Androgens and the Aging Male

Paul J. Turek, M.D.

Is it not strange that desire should so many years outlive performance?
(W.Shakespeare)
The average age of individuals in the US is projected to rise significantly over the next
50 years, and the largest increase will occur in persons > 65 years old. Therefore,
medicine
will witness a dramatic increase in age-related health problems, including cancer,
osteoporosis, cerebrovascular and ischemic heart diseases and hormone deficiencies.
Among
these, the health risks associated with age-related hormonal decline has been
addressed
mainly in women. However, there is now firm evidence that hormonal changes in the
aging
male may also be associated with significant health problems.
What is Male Menopause?
There is a progressive decline in androgen production associated with aging in men.
This phenomenon has been variously termed male menopause, male climacteric,
andropause,
or more appropriately, androgen decline in the aging male (ADAM). A key difference
from
female menopause, however, is that this hormonal change in men is far more gradual in
nature
compared to the precipitous fall in estrogens that women experience. In this sense then,
the
term male menopause is misleading, as it suggests a sudden drop in sex hormones
similar to
that in aging women. The ADAM syndrome is characterized by a variety of physical and
intellectual alterations that include:
1. Decreased sexual desire and increased erectile dysfunction
2. Changes in mood associated with fatigue, depression and anger with concomitant
decreases in intellectual activity and spatial orientation ability
3. Decreased lean body mass with associated diminution in muscle volume and
strength
accompanied by increases in visceral fat
4. Decreased body hair and skin alterations such as increases in facial wrinkling
5. Decreased bone mineral density resulting in osteoporosis
Not all of these clinical manifestations need to occur simultaneously to diagnosis the
syndrome. In fact, many of these symptoms are indeed multifactorial and one might
attribute
this clinical picture simply to the natural and unavoidable consequence of aging. For
example,
frailty associated with aging is a major socioeconomic as well as health care problem as
it
reduces the potential for independent living. Frailty may be due to many causes, some
of
which include loss of muscle strength, bone fractures, decreased mood, and impaired
cognition, symptoms typical of testosterone deficiency. The association of symptoms
with
documentation of testosterone deficiency certainly implicates ADAM as a possible
underlying
etiology.
Testosterone-A Hormone for Life
Testosterone is responsible for the growth and development of male sex organs and
maintains secondary sex characteristics. In the kidney and bone marrow, testosterone
stimulates production of erythropoietin and stem cells. In bone, testosterone accelerates
linear
growth and helps close the epiphyses. While pre-pubertal hypoandrogenism is
characterized
by undeveloped genitalia and a lack of virilization, post-pubertal hypogonadism
frequently
results in diminished libido, erectile dysfunction, infertility, gynecomastia, gynecoid body
habitus, reduction in body and facial hair, and osteoporosis. Additionally, mood
inventory
scores indicate that hypogonadal men report significantly higher levels of anger,
confusion,
depression, and fatigue than eugonadal men.
Serum testosterone levels in males fall progressively from the third decade to the end
of life, mainly due to a decline in testicular Leydig cell mass. This decline may be
associated
with changes in the hypothalamic-pituitary homeostatic control of luteinizing hormone
(LH)
secretion, which regulates testosterone production by Leydig cells. The age-related
onset, rate
and degree of change in testosterone production are all quite variable, such that no
single
factor can predict the course of age-related hypoandrogenism. Having said this, a
general rule
of thumb is that mean serum testosterone levels decrease approximately 1% annually
after the
age of 50. Associated with this hormonal decline is an increase in sex hormone-binding
globulin (SHBG) which, by binding to and inactivating testosterone, further lowers the
levels
of bioavailable androgens. Finally, there is also an aged-related loss of the
hypothalamicpituitary
circadian rhythm, which further exaggerates the fall in plasma testosterone levels. As
a result of these dynamic changes in hormones and binding proteins, the concentration
of
bioavailable testosterone in men decreases by as much as 50% between the ages of 25
and 75
years.
How is Androgen Deficiency Diagnosed?
There is considerable debate about the best way to diagnose androgen deficiency in
older men. The minimalist view is that a total serum testosterone should be measured
first. If
it is below 200 ng/dl, the diagnosis is likely correct; if it > 350 ng/dl, the diagnosis of
androgen deficiency is effectively ruled out. Total testosterone levels in the range of 200
ng/dl
to 349 ng/dl require further evaluation by assessment of the active or bioavailable
testosterone
levels, consisting of both the free (unbound) and albumin bound (lightly bound)
testosterone fractions. In other words, it is helpful to quantify all of the non-SHBG bound
testosterone. If the active or bioavailable testosterone levels are normal in this situation,
then
androgen deficiency is unlikely.
Despite that fact that most clinicians agree that, in the setting of appropriate clinical
symptoms, the diagnosis of androgen deficiency is confirmed by such laboratory
investigation, there still controversy surrounding the issue of whether or not the
diagnosis of
ADAM requires obvious clinical evidence of signs or symptoms. This is controversial
because many signs of hypogonadism are clinically silent, such as changes in bone
mineral
density. In addition, changes in mood, muscle strength and adiposity may also be very
subtle.
Even more controversial is whether men at risk for ADAM (age >60 years), should be
screened for testosterone deficiency in the absence of obvious signs or symptoms. Until
the
real risk:benefit ratio of testosterone replacement therapy is defined in the aging male,
these
questions will remain largely unanswered.
Can Androgen Replacement Turn Back the Clock of Age?
The potential benefits of testosterone replacement therapy in aging men include an
increase in bone mineral density and reduction in fractures. The magnitude of this
response in
men is equivalent to that seen in postmenopausal women receiving estrogen
replacement.
Testosterone therapy also results in increases in lean body mass and possibly strength
and a
decrease in fat mass and potential improves insulin sensitivity.
By stimulating erythropoietