contribute to % to % of the molar content of
androgens in the circulation of a middle-aged man.
However, the adrenal contribution to androgen bio-
activity is much less, because most adrenal androgens
have low or marginal bioactivity.
A recent study () measured by liquid
chromatography–tandem MS (LC-MS/MS) the ref-
erence intervals for  steroids (pregnenolone, pro-
gesterone, -deoxycorticosterone, corticosterone,
aldosterone, -oxycortisol, -hydroxycortisol,
-hydroxyprogesterone, -deoxycortisol, -deoxy-
cortisol, cortisol, cortisone, DHEA, DHEAS, andros-
tenedione, and T) in men and women between 
and  years of age. Strong negative correlation with
age was observed with all steroids, both of testicu-
lar and adrenal origin (with the exception of
-deoxycortisol). Of note was that the age-related
decrease of T lost significance in this study after ad-
justment for BMI.
Factors affecting blood levels of T in the elderly
Many of the factors discussed below are not directly
related to aging, but rather they contribute to the large
individual variability ( to  nmol/L) prevailing in
circulating total T levels. However, their importance
may vary during a man’s lifespan and become more
important in old age when the body’s compensatory
capacity is approaching its limits.
Ethnic differences
Limited and variable data exist on the effects of
ethnicity on T levels. Besides genetics, regional and
ethnic differences in lifestyle factors may confound
these findings. For example, Asian men have pro-
portionally more visceral fat compared with Euro-
pean men (), which may impinge differently on
their HPT function. Total T and calculated free T
concentrations have been reported to be lower in
Pakistani compared with white European and Af-
rican Caribbean men, all living in the United
Kingdom (). A similar study compared serum T
and several end manifestations of androgen action
[prostate-specific antigen (PSA), lean body mass,
bone density] in groups of Indian and European men
living in the United States, and it found total and free
T and phenotypic androgen manifestations to be
lower in Indian men (). A larger United States–
based study could not find differences in T between
white, black, and Hispanic men (). Another study
found higher T and DHT levels in - to -year-old
doi: 10.1210/er.2018-00178
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Afro-Caribbean than European men, but the dif-
ference disappeared in - to -year-old men,
and a reverse difference prevailed in DHEA and
DHEAS (). A meta-analysis demonstrated that, after
adjustment for age, black men have a modestly but
significantly .% to .% higher level of free T, but not
of total T, E, or SHBG, compared with white men
(). In contrast, a large study reported higher E, but
not T, levels in black men than white men (). A large
international study reported differences between older
men of different ethnic origins. The most conspicuous
finding was the significantly higher serum T con-
centrations, compared with European and African
American men, of Asian men living in Hong Kong and
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Japan, but not of Asian men living in the United States.
Furthermore, the differences were much narrower
after adjustment for BMI (). Hence, besides genuine
ethnic differences, lifestyle factors may be a major
contributing factor to the apparent ethnic differences
in hormone levels as well as to the large variation of the
findings.
A recent study () found that South Asian men
have lower T levels (and higher LH levels) than do
white European and Afro-Caribbean men, but there
were no differences in free T levels after controlling
for covariables (i.e., body fat). Total and free T levels
were not strongly related to adiposity in South Asian
men in contrast to the other two ethnic groups. These
findings may be important for the assessment of
suspected hypogonadism and for understanding its
mechanisms in different ethnic groups. They may
also explain why the aging-related decline of T has
not been found in some Asian populations (see
above).
Genetic differences
A number of candidate genes regulating androgen
synthesis, kinetics in circulation, metabolism, and
action in target cells have been found to contribute to
the actual circulating T concentration. Studies in twins
and siblings have shown a strong .% heritability in
serum T concentrations (–). Some genetic vari-
ants (polymorphisms) contributing to serum T levels
have already been detected, but most genetic factors
contributing to the wide variation of physiological
T concentrations at all ages still remain unknown.
Earlier studies used candidate gene approaches, but
also data from genome-wide association studies, are
now available.
With respect to individual genes, those most ex-
tensively studied have been androgen receptor (AR)
and SHBG. The polymorphic AR gene exon  CAG
repeat variant, whose length correlates inversely with
receptor activity, has minor effects on circulating T
levels, but they reach statistical significance with large
sample sizes (, ). A report from the EMAS cohort
confirmed direct associations of this repeat poly-
morphism with circulating levels of total and free T
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and E (). Also, another AR gene repeat poly-
morphism (GGN) has a small effect on circulating T
levels (). Several studies have reported ethnic dif-
ferences in the length of the CAG repeat with an
average of  in whites and  in blacks (). Another
study found the following ethnic differences of the
CAG repeat length: Afro-Caribbean (mean repeat
length, .) ,white (.) ,Hispanic (.) ,Thai
(.) (). The CAG repeat length of Indian men has
been reported to be similar to European men ().
Two studies have shown that the AR gene CAG repeat
affects serum T levels only in older men (, ), but
this finding could not be repeated in other studies (,
).
Several polymorphisms of SHBG have been found
to associate with circulating androgen and/or es-
trogen levels in men (–). A genome-wide as-
sociation study identified two single-nucleotide
polymorphisms (SNPs) at the SHBG locus and one
near FAMB on the X chromosome that were as-
sociated with low T concentration (). The SNP in
exon  affected the affinity of SHBG for binding T
and the measured free T fraction. The polymorphism
is rare, but it could in principle influence calculations
of free T based on the molar concentrations of T and
SHBG. The individual effects of the three SNPs on
serum T concentration were .%, .%, and .%.
Another SHBG polymorphism has been found to
associate with increased T (.%) and SHBG (.%)
levels ().
A number of polymorphisms have been reported
to affect circulating T levels in following genes: CYP
(), NCOA (), CYPA (), BHSD (),
UGTB (), FSHB (), JMJDC (), ESR and
ESR (), MMP and CD (), GSTM (),
FSHR (, ), ACTN (), VDR (), CLOCK
(), GPCRA (), MAMLD () SRDA (),
and GnRH (). Many potentially important
polymorphic influences have apparently not yet been
identified, and only a small fraction of the large
between-subject variation of serum T can so far be
explained by known polymorphisms. Whether ge-
netic factors affect the aging-related decline of T has
only been studied to a limited extent. Hence,
whether there is a genetic component affecting the
rate and depth of T changes upon aging remains
unclear.
Lifestyle-related factors
Overweight and obesity. Overweight and
obesity are the most obvious and most common
lifestyle factors that have important influence on cir-
culating T levels (, ). In men who are overweight/
obese, total T decreases concomitantly with decreased
SHBG, whereas free T decreases less or remains initially
unaltered and becomes clearly suppressed only in
massive obesity (, ). Data from the EMAS (, )
and Massachusetts Male Aging Study () describe the
914 Kaufman et al Aging and the Male Reproductive System
magnitude of T changes caused by changes in weight. In
the EMAS (Fig. ), in middle-aged and older men, total
and free T in those with BMI $ kg/m were ~ nmol/L
and  pmol/L lower, respectively, in comparison with
nonobese men. The former difference is more than that
caused by aging from  to  years, and the latter equals
~ years of aging. No concomitant increase in LH levels
occurs in men with obesity, indicating that their hypo-
gonadism is of the secondary hypothalamic–pituitary
type.
A reciprocal interaction prevails between T and
obesity. On the one hand, T therapy reduces the fat
mass (, ), and androgen deprivation therapy
(ADT) results in weight gain and increased adiposity
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(). In turn, changes of body weight affect T levels,
which increase upon weight loss, either through diet
or bariatric surgery (, ), and decrease upon
weight gain, which is the most important single
reason for aging-related decrease of serum T. The
effects of obesity on T appear more marked than vice
versa as illustrated by limited effects of severe T
lowering on BMI during  months in a controlled
study () (see also “Adipose tissue” under “Adipose
tissue and metabolic health” below). The fact that T
and LH rise after weight loss supports the causative
role of obesity in T suppression rather than the
opposite (, ). The weight loss–related improve-
ment of HPT function is more effective in younger
men, highlighting the multiplicity of mechanisms (in-
cluding deteriorating health) influencing the aging HPT
axis ().
What exactly causes the secondary hypogonadism
with gonadotropin suppression in men with obesity is
still incompletely understood. It is apparent that the
expanding adipose tissue and the multiple signaling
molecules produced by fat cells play a role. Leptin is
one candidate peptide produced by fat cells (). A
T–leptin link is suggested by the finding that T
treatment of men decrease their leptin levels ().
Most studies, however, demonstrate direct correlation
between leptin levels and gonadotropins, and leptin
resistance in obesity has been offered as a mechanism
for the tenuous involvement of this hormone in the
pathogenesis of obesity-associated secondary hypo-
gonadism (). Other candidates/mechanisms are the
proinflammatory cytokines produced by fat tissue (e.g.,
TNFa, IL-, and IL-), whose increased levels in
obesity might suppress gonadotropins (, ), as
well as central nervous system endocannabinoids ()
and central insulin resistance (). Furthermore,
adiponectin can modulate GnRH and gonadotropin
secretion ().
The long-held theory of increased adipose tissue
estrogen production and its increased feedback in-
hibition of GnRH/gonadotropin secretion may not
hold true in light of recent findings. Estrogen levels in
men with obesity are in fact low, rather than high,
(–) and increase only in men with extreme
Endocrine Reviews, August 2019, 40(4):906–972

obesity (, ). A recent study demonstrated that
hyperinsulinemia combined with elevated lipids
suppresses gonadotropin secretion through direct
pituitary action, which provides another candidate
mechanism for the obesity-associated hypogonado-
tropic hypogonadism (). Finally, the obesity-
associated decrease in SHBG production (see
below) might play a role by lowering the set point of
the hypothalamic–pituitary feedback inhibition in
relationship to circulating total T. Because in men
with obesity mainly total T, and to a lesser extent free
T, is suppressed, negative feedback inhibition of
gonadotropins can be achieved at a lower concen-
tration of total T. In conclusion, apparently multiple
simultaneous mechanisms in obesity participate in
the suppression of gonadotropins.
Diet. A relatively minor influence of dietary
factors has been reported on serum T levels ().
Macronutrient distribution in the diet has been shown
to affect hormone levels. A low-fat diet (#%), in-
dependent of weight reduction, is associated with
lower serum T concentrations when compared with
higher fat diet in men (–), and dietary intake of
energy in the form of fat and protein increases T levels
(). Weight loss in men who are overweight/obese
with high-protein or high-carbohydrate diets resulted
in an equal increase in free and total T, as well as
SHBG (). The reason for lower T production
upon a low-fat diet is not known, but fiber may reduce
the reabsorption of steroids excreted through the
biliary tract, or lower cholesterol may provide less
substrate for steroidogenesis. When the same weight
loss was achieved by diet alone and diet combined with
excercise, no difference in T elevation was observed
().
The short intermittent fasting of Ramadan sig-
nificantly reduces body weight and sexual desire and
activity without affecting serum T levels (). Upon
controlled nutritional intervention, argan and olive
oil consumption was reported to increase serum T
and LH concentrations in conditions with unaltered
body weight (). Some (), but not all (),
studies have shown that soy supplements in the diet
reduce serum T levels. Collectively, it is apparent
that the quality of diet, which may change during a
man’s lifespan, does not have major effects on HPT
function.
Psychological stress. Numerous studies have
reported a negative effect of psychological stress on
semen quality (, ), but data on the HPT axis are
variable. A recent study reported that in men with
elevated cortisol and norepinephrine levels, but not
with low levels, life events were associated with in-
creased serum LH and T (). Besides the
hypothalamic–pituitary–adrenal axis, acute psycho-
logical stress has been shown to activate the HPT axis,
leading to increased T levels (). An opposite
negative effect of adrenocortical activation on T
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production is found in animal experiments during
chronic stress (). Deslypere and Vermeulen ()
found that younger men respond to stress such as
hypoglycemia or cardiac infarction with suppression of
T, whereas such a response was not found in older
men. Low free T has also been associated with de-
pression (see below).
Physical stress and exercise. Short intense
exercise increases serum T levels independent of go-
nadotropin stimulation (). In contrast, T is sup-
pressed during more prolonged exercise stress,
probably through the combined effects of suppressed
gonadotropins and increased cortisol and cathecol-
amine levels. Endurance training in men induces
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subclinical hypothalamic–pituitary inhibition of the
HPT axis (, ).
Numerous studies have examined the effects of
aging on the response of the HPT axis and T pro-
duction to exercise. The increase of T following acute
physical stress has been found suppressed in -year-
old men in comparison with younger men (, ).
Studies on whether lifelong exercise training increases
circulating levels of T have yielded conflicting results
(–). Some studies indicate that lifelong physical
activity attenuates the aging-related decline of T (,
), but there are also negative findings (, ).
Although lifelong exercise may not affect T level, when
high-intensity training is initiated in sedentary men, “…healthy lifestyle, including
their total T, free T, and SHBG show significant in- good physical condition, may
creases (, , ). Taken together, these findings reduce the aging-associated
indicate that healthy lifestyle, including good physical decline of HPT function.”
condition, may reduce the aging-associated decline of
HPT function. In support of this conclusion, Yeap
et al. () reported that engagement of men .
years of age in healthy behaviors, with one of these
being physical exercise, predicts higher total T and
SHBG, but not free T. When a man engages in ex-
ercise, he most likely has also other health behaviors,
and the role of exercise in isolation is difficult to single
out.
Smoking. A recent meta-analysis summarized
information on the effect of smoking on T levels ().
It was found that in  studies on , men, with a
mean age of  to  years, smokers had on average
. nmo/L higher total T than did nonsmokers. The
increase has been found to parallel with increased
SHBG levels and with no significant change in free T (,
, ). The elevation of T is expected because nicotine
and/or its metabolites share the same disposal pathway
with androgens (). The SHBG elevation occurs
possibly because of the toxic effects of tobacco smoke
components on liver function. No studies exist on
possible age-related differences in the effects of smoking.
Alcohol. Acute alcohol intoxication suppresses
serum T levels, probably through direct testicular
effects, but concomitantly increased adrenal secretion
of cortisol may contribute to the effect (). Most
studies do not find an effect of moderate alcohol
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916 Kaufman et al Aging and the Male Reproductive System Endocrine Reviews, August 2019, 40(4):906–972
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Figure 2. (a) Relationships between age, weight changes, and hormone changes in the EMAS during an average 4.3 y follow-up
period. Values are the unadjusted mean changes of 10-y age bands with 95% confidence interval. The cohort was stratified according
to weight change into 3 groups: $10% loss (closed square), stable (within 10% of baseline, closed circle) and $10% gain (closed
triangle). Weight changes appeared to influence hormone levels similarly at all ages. [Reproduced with permission from Camacho
EM, Huhtaniemi IT, O’Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older
men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol
2013;168(3):445–455.] (b) Mean hormone changes by percentage weight change in the same EMAS population as in (a). The cohort
was stratified (x-axis) according to weight gain or loss into seven separate groups from .15% loss to .15% gain. The number 0 on
the x-axis represents the “within 5%” group. Error bars represent 61 SEM. Data are adjusted for baseline age and center, changes in
smoking status, alcohol consumption, comorbidities, and physical activity. Total and free T showed a cubic relationship, SHBG a
linear relationship, and LH a cubic relationship with weight change. Free T changed only with the highest level of weight change
(15%), which is a reflection of its derivation from T and SHBG. The linear change of SHBG buffers the changes of free T, which only
responds to extreme changes in weight. Hypothalamic–pituitary inhibition, reflected by LH levels, is lifted only following major
weight loss. Significantly different from (referent): *P , 0.05; **P , 0.01. [Reproduced with permission from Camacho EM,
Huhtaniemi IT, O’Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older

Downloaded from https://academic.oup.com/edrv/article/40/4/906/5381905 by guest on 11 February 2022

men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol
2013;168(3):445–455.]

consumption on serum T levels (, ). One study
reporting on drinkers found increased total and free T
levels, as well as decreased SHBG (), but another
study found lower T levels in drinkers (). No
correlation of alcohol consumption with serum T was
found in the EMAS (). A surprising finding was
made in a recent study on . men from Europe
and the United States with a linear association between
the amount of alcohol consumption and serum total
and free T, in the face of unaltered SHBG (). This
effect was explained by alcohol detoxification leading
to changed steroid metabolism in the liver. Alcohol
oxidation increases the NADH/NAD1 ratio and
changes the redox state in favor of androstenedione
conversion to T ().
Serum T levels are suppressed, and those of go-
nadotropins are elevated, in chronic alcoholics but
both normalize during abstinence, indicating that
ethanol-induced hypogonadism is primary in origin,
functional in nature, and transient in its evolution
(). Whether the HPT axis responds differently to
alcohol in older than younger men has not been
studied.
Medications
Several drugs interfere with T production, metabolism,
or actions. Although little is known about the possible
effects of aging on these actions, they play an in-
creasingly important role in T action in the elderly,
because most of them are used in the treatment of
comorbidities occurring in old age. Statins and
-hydroxy--methylglutaryl coenzyme A reductase
inhibitors decrease cholesterol production, and be-
cause it is the substrate of T production, there is some
concern on T suppression in statin users. There is
some evidence that this is the case, but the clinical
significance of the small suppression (average of ~.%,
i.e., 2. nmol/L; % CI, 2. to 2. nmol/L; in a
meta-analysis) is not clear (). Steroid sythesis
inhibitors (aminoglutethimide, ketoconazole) and
GnRH analogs, by virtue of their mechanisms of
action, bring about substantial suppression of circu-
lating T concentrations. Spironolactone, an inhibitor
of several steroidogenic enzymes, also suppresses T
production, besides having an AR antagonistic action.
In contrast to findings in experimental animals,
cimetidine, a weakly antiandrogenic H antagonist,
has not been found to suppress T levels in men treated
for peptic ulcer.
Opioids cause secondary hypogonadism by inhib-
iting GnRH secretion. Opioid users have a higher
likelihood of having low T (OR, .), and after con-
trolling for opioid use, the men . years of age have
an OR of . for low T compared to the men  to 
years of age, and the men with more than two
comorbidities have an OR of . compared to the men
with no comorbidities (). Dopamine agonists such
as bromocriptine increase, and antagonists such as
metoclopramide decrease, serum T concentrations
(). It is well documented that chronic glucocorti-
coid treatment suppresses T production by combined
inhibiton of gonadotropin secretion and testicular
steroidogenesis (). A recent study demonstrated
that ibuprofen reduces the Leydig cell sensitivity to LH
stimulation, inducing a condition reminiscent of
compensated hypogonadism with normal T and an
increased LH/T ratio (). Hypothetically, the use of
COX inhibitor–type pain killers may therefore amplify
the aging-related deterioration of Leydig cell function
and accelerate the transit from compensated to real
hypogonadism.
Disease-related factors
A major question with respect to functional hypo-
gonadism is the direction of causality between low T
and comorbidities. The question is important because
of its major impact on treatment strategies. In the
relationship with some symptoms or diseases, for
example, impaired sexual function, osteoporosis, and
anemia, low T seems obviously the causal factor (see
below). In those with other diseases (e.g., critical
illness), low T is most likely the response to

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REVIEW
pathophysiological stress caused by disease. Often,
however, the causality can work similar to a vicious
cycle in both directions. It is also uncertain whether
the comorbidity-associated suppression of HPT ac-
tivity is a pathological, neutral, or beneficial homeo-
static adaptation response to disease.
The physiological aging process is overlapped
by pathological mechanisms leading to aging-related
comorbidities, and many of them affect the HPT
function more dramatically than does chronological
aging (). Low serum T in acute and chronic disease
is fairly common and has a multifactorial cause,
including a combination of acute weight loss, stress,
specific medications, and infections. The most com-
mon and most important cause of aging-related
hypogonadism is overweight/obesity (), which
predisposes to CV diseases (CVDs), diabetes, mus-
culoskeletal disorders, and to some cancers. The re-
lationship between T levels and CVD is discussed in
“The CV system” below. Unlike the primary testicu-
lar failure due to chronological aging, the obesity-
associated aging is often associated with secondary
hypothalamic–pituitary failure with low T and sup-
pressed or inappropriately normal gonadotropin levels
(see above). The metabolic syndrome (MetS), type 
diabetes mellitus (TDM), and ischemic heart diseases
(IHDs) can be considered a continuum of the same
pathogenic mechanisms initiated by obesity-associated
insulin resistance, dyslipidemias, and chronic in-
flammation of fat tissue, all connected to secondary
hypogonadism. A similar decrease in T is found in
hepatic steatosis, which can be considered a hepatic
manifestation of the MetS (). In men with the more
advanced form of hepatic cirrhosis, androgen (T and
DHT) levels are decreased and estrogen levels are
increased (, ). The T levels keep falling as the
disease advances (), and low T levels are also in-
dependently associated with nonalcoholic fatty liver
disease (). The low T in liver cirrhosis can be caused
by direct testicular injury evoked by alcohol, but more
frequently it is associated with central hypogonadism
probably caused by inflammatory cytokines, with
subsequent secondary testicular failure (). The
hypogonadism is amplified by increased hepatic SHBG
production and consequently lower free T.
Gonadal dysfunction is common in men with
chronic kidney disease and with end-stage renal
disease. T deficiency is usually of the primary type,
accompanied by elevated serum gonadotropin con-
centrations (). Low T levels in patients on he-
modialysis may predict increased mortality risk (,
). Serum T concentrations are low in chronic
obstructive pulmonary disease, and the situation is
aggravated by glucocorticoid treatment (). Also,
this situation seems to be of the primary type, because
the patients have elevated gonadotropin levels ().
The mechanism may be direct inhibitory effect of
hypoxia on testicular function. In rheumatoid arthritis,
918 Kaufman et al Aging and the Male Reproductive System
but not in ankylosing spondylitis or lupus eryth-
ematosus disseminatus, serum total T and free T
concentrations are consistently low, but both elevated
() and normal/suppressed () gonadotropin
levels have been reported. Hemochromatosis is a rare
cause of male hypogonadism where both T and go-
nadotropins are suppressed due to combined hypo-
thalamic and pituitary malfunction (). Men with
HIV have reduced serum total T concentrations, no
change or increase in SHBG, and decreased free
T levels (, ). Findings on gonadotropins are
not uniform among studies, and apparently both
hypogonadotropic and hypergonadotropic forms of
hypogonadism occur in patients with HIV (,
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–). Of note, in a long-term longitudinal study,
although free T levels were lower, the rate of age-
related decline of free T was similar in men infected
with HIV compared with uninfected men ().
Mechanisms underlying age-associated changes
Leydig and Sertoli cell function
Although the mechanisms of the aging-related T
decline are difficult to address in men, one animal
model in particular, the brown Norway rat, appears to
display similar age-related primary decline of testicular
function as in men (, ). In aged brown Norway
rats, Leydig cells produce reduced levels of T in re-
sponse to maximal LH stimulation both in vitro and in
vivo (, ), which appears to be due to reduced
steroidogenic capacity per Leydig cell rather than to
reduced cell number (). T production decreases in
the face of increasing gonadotropin levels, indicating
primary testicular failure. In these animals, the
mechanisms of reduced steroidogenesis include a
decreased number of functional plasma membrane LH
receptors and a decreased cAMP response to LH
stimulation, probably due to impaired LH receptor/G
protein coupling (). Another in vitro study on
senescent Wistar rat Leydig cells confirmed these
findings and, additionally, demonstrated an aging-
associated decrease in MAPK activation and expres-
sion levels of several steroidogenic enzymes ().
Reduced cholesterol import, synthesis, and transport
to mitochondria may ultimately be the main mech-
anism, including reduced TSPO, StAR, and --
protein activities, behind the aging-related decline of
Leydig cell steroidogenesis (, ).
Experimental studies, especially on the brown
Norway rat, have also elucidated the extrinsic factors
that may participate in the aging-related decline of
Leydig cell function. They include hydrogen perox-
ide produced by testicular macrophages () and
endocrine-disrupting chemicals, many of which affect
Leydig cell function in a similar fashion with aging
(). In particular, increased oxidative stress is shared
by both: an imbalance between pro-oxidants and
antioxidants is typical of aging cells (). Aged Leydig
Endocrine Reviews, August 2019, 40(4):906–972

cells produce reactive oxygen species from several
sources, including the mitochondrial electron trans-
port chain and mitochondrial and microsomal cyto-
chrome P enzyme reactions (). T decreases with
aging, along with reduced Leydig cell antioxidant
capacity (), which may be responsible for the
decreased steroidogenesis. Experimental manipula-
tions support the cause-and-effects involvement of this
mechanism beyond correlations (). The specific
targets of an altered redox environment, as well as the
mechanisms of how the pro-oxidant environment
affects Leydig cell steroidogenesis, remain unclear.
The total number of Leydig cells in men between
 to  and  to  years of age was found to be
reduced by % (), which explains the primary
hypogonadism associated with aging. Ultrastructur-
ally, many Leydig cells of the aging testis preserve their
normal appearance, whereas others acquire cytoplas-
mic or intranuclear Reinke crystals or paracrystal-
line inclusions, multiple vacuoles, lipofuscin granules,
and lipid-laden cytoplasm, showing signs of de-
differentiation and involution (, ). There is an
apparent correlation between the amount of deformed
Leydig cells and the decrease of T production. The
decreased testicular perfusion is caused by athero-
sclerotic alterations in testicular arterioles (). These
changes may be the primary cause for the degenerating
changes in Leydig cells and their reduced steroidogenic
capacity.
The number of Sertoli cells per testis decreases
between  to  and  to  years of age by nearly
% (), but the germ cell/Sertoli cell ratio did not
change with age in this study. Ultrastructurally, aging
Sertoli cells contain abundant lipid droplets and cy-
toplasmic vacuoles with amorphous material, multiple
nuclei, mitochondria with tubular cristae, immature
nuclei, and sparse development of cytoplasmic or-
ganelles (). Many of the signs are indicative of
dedifferentiation.
Gonadotropin secretion and action
Gonadotropin secretion changes as the male ages. Part
of it is due to chronological aging, and partly it is due
to aging-associated comorbidities, of which weight
gain is most important.
According to the EMAS, primary gonadal failure
represents the pure form of aging-related hypo-
gonadism (, ). A failure of testicular T pro-
duction ensues, partly due to an aging-associated
decrease of Leydig cell number and the capacity to
respond to LH and to produce steroids (see above).
Older studies showed decreased testicular T responses
to human chorionic gonadotropin (hCG) stimulation
upon aging (, ), although they may not mimic
the physiological situation because of the long half-life
of hCG compared with LH, as well as the conse-
quential desensitization of Leydig cell steroidogenesis
in response to supraphysiological stimulation. However,
doi: 10.1210/er.2018-00178
REVIEW
very similar responses were observed in a more
physiological setting where, after GnRH antagonist-
suppressed gonadotropin secretion, elderly men re-
leased ~% less T than did young men in response to
the same pulsatile LH clamp (). In response to
recombinant LH challenge and sampling from the
spermatic vein, the same authors observed a reduced T
response with aging and in obesity, as well as aug-
mented Leydig cell downregulation (), with both
supporting the decreased Leydig cell capacity to
produce T. Young and elderly men exhibit similar LH
responses to GnRH stimulation (, ), and al-
though age is associated with increased LH pulse
frequency and reduced pulse size (, ), relatively
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small changes occur in the T feedback inhibition of LH
secretion (). Hence, aging per se has only minor
effects on functions at the central level of the HPT axis.
The situation is different with obesity (see below). The
altered LH secretory pattern was interpreted to in-
dicate reduced hypothalamic GnRH secretion, possi-
bly due to the milieu of lowered sex steroids, and more
generally to aging-associated failure of the integrative
neurohormone outflow.
The sequence of events upon male aging is that the
gradual loss of testicular capacity to produce T is
initially compensated for by increased gonadotropin
secretion, which is able to maintain normal T levels. A
“T decreases with aging along
situation termed “compensated hypogonadism” first
with reduced Leydig cell
arises, which is hallmarked by elevated gonadotropin antioxidant capacity, which
secretion in the face of unaltered T levels (). Men may be responsible for the
with this condition are initially asymptomatic (), decreased steroidogenesis.”
but as testicular capacity to maintain normal T se-
cretion in response to elevated LH is gradually lost, the
men develop the typically age-related primary hypo-
gonadism (). With a prevalence of .% of men in
the EMAS population, compensated hypogonadism
appears to be a relatively common, but in many cases
reversible, condition.
Another component in HPT suppression often
coincides with, but is independent of, chronologi-
cal aging, that is, secondary hypothalamic–pituitary
hypogonadism, characterized by low T and low or
inappropriately normal gonadotropin levels. It is more
common, encompassing about % of the hypo-
gonadism of aging men in the EMAS, and it is as-
sociated with overweight and obesity, but not with
chronological age (, ). As described above, other
common causes for HPT suppression are aging-
associated chronic illnesses, for example, diabetes
mellitus, the MetS, and IHD, where both the central
and testicular functions are variably affected. In many
cases, both the central and testicular impairment
overlap.
What still has not been thoroughly addressed is
how the function of kisspeptin in the HPT regulation
responds to aging and associated comorbidities. An
immunohistochemical study on human hypothalamus
detected an aging-related robust enhancement in
https://academic.oup.com/edrv 919
REVIEW
central kisspeptin signaling and a moderate en-
hancement in central neurokinin B signaling ().
Such changes are compatible with the known reduced
T negative feedback to kisspeptin neurons and may
participate in the elevated LH levels in the primary
hypogonadism of aging men. Similar studies on
obesity do not exist in humans, but rodent studies have
demonstrated an expected obesity-associated sup-
pression of Kiss expression in the hypothalamus and
impaired LH response to kisspeptin (). Recent
studies in rats (), but not in monkeys (), support
that kisspeptin neuronal activity is reduced in aging
males. It is likely that in the near future research will
Figure 3. Molecular mechanisms involved in obesity-associated decrease of hepatic SHBG
synthesis. Cytokines produced by fat tissue act as negative (TNFa, IL-1b) or positive (adiponectin)
regulators of SHBG expression by interacting with various signal cascades resulting in alterations of
HNF-4a levels that stimulate SHBG expression. Dietary factors such as carbohydrates or olive oil are
also able to regulate SHBG expression by affecting HNF-4a or PPARg levels, respectively. Thyroid
hormone levels can also regulate SHBG production by affecting HNF-4a expression. [Reproduced
with permission from Simó R, Saez-Lopez C, Barbosa-Desongles A, et al. Novel insights in SHBG
regulation and clinical implications. Trends Endocrinol Metab 2015;26(7):376–383.]
920 Kaufman et al Aging and the Male Reproductive System
elucidate further kisspeptin function in aging and
obesity in aging men.
In conclusion, it seems that the primary hypo-
gonadism specifically associated with aging is caused
by impaired Leydig cell function, with reduced gonadal
feedback and consequent increase in LH secretion,
whereas the hypothalamic–pituitary function remains
largely unaffected. It leads initially to a state of
compensated hypogonadism (), where T remains
normal but LH is inappropriately elevated. When the
reserve stimulated testicular capacity is exhausted, the
outcome is primary hypogonadism (low T, high LH).
Obesity and several other comorbidities cause pre-
dominantly secondary hypogonadism where multi-
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ple mechanisms impair the hypothalamic–pituitary
function.
SHBG levels
SHBG levels increase upon aging, but this is coun-
teracted by the concomitant decrease evoked by
obesity. Because SHBG is produced by the liver, it is
not inconsequential that the two opposite responses
seen upon aging and weight gain somehow reflect
changes in the metabolic state of this organ.
The reasons why SHBG levels increase in men
upon aging are not clearly understood. One reason
could be the aging-associated increase in levels of the
anti-inflammatory cytokine adiponectin (, ),
which has been shown to stimulate SHBG production
in cultured human liver cells by activating AMP-
activated protein kinase, reducing lipid content, and
activating hepatocyte nuclear factor (HNF)-a ()
(Fig. ). Lewerin et al. () observed that the aging-
related increase in adiponectin levels was inversely
associated with Hb. We could therefore speculate that
as adiponectin stimulates SHBG levels it indirectly
suppresses free T, which could then be responsible for
the suppressed Hb, a sign of hypogonadism. There
could even exist an SHBG–adiponectin–T regulatory
link, because men with hypogonadism have a high
adiponectin level that is suppressed by T treat-
ment (). Also, a decreased inhibitory effect of the
aging-related decrease of IGF- action as the cause
of increased SHBG with aging has been proposed
(–), and there are also in vitro data on cultured
liver cells indicating that IGF- can be a direct negative
regulator of SHBG synthesis ().
Recent research has emphasized that the obesity-
associated SHBG decrease is related to monosaccha-
ride (glucose and fructose)-induced liver lipogenesis
and fat content rather than to the body’s total and
visceral fat (, ) (Fig. ). SHBG may even
be a primary determinant of the MetS and TDM,
because a Mendelian randomization analysis has
shown that a genetic variant of SHBG that affects the
levels of this protein reciprocally influences the risk of
these diseases (, ). Obesity is associated with
increased production of proinflammatory cytokines by
Endocrine Reviews, August 2019, 40(4):906–972
 REVIEW

fat tissue and with low SHBG (). In vivo and in vitro
studies have demonstrated that TNFa reduces SHBG
production of HepG cells indirectly through nuclear
factor kB–mediated downregulation of HNF-a
(). A similar effect has been demonstrated for IL-
b (). An opposite relationship with obesity is
found with the anti-inflammatory cytokine adipo-
nectin (, ), which stimulates SHBG production
in HepG cells (). The long-held concept that
insulin negatively and directly regulates hepatic SHBG
production through an unknown mechanism does not
hold true in light of more recent research [reviewed in
(, )]. A recent study showed that low SHBG is
correlated with high leptin and low adiponectin levels,
in particular fructose, inhibit SHBG synthesis in
cultured hepatic cells by increasing de novo lipogenesis
(). An opposite effect was found with the olive oil
component oleate, which increases SHBG levels by
downregulating PPARg ().
Testosterone metabolism
Some older studies have compared endogenous ste-
roid profiles in testis tissue of young and elderly men as
potential signs of aging-related alterations in androgen
metabolism. In one study, the concentrations of nine
endogenous steroids were measured in the testis tissue
of men aged  to  years (oligozoospermia and
varicocele) and  to  years (prostatic carcinoma)

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irrespective of T levels ().
The twofold higher level of SHBG in women than
men () occurs apparently because of estrogen-
induced downregulation of hepatic peroxisome
proliferator-activated receptor g (PPARg) expression
(). Whether there is an additional sex-specific
reason for the lower SHBG levels in men remains
largely unknown. The human SHBG promoter does
not have androgen response elements. One explana-
tion could be the lower adiponectin level in male
circulation ().
Several components in the diet appear to have direct
regulatory effects on SHBG synthesis. Monosaccharides,
(Table ) (). The sum concentration of the steroids
was significantly higher (.%) in the young men
than in the elderly men, whose elevated LH levels
revealed a primary testicular defect. Because the
conversion of [H]pregnenolone to downstream
metabolites was similar in both age groups, it was
concluded that aging-related impairment in the mi-
tochondrial pregnenolone production, rather than in
the subsequent microsomal steps of steroid meta-
bolism, was the cause of reduced steroidogenesis.
However, there are also data showing that the activity
of microsomal steroidogenic enzymes is decreased in
aging testes (, ). Furthermore, decreased levels

Table 3. Concentrations of Endogenous Steroids Detected in the Testis Tissue (in nmol/L) of Young and Old Men in Two Studies
Study Takahashi et al. Vermeulen and Deslypere

Age groups, y 25–35 61–85 ,50 .65

Steroids

Pregnenolone 590 6 64 230 6 29a 793 6 93 532 6 70b

17-Hydroxypregnenolone 110 6 12 49 6 5.4a 41.6 6 5.4 23.2 6 3.5b

Progesterone 81 6 6.7 66 6 7.4 30.5 6 29 40.7 6 5.1b

17-Hydroxyprogesterone 54 6 5.3 30 6 4.7b 122 6 18 122 6 1.6

Dehydroepiandrosterone 290 6 23 220 6 31 10.8 6 0.9 8.5 6 1.0

5-Androstene-3b,17b-diol 270 6 30 140 6 20 c

59.3 6 7.0 37.6 6 5.8b

Androstenedione 99 6 14 72 6 12 16.5 6 2.0 17.0 6 4.1

Testosterone 1700 6 194 860 6 119 c

451 6 57 447 6 63

5a-Dihydrotestosterone 20.4 6 5.1 16.9 6 1.6

5a-Androstane-3a,17b-diol 20.0 6 4.2 18.5 6 2.2

Estradiol 19 6 1.9 9 6 1.6a 5.1 6 0.62 4.91 6 0.58

Total 3680 6 340 1940 6 210 c

1596 6 134 1267 6 128b

[Data from Takahashi J, Higashi Y, LaNasa JA, et al. Studies of the human testis. XVIII. Simultaneous measurement of nine intratesticular steroids: evidence for reduced mitochondrial
function in testis of elderly men. J Clin Endocrinol Metab 1983;56(6):1178–1187; and from Vermeulen A, Deslypere JP. Intratesticular unconjugated steroids in elderly men. J Steroid
Biochem 1986;24(5):1079–1083.]
aP , 0.001, vs young men.
bP , 0.05, vs young men.
cP , 0.01, vs young men.

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REVIEW
of D, but not D, steroids have been found, including
increased levels of progesterone and -hydrox-
yprogesterone, in the aging testis (, ) (Table ).
Bélanger et al. () measured circulating con-
centrations of a number of adrenal (see above) and
testicular steroids and their conjugates in men in the
age range of  to  years. Apart from the clear
decline of adrenal steroids and their metabolites,
several age-related changes of testicular steroids were
observed. The decline of T (.% per year) was par-
alleled by a similar decrease (.% per year) of another
testis-derived steroid, -hydroxyprogesterone. Unlike
the marked decline in the serum concentrations of
adrenal or testicular C steroids DHEA (.% per
year), -diol (.% per year), DHEAS (.% per year),
-diol-sulfate (.% per year), T (.% per year), and
androstenedione (.% per year), serum DHT con-
centration did not change, which could mean that
extratesticular a-reductase activity increases with age.
The fragmentary information available, often from
small studies with heterogeneous samples, suggests
that aging reduces the activity of all steroidogenic
enzymes with no specific aging-sensitive steps. Animal
experiments have demonstrated impaired LH receptor
function, possibly due to the accumulating load of free
oxygen radicals with age, as an important reason for
the impairment of Leydig cell steroidogenesis ().
There is in vivo evidence in humans that impaired
responsiveness of aged Leydig cells to LH stimulation
could be the primary cause for their weakened ste-
roidogenesis (, ). The ultimate reason for the
aging-related primary impairment of testicular func-
tion could be decreased perfusion and oxygen supply.
Clinical Correlates of Sex Steroid Levels in
Elderly Men
Bone metabolism and skeletal integrity
Sex steroids are major players in the regulation of bone
homeostasis and the preservation of skeletal integrity
in adult men. Their levels were reported to be asso-
ciated with several aspects of bone health in aging men,
including bone mineral density (BMD), bone loss, and
fracture risk. Direct sex steroid effects on bone appear
to be exerted predominantly by E, the major aro-
matization product of T, via estrogen receptor (ER)a.
An androgenic action of T and its a-reduced me-
tabolite DHT in the adult male skeleton via the AR is
exerted both directly on bone tissue and mainly in-
directly through effects on extraskeletal tissues, in
particular muscle [reviewed in ()].
Quantitative and structural skeletal changes
Acquired profound hypogonadism in aging men is
associated with high bone turnover bone loss as is
illustrated by the effects of ADT in patients with
prostate cancer (, ). These adverse skeletal
922 Kaufman et al Aging and the Male Reproductive System
effects of T deficiency can be fully prevented by
treatment with an estrogenic compound acting on
ERa (, ). A predominant role of estrogens
rather than androgens in the maintenance of skeletal
integrity in aging men is further indicated by the lack
of an effect on bone metabolism of antiandrogen
monotherapy in patients with prostate cancer (,
). Treatment of aging men with a a-reductase
inhibitor, which inhibits the conversion of T to the
more potent androgen DHT, appears also not to affect
bone metabolism (–).
Findings from observational studies also concur
in indicating that E is important for maintaining
skeletal integrity in aging men. Cross-sectional
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studies have consistently shown a direct associa-
tion of serum E and in particular its non–SHBG-
bound fractions with the areal BMD (aBMD) at
different skeletal sites and, less extensively docu-
mented, an inverse association with biochemical
markers of bone resorption [() and reviewed in
(, )]. Lower (non–SHBG-bound) E levels have
also been associated with less favorable volumetric
BMD (vBMD), bone geometric variables, trabecular
structure, and cortical porosity (–). Longi-
tudinal studies have shown inverse association of
(non–SHBG-bound) E with prospectively assessed
bone loss (–). Differences in prospectively
assessed BMD changes in older men have also been
associated with a polymorphism of the CYP gene
encoding the aromatase enzyme (, ). Although
not seen in all studies, there are indications for a
threshold for serum (non–SHBG-bound) E above
which bone mass in aging men is better preserved
(). This threshold may lie at ~ to  pg/mL ( to
 pmol/L) bioavailable E or ~ to  pg/mL ( to
 pmol/L) total E (, ), which is higher than
the  pg/mL ( pmol/L) that may be sufficient to
maintain bone mass in younger men as derived from
the results of an experimental intervention study
().
As to the relationship of serum T and its non–
SHBG-bound fractions with bone metabolism,
findings from observational studies in community-
dwelling aging men have been inconsistent and fail to
convincingly document an association independent
of E with either prevalent BMD, bone turnover
markers, or BMD changes [() and reviewed in
(, )]. Interestingly, a number of observational
studies in aging men have shown association of se-
rum SHBG levels, independent of serum T and E,
with prevalent BMD, levels of bone turnover markers,
and BMD changes (, –). In the MrOS US
study, the highest rate of bone loss was observed in the
men presenting the combined findings of the lowest
serum bioavailable T, lowest bioavailable E, and
highest levels of SHBG (). In this study there was a
threshold effect for serum SHBG at ~ nmol/L,
above which faster bone loss was observed.
Endocrine Reviews, August 2019, 40(4):906–972

Fracture risk
In men with ADT for prostate cancer, a model for
acquired profound hypogonadism, the high bone
turnover bone loss translates into increased fracture
risk (). In community-dwelling aging men, in line
with the well-documented role of E in restraining
bone turnover and preserving BMD, and notwith-
standing some discordant findings (–), there is
substantial evidence linking low serum (non–SHBG-
bound) E with increased fracture risk as reviewed
by Vanderschueren et al. (). Low serum E has
been associated with increased hip fracture risk in
aging men from the Framingham Study (), and
both low E and calculated free E were associated
with increased risk of clinical fractures in men from
the EPIC Study (). In the MrOS Sweden cohort,
calculated low free E was independently associated
with clinical vertebral, nonvertebral, and hip fracture
risk (). In the MrOS US cohort, the lowest quartile
of calculated bioavailable E (,. pg/mL or 
pmol/L) was associated with a higher risk of non-
vertebral fractures (). Also, in the MrOS Hong
Kong cohort () low E and calculated bioavailable
E were associated with increased risk of all fractures,
with the serum levels in the lowest quartiles being
associated with the highest risk. In these studies
the associations between (non–SHBG-bound) E
and fracture risk were attenuated when adjusted for
BMD, but they remained mostly significant. This
suggests that skeletal factors not captured by aBMD
assessed by dual-energy X-ray absorptiometry (DXA),
such as bone geometry or cortical porosity (), or,
hypothetically, some extraskeletal factors contribute to
the inverse association of serum E with fracture risk.
In most studies the association between E levels
and fracture risk was nonlinear, with a suggestion of
markedly increased fracture risk when serum levels
were below a threshold situated around  pg/mL (
pmol/L) for total E. This threshold is somewhat lower
than that reported as critical for accelerated bone loss
(). Finally, note that the evidence for association of
low E with fracture risk pertains almost exclusively to
clinical and nonvertebral fractures. Two recent studies
assessed vertebral fractures systematically by serial
radiographs in the MrOS US cohort () and in a
combined analysis of men from the MrOS Sweden and
MrOS Hong Kong cohorts (), respectively. In
neither of these two studies was the risk of radio-
graphically assessed vertebral fractures related to se-
rum E levels.
In most studies no independent association was
found between (non–SHBG-bound) T and risk of
incident fractures (, –). In contrast to these
consistently negative findings, independent association
of low serum T was reported for the Dubbo cohort,
even though BMD was related to serum E and not to
T (). Interestingly, findings of several studies not
showing independent associations of T with either
doi: 10.1210/er.2018-00178
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BMD changes or incident fractures did provide evi-
dence for interaction between T and E with an ad-
ditive effect on fracture risk of low T in the presence of
low E (, ) or for interaction between low
bioavailable T, low bioavailable E, and high SHBG
(). Serum T might influence fracture risk through
extraskeletal androgenic actions such as on muscle
mass and function. In the MrOS US and Sweden
cohorts, low T and bioavailable T were indeed asso-
ciated with an increased risk of falls (, ).
In several cohort studies (, , , ), but
not in all (, ), high serum SHBG was associated
independently of T and E levels with increased risk of
incident fractures and in particular also risk of in-
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cidental vertebral fractures (, ). In the MrOS US
cohort an interaction was observed between SHBG
levels and bioavailable T, with substantial fracture risk
in men combining low bioavailable T with high SHBG,
whereas the highest fracture risk was in men with high
SHBG, low bioavailable T, and low bioavailable E
(). The pathophysiological basis for the association
of serum SHBG with both maintenance of bone mass
and fracture risk remains to be established but may
involve (differential) modulation of T, DHT and E
action. The association may also result from residual
confounding, for example, as a reflection of low ac-
tivity of the somatotropic axis. Finally, the possibility
“Studies assessing…incident
of some yet-to-be-uncovered physiologically relevant
IHD or myocardial infarction
intrinsic action of SHBG or a SHBG–sex steroid failed overall to show an
complex cannot be excluded. Also note that in- independent association with
dependent associations between serum SHBG and baseline (free) T.”
bone phenotypes have also been observed in young
men ().
In summary, E is the main sex steroid needed for
preservation of skeletal integrity in aging men. Low E
is associated with lower BMD, higher bone turnover,
greater bone loss, qualitative bone changes, and in-
creased risk of mainly nonvertebral fractures. Also,
high SHBG, independently of sex steroid levels, is
associated with greater bone loss and increased frac-
ture risk of both nonvertebral and vertebral fractures.
The androgenic actions of T appear to play a more
marginal role in skeletal health and fracture risk, and
this most likely mainly through indirect extraskeletal
effects. The associations of bone health variables with
both E and SHBG are nonlinear, with a suggestion
of a low and high serum level threshold, respectively.
Note, however, that many of the reported associations
with E and SHBG in community-dwelling men ex-
plain only a limited fraction of the variability in BMD
changes and fracture risk, as these men in general are
not markedly hypogonadal. Recently, in an analysis of
the MrOS cohorts, Orwoll et al. () found that in
elderly men (aged  to  years at baseline; around
-year follow-up) measurement of E, SHBG, and T
did not contribute to prediction of BMD changes or
meaningfully to fracture risk assessment in a model
including clinical risk factors with BMD (FRAX ®
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REVIEW
algorithm). From this analysis, the authors concluded
that there is limited clinical utility of serum E, T, and
SHBG measurements for the evaluation of osteopo-
rosis risk in elderly men.
Body composition, metabolic health, and
physical performance
Aging in men is associated with profound changes in
body composition. Starting from mid-adult age,
healthy men on average gain fat and lose lean mass
(–), which in part leads to concomitant declines
in metabolic health and physical performance (,
, ). This is of importance, as resulting clinical
entities such as the MetS and TDM, but also sar-
copenia and frailty, are associated with quality of life,
morbidity, and mortality (–). As discussed
previously (), part of these changes in body com-
position in aging men appear mediated by the decline
in androgen exposure. However, these relationships
are confounded by concurrent changes in lifestyle,
illness, and other hormonal axes. Moreover, especially
for adiposity, this relationship is bidirectional in nature
and modulated by SHBG. In the following sections, we
discuss recent publications addressing these questions
in population-based cohorts of aging men.
Adipose tissue and metabolic health
Adipose tissue. Men with profound hypo-
gonadism gain fat mass and are prone to develop
related metabolic consequences such as the MetS or
TDM (). Correspondingly, most cross-sectional
studies in elderly men found inverse associations
between T levels and indices of adiposity (, , ,
, , –). However, many of these findings
are probably affected by residual confounding or
obscured by the effects of adiposity to decrease SHBG
levels. For instance, in the EMAS, adiposity indices
were higher in all men with low total T (whether free T
was low or normal) but not in men with low free T and
normal total T levels (). As total T levels are largely
determined by the SHBG concentration, solely relying
on total T to define hypogonadism will thus lead to an
overestimation of hypogonadism prevalence in sub-
jects with obesity (, ). Longitudinal studies are
also less convincing; for example, in the MrOS US
cohort, neither total T, bioavailable T, nor SHBG levels
were associated with changes in fat mass during .
years of follow-up (). Similarly, after adjusting for
confounders, neither baseline total T, free T, nor
SHBG levels were associated with changes in waist
circumference in the EMAS cohort (). Moreover, a
possible relationship is most probably reciprocal, as
longitudinal studies found that declines in total T and
free T are most pronounced in men remaining obese
or gaining weight with aging (in part mediated
through changes in SHBG levels) (, , , ,
) and that larger declines in total T and free T levels
were associated with higher fat mass at follow-up (,
924 Kaufman et al Aging and the Male Reproductive System
). Conversely, weight loss in men with obesity is
associated with rising total T, SHBG, and, if the weight
loss is extensive, free T levels (). This reciprocity
was addressed in a pooled cohort of studies [MrOS
Sweden, GOOD, Study of Health in Pomerania
(SHIP), SHIP Trend, and Inter] using a bidirectional
Mendelian randomization approach, which is sup-
posed to be free from residual confounding. Herein,
the genetic risk score on BMI was inversely associated
with serum total T levels (independent of the asso-
ciations with SHBG levels), whereas no association was
found between the genetic risk score on total T levels
and BMI (). In addition to androgen exposure,
there is some evidence suggesting a contribution of
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estrogen exposure to the regulation of fat mass and
metabolic health. For example, in men who are aro-
matase deficient, the metabolic profile improves
during estrogen treatment (, ), and to prevent
fat mass gain in men with hypogonadism by T
treatment, minimal E exposure by aromatization of T
seems required (). However, reports on the re-
lationship between E levels and adiposity in aging
men are equivocal. Although some cross-sectional
studies reported positive associations between (free)
E levels and indices of adiposity (, –, ),
this was not confirmed in other studies (, , ,
, ), and longitudinal analyses from MrOS and
EMAS did not find associations between E levels and
changes in fat mass (, ).
Metabolic health. The relationship between
serum sex steroid levels and the MetS, insulin re-
sistance, or TDM was addressed in many cross-
sectional studies in middle-aged and older men
(, , , , , –). Given the in-
terrelationships between sex steroids, body composi-
tion, and metabolic health we discuss herein only
prospective studies. In the Rancho-Bernardo study,
men with lower baseline total T levels were at higher
risk to develop insulin resistance or TDM during
follow-up, whereas this was unrelated to bioavailable
T, total E, or bioavailable E levels (). Similar
findings were reported from a Finnish study (), the
Massachusetts Male Aging Study (MMAS) (, ),
the Baltimore Longitudinal Study of Aging (), and
the Danish Inter study (), as well as from an
individual participant data meta-analysis of  ob-
servational studies () wherein men with low total T
or SHBG levels at baseline had a higher incidence of
the MetS or TDM, without finding associations with
estimates of non–SHBG-bound T. In the Concord
Health and Ageing in Men Project (CHAMP) study,
moreover, only low baseline SHBG was associated
with incident MetS after multivariate adjustment
(). In the EMAS, men with lower total T, free T, or
SHBG levels or a higher E/T ratio at baseline had an
increased risk of developing the MetS after . years
(). However, in a secondary analysis categorizing
participants according to total T and free T status, men
Endocrine Reviews, August 2019, 40(4):906–972

with low free T but normal total T levels had no
increased risk as compared with men with normal total
T and free T levels. Moreover, even the higher in-
cidence of the MetS in men with total T , ng/dL
(,. nmol/L) (whether free T was low or normal)
was no longer significant after adjusting for baseline
confounders (). In several other studies in elderly
men, despite cross-sectional associations between sex
steroid levels and prevalent MetS and TDM, only low
SHBG was predictive of incident MetS (, , )
and only total T in the SHIP () and estrone in the
Framingham Heart Study () was predictive of
incident TDM. Furthermore, in a Norwegian study
(), associations between baseline total T and SHBG
levels and incident TDM were no longer significant
after adjusting for waist circumference, but they did
find an independent association between total E
levels and incident TDM. Similar findings were re-
ported in the high-risk population from the Diabetes
Prevention Program (). However, neither of these
two studies corrected for baseline SHBG levels, and no
estimates of non–SHBG-bound E were evaluated.
Only in a smaller Finnish cohort (using immunoas-
says) was incident TDM associated with low baseline
total T and free T but not SHBG levels ().
Taken together, despite strong and consistent in-
verse associations between T and SHBG levels and
indices of adiposity and metabolic health in cross-
sectional studies, evidence from longitudinal studies is
less convincing. If any, the role for moderate decline in
androgen exposure in the increase of adiposity and
worsening of metabolic health during normal aging is
probably limited. Moreover, it cannot be excluded
that these results still are affected by residual con-
founding and that low T and SHBG levels are more a
risk marker rather than a true risk factor for these
changes.
Lean mass and physical performance
Lean mass. From observations in hypogonadal
men () and users of anabolic androgens (), a
relationship between the aging-related declines in
androgen exposure and lean mass could be expected.
Although positive associations between (appendicular)
lean mass and T levels were reported in the MINOS
(), the BACH/Bone (), and the MrOS Hong
Kong cohorts (), other cross-sectional studies did
not confirm this (, , , ). For instance, in
the MrOS US and Sweden cohorts, lean mass index
and appendicular lean mass did not differ according to
bioavailable T or free T levels (, , ), whereas
in another cohort of community-dwelling elderly men,
the association between total T or free T and lean mass
indices was only revealed after adjusting for SHBG
and/or total body weight (). In the CHAMP study,
however, total T, free T, total E, and estrone levels
were all positively associated with appendicular lean
mass (). These associations with estrogen levels
doi: 10.1210/er.2018-00178
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might seem surprising, but they are corroborated by
findings from the MrOS Hong Kong (), MrOS
Sweden (), and BACH/Bone () studies. In
longitudinal analyses from the MrOS US study, men
having higher baseline total T or bioavailable T (but
also SHBG) levels presented with less decline in ap-
pendicular lean mass. This finding, however, only
applied to men who lost weight during follow-up, and
no associations between E levels and changes in lean
mass were found (). In the MINOS study, no
relationship between baseline total T or free T levels
and loss of lean mass was found, although a more
rapid loss of lean mass was observed in men with total
T or free T levels below the normal range for young
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men (), whereas in the CHAMP study, -year
longitudinal changes in total T, free T, DHT, SHBG,
and estrone (but not E) were all associated with
contemporary changes in appendicular lean mass,
even after multivariate adjustment (). Finally,
changes in total T or free T levels were not associated
with lean mass at the second study visit in a British
study ().
Again, despite the established anabolic effects of
androgens in hypogonadal men (, ), the con-
tribution of androgen exposure to changes in lean
mass in population-based cohorts of aging men seems
rather limited, and it cannot be excluded that lower T “…the role for moderate
levels are a marker of mutual confounding factors. decline in androgen exposure
Additionally, and perhaps somewhat unexpectedly, in the increase of adiposity and
most studies did not show stronger associations be- worsening of metabolic health
tween lean mass and estimates of non–SHBG-bound during normal aging is
probably limited.”
T than with total T levels. Furthermore, although there
were limited reports on relationships with E and
DHT levels, and myocytes are known to express ERa,
ERb, and a-reductase, these findings are rather
unexpected and do not concur with results from
experimental studies (, ).
Physical performance. In addition to regula-
tion of lean mass, androgen exposure has been linked
to different measures of physical performance. For
instance, several studies found total T, bioavailable T,
or free T levels to be positively associated with muscle
strength (, , ), and in MrOS (United States
and composite cohorts), men with higher bioavailable
T levels had slightly better muscle strength and
physical performance (, , ). Similarly, in the
Framingham Offspring Study cohort, free T (but not
total T or SHBG) levels were positively associated with
physical performance battery score, walking speed, and
grip strength (). In contrast, in the MMAS (),
despite associations between total T, bioavailable T,
and DHEA/DHEAS levels and the physical perfor-
mance score, neither of these androgens was associated
with grip strength and only DHEA levels below a
certain threshold were associated with chair stand
score, whereas in the BACH/Bone study, associations
of total T levels with physical performance were only
weak or nonsignificant (). In longitudinal analyses
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REVIEW
from the MrOS US study, higher total T and bio-
available T (but not E or SHBG) levels were asso-
ciated with a lesser decrease in one measure of physical
performance (timed chair stands) only in participants
who lost weight during follow-up, a finding that was
partly explained by changes in lean mass (). In
contrast, in the Longitudinal Aging Study Amsterdam
and Health ABC cohorts, neither total T nor free T
levels were associated with declines in physical per-
formance or muscle strength (), and although
baseline free T levels in the Framingham Offspring
Study cohort were associated with lower risk of de-
veloping or worsening of mobility limitation, they
were not associated with changes in grip strength or
walking speed, nor were there any relationships be-
tween E levels and changes in physical performance
(). In the CHAMP study, self-reported functional
decline was no longer associated with total T or free T
after adjusting for baseline muscle mass or strength
(). This same study, however, recently reported
associations between changes in total T, free T, and
DHT with changes in muscle strength during a -year
period, independent from possible confounders, al-
though the authors did not adjust for baseline sex
steroid levels or baseline muscle strength ().
With respect to clinical entities such as sarcopenia
and frailty, the available literature is difficult to
compare owing to the use of different operating
definitions. In cross-sectional analyses, men from the
MINOS study with sarcopenia had lower total T and
free T levels (), whereas in Japanese men only free
T was associated with prevalent sarcopenia (). In
the MMAS (), only SHBG (and not total T or free
T) levels remained associated with prevalent frailty
after adjustment for possible confounders, whereas in
the MrOS US cohort, this was only so for bioavailable
T (and not total T, E, or SHBG) levels (). Lon-
gitudinal analyses from the MrOS US study found that
men with low baseline bioavailable T levels had higher
odds to have a more advanced frailty status at -year
follow-up (). Furthermore, although both total T
and free T levels were related to frailty status in the
Health in Men study, only baseline free T levels were
predictive of frailty status after  to  years of follow-up
(). In the CHAMP study, despite associations
between baseline total T, free T, DHT, total E, and
estron levels and the number of frailty components,
-year changes in total T and free T, but not baseline
levels, were associated with a higher risk to become
prefrail or frail according to one (Cardiovascular
Health Study) but not another (Study of Osteoporotic
Fractures) frailty index (). Finally, a recent analysis
from EMAS follow-up data showed that after ad-
justment for BMI, only free T (and not total T or
DHT) was related to a lesser worsening in the frailty
index ().
From these studies, androgen levels seem more
related to (changes in) composite entities of physical
926 Kaufman et al Aging and the Male Reproductive System
performance such as sarcopenia or frailty than to
direct muscle strength measurements. So, despite the
anabolic effects of T on muscle mass in men with
hypogonadism, the decline in androgen exposure in
aging men does not seem to fully account for their
decreases in muscle strength and physical perfor-
mance, and both processes are more likely to be related
to the underlying physiologic processes of aging per se.
Additionally, although most studies adjusted for
possible baseline confounders such as age, BMI, and
smoking and comorbidities such as CV or renal
disease, most statistical models only explain part of the
observed variance and probably suffer from residual
confounding.
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To summarize, changes in body composition in
aging men are associated with important clinical en-
tities and are thus of importance. Although a re-
lationship between androgen exposure and changes in
body composition is suggested from many population-
based studies in elderly men, the absolute direct
contribution in men during normal aging seems rather
limited, and many questions are still to be resolved.
Issues to be addressed are, for instance, the modulating
role of SHBG, as several studies reported associations
between SHBG levels and (changes in) indices of
adiposity (, , , , ), muscle mass (,
) and strength (), and physical performance
(), but also the role of intratissular metabolization
toward DHT, E, and other metabolites merits fur-
ther research. Finally, as mentioned earlier, the above-
mentioned relationships are also modulated by
changes in behavior, general health, and other hor-
monal axes (, , , , –). Although
most of the cited studies tried to account for this by
adjusting for comorbidities and/or medication use,
the possibility of residual confounding cannot be
excluded.
Erythropoiesis
Anemia is common in frank hypogonadism (), and
exogenous T administration is known for its stimu-
latory effects on erythropoiesis [reviewed in ()].
Although a considerable proportion of the elderly
present with unexplained anemia (–), it is
unclear whether and to what extent the aging-related
decline in androgen exposure in men contributes to
this phenomenon. In two specific studies in men with
TDM, anemia was more prevalent in those men with
low, as compared with those with normal, total or free
T levels (, ). Population-based data on this
association are still rather scarce, although recently
some evidence emerged supporting a relationship
between low T exposure and a decline in erythro-
poiesis in aging men. In the InCHIANTI study, a
positive association between total T, bioavailable T,
and Hb levels was found, and men in the lowest
quartile of bioavailable T levels were at higher odds to
be anemic. Moreover, among nonanemic participants,
Endocrine Reviews, August 2019, 40(4):906–972

those with both low total or bioavailable T levels at
baseline were at higher risk to be anemic at the -year
follow-up visit, independently from some common
baseline confounders (). Similarly, a cross-sectional
analysis of National Health and Nutrition Examina-
tion Survey data on adult men $ years of age
showed lower hematocrit (Hct) in the tertile of men
with the lowest free T levels (). Although this
finding persisted when limiting the study sample to
men $ years of age, there was insufficient power to
account for residual confounding from concomitant
illnesses or treatments. This was recently more ac-
curately addressed in the EMAS cohort, wherein it was
found that the proportion of elderly men diagnosed
with moderate or severe late onset hypogonadism
(LOH; with low total T, low free T, and the presence of
three sexual symptoms) present with a . to  g/L
lower Hb level as compared with eugonadal men,
differences that persisted after correcting for general
health status and comorbidities (). Also in the
EMAS, although unadjusted analyses suggested that
Hb levels were lower only in those men with low free
T, multivariate correcting for age, BMI, and prevalent
comorbidities also revealed lower Hb in men with low
total T but normal free T levels (). Furthermore, in
the Busselton Health Survey, total T, free T, DHT, and
total E levels were all positively correlated with Hb
level (), whereas in the MrOS Sweden cohort, total
E but not total T levels were independently associated
with Hb levels, and total E levels were lower in men
with anemia (). However, in the latter study no
estimates of the non–SHBG-bound sex steroid frac-
tions were evaluated, and the analyses were not ad-
justed for SHBG levels. Prospective data from the
EMAS revealed that both men with persisting or in-
cident primary hypogonadism presented with lower
Hb levels at .-year follow-up as compared with men
who remained eugonadal (). Again, this finding
persisted after adjusting for age and chronic illnesses
although the statistical power of these models was low
given the overall low incidence of primary hypo-
gonadism in this cohort. Finally, longitudinal analyses
from the CHAMP study showed that changes in
total T, free T, DHT, SHBG, E, and estron levels
were all related to contemporary changes in Hb level,
independent of baseline age, BMI, smoking, and
comorbidities (). Overall, these data suggest that
hypogonadism in elderly men is an independent risk
factor for development of a lower Hb level and anemia.
However, the origin of anemia in the elderly is mul-
tifactorial (), and the decrease in androgen exposure
probably only accounts for a minor part of the overall
decline in erythropoiesis in aging men.
Biomolecular mechanisms by which T stimulates
erythropoiesis remain incompletely resolved. Stimu-
lation of erythropoietin production and/or sensitivity
has been suggested by some researchers (–),
whereas others demonstrated direct effects of androgens
doi: 10.1210/er.2018-00178
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on erythroid progenitor cells (, ), or suggested
effects on iron bioavailability (, , ). However,
negative findings on the mechanisms underlying T
effects on erythropoiesis have been published as well
(, ). Furthermore, as suggested in some studies
but not in others, and only supported by circumstantial
evidence, part of the effects of T on erythropoiesis might
be mediated through conversion into E (, , ,
) or DHT (, ). Finally, contributing or
modulating effects of other hormones, lifestyle, con-
comitant illnesses, and treatments might play a role
both in aging-associated as well as hypogonadism-
associated anemia. For instance, a study in men un-
dergoing ADT for localized prostate cancer suggested
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a contribution of impaired IGF- signaling in the ob-
served decline in red blood cells (), and in the MrOS
Sweden study, smoking was associated with Hb
level ().
The CV system
Low T or diagnosis of LOH have been linked to a
variety of risk factors for atherosclerosis and CVD,
such as obesity, the MetS, TDM, increased blood
pressure, dyslipidemia, or endothelial dysfunction (,
, ). However, observed associations between
low serum T and a less favorable CV risk profile might
in many instances reflect either reverse causality, with
“Overall, …data suggest that
low T being the consequence rather than the cause of
hypogonadism in elderly men
the unfavorable clinical profile, or a bidirectional in- is an independent risk factor
terrelationship between low T and CV risk factors. A for development of a lower Hb
number of cross-sectional studies looked at associa- level and anemia.”
tions between prevalent CVD () or preclinical
markers of atherosclerosis such as carotid artery
intima–media thickness (IMT) (–), coronary
artery and aortic calcifications (, ) or abdominal
aorta aneurysm (), and endogenous sex steroid
levels. They reported mixed and overall inconclusive
findings of either an inverse relationship with serum
(free) T or no association independent of known CV
risk factors. Moreover, positive reports carry a high
risk of residual confounding, whereas some of the
negative studies suffer from low power.
Older observational studies that evaluated the
relationship between endogenous T levels and pro-
gression of atherosclerosis as assessed by a variety of
parameters such as progression of carotid artery IMT,
peripheral vascular disease, arterial stiffness, or pro-
gression of abdominal aorta or carotid artery ath-
erosclerosis showed either no association or only a
weak association of low T with progression of ath-
erosclerosis, and they did not reveal a significant trend
when meta-analyzed [reviewed in ()]. A more
recent study from the German Study of Health in
Pomarania also reported negative findings for asso-
ciation of serum T with progression of parameters of
subclinical atherosclerosis ().
As to prospective observational studies assessing
CV events, those that focused specifically on incident
https://academic.oup.com/edrv 927
REVIEW
IHD or myocardial infarction (MI) failed overall to
show an independent association with baseline (free)
T. Indeed, mostly negative findings from earlier studies
[reviewed in (, )] are being confirmed by more
recent studies based on substantial numbers of ob-
served events and MS-based hormone assay tech-
nology. In the Western Australian Health in Men
Study (HIMS),  MIs occurred during a mean of .
years in  community-dwelling men aged  to 
years at baseline (). In analyses adjusting for age,
other risk factors, and comorbidities, the incidence of
MIs was not significantly related to either total T,
calculated free T, DHT, or E. In the United
States–based Atherosclerosis Risk in Communities
study,  coronary heart disease (CHD) events (i.e.,
definite or probable MI, definite coronary death, or
coronary revascularization procedure) occurred in
 men with a mean baseline age of . years
during a median follow-up of . years. Following
multivariable adjustment there was no association of
quartiles of T with incident CHD; no other T fractions
or sex steroids were tested in this study ().
In contrast to the negative findings for association
with CHD, there is limited evidence indicating a re-
lationship between serum sex steroid levels and the
risk for stroke in aging men. It had previously been
reported from the Honolulu–Asia Aging Study that
men in the highest quintile of serum E had a twofold
increased risk of stroke, with no association of stroke
risk with serum T (). However, in the HIMS, serum
total and free T in the lowest quartile [, ng/dL
(,. nmol/L) and ,. ng/dL (, pmol/L),
respectively] were found to predict a higher risk of
incident stroke or transient ischemic attack ().
Association of stroke risk with serum androgen levels
was subsequently confirmed in an updated analysis of
the HIMS based on  events of stroke observed
during a mean .-year follow-up of  men ().
Men with higher total T, free T or DHT had a lower
incidence of stroke in fully adjusted analyses: the HR
for the highest vs the lowest quartile of serum level
was ., ., and . for total T, free T, and DHT,
respectively. In this study there was no association
between stroke incidence and serum E levels. In the
Cardiovascular Health Study () among  men
(mean age,  years),  had an incident ischemic
stroke. In analyses adjusting for stroke risk factors,
which had a somewhat limited statistical power,
total and free T were not associated with stroke risk.
However, a curvilinear relationship between serum
DHT and stroke incidence was observed with the
lowest risk of stroke at a serum DHT of  to  ng/
dL and a greater risk for levels . and , ng/dL.
The findings from studies looking at more het-
erogeneous composite endpoints of CVD, including
events of CHD, stroke, and CVD death, and in
some studies also peripheral arterial disease and heart
failure, reported mixed findings with some studies
928 Kaufman et al Aging and the Male Reproductive System
reporting associations of incident events with total
and/or free or bioavailable T, some reporting no as-
sociation with (free/bioavailable) T, and some reporting
associations with other sex steroids. In the MrOS
Sweden study, high T predicted a reduced risk of CV
events (). In a case-cohort design analysis from the
French Three-City prospective cohort study, there
was a J-shaped relationship of serum total and bio-
available T with incident ischemic arterial disease
(ischemic stroke, fatal and nonfatal CHD), with both
low and high T levels associated with increased CVD
risk in elderly men (). In the Cardiovascular Health
Study, total and free T were not associated with in-
cident CVD in analyses adjusting for CV risk factors,
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although there was a curvilinear association of DHT
with incident CVD (). In an analysis of the Fra-
mingham Heart Study, serum T was not significantly
associated with incident CVD, but men with higher
E levels were at lower risk of CVD (). In a later
analysis from the Framingham Heart Study there was
no association of baseline sex steroids and gonado-
tropin levels or their trajectories with incident CVD
during  and  years, but the numbers of men and
events in this analysis were rather limited (). A
systematic review with meta-analysis of  studies did
not provide evidence for a pronounced harmful or
beneficial effect of E on incident CVD ().
Finally, a number of studies addressed the re-
lationship between sex steroid levels and CVD mor-
tality. A systematic review and meta-analysis of studies
up to  looking at incident CVD mortality in-
cluding , men from seven studies followed for a
mean of . years is suggestive of an association of
lower serum total T with increased CV mortality [RR,
.; % CI, . to .; for the lowest vs highest T
tertile], but heterogeneity among studies limited the
validity of the summary estimate (). Overall, the
findings from more recent studies, although rather
disparate, tend to confirm the existence of a modest
inverse association of serum androgen levels with
CVD mortality. In an analysis of the Third National
Health and Nutrition Examination Survey (), 
deaths from CVD occurred in  men during a
-year follow-up. For decreases equal to the differences
between the th and th percentile of the sex
hormone distribution, lower free T, total E, and free
E, but not total T, were associated with increased risk
for CVD mortality. However, the young mean age of
 years at baseline limits the relevancy of this study in
the context of aging. In  men from the German
prospective Study of Health in Pomerania,  deaths
occurred during an average follow-up of . years, of
which  were attributed to CVD (). A total T
of , ng/dL (. nmol/L), but not serum total T as a
continuous variable, was associated with increased risk
of all-cause mortality after multivariable adjustments
(HR, .; % CI, . to .) and was also predictive
of cause-specific death from CVD (HR, .; % CI,
Endocrine Reviews, August 2019, 40(4):906–972

. to .); the effect of low T on mortality was
strongest in men $ years of age. The authors later
reported that they could not establish a causal re-
lationship between serum T and mortality when
performing a Mendalian randomization analysis ().
In  men of the HIMS with a mean age of  years
there were  deaths during a mean follow-up period
of . years, of which  were due to CVD ().
Lower free T [. vs . ng/dL ( vs  pmol/L)]
(HR, .; % CI, . to .) and higher LH and
SHBG were associated with all-cause mortality,
whereas lower free T (HR, .; % CI, . to .)
and higher LH also predicted cause-specific mortality
from CVD. In a subsequent report of an updated
analysis of the HIMS encompassing  deaths (
from IHD) in  men  to  years of age during a
mean .-year follow-up (), the authors reported
that after allowance for other risk factors, midrange
serum total T, free T, and DHT were associated with
the lowest all-cause mortality (lowest mortality for
values corresponding to the third quartile); similar
nonsignificant trends were observed for the association
of total and free T with IHD mortality, whereas higher
DHT was significantly associated with lower IHD
mortality (third quartile/first quartile, adjusted HR,
.; fourth quartile/first quartile, HR, .). In the
Cardiovascular Health Study,  deaths were re-
ported in  men during a median -year follow-up
(): the authors reported a curvilinear association of
serum DHT with all-cause mortality, similar to the
association of DHT with incident CVD, and no as-
sociation of mortality with total or free T; an asso-
ciation with cause-specific CVD mortality was not
reported. In an analysis of mortality in the Athero-
sclerosis Risk in Communities study ( deaths in
 men during a median of . years), quartiles of
total T were not associated with total mortality and not
with cardiac-associated mortality, of which there were,
however, only  cases (). In an analysis of the
Danish Monitoring Trends and Determinants of
Cardiovascular Disease (MONICA) study, the authors
assessed the association of intraindividual hormone
changes with mortality (). From  men ( to
 years of age) in MONICA  who had a second
examination  years later (MONICA ),  died
during a subsequent mean follow-up of . years.
Independently of baseline serum T, men with the most
pronounced total T decline (T ,th percentile) had a
higher all-cause mortality risk compared with men
within the th to th percentile (HR, .; % CI,
. to .); there were no consistent associations for
changes in free T, SHBG, or LH and not for changes in
total T and CVD-specific mortality. In an analysis of
the EMAS cohort involving  men aged  to 
years,  deaths were registered during a median
follow-up of . years, of which  were from CVD
(). Although total and free T were not associated
with mortality,  men categorized as having LOH on
doi: 10.1210/er.2018-00178
REVIEW
the basis of the combination of a low total T and free T
with the presence of three sexual symptoms had a
higher risk of all-cause and CVD mortality: the HR for
CVD mortality was . (% CI, . to .) for  men
categorized as moderate LOH [i.e., total T , ng/dL
( nmol/L) and $ ng/dL ( nmol/L), free
T ,. ng/dL ( pmol/L), and three sexual
symptoms] and was . (% CI, . to .) for 
men with severe LOH [i.e., total T , ng/dL
( nmol/L), free T ,. ng/dL ( pmol/L), and
three sexual symptoms]; although the low T con-
tributed to the increased risk, the presence of the three
sexual symptoms was associated with mortality irre-
spective of serum T when compared with asymp-
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tomatic men.
In summary, although suggesting the existence
of a modest relationship between CVD and (non–
SHBG-bound) T, the overall picture on the asso-
ciation between endogenous sex steroid levels and
CVD is rather disparate. The variability of findings
and the many inconsistencies might indicate re-
sidual confounding and, in particular, the possibility
of reverse causality related to general health status.
Yet, some facts appear to emerge. First, the data
clearly do not support the existence of an association
between endogenous sex steroid levels and incident
IHD and MI in aging community-dwelling men.
“There is limited evidence
Second, the data suggest an association of endog-
indicating a relationship
enous androgen levels with incident stroke and with between serum sex steroid
CVD-specific as well as all-cause mortality. Whether levels and the risk for stroke in
the nature of the relationship is either a threshold aging men.”
effect, a linear or a curvilinear association needs
further clarification. In view of the unclear physi-
ological role in men of circulating DHT, which
originates predominantly from hepatic T meta-
bolism, there is a need to learn more on the sig-
nificance of observed associations of stroke and
mortality with DHT, in particular where this oc-
curred in the absence of a parallel similar association
with T. Do these findings indicate real differential
pathophysiological relationships for circulating T
and DHT or do they rather result from methodo-
logical and statistical coincidences? Also needing
further unraveling is the nature and underlying
mechanisms of reported curvilinear relationships
between serum androgens and both stroke and
mortality. Finally, for none of the reported associ-
ations can a causal relationship be considered as
established. In this context it is interesting that
despite known metabolically undesirable effects of
ADT for prostate cancer such as weight gain and
increased insulin resistance (), in a meta-analysis
of randomized trials CVD-associated mortality was
not different and overall mortality was lower in
nonmetastatic patients with prostate cancer treated
with ADT compared with controls in either studies
of at least  years’ duration or short-term studies of
 months or less ().
https://academic.oup.com/edrv 929
REVIEW
Sexual function
Sexual problems are rarely discussed with doctors,
but they are common in older men and may have
physical and/or psychological causes (). For
physicians and researchers, it is important to make a
distinction in the evaluation of impaired so-called
“overall sexual function” from lack of sexual desire,
infrequent spontaneous erections or morning erec-
tions, premature ejaculation, erectile dysfunction
(ED) during masturbation or intercourse, limited
penile flow measured by Doppler, inability to reach
climax, sexual function distress, or sexual pain. Re-
search often ignores that some men will engage in
sexual activity that does not involve penetration and
are still sexually active. Also, the role of a (sexually
attractive) partner willing or able to have sexual
intercourse cannot be underestimated, and there
is a lack of data on the sexual function of non-
heterosexual older men.
Most available studies in aging men focus on
sexual desire and ED. In most research, an association
of low serum T with low sexual desire is described.
Low sexual desire can also result from medical and
mental health conditions (). ED is similarly more
likely to be the result of atherosclerosis, neurologic
impairment, medication use, or psychogenic causes.
The evidence that T treatment is beneficial for im-
proving decreased sexual desire is not consistent but
is overall supportive, and for ED T supplementation
is considered a second-in-line pharmacotherapy after
phosphodiesterase  (PDE) inhibitors (see “Treat-
ment of Hypogonadism in Elderly Men” below).
Prevalence of sexual problems in older men
In the HIMS, % of  men  to  years of age
provided data on sexual activity. Increasing age,
partner’s lack of interest, partner’s physical limitations,
osteoporosis, prostate cancer, diabetes, antidepressant
use, and beta-blocker use were independently asso-
ciated with reduced odds of sexual activity (). In
this study population, sexual problems were highly
prevalent: overall, % reported at least one problem,
.% reported ED, .% lacked interest in sexual
activity, .% of participants were unable to reach
climax, and .% were anxious about their ability to
perform sexually. Unpleasurable or painful sex was less
frequently reported. Low T levels were associated with
lack of interest, but not with any of the other com-
plaints. Medical comorbidity, rather than T, seemed to
be the main predictor of sexual problems in older men
(). In the -year longitudinal MMAS cohort with
 men aged  to  years at baseline, significant
negative changes were shown in all domains of sexual
function (sexual intercourse, erection frequency, sex-
ual desire, satisfaction with sex, and difficulty with
orgasm), except for frequency of ejaculation with
masturbation. Adjusted for baseline sexual function,
all outcomes were strongly related to age ().
930 Kaufman et al Aging and the Male Reproductive System
Associations with sex steroids
The importance of T in the maintenance of normal
sexual function is well established in young eugonadal
men and in men with hypogonadism (), but its role
in aging men’s sexual function is still controversial. In
cross-sectional studies, men with lower T tend to have
less sexual activity and desire, and more ED. It has
been suggested from these studies that sexual symp-
toms may be the most helpful in identifying men likely
to have adult-onset hypogonadism. Decreased spon-
taneous erections and low sexual desire were the most
prevalent clinical symptoms in both younger and older
men in the validation of the New England Research
Institute hypogonadism screener. In addition to these
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two symptoms, difficulty achieving or maintaining an
erection was a symptom that significantly discrimi-
nated the low T group from the control group in both
age categories (). In the EMAS, with  men aged
 to  years, low levels of total and free T were
modestly associated with less frequent sexual thoughts,
ED, and poor morning erections. The authors pro-
posed criteria for LOH based on the presence of these
three sexual symptoms, in addition to a total T
level , ng/dL (, nmol/L) and a free T level ,
pg/mL (, pmol/L) (). When adjusted for age,
BMI, and medical comorbidity, the associations be-
tween T levels and sexual symptoms did not persist
(). Moreover, there was ~% background preva-
lence in sexual symptoms irrespective of total T
concentration, suggesting other contributory factors
than only low T. In a consecutive series of  pa-
tients with sexual dysfunction (mean age, . years),
an inverse relationship between T levels and the
prevalence of severe ED and a positive relationship
with intercourse frequency was reported for the older
quartile ( to  years of age). For this older group,
there was an association between higher T levels and
better penile flow at penile color Doppler ultrasound
(). In the MMAS cohort, at the population level,
sexual desire and serum T concentrations were
strongly related. However, a simple individual report
of “low libido” had a low predictive value in indicating
low T levels below commonly applied total T
thresholds, with a positive predictive value for total T
values , and  ng/dL (. and . nmol/L) of
% and %, respectively (). A recent systematic
review on  ptients evaluated for ED and 
patients evaluated for decrease in sexual desire showed
that the presence of these findings were associated with
positive likelihood ratios of . (% CI, . to .) and
. (% CI, . to .), respectively, for finding T levels
below threshold T ().
Some evidence suggests that metabolites of T, such
as E and DHT, may play a role in (the age-related
decline of) sexual function (, ), but in the EMAS
cohort it was only total and free T (, ), and not
E or DHT, that were associated with overall sexual
function. In fully adjusted models, higher free T was
Endocrine Reviews, August 2019, 40(4):906–972

specifically associated with greater masturbation fre-
quency and less ED. Higher serum E was associated
with greater sexual function–related distress. The role
of DHT in these relationships has been inadequately
explored. However, in an experimental setting in
healthy younger men with suppressed endogenous T
with a GnRH agonist and administration of graded
doses of exogenous T, inhibition of a-reduction of T
to DHT did not modify T effects on sexual function
(). In the  participants in the US–based Tes-
tosterone Trials (TTrials) aged $ years with evi-
dence of sexual dysfunction, diminished vitality, and/
or mobility disability and with an average of two total
T , ng/dL (,. nmol/L), and in particular in the
subgroup of  men participating in the Sexual
Function Trial [reduced libido; score # on the
Sexual Desire Domain of the Derogatis Interview for
Sexual Function (DISF-SDD); partner willing to have
sexual intercourse at least twice a month], baseline
total and free T, but not E or SHBG, had small
significant cross-sectional associations with measures
of sexual desire, erectile function, and sexual activity
().
As to longitudinal data in the HIMS for  men
with sex hormone data, higher free and total T at
baseline ( to ) predicted higher sexual activity
in the  months preceding the follow-up examination
( to ): in a multivariable-adjusted analysis, for
each  SD increase of baseline free T the odds of
having sex in the  months preceding the follow-up
visit increased by % (). In a longitudinal study
from the Concord Health and Ageing in Men Project
study, with  men at baseline and  at -year
follow-up, whereas baseline levels of total and calcu-
lated free T, DHT, E, and estrone did not predict a
decline in sexual function, the decline of total and
calculated free T (but not of DHT, E, or estrone)
during follow-up was associated with a decline in
sexual activity and desire, but not in erectile function.
However, this decrease in serum T was quantitatively
minor (,%), being too small to fully account for the
decrease in sexual desire or activity ().
In conclusion, overall, the evidence supports the
existence of an association of lower total and free T
levels with lower sexual desire and function in aging
men. To what extent the reported associations are
explained by residual confounding rather than a causal
relationship remains uncertain.
Mental health
Cognition
The methodology of studies assessing relationships
between sex steroid levels and cognition in aging men
is heterogeneous with, in particular, a variety of dif-
ferent tests to evaluate cognition. Several studies
evaluated global cognition with the Mini-Mental State
Examination (MMSE), which is well established but
doi: 10.1210/er.2018-00178
REVIEW
not sensitive to detect subtle changes in relatively
healthy community-dwelling aging men, whereas
other tests have been used to assess different specific
cognition domains such as verbal and visual mem-
ory, concentration, verbal fluency, and visuospatial
and visuoperceptual function. Still other studies have
focused on the association of sex steroids with
Alzheimer’s dementia (AD). This makes it arduous to
reliably discern overall trends. Nevertheless, al-
though some studies reported negative or even op-
posite findings, several earlier cross-sectional studies
concurred, reporting an association of either higher
or optimal levels of T and, in particular, levels of
non–SHBG-bound (free or bioavailable) T with
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better performance in MMSE or tests addressing
specific aspects of cognition. More limited evidence
suggested that E levels might be inversely associ-
ated with cognitive performance [see , ) for
reviews].
As to longitudinal observational studies, in an
analysis of the Baltimore Longitudinal Study of Aging,
 men aged  to  years at baseline where followed
for an average of  years (). A higher ratio of T/
SHBG was associated with better scores on visual and
verbal memory, visuospatial functioning, and visuo-
motor scanning and with a reduced rate of longitu-
dinal decline of visual memory, whereas there were no
“…the evidence supports the
associations of T or the ratio of T/SHBG with mea-
existence of an association of
sures of verbal knowledge. In a subsequent analysis lower total and free T levels
from the Baltimore Longitudinal Study of Aging, with lower sexual desire and
among  community-dwelling men  to  years of function in aging men.”
age followed for a mean of . years,  developed
AD (). In multivariable-adjusted analyses, a di-
agnosis of AD was inversely associated with the ratio of
T/SHBG at both baseline and last measurement; each
-unit (nmol/nmol) increase of the ratio of T/SHBG
was associated with an ~% lower risk for AD. When
considered separately, T and SHBG did not predict
risk of AD. In the Honolulu–Asia Aging Study, de-
velopment of dementia and decline of cognitive
function according to the Cognitive Abilities Screening
Instrument was assessed during an average of  years in
 men  to  years of age without dementia ().
A total of  men developed AD, including  cases
with contributing cerebrovascular disease. After ad-
justment for cofounders, bioavailable T was not asso-
ciated with incident dementia or cognitive decline.
Alternatively, higher bioavailable E was associated with
greater cognitive decline and with risk of AD (HR per
SD increase, .; % CI, . to .) and of AD with
cerebrovascular disease (HR, .; % CI, . to .).
In  men with mean age of  years participating in
the Health ABC study, free T was not associated with
cognitive decline (). In  men with a mean age of
. years from the Medical Research Council Cognitive
Function and Ageing Study, the men with cognitive
decline after  years according to the MMSE had lower
total T and higher SHBG serum levels; there were no
https://academic.oup.com/edrv 931
REVIEW
significant associations with verbal memory (story re-
call) or the modified MMSE (MS) scores (). In the
MrOS US study cohort,  men $ years of age
with sex steroid measurements by immunoassay, of
whom  randomly selected men also had sex
steroid measurements by MS at baseline, were sub-
jected at baseline and . years later to two tests
of cognitive function, that is, Trails B (executive
function and motor speed) and MS (global cognitive
function) (). In analyses adjusting for con-
founders, baseline free T and free E as well as total T
and E were not associated with cognitive perfor-
mance or change in cognition. However, higher
SHBG was associated with worse cognitive perfor-
mance at follow-up testing (Trails B and MS) and
with greater decline on MS performance in mul-
tivariate adjusted models also including free T and
free E. Men $ years of age participating in the
Australian CHAMP study were assessed at baseline
(n 5 ), -year follow-up (n 5 ), and -year
follow-up (n 5 ) with measurements by MS of sex
steroids (T, DHT, E, and estrone) and cognitive
testing with the MMSE (). None of the baseline
hormone levels was predictive of cognitive decline
during  years. In multivariable-adjusted models
accounting for potential confounders, men with
declining levels of total T, calculated free T, DHT, or
estrone during the follow-up period were more
likely to have cognitive decline according to the
MMSE. The absence of association of baseline sex
steroid levels with cognitive decline might suggest
the existence of common factors underlying the
parallel temporal evolutions of hormone levels and
cognitive function rather than a direct causal re-
lationship between them. In a recent report from the
Study of Health in Pomerania (), baseline T and
androstenedione by MS as well as calculated free T
in  men (mean age, . years) were not as-
sociated with - and -year changes in MMSE
score.
Finally, although it has been suggested that ADT
for prostate cancer may be associated with adverse
effects on cognition (), a recent large population-
based British study did not reveal an increased risk of
dementia (). Using the United Kingdom’s
Clinical Practice Research Datalink, the authors
assembled a cohort of , men newly diagnosed
with nonmetastatic prostate cancer. During a mean
follow-up of . years,  patients were newly di-
agnosed with dementia. Compared with nonuse,
ADT use was not associated with an increased risk of
dementia (incidence, adjusted HR, .; % CI, .
to.).
In conclusion, several studies do suggest that low or
suboptimal (free) T may be associated with cognitive
decline. However, in most prospective studies, in-
cluding more recent large cohort studies with MS-
based hormone assays, baseline sex steroid levels failed
932 Kaufman et al Aging and the Male Reproductive System
to predict cognitive decline or incident AD. Overall,
the evidence from observational studies does not
support an important causative role of altered sex
steroid levels in the decline of cognitive function in
older men.
Depression
The lower prevalence of depression in men compared
with women and findings of lower T levels in men
with depression compared with controls in some
earlier reports have been suggested to indicate a
protective role of T against depression. Compatible
with such a protective role of T are findings of ob-
servational cross-sectional studies in aging men of an
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inverse association of (free or bioavailable) T with
depressive symptoms or prevalence of depression
and more in particular association of clearly low T
levels (e.g., lowest quartile or quintile) with de-
pression. However, these studies cannot establish a
causal relationship, and other studies failed to reveal
such associations (see (, ) for reviews). In his-
torical longitudinal cohort studies in a health care
setting for US veterans, a low T level in the hypo-
gonadal range [total T # ng/dL (#. nmol/L) or
free T #. ng/dL (# pmol/L)] in men $ years of
age () and a low total T # ng/dL (#. nmol/L)
in men $ years of age (), respectively, were
associated with a higher -year incidence of depressive
illness.
Prospective longitudinal studies have produced
mixed results. In volunteering men ( to  years of
age) participating in the Baltimore Longitudinal Study
of Aging and followed for an average of  years,
baseline and mean values for total T and the ratio of T/
SHBG were not associated with depressive symptoms
assessed with the Center for Epidemiologic Studies
Depression Scale (CES-D) either in cross-sectional
(n 5  men) or longitudinal (n 5  men) an-
alyses (). In community-dwelling elderly men
(mean age, . years) followed for  years (), total
and free T were not associated with the score on the
-item Geriatric Depression Scale (GDS) in cross-
sectional analyses either at baseline (n 5 ) or at
endpoint (n 5  men); presentation with a GDS
score . indicating possible depression at the end of
follow-up was not related to baseline (free) T, and
changes in (free) T levels during follow-up were not
associated with GDS score. In ~ men with hor-
mone values participating in the Study of Health in
Pomerania (), total and free T and androstenedione
levels were not associated with depressive symptoms
defined as two self-reported questionnaire items of the
Composite International Diagnostic–Screener either
in a cross-sectional analysis or during - and -year
follow-up in a longitudinal multivariable adjusted
analysis.
At variance with these negative findings, other
studies have reported that low T is predictive of
Endocrine Reviews, August 2019, 40(4):906–972

incident depressive symptoms. In multivariable ad-
justed analyses in  men $ years of age followed
in the Longitudinal Aging Study Amsterdam, baseline
free T below a threshold of . ng/dL ( pmol/L) was
associated with baseline depressive symptoms assessed
with the Center for Epidemiologic Studies Depression
Scale, and baseline free T in the lowest quintile
[i.e., ,. ng/dL ( pmol/L)] predicted the onset of
depressive symptoms in a longitudinal analysis; total T
was not associated with depressive symptoms (). In
the HIMS,  men developed depression among 
older men ( to  years of age) during a .-year
median follow-up (). Men with depression were
older and more likely to have CVD. Low serum total T
[, ng/dL (. nmol/L)], as measured by LC-MS/
MS, was associated with incident depression after
adjustment for potential confounders (HR, .; %
CI, . to .). Low levels of calculated free T, DHT,
and E were not associated with risk of depression
().
In conclusion, the mixed findings leave open the
possibility that markedly low T levels in older men
are associated with increased prevalence and in-
cidence of depressive symptoms. However, in view
of a substantial body of negative results, the whole of
the findings from observational studies are in-
conclusive. In particular, there is only limited evi-
dence that moderate declines of androgen levels in
aging men play a role in the occurrence of depressive
symptoms.
Diagnosis of Hypogonadism in Aging Men
The classical definition of male hypogonadism entails
a clinical syndrome where the testes fail to produce
physiological concentrations of T and/or a normal
number of spermatozoa due to organic pathology of
one or more levels of the HPT axis (). Reduced T
production almost always leads to reduced sper-
matogenesis (with Pasqualini syndrome, i.e., fertile
eunuch, as an exception), but spermatogenic failure
can occur in men with normal T production (e.g.,
obstructive and idiopathic azoospermia). Failure at
the testicular level (low T, high gonadotropins)
is termed primary hypogonadism, and failure at
the hypothalamic–pituitary level (low T, low or in-
appropriately normal gonadotropins) is termed sec-
ondary hypogonadism. Hypothalamic–pituitary and
testicular impairment can also occur in the same indi-
vidual, typically in the hypogonadism of older men who
are obese.
The causes of primary and secondary hypo-
gonadism are listed in Table . They can be divided
into two etiologically distinct types. One is the
“classical” organic hypogonadism caused by perma-
nent dysfunction at the hypothalamic, pituitary, or
testicular level due to intrinsic structural, destructive,
doi: 10.1210/er.2018-00178
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or congenital pathology. It is irreversible but treatable
by gonadotropin or androgen replacement. The other
type is functional hypogonadism with no organic
cause, and it is therefore potentially reversible when
the underlying etiology is treated. Hypogonadism of
the aging male is usually primary when due to
chronological aging alone, and secondary when as-
sociated with obesity or other comorbidities common
in old age. The frequently used term “late-onset
hypogonadism” is in fact a misnomer, because in
% of cases it is caused by obesity or other comor-
bidities with no association with chronological age
().
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Clinical evaluation
Algorithms have been developed for the clinical
workup of an older male patient with suspected
hypogonadism [see, e.g., Fig.  ()]. The first task
in the clinical evaluation is to define whether the
patient is genuinely hypogonadal, because many of the
symptoms are nonspecific and not necessarily caused
by androgen deficiency. Hypogonadal symptoms, of
which the sexual ones are most specific (), com-
bined with low serum T are the starting point of
making the diagnosis. If the man is androgen deficient
(repeatedly low serum T), the next step is to dis-
criminate whether he has organic or functional “…there is only limited
hypogonadism. It is not unusual that a Klinefelter evidence that moderate
syndrome patient remains undiagnosed in young declines of androgen levels in
age. We concentrate here only on hypogonadism aging men play a role in the
diagnosis of aging men, that is, the functional occurrence of depressive
symptoms.”
hypogonadism.
Diagnosis of functional hypogonadism should
only be made in men with unequivocally low T (see
below) and specific clinical symptoms. The latter can
be subdivided into physical, psychological, and sexual
domains (Table ). Most typically they include re-
duced sexual function, loss of muscle mass and
strength, declined physical activity and performance,
and a decrease of some cognitive abilities and de-
pressive symptoms (). From these, sexual symp-
toms are more specific whereas specificity of
decreased cognition and depressive symptoms is
questionable (see “Clinical Correlates of Sex Steroid
Levels in Elderly Men” above for a more extensive
review of the clinical correlates of low T). In surveys
of community-dwelling men, decreased sexual desire,
and ED, as well as less specific symptoms such as
reduced physical performance, insomnia, fatigue,
irritability, and low mood, have been associated with
low T (, ). In the EMAS, only three sexual
symptoms (poor morning erections, ED, and reduced
sexual thoughts) showed clear syndromic association
with low T (). Many of the symptoms are non-
specific and overlap with those of chronic diseases
common in old age (the MetS, TDM, and CV, renal,
and pulmonary diseases). Important metabolic pa-
rameters include BMI and waist circumference, as
https://academic.oup.com/edrv 933
REVIEW

Table 4. Causes of Organic and Functional Primary and Secondary Male Hypogonadism
[Adapted with permission from
Grossmann M, Matsumoto Organic
AM. A perspective on middle-
aged and older men with Primary Secondary
functional hypogonadism:
Klinefelter syndrome Hyperprolactinemia
focus on holistic management. J
Clin Endocrinol Metab 2017; Cryptorchidism Stalk section or disease
102(3):1067–1075.]
a
Combined primary and Cancer chemotherapy Hemochromatosis
secondary.
Irradiation to the testes Idiopathic hypogonadotropic hypogonadism

Testicular trauma Kallmann syndrome

Testicular torsion Hypothalamic or pituitary tumors or infiltrative diseases

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Infectious orchitis Pituitary surgery or radiation

HIV infectiona

Anorchia, castration

Myotonic dystrophy

Old age (no comorbidities)a

Functional

Primary Secondary

Medications (inhibitors of androgen synthesis) Hyperprolactinemia

Renal disease Use of opioids and anabolic steroids

Alcohol use Use of glucocorticoidsa

Old age (with comorbidities)a

Chronic illnessa

Obesity, type 2 diabetes mellitus

Excessive exercise, malnutrition, wastinga

Anorexia/excessive exercise

Androgen deprivation therapy with GnRH analogs

Anabolic-androgenic steroid withdrawal syndrome

many older men with documented hypogonadism
are obese. It is also important to assess the man’s
general health with respect to systemic illness, eating
disorders, exercise habits, and use of prescription and
recreational drugs that may affect T synthesis or
metabolism. More specific organic findings sug-
gesting androgen deficiency may include osteopo-
rosis and anemia.
There are several self-reported questionnaires on
symptoms of hypogonadism, such as the Aging Males’
Symptoms scale (), the Androgen Deficiency in the
Aging Male scale (), the Massachusetts Male Aging
Study scale (MMAS) (), and the New England
Research Insitute hypogonadism screener (), but
they all are hallmarked by high sensitivity com-
bined with poor specificity (), thus potentially
leading to overdiagnosis of hypogonadism. A
structured interview (Androtest) concentrating on
sexual symptoms may have higher specificity ().
These case-finding tools are not recommended for
detecting T deficiency in men receiving health care for
unrelated reasons.
Hormonal evaluation
The critical hormonal parameters in the diagnosis of
male hypogonadism are total T, free T, SHBG, and
gonadotropins. Although the currently available im-
munoassays for SHBG and gonadotropins appear
adequate, a fair amount of uncertainty and contro-
versy still surrounds the approaches on how to
monitor circulating T levels, both total and free.
For the diagnosis of hypogonadism, serum T
should be consistently and unequivocally low as
measured on two separate occasions in blood

934 Kaufman et al Aging and the Male Reproductive System Endocrine Reviews, August 2019, 40(4):906–972
 REVIEW

Figure 4. Algorithm for the diagnosis and treatment of LOH [Huhtaniemi and Forti (461)]. If the clinician suspects LOH, the diagnosis
and choice of treatment can be obtained by following the flowchart from top to bottom, and choosing the next alternative on the basis of
the findings. Patients who present with symptoms of LOH should have a morning total T measurement. The results of this test, and a
subsequent free T determination (measured or calculated), will determine whether the patient should be assessed for his suitability for T
replacement. The hormone levels will vary with local protocols, so those presented are merely illustrative, and the clinician should use
local reference ranges for the assays in making their diagnosis. DRE, digital rectal examination; PRL, prolactin. [Reproduced with
permission from Huhtaniemi I, Forti G. Male late-onset hypogonadism: pathogenesis, diagnosis and treatment. Nat Rev Urol 2011;8(6):
335–344.]

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samples obtained mandatorily in the morning and
preferably in a fasting condition. For positive di-
agnosis, both values have to be subnormal. There is
no consensus among the guidelines on what is
considered subnormal, with the cutoff values for
total T varying from  to  ng/dL ( to
. nmol/L) (, ). Moreover, reference ranges
vary between laboratories due to methodological
issues related to both T assay standardization and
generation of reference ranges. Therefore, in a recent
update of the American Endocrine Society clinical
practice guideline on T therapy in men with
hypogonadism (), the only lower total T limit put
forward is a total T of  ng/dL (. nmol/L) that
can be used for assays that are calibrated against the
Centers for Disease Control and Prevention stan-
dard (). This is based on a project supported by
the American Endocrine Society and the Partnership
for the Accurate Testing of Hormones in which
harmonized T reference ranges were generated
from data from US- and Europe-based cohorts of
community-dwelling men by cross-calibrating the
LC-MS/MS T assays used in each cohort against a
method and calibrator developed by the Centers for

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REVIEW
Disease Control and Prevention: the harmonized
reference range (.th to .th percentile) for
nonobese men  to  years of age was  to
 ng/dL (. to . nmol/L) (). Furthermore, it
is considered that a patient with T , ng/dL
(, nmol/L) is most likely hypogonadal and may
benefit from T replacement therapy, and those with
T . ng/dL (.. nmol/L) do not (). In
general, the lower limit of T of young men can be
used as the limit, but access to a reliable assay with a
validated reference range is important. If T is re-
peatedly and unequivocally low, gonadotropin
measurements should be conducted to discriminate
between primary and secondary hypogonadism.
Inflection points were identified in the EMAS for
the different symptoms to be significantly associated
with T (): , ng/dL ( nmol/L) for decreased
vigorous activity, , ng/dL ( nmol/L) for
Table 5. Signs and Symptoms Associated With T
Deficiency Syndrome
Sexual
Decreased libido
ED
Decreased frequency of morning erections
Decreased performance
Somatic
Increased visceral body fat/obesity
Decreased lean muscle mass
Decreased strength
Fatigue/loss of energy
Decreased physical activity/vitality
Low BMD
Anemia
Hot flushes
Loss of facial, axillary, and pubic hair/slow beard growth
Decline in general feeling of well-being
Frailty
Psychological
Depression/depressed mood
Mood changes
Irritability
Lack of concentration
Insomnia/sleep disturbances
936 Kaufman et al Aging and the Male Reproductive System
decreased morning erections, , ng/dL (. nmol/
L) for ED, and , ng/dL (. nmol/L) for low sexual
thoughts. The free T inflection point for decreased
sexual thoughts, fatigue and sadness was found
at ,. ng/dL ( pmol/L) and for ED and decreased
morning erections at , ng/dL ( pmol/L). The lack
of specificity of even the most specific symptoms was
highlighted by their high background prevalence of
% to % irrespective of the T concentration
measured. Multiple correspondence analysis revealed,
most conspicuously, that the three sexual symptoms
were clustered with a low total T level , ng/dL
( nmol/L) and , ng/dL ( nmol/L), and a free T
level ,. ng/dL ( pmol/L) in syndromic associ-
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ations. The symptoms that were significantly associ-
ated with a low T level included the aforementioned
three sexual symptoms and a total T , nmol/L (OR,
.; % CI, . to .). The addition of the
threshold of free T ,. ng/dL ( pmol/L) increased
the OR to . (% CI, . to .). These limits, that
is, three sexual symptoms, total T , nmol/L, and
free T , pmol/L, can be regarded as evidence-
based criteria for the LOH diagnosis. They are,
however, not sufficient without the ancillary general
health information. The association was attenuated by
adjustment for age, BMI, and the number of coexisting
illnesses. The practicability of applying these rather
complex criteria in daily clinical practice may be an
issue.
T assay: by immunoassay or MS?
The recent onslaught of MS for steroid hormone
measurements, including unconditional demands for
them to be the only acceptable method (), has
confused clinicians and scientists who have relied for
nearly  years on various immunoassay methods. The
superior specificity of MS methods will undoubtedly
make them the future mainstay in steroid hormone
measurement. However, for purely practical reasons,
many clinical steroid measurements will continue to
be carried out using immunoassays because of their
high sensitivity, technical ease, output speed, and
capacity, as well as cost and availability of commercial
reagents. It is unrealistic and unnecessary to replace
them immediately with MS-based assays, because their
availability is still limited by cost, need of expensive
equipment, technical demands, and limited com-
mercial applications.
The problems with immunoassays, including their
cross-reactivity with similar analytes and standardi-
zation and sensitivity issues, are well recognized ().
The Endocrine Society Council established a “Sex
Steroid Assays Reporting Task Force” (), which
defined the necessary performance criteria for
methods to be used in clinical and nonclinical studies
and recognized the need of high-quality, well-validated
assays, irrespective of the technique (MS or im-
munoassay), to improve the quality of work, including
Endocrine Reviews, August 2019, 40(4):906–972

the assay traceability to a certified standard (). The
pros and cons of MS and immunoassay in steroid
analysis have been recently discussed (), but the
debate continues (). The poor quality of T assays
has been a long-time target of complaints (, ).
Important reasons for this are the various shortcuts
taken when the methodology was introduced to
routine clinical laboratories, exhibiting reduced sen-
sitivity, hard-to-control matrix effects, interference
with plasma steroid binding proteins, and nonspecific
competition with the assay antibodies.
Several recent studies on large sample numbers
have demonstrated that the new platform T immu-
noassays are fully adequate for samples from men at all
concentrations [see, e.g., (–)]. One of them
concerned a large comparative study on T measure-
ments by a well-standardized immunoassay and a
comparator LC-MS/MS method in serum samples
of . men (). T measurements by immuno-
assay offered good accuracy at all concentrations
found in eugonadal men and in men with hypo-
gonadism. Importantly, the platform immunoassay for
T had sensitivity and specificity also in the hypo-
gonadal male range, although with somewhat lower,
but still acceptable, accuracy than in the eugonadal
range. Not all immunoassays used in clinical T
measurements are likely to have the same high quality.
If MS assays are not available, a good practical ap-
proach is to test the immunoassay’s accuracy by
comparing T concentrations measured by immuno-
assay and MS from a representative subset of samples
(e.g., n 5 ).
Free T measurement
According to the free hormone hypothesis, still
lacking robust experimental proof, only the un-
bound (free) hormone is representative of the bi-
ological activity in the target tissues (, ).
Consequently, it is important to be able to measure
accurately the partitioning of T in plasma between
protein-bound and free fractions to assess its real
biological activity. T is bound partly (~%) with
high affinity to SHBG and with low affinity (~%) to
albumin, to a lesser extent to cortisol-binding
globulin and orosomucoid, and the remaining
~.% is referred to as free T. The sum of free T and
loosely albumin-bound T, which may dissociate at
least in part in the microcirculation, is often referred
to as bioavailable T.
The free T fraction can be measured following
equilibrium dialysis or ultrafiltration of serum (either
indirectly with use of a radioactive T tracer or by direct
MS-based T measurement), or estimated by calcula-
tion from total T, SHBG, and albumin concentrations
using published algorithms either based on the law of
mass action (–), empirically derived (), or
based on a recently proposed alternative dynamic
allosteric model of T binding (), All algorithms
doi: 10.1210/er.2018-00178
REVIEW
are fraught with some potential problems, including
poor precision, inaccuracy, and low specificity. Un-
certainties on the dynamics of T binding to albumin,
orosomucoid, and CBG represent another caveat.
Nevertheless, there are clinically relevant differences in
their performance with, in particular, the algorithm
based on the allosteric T binding model (), pro-
ducing results far off target compared with equilibrium
dialysis ().
For measurement of free T, the equilibrium dialysis
method is considered the reference method. It is
technically demanding, sensitive to errors, and seldom
available for clinical diagnostics. Direct analog im-
munoassays are not recommended for free T mea-
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surement because of their poor accuracy (). Salivary T
shows good correlation with serum free T when re-
liably measured, preferably by MS (), but pre-
analytical issues, for example, blood contamination
and metabolism of T in salivary gland (), may
reduce its accuracy to monitor serum free T. Mea-
surement of bioavailable T is based on precipitation of
SHBG-bound T and assay of remaining T in the
supernatant. However, because of the high levels of
imprecision and inaccuracy of this method it is not
recommended for clinical practice (); estimates of
bioavailable T can also be calculated with the algo-
rithms based on the law of mass action similarly as for
free T.
For the above reasons, computational algorithms
for estimation of free and bioavailable T remain the
most practical alternatives for clinical diagnosis.
Therefore, calculated free T using high-quality T and
SHBG assays has been considered the most useful
clinical marker (). The calculated free T algorithms
suffer from multiple inaccuracies, including ignoring
the nonlinear nature of T–SHBG binding, using dif-
ferent association constants for SBHG and albumin
binding, and variable association with equilibrium
dialysis data (). However, much of the critique of
calculated free T is not in keeping with the experi-
ence from clinical practice, where the linear model
algorithms (in particular the most commonly used
Vermeulen equation) appear to give, despite their
shortcomings, acceptable data for clinical praxis and
research (, ).
Proof for the usefulness of free T assesment in the
diagnosis of hypogonadism of elderly men was pro-
vided by the EMAS data (, ) and some other
studies (). They revealed in a cross-sectional
analysis that men with normal total T but low free
T concentrations had higher LH levels, reported more
hypogonadism-associated sexual and physical symp-
toms, and had lower Hb values and BMD than did
men with normal total and free T, and, conspicuously,
than did men with low total T but normal free T. Use
of total T alone is likely to result in overdiagnosis of
hypogonadism, especially in men who are obese and
when the total T levels are borderline decreased. The
https://academic.oup.com/edrv 937
REVIEW
usefulness of free T measurements in fine-tuning the
diagnosis was apparent in the borderline range of 
to  ng/dL ( to  nmol/L), but not below or above.
In a recent longitudinal analysis of the EMAS data
(), the same finding was made in men developing
secondary hypogonadism during a .-year follow-up
period: the agreement with hypogonadal symptoms
was only found in men with low total and free T, but
not in those with low total and normal free T.
All current guidelines (, , , , ) rec-
ommend free T assessment only as a complementary
tool in symptomatic men whose total T is near the
lower limit of the normal range and in conditions that
affect SHBG concentrations and render total T a less
reliable index of gonadal function. The only exceptions
are a recommendation from Japan for preferential use
of free T (), and from Australia against the use of
free T in clinical decision-making ().
Reference range of T for aging men
One of the problems in the diagnosis of hypogonadism
of older men has been the lack of age-dependent
reference ranges, and the diagnosis is usually made
on the basis of data from healthy young men. Rig-
orously established age-dependent reference ranges for
T have been missing so far. It has also remained
unclear whether the reference ranges differ between
populations, and to what extent their variability is due
to analytical variation and to biological variation.
To improve the situation, Travison et al. ()
recently established harmonized reference ranges for
total T, applicable across laboratories by cross-
calibration of assays to a reference method and stan-
dard. The data are based on serum samples from .
community-dwelling men from four cohort studies
from Europe and the United States. The influence of
systematic methodological differences was minimized
by harmonizing all measurements to a higher order
standard prior to the estimation of reference ranges.
Preanalytical differences were minimized by using
samples collected in a similar fashion (fasting morning
samples, storage at 2°C). T concentrations were
measured by the reference LC-MS/MS method from a
subset of samples from each cohort. Normalizing
equations were used to generate harmonized values,
which were used to derive standardized, age-specific
reference ranges of the whole sample cohort.
The harmonization process reduced intercohort
variation, and the reference range calculated from
all serum samples in - to -year-old nonobese
(BMI , kg/m) European and American men was
found to be  to  ng/mL (. to . nmol/L).
Whereas the .th percentile remained stable upon
aging, the median (th percentile) and .th per-
centile decreased in older age groups (Table ). After
methodological harmonization, the differences be-
tween the different cohorts were minimal. The same
trends were observed when the data on nonobese men
938 Kaufman et al Aging and the Male Reproductive System
and men with obesity were compared, although the
former had higher average levels of T. Hence, although
there is minimal variation in T levels between Eu-
ropean and American cohorts of men, more variability
has been found between and within multiethnic,
multiracial, and geographically diverse populations in
some (, ), but not all (), studies. Whether the
reference ranges should be established with men from
the general population or men in perfect health
remains a topic of discussion. Another issue is how to
take into account the known decreasing effect of
obesity on free and total T, SHBG, and gonadotropins
in otherwise healthy men ().
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Treatment of Hypogonadism in Elderly Men
In younger men with low T and an established di-
agnosis of hypogonadism, owing to a defined con-
genital or acquired irreversible cause, T replacement
therapy is a common clinical practice. The aim of such
replacement therapy is to reestablish “physiological”
serum T levels within the reference range for young
adult men. This practice is generally not challenged,
even though for historical and ethical reasons it is
mostly based on a rational concept and clinical ex-
perience rather than controlled data. Any treatment
involving T administration is a pharmacological
treatment, and although probably acceptable in this
context in young men, the term “replacement therapy”
should be avoided in the context of newly initiated T
therapy in older men. Indeed, it is a misnomer because
we do not really know what the physiological, desired,
or ideal serum T levels are in older men. Also, whereas
there appears to be a dose ceiling effect for some T
actions with no additional effect for T levels above the
normal range, this is obviously not the case for some
important actions of T. Indeed, for T effects such as on
muscle and erythropoiesis, there is a progressive re-
sponse from infraphysiological, over physiological, up
to frankly supraphysiological dosages without obvious
threshold or ceiling effects around the serum T ref-
erence range. Moreover, a critical appraisal indicates
that in many studies on T therapy in older men, mean
T exposure during T treatment tended to be supra-
physiological. This is certainly so relative to age-
specific mean T levels, but also relative to serum T
levels in young men when taking into account factors
such as the marked physiological circadian variation of
serum T in young men, preparation-specific T
pharmacokinetics, and the slower T clearance in older
men (). Finally, the term “replacement therapy”
tends to have a potentially misleading connotation of
something physiological and thus innocuous, which
may not need to be supported by the same level of
evidence as other pharmacologic interventions. This
long-prevailing misconception is likely to be one of
several explanations for the rather limited and mostly
Endocrine Reviews, August 2019, 40(4):906–972
 REVIEW

Table 6. Model-Based Estimates of Population Centiles for Total T Concentrations (ng/dL) Based on Data From Nonobese
Men (N 5 6933) and All Men (N 5 9054) in Four Harmonized Cohorts
Age (y)
Percentile 19–39 40–49 50–59 60–69 70–79 80–99
To convert from ng/dL to
All nonobese men nmol/L, multiply by 0.0347.
[Reproduced with permission
2.5 267 235 219 218 218 157 from Travison TG, Vesper HW,
Orwoll E, et al. Harmonized
5.0 304 273 256 254 252 218 reference ranges for circulating
testosterone levels in men of
10.0 344 310 297 296 292 278 four cohort studies in the
United States and Europe. J Clin
25.0 424 386 374 374 372 362 Endocrinol Metab 2017;102(4):
1161–1173.]

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50.0 531 481 477 477 477 476

75.0 643 608 605 604 604 604

90.0 774 749 749 749 749 749

95.0 850 839 839 839 839 839

97.5 929 929 929 929 926 913

All men

2.5 229 208 192 190 190 119

5.0 273 243 222 221 220 203

10.0 318 283 262 260 259 256

25.0 396 358 341 340 340 338

50.0 507 461 446 446 446 446

75.0 626 588 573 572 572 572

90.0 755 729 720 720 720 720

95.0 834 813 812 812 812 812

97.5 902 902 902 902 902 902

only recent evidence from controlled trials on T
therapy in older men. As for all pharmacological in-
terventions, clinical practice should preferably be
supported by sufficient information on safety and
efficacy of T therapy for defined clinical outcomes and
for treatment durations relevant for the intended
clinical use. To date, the evidence base from controlled
trials, besides being limited, is characterized by great
heterogeneity that pertains to inclusion criteria (age,
serum T levels, presence of hypogonadism symptoms,
and/or comorbidities), evaluation criteria and tools, as
well as modality, dosage, and duration of T therapy.
Older studies mostly included only small numbers of
subjects, and RCTs of .-year duration are rare.
Efficacy of T therapy
Sexual function
The findings from older studies on the effects of T
therapy on sexual function have been inconsistent and
may suffer from publication bias. Overall, they nev-
ertheless suggest a beneficial effect of T administration
on erectile function and sexual desire in those men
with initially low serum T, independently of age (,
).
Recently, Corona et al. () performed an updated
meta-analysis of results of T therapy on sexual function
based on International Index of Erectile Function (IIEF)
scores, which included  studies enrolling  par-
ticipants with a mean follow-up of . weeks and mean
age of . 6 . years. They found that T therapy
significantly (P , .) improved erectile function
compared with placebo according to the IIEF Erectile
Function Domain, although the effect size was modest
[. (. to .) and . (. to .) using a fixed
and random model, respectively], and the absolute
changes in IIEF Erectile Function Domain score may
not be clinically significant in many subjects, in par-
ticular in those with more severe ED (). The
treatment effect was greater in studies including men

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REVIEW
with baseline T , ng/dL (, nmol/L) compared
with those including men with T , ng/dL
(, nmol /L). They found that T therapy also im-
proved scores for the other IIEF domains, including
sexual desire domain, intercourse satisfaction domain,
orgasmic domain, overall sexual satisfaction, and IIEF-
 total score ().
This meta-analysis included the results of the re-
cent Sexual Function Trial, which is part of the co-
ordinated set of T trials constituting the TTrials. This
randomized placebo-controlled trial () is highly
relevant in the context of this review, as it included
older men ($ years of age; mean age,  years) with
low sexual desire (score , on the DISF-SDD, with a
score range from  to ) and unequivocally low serum
T [average of two early morning T , ng/dL
(,. nmol/L)] treated  year with placebo or T gel
(initial dosage of  mg daily by % gel), aiming at
serum T levels in the midrange for young men. The
men treated with T (n 5 ) reported a significantly
greater (P , .) increase of sexual activity (Psy-
chosexual Daily Questionnaire question ), increase of
sexual desire (DISF-SDD), and improvement of
erectile function (IIEF score) than did the men treated
with placebo gel (n 5 ). The men treated with T
were more likely than those treated with placebo to
report improved sexual desire since the beginning of
the trial (P , .). Additional analyses () in-
dicated that compared with placebo, T therapy in-
creased  out of  Psychosexual Daily Questionnaire
question  measures of sexual activity, including sexual
daydreams, anticipation of sex, sexual interactions
with partner, “flirting by you,” orgasm, ejaculation,
intercourse, masturbation, night spontaneous erec-
tions, and erection in response to sexual activity; there
was a nonsignificant treatment effect for the items
“flirting with you by others” and “day spontaneous
erections.” Interestingly, in T-treated subjects, in-
cremental increases in total T, free T, and E were
associated with improvements in sexual activity and
desire, but not in erectile function. No threshold T
level was observed for any outcome. In general
treatment effect size was low to moderate, with the
effect size on erectile function less than what has been
reported for treatment with PDE inhibitors ().
The efficacy results from this study are consistent with
the findings of another recent trial involving  men
with low sexual desire or low energy and low serum T
(, ng/dL or . nmol/L), but of younger mean
age of . years (). The men randomized to  mg
of topical % T solution daily for  months reported a
greater increase of sexual drive, sexual activity, and
erectile function compared with placebo-treated men.
In the Testosterone’s Effects on Atherosclerosis pro-
gression in Aging Men (TEAAM) trial, involving 
men $ years of age with low-normal serum T [total
T,  to  ng/dL (. to  nmol/L); free T, , pg/
mL (, pmol/L)], treatment with . g of % T gel,
940 Kaufman et al Aging and the Male Reproductive System
aiming at T levels in the upper normal range for young
men ( to  ng/dL), failed to significantly improve
sexual function (sexual desire, erectile function, overall
sexual function scores, partner intimacy) compared
with placebo. In this trial improvement of sexual
function was a secondary outcome, and presence of
sexual symptoms was not an inclusion criterion.
In the Sexual Function Trial () none of the
 considered baseline patient characteristics pre-
dicted responsiveness to T therapy. In particular, a
BMI . kg/m and/or diabetes, which were present
in as many as % and % of the study population,
respectively, were not predictive of outcome. This is at
variance with findings of meta-analyses suggesting that
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the effects of T therapy on sexual function may be
somewhat less in men with obesity and diabetes (,
).
Studies addressing potential additive effects of T
therapy to improve erectile function in men with ED
treated with a PDE inhibitor are heterogeneous in key
variables such as the gonadal status at inclusion.
Findings are not univocal (, ). Overall, available
evidence is inconclusive and does not support the use
of T treatment to potentiate therapeutic effects of
PDE inhibitors. In particular, meta-analysis has
shown positive effects in uncontrolled studies but not
in controlled trials (). In a controlled trial in men
with low serum T and ED who were first optimized
with sildenafil, T therapy had no added beneficial effect
on mood and general well-being compared with
placebo ().
In conclusion, T therapy can improve various
aspects of sexual function, including sexual desire,
erectile function, and overall sexual activity. These
beneficial effects are largely limited to men with un-
equivocally low serum T and prevalent symptoms of
sexual dysfunction. The effect size is mostly only
moderate, with effects on ED lesser than those re-
ported for PDE inhibitors, and there is presently no
convincing demonstration that cotreatment with T
potentiates the effect of PDE inhibitors on erectile
function.
Body composition, metabolic profile, and
physical performance
Body composition, muscle mass and
strength, and physical performance. Healthy
older men ( to  years of age) with suppressed
endogenous T production by administration of a long-
acting GnRH agonist and treated with graded doses of
T ( to  mg T enanthate weekly for  weeks)
respond with a dose- and blood T concentration–
related increase of fat free mass, skeletal muscle mass,
and muscle strength and with a decrease of fat mass
(). This important experiment, besides showing that
the anabolic response to T in older men is proportional
to the T dose up to frankly supraphysiological T levels,
has also shown that the anabolic response to T in older
Endocrine Reviews, August 2019, 40(4):906–972

men is similar to that in younger men ( to  years of
age). In recent studies with a similar general design in
younger men, it was further shown that a-reduction of
T to DHT is not essential for mediating these anabolic
effects of T () and that aromatization of T to E,
which does not intervene in the anabolic action of T on
skeletal muscle, appears to be required for full ex-
pression of T action to reduce fat mass ().
In a meta-analysis of  earlier RCTs, including a
total of  men [weighted mean age, . years;
mean T,  ng/dL (. nmol/L); range,  to
 ng/dL (. to  nmol/L)], of whom  were
randomized to T treatment (), the authors found
that T treatment decreased total body fat mass by a
mean of . kg (.% of initial body fat) and increased
fat-free mass by a mean of . kg (.%), whereas the
effects on muscle strength were heterogeneous, with a
tendency toward improvement only for leg/knee ex-
tension and grip strength in the dominant arm (pooled
effect size, .; % CI, . to .). Another meta-
analysis of earlier trials ( trials;  men; mean age,
. years) also concluded that treatment with T (or
DHT) produced a small to moderate increase of
muscle strength ().
Several relevant randomized, controlled trials have
more recently been reported. In older men (mean age,
 years) with at least one criterion of frailty, a low to
low-normal serum T and a hip BMD T-score # 2 or
less or a history of nontraumatic fracture, randomized
to treatment daily with  mg of transdermal T (%
gel) (n 5 ) or placebo (n 5 ), T therapy for
 months resulted in a significant difference above
placebo of .% lean mass and .% appendicular
skeletal muscle mass, and a trend toward decreased
body fat (). There was no treatment effect for a
battery of tests of muscle strength and physical per-
formance. However, in this study baseline T levels
were rather high, and the achieved T increase during
treatment appeared small.
Srinivas-Shankar et al. () randomized
community-dwelling elderly intermediate-frail and
frail men [mean age, . years; T # ng/dL
( nmol/L) or free T #. ng/dL ( pmol/L);
% with only one or two out of five frailty criteria]
to  months of transdermal treatment with  mg of T
daily (% gel) (n 5 ) or to placebo treatment (n 5
). Treatment resulted in a mean increase of lean
body mass by . kg and decrease of fat mass by
. kg. Isometric knee extension peak torque (primary
outcome) improved in the T-treated men and declined
in the placebo group, resulting in a significant treat-
ment effect. The treatment effect was not significant
for either isokinetic knee extension peak torque,
isometric and isokinetic knee flexion peak torque, or
handgrip strength. Moreover, there was no treatment
effect for any physical function test, including the
Aggregate Locomotor Function test (ALF), the
Physical Performance Test (PPT), the -minute walk
doi: 10.1210/er.2018-00178
REVIEW
test, and the Tinetti gait and balance test, or for self-
reported physical activity (Physical Activity Scale of the
Elderly). In post hoc analyses, there was a significantly
greater improvement in the Aggregate Locomotor
Function test and PPT in the men with at least two
frailty criteria and of the PPT in men at least  years
of age. The authors subsequently reported that, not
surprisingly, the treatment effects on muscle strength
and lean mass after the -month T treatment were not
maintained  months after treatment ().
In older men on optimal medical therapy for stable
chronic heart failure [New York Heart Association
functional class II/III; median age,  years; % with
T , ng/dL (,. nmol/L)], parenteral T ther-
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apy for  months with long-acting T undecanoate
( mg at , , and  weeks) (n 5 ) compared
with placebo (n 5 ) increased quadriceps isometric
and isokinetic strength, peak oxygen consumption,
and peak work load during a cardiopulmonary ex-
ercise test, as well as the distance walked in the
-minute walk test. Baseline T was directly related to
baseline isometric strength, peak oxygen consumption,
and -minute walk test distance, and changes in serum
T in T-treated subjects correlated with changes in peak
oxygen consumption and isometric strength ().
This finding of improved functional capacity in
T-treated men with heart failure was confirmed in a “The findings on the impact of
meta-analysis of this and three other trials (). T treatment on physical
In a subgroup analysis of the TOM trial, treat- function have…been rather
ment of mobility-limited men $ years of age with disappointing…with mostly
low T [total T,  to  ng/dL (. to . nmol/L) small effect size and of
uncertain clinical significance.”
or free T , ng/dL ( pmol/L)] with  mg of T
daily by gel during  months (n 5 ) attenuated the
age-related fall in aerobic function compared with
placebo-treated subjects (n 5 ) (). In the
TEAAM study in community-dwelling men with low
to low-normal serum T [ to  ng/dL (. to
. nmol/L) or free T , ng/dL (, pmol/L)],
treatment with  mg of T (% gel) daily for  years
(n 5 ; mean age, . years; mean BMI, . kg/
m) compared with placebo treatment (n 5 ;
mean age, . years; mean BMI, . kg/m) was
associated with a small increase in lean mass of . kg
(. to . kg; P , .), which in the T-treated men
was related to the changes in total and free T (). T
treatment compared with placebo was associated
with significantly greater increases in chest-press
strength and in chest-press and leg-press power,
which were related to changes in T levels. T sup-
plementation was also associated with greater improve-
ment in both unloaded and loaded stair-climbing
power, which was associated with the improvement in
leg-press power. Although the visit-by-treatment in-
teraction was not statistically significant, numerically
the treatment effects were maximal at the -month
visit and tended to wane with time. In general,
treatment effect size was small and of uncertain clinical
significance.
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REVIEW
The Physical Function Trial, part of the TTrials,
included men $ years of age with T , ng/dL
(,. nmol/L), with self-reported difficulty walking or
climbing stairs and with a gait speed of ,. m/s on
the -minute walk test. Between men randomized to
 months of treatment with T gel aimed at achieving
levels in the midrange for young men (n 5 )
compared with men randomized to placebo treatment
(n 5 ), there were no significant differences for
either the percentage of men whose -minute walk
distance increased by at least  m (primary outcome),
the changes from baseline of the -minute walk dis-
tance, or the percentage of men whose score on the
-item Physical Functioning Scale (score range,  to
) of the SF- survey increased by at least  points.
There was a difference between groups for increase of
the -item Physical Functioning Scale score from
baseline (. points; P 5 .). For these four efficacy
outcomes, there was a significant difference in favor of
T treatment when statistical power was increased by
considering the larger combined group of participants
to the different TTrials (P 5 . to .) ().
Hildreth et al. () randomized community-
dwelling healthy and highly functioning men with a
mean age of  years and low-normal serum T ( to
 ng/dL or  to . nmol/L) to treatment with
transdermal T % gel [ doses aiming at  to  ng/
dL (. to  nmo/L) and  to  ng/dL (. to
. nmol/L) levels, respectively] or placebo, and to
either progressive resistance training (PRT) or no
exercise for  months. In the PRT group (n 5 ),
functional performance (a battery of tests including
the -minute walk test) and upper and lower body
strength were not different between T- treated (n 5
) and placebo-treated (n 5 ) men, despite a
greater reduction of fat mass and increase of fat free
mass in the T-treated subjects. In non-PRT men (n 5
) T treatment (n 5 ) compared with placebo (n 5
) had no effect on functional performance, but it
reduced fat mass, increased fat-free mass, and im-
proved upper body strength but not lower body
strength. The findings in this study, although in-
dicating additive effects of T and exercise on changes
in body composition, did not offer support to the
hypothesis that T treatment might enhance the effects
of exercise on muscle strength or functional perfor-
mance in older men. More studies are needed to
answer the question whether this may have resulted
from suboptimal exercise intensity or required
achievement of higher, supraphysiological T levels
().
In summary, T therapy in older men with low to
low-normal serum T, whether they are generally
healthy or have physical function impairments, is
consistently associated with improvement of body
composition with a quantitatively modest decrease of
total body fat mass, increase in fat-free mass, and
increase or prevented decrease of skeletal muscle mass.
942 Kaufman et al Aging and the Male Reproductive System
The small, but consistent improvements in lean mass
are associated with more variable effects on muscle
strength and power, with limited improvements or no
effect depending on the considered study or within
single studies depending on the considered muscle
group and test. The findings on the impact of T
treatment on physical function have in turn been
rather disappointing, with negative findings or positive
findings with mostly small effect size and of uncertain
clinical significance. Although not formally estab-
lished, it appears from the whole of available data that
higher T doses, longer treatment duration, lower
baseline serum T, and the presence of baseline
functional capacity limitations are factors that may be
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associated with greater treatment responses.
Body composition and metabolic profile.
Corona et al. () performed a meta-analysis of 
RCTs ( placebo-controlled), with a mean trial du-
ration of . months and that included a total of 
subjects in the T therapy group and  in the control
group, respectively. Mean age, BMI, and baseline T
levels of enrolled men were . years, . kg/m, and
 ng/dL (. nmol/L), respectively. Studies differed
in administered T doses, T formulations, and cohort
characteristics. The authors found T therapy was not
associated with a decrease in weight ( trials), waist
circumference, or BMI, but they confirmed a signifi-
cant decrease in fat mass ( studies) and increase in
lean mass ( studies). T therapy was associated with a
reduction in fasting glycemia and insulin resistance
according to the homeostatic model assessment
(HOMA) of insulin resistance (HOMA-IR): consid-
ering only placebo-controlled RCTs, standardized
means were 2. (2. to 2.) and 2.
(2. to 2.) for glycemia and the HOMA index,
respectively (both P . .); the between-group
differences for glycemia and HOMA-IR were found
to be related to modifications in lean mass but not in
fat mass. The effect on fasting glycemia was greater in
RCTs enrolling subjects with metabolic disease (n 5
) compared with those evaluating elderly subjects
(n 5 ). When considering only placebo-controlled
RCTs, T therapy was associated with a decrease of total
cholesterol [2. (2. to 2.)] and triglycerides
[2. (2. to 2.)]; there was no significant
effect on high-density lipoprotein (HDL) cholesterol
levels, systolic blood pressure, and diastolic blood
pressure ().
In a study in older men (median,  years of age)
with low-normal baseline T, treated with transdermal
T ( mg/d T patch) [n 5 ; baseline median T,
 ng/dL (. nmol/L)] or placebo patch [n 5 ;
baseline median T,  ng/dL (. nmol/L)] the
subjects ingested a labeled mixed meal and under-
went a frequently sampled labeled IV glucose tolerance
test before and after a -year treatment. Compared
with placebo treatment, T did not improve carbo-
hydrate tolerance or alter insulin secretion, insulin
Endocrine Reviews, August 2019, 40(4):906–972

action, glucose effectiveness, hepatic insulin clearance,
or the pattern of postprandial glucose metabolism
(). In the previously discussed study showing that T
therapy improved muscle strength and functional
capacity in elderly men with heart failure, treatment
also improved insulin sensitivity as assessed by
HOMA-IR ().
As to relevant recent trials, in the older men with
low serum T participating in the TTrials (% with
BMI . kg/m; % with diabetes) -month T
therapy (n 5 ) compared with placebo treatment
(n 5 ) resulted in a significant decrease of total
cholesterol (adjusted mean difference, 2. mg/dL;
P , .), HDL cholesterol (2. mg/dL; P , .),
and low-density lipoprotein cholesterol (2. mg/dL;
P 5 .), but not of triglycerides. There was a small
significant decrease in fasting insulin (2. mIU/mL;
P 5 .) and HOMA-IR (2.; P 5 .), but not of
fasting glucose or HbAc levels. There was also no
treatment effect on weight, BMI, or waist/hip ratio
(). In the TEAAM trial a subset of  nondiabetic
men (mean age, . years) underwent an octreotide
insulin suppression test at baseline and at  and
 months after randomization to T therapy ( mg
daily by % gel) or placebo. Insulin sensitivity, esti-
mated as the steady-state glucose concentration at
equilibrium during octreotide and insulin infusion,
was not significantly different between T-treated (n 5
) and placebo-treated (n 5 ) men across the
 months of treatment (P 5 .); stratification
according to baseline T # ng/dL (. nmol/L)
and . ng/dL, or according to age # years or .
 years, did not show significant treatment effects for
any subgroup ().
Studies focusing more specifically on T effects in
men with obesity, the MetS, or TDM have reported
inconsistent findings. In an RCT, middle-aged (me-
dian,  years of age) men with obesity (BMI $ kg/
m) on a hypocaloric diet were randomized to
 weeks of -weekly intramuscular T undecanoate
(n 5 ) or placebo (n 5 ). Although there was no
difference in weight loss between groups, men re-
ceiving T showed a greater reduction in body fat mass
and visceral fat and less loss of lean mass. These
relative differences in body composition changes did
not translate in an effect of therapy on metabolic
parameters, with no difference between groups for
fasting glucose, HOMA-IR, HbAc, triglycerides, or
cholesterol fractions (). Aversa et al. () reported
that treatment of middle-aged men (mean age, 
years) with the MetS and T # ng/dL ( nmol/L)
for  months with T undecanoate injections ( mg
every  weeks) (n 5 ) improved HOMA-IR
compared with treatment with placebo gel (n 5
), which resulted mainly from an increase in the
placebo group and only a marginal decrease in the T
group. Hackett et al. () randomized men with
TDM [mean age, . years; mean baseline T,
doi: 10.1210/er.2018-00178
REVIEW
 ng/dL (. nmol/L)] to  weeks treatment
with T undecanoate (-mg injections at , , and
 weeks) (n 5 ) or placebo injections (n 5 ). At
the  weeks study endpoint there was a marginal
decrease of waist circumference [estimated mean, 2.
(2. to 2.) cm] and total cholesterol [2.
(2. to .) mmol/L], but there was no treatment
effect on HbAc, HOMA-IR, fasting glucose, HDL
cholesterol, low-density lipoprotein cholesterol, tri-
glycerides, body weight, or BMI. Jones et al. ()
randomized men (mean age, . years) with TDM
and/or the MetS and baseline T # ng/dL (nmol/
L) or free T #. ng/dL ( pmol/L) to daily
treatment with  mg of transdermal T (% gel)
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(n 5 ) or placebo gel (n 5 ) for  monts (the
TIMES study). There was a % reduction in
HOMA-IR in T-treated men compared with the
placebo group and a reduction in lipoprotein a and
HDL cholesterol, but there was no treatment effect on
HbAc, fasting insulin and glucose levels, HOMA-B,
triglycerides, abdominal obesity, percentage body fat,
waist circumference, or BMI. Gianatti et al. ()
randomly assigned men (median age,  years) with
TDM and serum T # ng/dL ( nmol/L) to
 weeks of intramuscular T undecanoate injections
(n 5 ; baseline median HbAc,  mmol/mol or
.%) or matching placebo (n 5 ; baseline HbAc, “…although T therapy in aging
 mmol/mol or .%). Treatment reduced fat mass men with low to low-normal T
[mean adjusted difference, 2. kg (2. to 2.)], can modestly improve insulin
with a decrease of subcutaneous but not visceral ab- sensitivity, overall the data on
dominal fat, and increased lean mass [. kg (. to metabolic effects…are
inconsistent.”
.)], but T therapy failed to improve HOMA-IR
[2. (2. to .)] or glycemic control accord-
ing to HbAc [.% (. to .)]. Grossmann et al.
() performed a meta-analysis of seven RCTs (the
RCTs discussed above included) on the effects of T
therapy in men with TDM and the MetS, enrolling a
total of  men. Although there was heterogeneity
among trials depending on the method of calculation of
HOMA-IR, the meta-analysis suggests that T therapy
modestly improves insulin resistance [standardized
mean difference, 2. (-. to 2.); P , .].
There is no effect of treatment on glycemic control as
assessed by HbAc [standardized mean difference,
2. (2. to .); P 5 .].
In conclusion, although T therapy in aging men
with low to low-normal T can modestly improve
insulin sensitivity, overall the data on the metabolic
effects of T therapy are inconsistent. It does not appear
that the evidence available supports the use of T
therapy with the aim of improving metabolic status
either in older men with low to low-normal T in
general or more in particular in older men with TDM
or the MetS.
Bone health
There are few controlled studies on the effects of T
therapy on the bone health of (older) men. Their focus
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REVIEW
is on the effects on BMD as a surrogate marker of bone
strength and they are mostly of only short duration. A
meta-analysis by Tracz et al. () included  men
from eight placebo-controlled trials (). Six of these
trials included men with a mean age of  years or
older. However, in seven out of eight trials mean
serum total T at baseline was within the normal range,
that is,  to  ng/dL (. to . nmol/l). Only
one study included men with prevalent fractures,
whereas half of the studies included men at risk for
secondary osteoporosis (glucocorticoid use, rheuma-
toid arthritis, AIDS wasting); two studies included
observations during  months, the others were
of #-year duration. Meta-analysis showed a small
significant effect of T treatment on lumbar spine
aBMD assessed by DXA (effect size, .; % CI, .
to .) corresponding to a % (.% to %) increase.
There was no significant treatment effect at the
femoral neck [effect size, . (2. to .)]. The
effect of T on spine aBMD was significant for five trials
with intramuscular injection of T esters [effect size,
. (. to .)] corresponding to an % (% to
%) aBMD increase, but it was not significant for
three trials using transdermal treatment with patches
[effect size, 2. (2. to .) ().
Three studies in this meta-analysis included older
men without secondary causes of osteoporosis, who
are more representative of community-dwelling aging
men. Amory et al. () reported that T therapy in-
creased aBMD at the spine and total hip, but not at the
femoral neck, in men (mean age,  years) treated
 months with intramuscular injections of  mg of
T enanthate or placebo every  weeks. They also
showed that the T treatment effect was not altered by
cotreatment with the a-reductase inhibitor finas-
teride; the treatment effect was independent of
baseline hormone levels but positively related to the
magnitude of the increase of both T and E serum
levels during treatment. Kenny et al. () reported for
men (mean age,  years) treated for  year daily with
 mg of transdermal T or placebo a marginal beneficial
effect on femoral neck aBMD (.% increase from
baseline compared with .% decrease under placebo;
P 5 .), but no significant treatment effect for
either hip trochanter, lumbar spine, or whole-body
BMD. Snyder et al. () observed in men (mean age,
 years) treated for  months daily with  mg of
transdermal T or placebo by scrotal patches no
treatment effect on aBMD at either the lumbar spine
or the hip. A post hoc analysis revealed a negative
interaction between baseline T levels and T treatment
effect, with lumbar spine BMD increases above pla-
cebo mainly restricted to the men with initial serum
T # ng/dL (. nmol/L).
Reported effects of T treatment on levels of bio-
chemical markers of bone turnover have been in-
consistent and essentially limited to decreases in the
markers of bone resorption observed in only some
944 Kaufman et al Aging and the Male Reproductive System
studies. An effect of T therapy to decrease the levels of
bone resorption markers was confirmed in a meta-
analysis ().
As to more recent studies, Kenny et al. ()
randomized  men (mean age,  years) to daily
treatment with  mg of transdermal T (% gel) or
placebo. Patients were recruited on the basis of
age $ years, at least one criterion of frailty, a low to
low-normal serum T, and a hip aBMD T-score of 2
or less or a history of nontraumatic fracture in the past
 years. They reported a small positive treatment effect
at  months on aBMD at the lumbar spine, no effect
at the hip, and a negative treatment effect at the
forearm. Interpretation of this study is, however,
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hampered by a large patient dropout, mean baseline T
level well within the normal range, and only limited
serum T increases achieved during treatment. The
Bone Trial, part of the TTrials (), included men on
the basis of age $ years and low serum T , ng/
dL (. nmol/L), but not of low BMD or fracture
history. A total of  men with a mean age of .
years, mean BMI of . kg/m, and normal aBMD
mean T-scores (. at the lumbar spine, . at the total
hip, 2. at the femoral neck) were randomized to
 months of transdermal T treatment with adjusted
doses of T gel aiming at serum T in the normal range
for young men or with placebo. Compared with
placebo, T treatment resulted in an increase of spine
trabecular bone vBMD by quantitative CT (QCT;
treatment effect, .% (.% to .%); P , .] and
estimated strength by finite element analysis of QCT
data [treatment effect, .% (.% to .%); P ,
.]; increases of vBMD were significantly associated
with the increases in serum T and E during treatment.
Compared with the effects on spine trabecular bone,
increases of vBMD were slightly smaller and increases
of estimated strength were similar for spine peripheral
bone and whole bone. Highly significant positive
treatment effects are also seen on vBMD and estimated
strength at the hip trabecular bone, peripheral bone,
and whole bone, although of clearly smaller amplitude
than at the spine. It is well known that vBMD by QCT
is more sensitive to treatment-induced bone changes
than aBMD by DXA. Accordingly, in sharp contrast
with the QCT data, there was an only small positive
treatment effect for lumbar spine aBMD [.% (. to
.); P 5 .] and no significant treatment effect at
the femoral neck [.% (2. to .); P 5 .] and
total hip [.% (2. to .); P 5 .] (). These
findings for aBMD are in line with the earlier DXA-
based studies and indicate that DXA underestimates
the effects of T treatment on the bone. Therefore, the
robustness of the reported bone effects of T treatment
in the Bone Trial compared with earlier trials is due
primarily to the use of QCT-based endpoints. How
much the inclusion of men who are clearly hypo-
gonadal in this study may have contributed to the
robustness of the QCT data cannot be concluded.
Endocrine Reviews, August 2019, 40(4):906–972

In summary, there is a striking knowledge gap as to
the effects of T therapy for skeletal health in aging
men: (i) there is no reliable data on T treatment in
older men with osteoporosis; (ii) except for a couple of
studies, trials did not include older men with un-
equivocally low serum T; and (iii) there are no data at
all on the effect of T therapy on fracture risk, the most
relevant clinical evaluation criterion. The data avail-
able suggest that T therapy in older men has a modest
suppressive effect on bone resorption, produces a
limited increase of aBMD at the lumbar spine, and
inconsistent, marginal, and overall nonsignificant in-
creases of aBMD at the hip as assessed by DXA.
Treatment with T produces more substantial increases
of vBMD at the spine and significant increases of
vBMD at the hip as assessed by QCT. Evidence from
several trials indicates that the increase of BMD during
T therapy is related to the magnitude of the increase in
serum T and E, which might explain why in older
studies significant aBMD increases were observed only
in studies with T administration by intramuscular
injections and not in studies with transdermal T ad-
ministration with patches. Finally, although there is
some low-quality evidence suggesting a greater BMD
response to T treatment in men with initially low
serum T, the limited data available do not allow
conclusions on this point.
In conclusion, although modest favorable effects on
the maintenance of skeletal integrity may be an added
benefit of T treatment initiated for another indication in
older men with low serum T, there are presently clearly
insufficient data to support its use to treat osteoporosis.
Osteoporosis is neither a specific nor sufficient in-
dication for T therapy. Specific osteoporosis treatment
(e.g., with a bisphosphonate) should be initiated in
hypogonadal older men at high risk of fracture, re-
gardless of whether they are also treated with T to
alleviate other symptoms of hypogonadism (, ).
Mental health
Cognition. Studies on the effects of T therapy
on cognition in aging men have been heterogeneous
in key aspects such as cognitive domains and as-
sessment tools and baseline cognitive status and T
levels. Not surprisingly, findings have been variable.
Although earlier studies suggested that T therapy
might enhance cognitive function in older men
with low serum T, most of these studies included
only small number of subjects, and improvements
were variable depending on cognitive domain and
methodology [see (, ) for reviews]. Similarly,
earlier studies reporting that T treatment might slow
cognitive decline in men with mild cognitive im-
pairment or Alzheimer’s disease are also small in
scale and they included almost exclusively eugonadal
men (). Findings from more recent and lager
scale studies on the effects of T therapy on cognition
in older men have been negative.
doi: 10.1210/er.2018-00178
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In an experimental setting in healthy older men (
to  years of age) with manipulation of sex steroid
levels for a duration of  weeks, there were no dif-
ferences in cognitive function (memory, executive
function, spatial cognition) when comparing men with
induced hypogonadal T levels (GnRH agonist), men
with T and E levels in the eugonadal range (GnRH
agonist plus T-gel), men with T levels in the eugonadal
range and low E (GnRH agonist plus T-gel plus
aromatase inhibitor), or all placebo-treated men.
These are negative findings, even though free T was
positively related to spatial cognition and E was
negatively associated with working memory in post hoc
analyses of the combined treatment groups ().
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Emmelot-Vonk et al. () randomized healthy men
aged  to  years (mean,  years) with low to low-
normal T (, ng/dL or . nmol/L) to oral
treatment with  mg of T undecanoate twice daily for
 months [n 5 ; baseline mean T,  ng/dL
( nmol/L)] or matching placebo [n 5 ; baseline
mean T,  ng/dL (. nmol/L)]. Although T
treatment resulted in an increase of lean body mass
and a decrease of fat mass, there was no treatment
effect on the results of a battery of eight memory and
cognition tests. However, interpretation is limited by
the fact that it is not documented whether the oral T
administration substantially increased mean T levels.
Huang et al. () in the TEAAM study randomized
“Osteoporosis is neither a
men $ years of age with low to low-normal serum T specific nor sufficient
[ to  ng/dL (. to . nmol/L) or free indication for T therapy.”
T , ng/dL ( pmol/L)] to treatment with . g of
% gel daily or placebo. There was no effect of
treatment of eight memory and cognition tests in
T-treated men [n 5 ; mean baseline T,  ng/dL
(. nmol/L); mean follow-up,  months] compared
with placebo-treated men [n 5 ; mean baseline T,
 ng/d/L (. nmol/L); mean follow-up,  months].
In the Cognition Function Trial, which is part of the
TTrials, Resnick et al. () assessed the effects on
cognition of treatment with T gel in men with low
serum T (, ng/dL or . nmol/L) and impaired
sexual function, physical function, or vitality and with
age-associated memory impairment. From  men
included in the TTrials, a subgroup of  men [mean
age, . years; mean baseline T,  ng/dL (. nmol/
L)] met criteria for age-associated memory impairment
based on baseline subjective memory complaints and
objective memory performance. There was no signifi-
cant mean change from baseline to  and  months in
men treated with T (n 5 ) and placebo (n 5 ) for
scores for delayed paragraph recall, visual memory,
executive function, or spatial ability.
Thus, the overall findings from randomized,
controlled studies do not indicate that T treatment has
significant beneficial (or adverse) effects on memory or
other aspects of cognition in elderly men with low or
low-to-normal serum T, regardless of whether they
have preexistent memory impairment.
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Depression, mood, and well-being. Earlier
studies, although reporting variable results, provided
some evidence that therapy can improve indices of
mood in men with low to low-normal serum T ().
Nevertheless, in an earlier larger placebo-controlled
study including  men with a median age of 
years (% $ years of age) and mean baseline
serum T ~ ng/dL ( nmo/L), T treatment (three T
treatment groups, that is, two different doses of T-gel
and a T patch) had no effect above placebo gel on
categorical mood scores (), and in the above-
discussed study by Emmelot-Vonk et al. () there
was no treatment effect of oral T undecanoate on the
SF-  questionnaire scores, including the scores
related to mental health, emotional role, and social
functioning, and no effect on the scores for the
Questions on Life Satisfaction Modules. The results
of randomized placebo-controlled trials addressing
the effects of T therapy in men with depression were
also variable (), with the only larger trial ()
reporting negative findings. A meta-analysis of 
controlled clinical trials using common depression
rating scales, which included a total of  men,
showed a significant positive impact of T therapy on
mood. However, in subgroup analyses the effect size
was larger in subclinical depression compared with
major depression and was not statistically significant
in eugonadal men and in men . years of age
().
The Vitality trial, part of the TTrials, included
men $ years of age with low T (, ng/dL or
. nmol/L) and self-reported low vitality and a score
of , on the Functional Assessment of Chronic
Illness Therapy (FACIT)–Fatigue scale (range  to
; higher score indicates less fatigue). At  and
 months of treatment there was a significant dif-
ference in favor of T treatment compared with
placebo for the SF- vitality score, the Positive and
Negative Affect Schedule scores, and the Patient Health
Questionnaire- depression score. However, the treat-
ment effect was small, with all effect sizes ,.. The
primary efficacy criterion (i.e., $ point increase on the
FACIT-Fatigue score) was not reached. When analyzing
the FACIT-Fatigue score as a continuous variable, a
positive treatment effect was present, which became
significant only when considering the whole TTrials
study population ().
The whole of the available information suggests
that T therapy can improve mood, depressive symp-
toms, and vitality in older men with low serum T.
However, these effects appear of small amplitude, and
this conclusion is driven primarily by the recent
findings from the TTrials. There is no convincing
documentation of an effect of T on mood or de-
pressive symptoms in older men with initially no low
serum T. There is also no convincing evidence to
support the use of T therapy to help treat depression
in older men.
946 Kaufman et al Aging and the Male Reproductive System
Safety of T treatment
The assessment of the risk/benefit balance of T therapy
in older men with low serum T and thus also eval-
uation of the desirability to initiate such treatment in
an older individual is hampered by a knowledge gap as
to its long-term safety. Indeed, none of the performed
RCTs in older men or in men in general had the
required power and duration to reliably establish
long-term CV safety and cancer risk of T therapy.
Alternatively, findings from observational studies, in
particular those pertaining to CV safety, have gener-
ated controversy. Besides dosage and duration of T
therapy, the formulation and route of T administra-
tion might be relevant to safety aspects because of
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formulation-specific pharmacokinetics with marked
differences between formulations in the achieved
profiles of serum T levels as well as differences in the
production of the bioactive metabolites DHT and E.
Finally, RCTs on T therapy in older men have gen-
erally excluded men at higher risk of adverse events so
that the safety data do not apply to such patients.
Commonly applied exclusion criteria have been
prostate abnormalities or estimated increased risk for
prostate cancer, moderately severe lower urinary tract
symptoms, (borderline) high Hct or Hb, recent CV
events such as stroke and MI, markedly high blood
pressure, and severe obstructive sleep apnea (OSA).
Erythropoiesis
Given the hematopoietic effects of androgen exposure,
development of polycythemia (Hct .% to %;
Hb .. to . g/dL) during T therapy is a concern.
Moreover, older men appear to be at higher risk. In an
experimental setting in men with suppressed gonad-
otropins exposed to graded doses of T, increases in Hb
and Hct were dose-related and greater in older men
( to  years of age) than in younger men ( to 
years of age), also after adjusting for serum T or free T
levels (age effect P # .) (, ).
Meta-analyses of interventional studies found that
middle-aged and older men on T therapy had higher
odds than did men on placebo to develop poly-
cythemia (in the literature interchangeably also re-
ferred to as erythrocytosis) (, ), with an overall
incidence of .% among actively treated participants
(). Similarly, other studies in elderly men report
polycythemia in % to % of participants (, ,
, –), although incidences up to % have
been reported (). In a recent meta-analysis of RCTs
in middle-aged and older men with low serum T
(, ng/dL or . nmol/L) and at least one or more
symptom or sign of hypogonadism, the RR of poly-
cythemia in T-treated men compared with placebo
was . (% CI, . to .) (). In some studies,
supraphysiologic T levels were found at the time of
polycythemia (). The risk for polycythemia in
hypogonadal men under T therapy has been associated
with androgen sensitivity (as per CAG repeat length of
Endocrine Reviews, August 2019, 40(4):906–972

the AR gene) and with through levels of T between
repeated injections of long-acting depot T preparation
(, ). Furthermore, polycythemia appears to
occur more frequently in men treated with (mainly
short-acting) injectable T as compared with oral or
transdermal T (, ).
Taken together, clinically meaningful polycythemia
is a relatively frequent adverse effect of T therapy in
older men and carries a risk of severe complications
(, ). This makes periodic screening of Hb or Hct
levels during treatment warranted, especially in men
with other risk factors such as smoking, chronic
pulmonary disease, or apnea syndrome.
Prostate and lower urinary tract symptoms
Considering the important role of T in normal growth
and maintenance of the prostate gland and of AR
signaling in stimulation of metastatic prostate cancer
growth, the potential for adverse effects of T therapy
on prostate health has been a concern. Several meta-
analyses of RCTs have addressed this concern (,
, , ). Although their findings may seem
rather reassuring, they also show that the low number
of men enrolled in RCTs of longer duration and the
very low number of observed events preclude de-
finitive conclusions as to longer-term prostate cancer
risk. Calof et al. () performed a meta-analysis of 
earlier RCTs of  months’ median duration ( days to
 years) enrolling  T-treated and  placebo-
treated men and found increased odds of the com-
bined occurrence of prostate adverse events (OR, .;
% CI, . to .), including a PSA . ng/mL or
. ng/mL increase during the study, an increase in
International Prostate Symptom Score (IPSS) by .
points, acute urinary retention, prostate biopsies, and
prostate cancer. For none of the individual events was
there a significant difference between T and placebo;
prostate biopsies and PSA . ng/dL were numeri-
cally higher in the T group. The meta-analysis by
Fernández-Balsells et al. () included low- to
medium-quality randomized and nonrandomized
comparative trials (T vs placebo or no T) of at least
 months’ study duration enrolling men with low or
low-normal baseline T. They found no significant
differences between groups for individual prostate
outcomes or the composite outcome; prostate biopsies
were numerically higher in the T-treated men (RR,
.; % CI, . to .). Cui et al. ()
performed a meta-analysis of  RCTs of T treatment
involving a total of  men with hypogonadism, of
which  were of duration shorter than  months and
 were of  months to  years’ duration. Short-term
T treatment was more likely than placebo treatment to
increase PSA levels (P , .). For none of the
formulations (injectable, transdermal, or oral) was
there a significant increased risk for prostate biopsy,
prostate nodule, or prostate cancer. In the studies of
longer duration, prostate biopsy and cancer were
doi: 10.1210/er.2018-00178
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numerically higher in the subjects treated with injected
or transdermal T compared with placebo, but overall
there were only  prostate cancer events in both the
short-term and long-term RCTs. In their meta-
analysis, Boyle et al. () found that in  RCTs
there was no change in PSA (effect size, . ng/mL;
% CI, 2. to .). For  trials reporting on
prostate cancer cases, the summary OR for prostate
cancer was . (. to .), which was based on 
prostate cancer cases. Kohn et al. () focused on
lower urinary tract symptoms in a meta-analysis of 
RCTs of T treatment of LOH involving  men
with a mean age of . years and an average follow-up
of . months. They found no significant difference in
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pooled IPSS change from baseline to follow-up between
men treated with T [-. points (2. to .)] or with
placebo [. points (2. to .)], suggesting that T
treatment in aging men with hypogonadism does not
worsen lower urinary tract symptoms.
In the recent TTrials,  out of  T-treated men
compared with  out of  placebo-treated men
increased their PSA levels by $ ng/mL. From the 
men with PSA above the trigger value during the year
of treatment or the year after treatment and referred
for urologic evaluation, only  had prostate biopsies; 
man in the T group had a diagnosis of prostate cancer
during the year of treatment, and  more men in the T
group and  man in the placebo group had prostate “…clinically meaningful
cancer diagnosed in the year following treatment. In polycythemia is a relatively
the TTrials the number of men with increased frequent adverse effect of T
IPSS . was not different between T-treated men therapy in older men….”
(n 5 ) and placebo-treated men (n 5 ) ().
Considering the modest number of enrolled
subjects, the short duration of T exposure, and the
small number of events, neither the individual RCTs
reported as to date nor their meta-analyses provide
reliable information on the longer-term prostate
cancer risk. Observational studies, which suffer from
known limitations of high risk of bias and con-
founding, nevertheless provide the only available
information on longer T exposure in substantial
numbers of men with hypogonadism. In a combined
analysis of three parallel, prospective cumulative
registry studies including a total of  hypogonadal
men treated with T undecanoate injections ( mg
every  weeks) for a median duration of  years,
prostate cancer was diagnosed in  patients: in the
first cohort with a mean age of . years there were 
cases in  men (.%) with an incidence rate of .
per , patient-years; in the second cohort with a
mean age of . years, there were  cases in  men
(.%) with an incidence rate of . per ,
patients-years, whereas in the third cohort with a mean
age of  years, there were no cases in  men. It
was concluded that the incidence rate of prostate
cancer in these T-treated men was not higher (and
even somewhat lower) than expected according to
data from population screening studies (). A
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multinational prospective registry study reported on
up to  months’ follow-up of  newly diagnosed
hypogonadal men, of which  received T therapy
and  remained untreated (mean age, . years; 
treated and  untreated men $ years of age).
There were in total  cases of prostate cancer–positive
biopsies. Overall, the proportion of biopsies that were
positive for cancer, the primary outcome of the study,
did not differ between T-treated subjects (.%) and
untreated men (.%), and the prostate cancer rate in
the T-treated men was not higher than in untreated
men or than expected in the general population.
Treatment was associated with a limited PSA increase
during the first  months, which stabilized thereafter
and with no increase in IPSS. The authors concluded
that there was no evidence of increased prostate cancer
rate or progression of lower urinary tract symptoms in
newly diagnosed hypogonadal men treated with T
(). Note that in these observational studies a
substantial proportion of men were , years of age,
and the number of events was low. Moreover, in the
latter registry the duration of observation is rather
short and the reasons for no treatment vs T treatment
are unknown ().
In summary, overall the evidence available in-
dicates that T treatment in aging men with low serum
T may result in a small increase of PSA level occurring
within the first year of treatment. Treatment with T
does not worsen lower urinary tract symptoms as
assessed with the IPSS. This applies only to men with
an initial IPSS ,, as men with more severe urinary
tract symptoms have usually been excluded from
RCTs. The available data from RCTs and observa-
tional studies do not reveal any alarming signal as to
prostate cancer risk and appear reassuring as to the
short-term prostate safety of T treatment in aging men.
However, a critical appraisal of the data shows that
somewhat stronger evidence is in fact available for not
much more than the first year of treatment. Owing to
the generally short duration of RCTs and their low
power (i.e., a small to modest number of enrolled
subjects and a small number of events) and to
the methodological and other limitations of obser-
vational studies, the longer-term risk of prostate cancer
associated with T treatment in older men remains
unknown.
Cardiovascular and venous thromboembolic events
The CV effects of T in aging men and in particular
the effects of exogenously administered T are the
subject of ongoing debates, fueled by inconsistent
findings from observational studies and by the lack
of adequately powered RCTs with clinical CV events
as the primary outcome (). Scrutiny of the CV
safety of T treatment has been intensified after
publication of the report () on an RCT in older men
(mean age,  years) with limited mobility and low T
treated with a relatively high dose of transdermal T
948 Kaufman et al Aging and the Male Reproductive System
( mg/d; % gel), which was prematurely inter-
rupted because of the higher rate of CV-related
adverse events in the T-treated men ( in 
men) compared with placebo-treated men ( in 
men). The reported events were diverse in nature
and pathophysiology.
In their meta-analysis of randomized and non-
randomized comparative intervention studies (T vs
placebo/nonintervention), Fernández-Balsells et al.
() found no significant differences in rates of death,
MI, or revascularization procedures. In a meta-analysis
by Ruige et al. () of  double-blind RCTs of T vs
placebo, which included . men and reported on
CV events, there was no significant difference in event
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rate between groups (estimated RR, .; % CI, .
to .). The power was low with only  highly di-
verse events. Xu et al. () performed a meta-analysis of
placebo-controlled RCTs of T therapy of at least
 weeks’ duration and reporting CV-related events.
The  selected trials included  mainly middle-
aged and older men with low T and/or chronic dis-
eases, who experienced a total of  CV-related
events, defined as any event reported as such by the
authors or where the description fell within a corre-
sponding category of the International Statistical
Classification of Diseases. The authors found that T
treatment increased the risk of CV-related events in a
fixed effects model (OR, .; % CI, . to .)
with a similar finding when the analysis was restricted
to serious events (OR, .; % CI, . to .) and
similar odds for CV-related death (OR, .; % CI,
. to .). The authors further reported that the risk
of a CV event varies by the source of funding (P for
interaction , .), with increased risk in  trials
( men included) not funded by the pharmaceu-
tical industry (OR, .; % CI, . to .) but not
in  trials ( men included) sponsored by industry
(OR, .; % CI, . to .). The validity of the
findings of this meta-analysis has been challenged by
some on the basis that as much as one third of the
events in T-treated men in the  trials not sponsored
by industry are contributed by only  trials, whereas
for the first of these  trials () a substantial proportion
of events were not “classical” major adverse CV events,
and the second trial () pertains to treatment of men
with cirrhosis of the liver with very high doses of
an unapproved oral formulation of micronized T
resulting in markedly high T levels and for which the
CV events taken into account possibly included
(esophageal) bleedings (). In a recent systematic
review and meta-analysis of the CV risk of exogenous
T, Alexander et al. () included  RCT and 
observational studies. They retained  placebo-
controlled RCTs for meta-analysis, with death from
all causes, MI, and stroke as primary outcomes, and
other CV endpoints such as arrhythmias, heart failure,
coronary angiography, pulmonary embolism, or ve-
nous thrombosis as secondary endpoints. Compared
Endocrine Reviews, August 2019, 40(4):906–972

with placebo, T treatment did not show any significant
increase in the risk of MI ( RCTs; OR, .; % CI,
. to .), stroke ( RCTs; OR, .; % CI, . to
.), or mortality ( RCTs; OR, .; % CI, . to
.). There was no significant increased risk for the
composite outcome of MI, stroke, and death ( RCTs;
OR, .; % CI, . to .). The strength of the
evidence for the different outcomes was determined as
low.
In the TTrials in older men with low T, the oc-
currence of CV events was similar in T-treated and
placebo-treated men with in both groups  out of 
men with a major CV event during the -month
study; in both groups five out of the seven major CV
events were stroke (). In a substudy of the TTrials,
during the -year duration of the study, an increase in
coronary artery noncalcified plaque volume, as mea-
sured by coronary CT angiography, was significantly
greater (P 5 .) in T-treated men (n 5 )
compared with placebo-treated men (n 5 ); there
was also an increase in total plaque volume (P 5
.) but not in coronary artery calcification score
(). In the TEAAM study men $ years of age
(mean, . years of age) with low to low-normal T
( to  ng/dL or . to . nmol/L) were ran-
domized to  mg of transdermal T (% gel) or placebo
for  months. Between T-treated (n 5 ) and
placebo-treated (n 5 ) men there was no difference
in the rate of change during  years in common carotid
artery IMT (P 5 .) or in coronary calcium score
(P 5 .), the primary outcomes of this study. Al-
though the authors reported that the small number of
unadjudicated CV events and major adverse CV
events did not differ between groups, the overall rate of
MI, coronary revascularization, stroke and death of
CV event was nevertheless numerically higher in the
T-treated men (n 5 ) compared with the placebo
group (n 5 ) ().
Observational studies on CV risk and mortality of
exogenous T treatment as reviewed by Alexander et al.
() are characterized by substantial clinical and
methodological heterogeneity, and the evidence was
rated as of very low quality owing to the high risk of
bias, imprecision, and inconsistency. The findings have
been disparate, with some studies reporting that T
treatment is associated with increased risk of
CV events, including MI, stroke, and/or mortality
(–), others reporting no effect on the risk of MI
() and mortality (), and still others reporting
reduced risks in (subgroups of) T-treated men (,
, ). A detailed discussion of their respective
merits and limitations falls, however, beyond the scope
of this review.
Recent observational studies deserving mention
have once more delivered mixed messages. Cheetham
et al. () reported on a retrospective cohort study of
men with hypogonadism [T , ng/dL (. nmol/
L) or coded diagnosis of hypogonadism] conducted
doi: 10.1210/er.2018-00178
REVIEW
within an integrated health care delivery system,
comparing the hypogonadal men ever dispensed a T
prescription (.%; n 5 ; mean age, . years;
.% prior CV disease; .-year median follow-up)
with those never dispensed T (.%; n 5 ,;
mean age, . years; .% prior CV disease; .-year
median follow-up); % of the men were . years
of age. The primary outcome was a composite
CV endpoint including acute MI, coronary re-
vascularization, unstable angina, stroke, transient is-
chemic attack, and sudden cardiac death. The rates of
the composite CV endpoint were lower in the men
ever dispensed T than in those never dispensed T (.
and . per  person-years, respectively); the
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adjusted HR for the composite endpoint in the men
ever dispensed T was . (% CI, . to .). The
findings were similar for endpoints restricted to stroke
and transient ischemic attack (HR, .; % CI, .
to .) or restricted to the combined cardiac events
(HR, .; % CI, . to .). It is concluded that
among men with androgen deficiency, dispensed T
prescriptions were associated with a lower risk of CV
outcomes during a median duration of . years ().
Wallis et al. () reported a more nuanced picture in
their intention-to-treat observational cohort study.
This was a population-based study using different
Canadian health care–related databases, comparing “…findings from RCTs and
men $ years of age newly treated with T (n 5 observational studies do not
,; .-year median follow-up) and controls allow us to draw conclusions
matched for region of residence, comorbidity, diabetes as to the CV safety of T
status, and index year (n 5 ,; .-year median treatment in aging men with
low T….”
follow-up). Men treated with T had a lower mortality
than did controls (HR, .; % CI, . to .).
However, when looking at cumulative exposure ef-
fects, men in the lowest tertile of T exposure duration
(median of  months) had an increased risk of
mortality (HR, .; % CI, . to .) and com-
posite CV events (HR, .; % CI, . to .),
whereas in contrast the men in the highest tertile of T
exposure had a lower risk of mortality (HR, .; %
CI, . to .) and composite CV events (HR, .;
% CI, . to .) with a significant trend across
tertiles (P , .). A limitation of this latter ob-
servational study compared with the former is the
absence of information on serum T with controls
matched for CV risk factors but not for hypogonadal
status. Therefore, the higher mortality and CV events
in the shorter duration exposure might represent an
effect of either treatment and/or of the (causes for the)
hypogonadal status itself. For both studies it is not
possible to exclude that the apparent longer-term
favorable effects of T treatment on CV risk and
mortality represent at least in part a healthy user effect
and residual confounding. In a retrospective cohort
study of older men identified with low T, Sharma et al.
() reported that those treated with T and nor-
malizing their T level (n 5 ,; median age, 
years) had a lower risk of atrial fibrillation compared
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with men treated with T without normalization of T
(n 5 ,; median age,  years) (HR, .; % CI,
. to .) and men who did not receive T therapy
(n 5 ,; median age,  years) (HR, .; % CI,
. to .), suggesting that normalization of T in
older men with low T is associated with a lower risk of
atrial fibrillation.
Martinez et al. () performed a population-based
case-control study involving , patients with
confirmed venous thromboembolism, comprising
deep venous thrombosis and pulmonary embolism,
and , age-matched controls and reported an
increased risk of venous thromboembolism in the first
 months of T treatment (rate ratio, .; % CI, .
to .); after . months of therapy the rate ratio
declines to . (% CI, . to .) and after ces-
sation of treatment to . (% CI, . to .).
Baillargeon et al. () performed a cohort study
involving  cases of venous thromboembolism
(% $ years) and , matched controls. Having
filled a prescription for T therapy in the  days
preceding the event was not associated with an in-
creased risk of venous thromboembolism:  cases
(.%) vs  controls (.%) with filled prescription
in the  days preceding the corresponding index
dates; adjusted OR of . (% CI, . to .) with
similar results when the window of prescription is
extended to  or  days preceding the event. None of
the examined specific routes of T administration was
associated with an increased risk of venous throm-
boembolism. In their cohort study of men with low T,
Sharma et al. () found no increased risk of venous
thromboembolism in men with normalized serum T
under T treatment ( cases in , men) com-
pared with untreated hypogonadal men ( cases in
, men) with an adjusted HR of . (% CI, .
to .) or compared with T-treated men with still low
T ( cases in , men) with an adjusted HR of .
(% CI, . to .).
As to possible differences in CV risk associated
with T therapy among different modalities of T ad-
ministration, available information is limited and
inconsistent. Layton et al. () in a retrospective
cohort analysis of , men having initiated T
therapy compared men treated with T injections,
T-gels, or T patches. They found that compared with
treatment with T-gel, treatment by T injections was
associated with a greater risk of death, hospitalization,
and CV events, but not venous thromboembolism,
whereas the risk profile was similar for gels and
patches. In contrast, in the observational study by
Cheetham et al. () there was a significant, albeit
small, higher CV risk associated with topical T
treatment. Further blurring the picture, Borst et al.
() from their meta-analysis of RCTs concluded that
oral T treatment was associated with a significant CV
risk, which was not the case for injected and trans-
dermal T administration; although CV risk associated
950 Kaufman et al Aging and the Male Reproductive System
with transdermal T was not significant, the point
estimate was higher than for T injections. This led the
authors to postulate a detrimental effect resulting from
higher DHT serum levels under oral (and transdermal)
treatment.
In summary, the findings from RCTs and obser-
vational studies do not allow us to draw conclusions as
to the CV safety of T treatment in aging men with low
T because the data are insufficient and inconsistent.
The data from RCTs and meta-analyses of RCTs
might seem predominantly reassuring as to the ab-
sence of risk of MI and other major cardiac events,
stroke, and mortality, but there are also discordant
findings. Moreover, the data on CV safety from RCTs
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suffer from major limitations. They are mostly not
designed as studies with hard CV endpoints as primary
or secondary outcomes, they have enrolled too few
subjects and most were of short duration, and the
number of observed events was too low so that the
power of RCTs and their meta-analysis was in-
sufficient to make conclusions. Observational studies,
both earlier and recent large observational cohort and
case-control studies, have delivered even more con-
flicting results, which is not surprising in view of the
intrinsic limitations of observational data and their
methodological heterogeneity. As to the risk of venous
thromboembolism (deep venous thrombosis and
pulmonary embolism), the more limited data have also
been conflicting, precluding definitive conclusions.
In conclusion, the CV risk profile and the risk of
venous thromboembolism associated with T therapy
in older men with low serum T remain to be further
elucidated. This requires data from adequately pow-
ered RCTs specifically designed to this end.
Sleep and OSA
Men suffering from OSA not uncommonly have a low
serum T, in particular when they are also obese. Serum
T levels in men with OSA tend to be inversely related
to the severity of hypoxemia. Severe (untreated) OSA
is traditionally listed among contraindications for
initiation of T therapy (, ), which for a long time
was based on no more than a few case reports of
worsening of OSA under T therapy. Liu et al. (),
in a randomized sequence, double-blind, placebo-
controlled, crossover study in healthy, community-
dwelling men . years of age (mean age, . years of
age), showed by overnight polysomnography that
short-term injection of markedly supraphysiological
doses of T resulted in reduced total time slept by about
 hour, increased duration of hypoxemia, and dis-
turbed breathing during sleep. Hoyos et al. ()
performed an -week placebo-controlled trial in men
with obesity (BMI . kg/m) with OSA. All men
were put on a hypocaloric diet and were randomized
to T injections ( mg T undecanoate at week , ,
and ) (n 5 ; mean age,  years) or placebo
injections (n 5 ; mean age,  years). Therapy with
Endocrine Reviews, August 2019, 40(4):906–972

T compared with placebo worsened the oxygen
desaturation index and nocturnal hypoxemia at the
first evaluation at week , but no longer at the final
evaluation at week  when the subjects had also lost
weight. This effect was independent of baseline T.
Overall, the limited data available thus tend to
confirm that caution is to be recommended as to the
initiation of T therapy in men with (untreated) severe
OSA.
Summary of risks/benefits and indications for
T treatment
As discussed in prior sections of this review, low
sexual desire and function are probably the symptoms
most consistently associated with low serum T in
elderly men (see “Sexual function” and “Diagnosis of
Hypogonadism in Aging Men” above). In RCTs,
sexual desire and function are also the clinically rel-
evant endpoints most consistently improved by T
therapy in elderly men with low T. Nevertheless, the
observed improvements by T therapy are mostly of
modest amplitude, and the effect on ED, in particular,
appears less than that reported for the use of PDE
inhibitors and has not been convincingly documented
to be additive to that of PDE inhibitors in combined
therapy (see “Sexual function” above). At the dosages
used in RCTs, T therapy in aging men improves body
composition with consistent but quantitatively small
decreases of fat mass and increases in lean mass and
skeletal muscle mass. The latter translates variably in
either no gain or only limited gain in muscle strength
and power and thus, not surprisingly, in an overall
disappointing impact on physical function, with RCTs
reporting small positive effects of uncertain clinical
significance or negative findings. Clearly, the data
available as to date do not allow considering im-
provement of physical function, sarcopenia, or frailty
as a valid indication for T therapy in older men with or
without low serum T (see “Body composition, muscle
mass and strength, and physical performance” above).
The beneficial effects of T therapy on body compo-
sition are consistently associated with small reductions
in fasting blood glucose and modest improvement in
insulin sensitivity. However, in the results of RCTs this
again fails to translate into consistent and clinically
relevant improvements of metabolic status. Therefore,
to improve the metabolic state in older men with low
or low-normal T is not a valid indication for T therapy,
neither in general nor more specifically in men with
the MetS or TDM (see “Body composition and
metabolic profile” above). Whereas T therapy in el-
derly men tends to reduce bone turnover and results in
small increases in aBMD as assessed by DXA and
somewhat larger beneficial effects on vBMD by QCT,
low bone mass and osteoporosis are not valid in-
dications for T therapy in elderly men. Indeed, there is
no data on the ability of T therapy to reduce fracture
risk or data comparing the effects of T with established
doi: 10.1210/er.2018-00178
REVIEW
osteoporosis treatments (see “Bone health” above).
The findings from RCTs do not indicate that T therapy
has a significant beneficial effect on cognition in older
men with low T, regardless of whether they have
preexisting cognitive impairment (see “Cognition”
under “Mental health” above). Available data do in-
dicate that T therapy in elderly men with low T can
improve mood, vitality, and depressive symptoms
with, however, only a small effect size. Such an effect
has not been shown in older men without low T, and T
therapy has not been shown to help treat depression
(see “Depression, mood, and well-being” under
“Mental health” above). Finally, T therapy can increase
Hb in older men with low T and otherwise un-
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explained anemia ().
Thus, in terms of clinically relevant endpoints, the
global picture from available RCTs on the efficacy of T
therapy in older men with low T appears rather bleak.
As far as efficacy is concerned, amelioration of sexual
function in older men with low T and sexual symp-
toms may be the only relatively well-defined clinical
indication justifying consideration of the initiation of
T therapy, even though treatment effects are of
moderate amplitude and of uncertain longer-term
durability. Because of the difficulties in defining
low vitality and mood, and categorizing depressive
symptoms in clinical practice, and considering the only
small effect size of T therapy, these conditions as such “…caution is to be
are probably not sufficient to justify T treatment. recommended as to the
Nevertheless, when present in the former context of initiation of T therapy in men
sexual complaints in elderly men with low T, they may with (untreated) severe OSA.”
be seen as strengthening the indication for T treat-
ment, as does the presence of otherwise unexplained
anemia. In the present state of the art, the effects on
body composition, physical function, insulin sensi-
tivity, bone turnover, and BMD do not as such
constitute indications for T therapy and should
rather be regarded as fringe beneficial effects of a T
therapy initiated for another indication such as sexual
dysfunction.
As to the risks linked to T therapy in aging men,
clinically meaningful polycythemia is sufficiently
common to require regular monitoring of Hct and Hb
(see “Erythropoiesis” above). Treatment does not
worsen lower urinary tract symptoms, but this has not
been studied in men with initially severe symptoms.
The data appear reassuring as to the short-term (up to
 year of T therapy) prostate safety, but longer-term
safety has not been established (see “Prostate and lower
urinary tract symptoms” above). Even though the data
from RCTs may seem rather reassuring as to major CV
events (MI, stroke, CV death), these data suffer from
significant methodological limitations in this context
and there are also discordant findings, and the findings
from observational studies have been conflicting and
inconclusive. Whereas the longer-term safety is a
concern because of lack of controlled data, the risk of
thromboembolic events (DVT, pulmonary embolism)
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might already be increased early after initiation of
treatment. From a critical appraisal it can only be
concluded that the CV and thromboembolic safety
profile of T therapy in older men with low T has yet to
be fully established. Finally, T therapy may worsen
preexisting untreated sleep disorders, in particular
obstructive sleep apnea (see “Sleep and OSA” above).
The global safety profile of T therapy in elderly men
with low T is thus primarily characterized by un-
certainty on long-term (CV and prostate) safety
rather than by major concerns for short-term (
year) safety. Nevertheless, adverse events such as
fluid retention, polycythemia, DVT, and pulmonary
embolism can occur within the first months of
treatment.
Taken together, the benefit/risk profile of T therapy
to aging men with low T is that of an only limited
established efficacy in the face of an uncertain (longer-
term) safety. This current state of the art clearly
demands caution and restraint in the clinical approach
to T therapy in elderly men. Whereas this is indeed
reflected in warnings from health authorities () and
recently published clinical practice guidelines (, ),
the current widespread use and misuse of T world-
wide, but in particular in the United States (), is
strikingly at odds with this appraisal.
Before considering T therapy for hypogonadism in
elderly men, the first requirement is a firmly estab-
lished diagnosis of hypogonadism (see “Diagnosis of
Hypogonadism in Aging Men” above); that is, the
patient should have unequivocally and persistently low
(free) T and symptoms suggestive of hypogonadism.
Although this may seem evident good clinical prac-
tice, it is disquieting that this is apparently the case
in only a minority of men prescribed T. Indeed,
in many, a single low T was not confirmed by a
second measurement; moreover, many are treated
notwithstanding a normal serum T, and many are
treated even without any prior assessment of serum T
(). Second, when there are potentially reversible
causes of hypogonadism involved, such as obesity,
some comorbidities, and medications, it seems ap-
propriate to first pursue resolution or mitigation of the
impact of these causal factors whenever possible before
considering T therapy. Third, treatment should not be
initiated when there are contraindications. Commonly
considered as (absolute or relative) contraindications
are (metastatic) prostate cancer, unevaluated prostate
nodule or elevated PSA (. ng/mL or . ng/mL
in men at higher risk of prostate carcinoma), severe
lower urinary tract symptoms (IPSS .) associated
with benign prostate hypertrophy, breast cancer,
polycythemia (Hct .% to %), thrombophilia,
recent history of MI or stroke (within the past
 months), poorly controlled congestive heart failure,
and untreated severe OSA (, , ). Of note, older
age per se is not listed as a contraindication for ini-
tiation of T therapy, and some position and consensus
952 Kaufman et al Aging and the Male Reproductive System
statements (, ) explicitly state that age is not a
contraindication.
What about older men who fulfill the above re-
quirements for T therapy, that is, they have a con-
firmed diagnosis of symptomatic hypogonadism, no
unaddressed reversible causes of hypogonadism, and
no contraindications for T treatment? Whether they
can or should be proposed T therapy is an area of less
consensus, but systematic initiation of treatment does
not seem an option in view of the unconvincing
benefit/risk profile of therapy. On this point, recom-
mendations are not univocal and tend to be ambig-
uous. The FDA, concerned by the extensive use of T in
an attempt to relieve symptoms in men with low T for
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no apparent reason other than aging, took a clear and
restrictive stance in a  Drug Safety Communi-
cation. They stated that T is FDA approved as re-
placement therapy only for men with low T due to
certain medical conditions, that is, disorders of the
testis, pituitary, or brain that cause hypogonadism, and
that the benefits and safety of T have not been
established to treat men with low T due to aging, even
when they have symptoms that seem related to low T
(). The FDA required that manufacturers change the
labeling of approved T products to clarify the ap-
proved uses and further to include information on
possible increased risk for heart attacks and stroke in
patients taking T. Also in , there was a com-
munication by the European Medicine Agency on
T-containing medicines (). The Pharmacovigilance
Risk Assessment Committee of the European Medi-
cine Agency conducted a review of T-containing
medicines and concluded that they did not find
consistent evidence that the use of T by men with
hypogonadism increases the risk of heart problems.
Nevertheless, the Pharmacovigilance Risk Assessment
Committee further recommended that the product
information should make it clear that T should only be
used when an abnormally low level of the hormone
has been confirmed by signs and symptoms and ap-
propriate laboratory tests. It is further stated that
“Testosterone levels naturally fall somewhat with age,
but restoration of these levels in healthy older men is
not an authorized use of the medicine in the EU.” In
the recent update of the Endocrine Society clinical
practice guideline on T therapy in men with hypo-
gonadism (), the authors “suggest” against routinely
prescribing T therapy to all men $ years of age with
low T. They then pursue with the following non-
committal recommendation: “in men . yr who
have symptoms or conditions suggestive of T de-
ficiency (such as low libido or unexplained anemia)
and consistently and unequivocally low morning T
concentrations, we suggest that clinicians offer T
therapy on an individualized basis after explicit
discussion of the potential risks and benefits.” A
consensus statement by several andrological and
urological associations () formulated the following
Endocrine Reviews, August 2019, 40(4):906–972

similarly noncommittal summary recommendation:
“Age is not a contraindication to initiate testosterone
treatment. Individual assessment of co-morbidities (as
possible causes of symptoms) and potential risks
versus benefits of testosterone treatment is particularly
important in elderly men.” An Endocrine Society of
Australia position statement on male hypogonadism
() states that, “T replacement therapy is warranted in
men with pathological hypogonadism, regardless of
age” and that “Currently, there are limited data from
high-quality randomized controlled trials with clini-
cally meaningful outcomes to justify testosterone
treatment in older men, usually with chronic disease,
who have low circulating testosterone levels but
without hypothalamic, pituitary or testicular disease.”
In conclusion, there is apparent consensus that in
men with a pathological hypogonadism, with an
established (organic) testicular, pituitary, or hypo-
thalamic disorder, age is not a contraindication for T
therapy. As to men with hypogonadism related to
aging, often with contributions of other factors such as
overweight and comorbidities, drug agencies have
expressed clear restrictive views, whereas recom-
mendations of several scientific associations tend to be
more evasive and noncommittal, leaving the evalua-
tion of the benefit/risk balance with individual pre-
scribers and patients.
Alternatives to T treatment
In many instances hypogonadism in elderly men is
potentially at least partly reversible, and there is limited
evidence that it can respond to lifestyle measures and
optimization of comorbidities (). For several spe-
cific clinical signs and symptoms associated with
hypogonadism, there are established nonhormonal
treatments, for example, metformin, diet, exercise for
insulin resistance and TDM, PDE inhibitors for ED,
and bisphosphonates for osteoporosis. A discussion of
their place in elderly men with low T falls beyond the
scope of this review.
Several hormonal alternatives for T therapy in
(older) men with hypogonadism have been the subject
of small-scale studies or are the subject of ongoing
drug development programs. However, for most, the
data available are very limited and their use in this
context is off-label or in clinical trials. As to date,
owing to insufficient data, none can be considered as
an established or valid alternative for T therapy in
aging men. We will therefore limit the discussion to
some general remarks.
Potential hormonal alternatives for T therapy can
be grouped in three categories: (i) T precursors (e.g.,
DHEA) or metabolites (e.g., DHT); (ii) compounds
stimulating endogenous T production, that is, hCG,
selective ER modulators (SERMs), and aromatase
inhibitors; and (iii) synthetic compounds acting on
the AR, that is, anabolic steroids and selective AR
modulators.
doi: 10.1210/er.2018-00178
REVIEW
Endogenous levels of DHEA and DHEAS decline
substantially with aging (). As “replacement therapy,”
DHEA is usually administered orally and it is partly
converted into both T and E. In men, contribution to
circulating T levels is at best marginal relative to
prevailing T levels and unlikely to be of clinical sig-
nificance even in older men with low T, whereas the
contribution to E levels is more significant. Whether
T and E concentrations in target tissues are signifi-
cantly increased by local DHEA metabolism is un-
known. In a meta-analysis of placebo-controlled RCTs
of DHEA supplementation in elderly men, there was
no significant clinical effect of treatment, except for a
small decrease of fat mass (). DHT, the bioactive T
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metabolite and major androgen in the prostate tissue,
is a strong AR agonist. There are scarce data from
RCTs on transdermal therapy with DHT gel in aging
men with low-to-normal or normal serum T. Treat-
ment results in an expected marked increase in serum
DHT levels while decreasing serum T levels. The
therapy appears to induce effects such as a modest
decrease in fat mass and an increase in lean mass, as
well as some improvement in sexual function, with-
out major short-term prostate effects (, –).
However, clinical data on DHT therapy are presently
too limited. Moreover, treatment is not equivalent to T
therapy, as DHT is not aromatized to estrogens, which “Several hormonal alternatives
for T therapy in (older) men
may likely adversely affect long-term bone health [see
with hypogonadism have been
“Bone metabolism and skeletal integrity” as well as the subject of small-scale
“Bone health” (under “Efficacy of T therapy”) above] studies or are the subject of
and may also limit other treatment effects compared ongoing drug development
with T therapy (). programs.”
In the absence of major testicular failure indicated
by markedly elevated gonadotropins, serum T in-
creases in response to hCG injections. Whereas re-
peated hCG injections, whether in association with
FSH injections, has a place in the treatment of (usually
younger) men with hypogonadism with a desire for
fertility, such a treatment has not been studied and
would be impractical for longer-term therapy in older
men with low T. Moreover, T response to hCG is
diminished in older men with low T (, ). An
alternative to hCG injections is stimulation of en-
dogenous gonadotropin secretion. Circulating E
plays a major role in the negative feedback regulation
of LH secretion, and in the absence of organic dis-
orders of the gonadal axis, decreasing E hypothalamic
negative feedback action results in increased LH and T
serum levels. This can be achieved either by treatment
with SERMs, having (partial) antagonistic effects on
hypothalamic ERs, for example, clomiphene citrate (or
its trans isomer enclomiphene citrate), tamoxifen, and
raloxifene (–), or by decreasing circulating E
levels with an aromatase inhibitor, for example,
letrozole and anastrozole (–). These several
drugs have been used off-label as treatment of
hypogonadism, mostly in younger men with a desire
for fertility or for treatment of decreased fertility with
https://academic.oup.com/edrv 953
REVIEW
low sperm count (, ), but also in aging men with
obesity with secondary hypogonadism as an alterna-
tive to T therapy (, , , –). Data on the
benefits and risks of therapy with SERMs and aro-
matase inhibitors in elderly men are presently very
limited, in particular in view of the complexity of their
effects. Indeed, potential beneficial effects and risks of
therapy with SERMs in elderly men are dependent on
the rise of T and E levels and the tissue-specific
modulation of E effects. They can vary according to
the considered target tissue and factors such as sex
steroid levels both before and during treatment; for
example, the effects of SERMS on bone metabolism
differ according to pretreatment E levels (, ).
The effects of aromatase inhibitors, in turn, depend on
the rise of T levels and the degree of suppression of E
levels. The latter is usually only partial in men
responding to aromatase inhibition with increased T
production, and the degree of E suppression may vary
according to treatment modalities. This is a relevant
issue, as suppressed E levels may not only adversely
affect bone health (), but they also may have other
treatment effects such as on fat mass and even on
sexual function (, ).
As possible alternatives for T therapy, there has
long been interest in compounds that may prefer-
entially exert wanted androgenic effects, in particular
anabolic effects on muscle, with less risk of adverse
effects, such as on prostate and the CV system. Older
steroidal anabolic compounds, which are massively
abused in sports and body building, are not candidates
as alternatives to T therapy in older men with low T
because of both lack of data and a pharmacological
profile not documented to compare favorably with T
in this context. There are ongoing efforts of the phar-
maceutical industry to develop more selective non-
steroidal selective AR modulators, with a focus primarily
on selective anabolic action on muscle and improved
physical function (, ), which of course is only one
aspect of health and well-being of aging men.
Conclusions and Perspectives
In this review, we summarized the present state of
knowledge on the male reproductive system changes
observed during aging and their clinical implications.
Although changes affecting fertility are reviewed, the
main focus is on the hormonal changes, being clini-
cally of greater potential significance in older men.
We reviewed possible underlying pathophysiological
mechanisms as well as the clinical correlates of the
hormonal changes. We discussed androgen deficiency
and the diagnosis of hypogonadism in older men and
where we stand in the appraisal of the risks and
benefits of, as well as indications for, T therapy in older
men. Since an extensive review of the topic was
published in this journal in  (), a considerable
954 Kaufman et al Aging and the Male Reproductive System
amount of new data became available, and the vast
majority (i.e., %) of the work cited herein was
published after the  review. Qualitative steps
forward in the literature have mainly been in three
areas: substantially more prospective observational
data on large cohorts; more clinical data based on
state-of-the-art sex steroid hormone assays; and
considerably more data from RCTs on T therapy in
older men with documented low T. Our appraisals of
the literature on the clinical correlates of altered sex
steroid levels in aging men and on the effects of T
therapy are summarized in Table . Notwithstanding
the wealth of new data, the conclusions that can be
drawn from the present review do not differ essentially
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from those made more than a decade ago. Although
we now have improved documentation of the hor-
monal changes and their clinical correlates in older
men, important areas of uncertainty persist, in par-
ticular concerning the direction and causality of the
relationship between some hormonal and clinical
changes, as well as pertaining to the long-term benefits
and risks of T therapy.
Overall, the data from prospective observational
studies confirm and extend prior findings from cross-
sectional studies on reproductive hormone changes.
Aging is accompanied by a modest decline of total T,
an increase of SHBG, and a more pronounced decrease
of free T. This occurs with large between-subject
variability, and observations in cohorts of community-
dwelling men have indicated the contribution of
comorbidities to these changes, with, in particular,
increased prevalence of overweight and obesity in
aging men being a significant contributing factor. As to
the clinical implications of these hormonal changes, in
the  review, acknowledging the limitations of the
then mostly cross-sectional available data, it was
concluded that whereas the age-related hormonal
changes are likely to play at least in some men a
contributory role in part of the clinical alterations that
accompany aging, it is also clear that for many signs
and symptoms in elderly men that are reminiscent of
the clinical picture in young men with hypogonadism,
the data are inconclusive as to a role of an age-related
partial androgen deficiency. It was further stated that
“Overall, there is presently little if any conclusive
evidence for a role of ‘physiological’ age-related decline
of sex steroid production on morbidity or deteriora-
tion of quality of life in elderly men; nevertheless this
does not mean that elderly men cannot suffer ‘path-
ological’ hypogonadism with markedly subnormal
testosterone.” On the basis of the present updated
review of the evidence, these conclusions can be largely
upheld. In fact, in several areas where cross-sectional
associations suggested a role of altered T levels in
aging-related clinical changes, prospective studies ei-
ther did not confirm the association, gave variable
results, or suggested a reverse or bidirectional causal
relationship.
Endocrine Reviews, August 2019, 40(4):906–972

Among the most consistent associations with low T
in elderly men, according to the more recent literature,
are the occurrences of sexual symptoms and lower Hct,
and both seem at least partly responsive to T therapy.
Longitudinal data have confirmed the association
between low sex steroid hormone levels and altered
bone metabolism with increased bone loss and higher
fracture risk, but these associations are mainly with
lower E and higher SHBG, with a less prominent role
for T levels. As to the association of altered T levels
with changes in body composition, metabolic health,
and physical performance, the picture emerging from a
large amount of observational data is complex, with
indications of bidirectional association and an im-
portant component of reverse causality. In RCTs, T
therapy in elderly men with low-to-normal T con-
sistently resulted in limited decreases of fat mass and
increases of lean mass, but the effects on metabolic
health and physical function have been minimal,
unlikely to be of clinical significance, and they are
inconsistent across studies. The data from prospective
studies do not consistently show an association of low
T in aging men with a decline of cognitive function or
incident AD and, accordingly, findings from RCTs
failed to reveal beneficial effects of T therapy on
cognition in elderly men. The findings on the asso-
ciation of low T with depressive symptoms are mixed
and inconclusive. Whereas markedly low T may
possibly be associated with the occurrence of de-
pressive symptoms in elderly men, there is little evi-
dence for a role of moderate androgen decline. The
whole of the information from RCTs suggests that T
therapy has small-amplitude beneficial effects on
mood, depressive symptoms, and vitality in elderly
men with clearly low T. Findings from a large body of
observational data on the association of serum an-
drogens with CVD in aging men have been variable,
most likely due to residual confounding and reverse
causality related to general health status. A critical
appraisal of the data does not indicate an association
between T levels and the occurrence of IHD or MI. An
association has been found of lower T (and/or DHT)
with the occurrence of stroke and with CV and all-
cause mortality. In particular, the relationship between
low T and increased mortality most likely reflects
reverse causality, with low T in elderly men as a marker
of poorer health status. The long-term CV effects of T
therapy in elderly men are yet to be determined.
Globally, neither the severity of documented ad-
verse consequences linked to low T, nor the nature and
magnitude of beneficial treatment effects justify the
concept of a broadly applied T replacement therapy in
older men with low T. Although there are areas in
need of further clarification concerning clinical con-
sequences of low T and T treatment benefits, it seems
unlikely that additional data will fundamentally alter
this appraisal. This conclusion is, moreover, in-
dependent of the unresolved issue of the long-term
doi: 10.1210/er.2018-00178
REVIEW
safety of T therapy, which in any case demands re-
strictive indications for T prescriptions to older men.
In this regard, there are presently no data suggesting
that age per se is a contraindication for T therapy in
older men with symptomatic hypogonadism due to
hypothalamic, pituitary, or testicular disease.
There are many areas for further research, and we
mention here only a few. In several observational
studies, free or non–SHBG-bound T levels were found
to be more closely associated with clinical change than
was total T. Moreover, associations of SHBG with
clinical changes, independent of sex steroid levels, have
also been reported. The role of SHBG as a modulator
of sex steroid action but also as an integrating marker
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of diverse metabolic and hormonal influences (i.e.,
insulin, adipokines, IGF-, sex steroids, thyroid hor-
mone) in elderly men deserves further exploration.
There is also still much work to be done to standardize
methodology to assess free T and to validate free T
reference ranges. Another area deserving further ex-
ploration is the role of bioactive T metabolites, that is,
E and DHT. In particular, the meaning and possible
mechanisms of reported associations of DHT with
clinical events such as stroke and death need clarifi-
cation. Low T in elderly men has been associated with
all-cause mortality, but whether low (free) T can be a “Among the most consistent
clinically useful biomarker of poor health status, re- associations with low T in
sponsive to lifestyle measures and optimized man- elderly men, according to the
agement of comorbidity, is an intriguing but yet more recent literature, are
unexplored possibility. Also deserving exploration is the occurrences of sexual
the question of whether suppressed activity of the symptoms and lower Hct, and
both seem at least partly
gonadal axis might somehow be a desirable adaptive responsive to T therapy.”
phenomenon to ill health that might be undesirable to
reverse with T therapy.
The setup of an adequately powered study of
sufficient duration to assess long-term (CV and
prostate) safety of T therapy in aging men is still
needed and has been requested by the FDA. However,
even if the outcome is reassuring as to the long-term
safety of T, this should not signal broad application of
T replacement therapy in aging men with low T.
Indeed, as discussed earlier (see the introductory
comments under “Treatment of Hypogonadism in
Elderly Men” above), the concept of T replacement is
vague and outdated. If T therapy in older men will
acquire a place, beyond the treatment of a small
number of older men with symptomatic hypo-
gonadism due to hypothalamic, pituitary, or testicular
(organic) disorders, it is more likely to be as “phar-
macotherapy” for well-defined indications in well-
defined patient groups, for example, to improve
specific aspects of physical function in older men with
low T and chronic pulmonary disease or for those
recovering from surgery. It is conceivable that for some
indications clinical meaningful effects may require
supraphysiological T doses, which might be acceptable
only when a favorable benefit/risk balance is dem-
onstrated in specifically tailored RCTs with defined
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REVIEW

Table 7. Summary of Appraisal of the Literature on the Clinical Correlates of Altered Endogenous Sex Steroids Levels in Aging Men and of the Literature on
the Effects of T Therapy in Aging Men With Low Serum T
System/Function Associations With Endogenous Sex Steroids Effects of T Therapy

Bone health , (Free or bioavailable) E2 with , Serum markers bone resorption (small effect)

, BMD; . bone turnover; . bone loss; . nonvertebral fractures . Areal vertebral BMD by DXA (small effect size)

. SHBG (independent of T and E2) with 5 Areal BMD femoral neck by DXA (mostly negative findings)

. Bone loss; . nonvertebral fractures; . vertebral fractures . Volumetric vertebral BMD by QCT

Androgenic T action more marginal and indirect . Volumetric hip BMD by QCT
(i.e., on muscle, falls)

(? effect in osteoporosis and fracture risk)

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(osteoporosis not indication for T therapy)

Body composition, , SHBG and total T with , Total body fat mass;
metabolic health, and
physical performance . Fat mass, obesity . Fat-free mass;

, SHBG and total T and free T with . (Prevented ,) skeletal muscle mass;

.. Fat mass, morbid obesity (quantitatively modest changes)

Reciprocal relationship , T and . fat mass with . Insulin sensitivity

predominant reverse causality

, Total T and/or SHBG cross-sectional with (modest effect size)

. Insulin resistance, MetS, T2DM (data do not support T treatment to improve metabolic status
in older men with low T in general or with MetS or T2DM)

, Total T and/or SHBG longitudinal with $ Muscle strength and power

. MetS and T2DM (variable: limited to no effect)

(inconsistent and not with free/bioavailable T) $ Physical function

. (Free/bioavailable) T with (no effect or small effects of uncertain clinical significance)

. Lean mass, , lean mass decline

(inconsistent findings)

. (Free/bioavailable) T with

. Indices muscle strength and /or physical

performance (findings inconsistent)

. Free/bioavailable T with

. Indices of frailty

Erythropoiesis , (Free/bioavailable) T and hypogonadism with . Risk of polycythemia

, Hemoglobin; . decline Hb . Hct, Hb in men with unexplained anemia

Cardiovascular disease Sex steroids with CVD: disparate, inconsistent ? MI, other major cardiac events, stroke
and mortality findings; residual confounding, reverse causality

Sex steroids not with

IHD, MI

, Or “not optimal” T (and/or DHT) with Thromboembolism (data not conclusive)

. Stroke (although they seem predominantly reassuring (i.e., 5) for short

term, data not conclusive and no reliable long-term data ?)

. CVD-specific and all-cause mortality

(Continued )

956 Kaufman et al Aging and the Male Reproductive System Endocrine Reviews, August 2019, 40(4):906–972
 REVIEW

Table 7. Continued
System/Function Associations With Endogenous Sex Steroids Effects of T Therapy

Sexual function , (Free/bioavailable) T with . Sexual desire, . erectile function,

, Sexual desire; . Overall sexual activity

, indices of sexual function (moderate amplitude;

only if initially unequivocally low T and

prevalent sexual symptoms;

effect on erectile function less than

PDE5 inhibitors;

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no potentiation of PDE5 inhibitors)

Mental health , Or suboptimal (free/bioavailable) T not consistently 5 Memory

with cognitive decline or incident Alzheimer’s disease

, (Free/bioavailable)T with 5 Other aspects of cognition

. Depressive symptoms (mixed findings; only limited . Mood, vitality

evidence for role of moderately low T)

, Depressive symptoms (small effect size; depression not

indication for T therapy)

See text for details.

Bold text indicates hormonal changes; clinical correlates accompany the changes listed.
Abbreviations: ., higher, more, increase; ,, lower, less, decrease; 5, unchanged, no effect; ?, not known.

hard clinical endpoints, in subjects representative of been shown to offer added value on top of non-
the target population for treatment, and for treatment pharmacologic measures (e.g., exercise, weight loss)
modalities and durations relevant for the intended and compared with, or on top of, existing pharma-
clinical use. Moreover, such T treatment should have cologic treatments for the same indication.

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Acknowledgments
Current Affiliation: I. T. Huhtaniemi’s current affiliation is
the Research Centre for Integrative Physiology and Phar-
macology (formerly the Department of Physiology), Institute
of Biomedicine, University of Turku, 20520 Turku, Finland.
Correspondence and Reprint Requests: Jean-Marc
Kaufman, MD, PhD, Department of Endocrinology, Ghent
University Hospital, Corneel Heymanslaan 10, 9000 Ghent,
Belgium. E-mail: jean.kaufman@ugent.be.
Disclosure Summary: G.T. has received scientific grants
as a prinicipal investigator from Ipsen, Bayer Shering, and
Sandoz; consulting fees as an advisory board member from
Ipsen and Novartis; and lecturer fees as a speaker from Ferring
and Novartis. The remaining authors have nothing to
disclose.
Abbreviations
3MS, modified MMSE; 5-diol, 5-androstene-3b,17b-diol;
aBMD, area BMD; AD, Alzheimer’s dementia; ADT, an-
drogen deprivation therapy; AR, androgen receptor; BMD,
bone mineral density; BMI, body mass index; CHAMP,
Concord Health and Ageing in Men Project; CHD, coronary
Aging and the Male Reproductive System
heart disease; CV, cardiovascular; CVD, CV disease; DHEA,
dehydroepiandrosterone; DHEAS, DHEA sulfate; DISF-SDD,
Sexual Desire Domain of the Derogatis Interview for Sexual
Function; DXA, dual-energy X-ray absorptiometry; E2, es-
tradiol; ED, erectile dysfunction; EMAS, European Male
Aging Study; ER, estrogen receptor; FACIT, Functional
Assessment of Chronic Illness Therapy; FDA, Food and
Drug Administration; GDS, Geriatric Depression Scale; hCG,
human chorionic gonadotropin; Hct, hematocrit; HDL,
high-density lipoprotein; HIMS, Health in Men Study; HNF,
hepatocyte nuclear factor; HOMA, homeostatic model
assessment; HOMA-IR, HOMA of insulin resistance; HPT,
hypothalamic–pituitary–testicular; HR, hazard ratio; ICSI,
intracytoplasmic sperm injection; IHD, ischemic heart
disease; IIEF, International Index of Erectile Function; IMT,
intima–media thicknes; IPSS, International Prostate
Symptom Score; IVF, in vitro fertilization; LC-MS/MS, liquid
Downloaded from https://academic.oup.com/edrv/article/40/4/906/5381905 by guest on 11 February 2022
chromatography–tandem MS; LOH, late-onset hypo-
gonadism; MetS, metabolic syndrome; MI, myocardial in-
farction; MMAS, Massachusetts Male Aging Study; MMSE,
Mini-Mental State Examination; MONICA, Monitoring
Trends and Determinants of Cardiovascular Disease; MS,
mass spectrometry; OSA, obstructive sleep apnea; PDE5,
phosphodiesterase 5; PPARg, peroxisome proliferator-
activated receptor g; PPT, Physical Performance Test;
PRT, progressive resistance training; PSA, prostate-specific
antigen; QCT, quantitative CT; RCT, randomized controlled
trial; RR, relative risk; SERM, selective ER modulator; SHIP,
Study of Health in Pomerania; SNP, single-nucleotide
polymorphism; T, testosterone; T2DM, type 2 diabetes
mellitus; TEAAM, Testosterone’s Effects on Atherosclerosis
Progression in Aging Men; TTrials, Testosterone Trials;
vBMD, volumetric BMD..
Endocrine Reviews, August 2019, 40(4):906–972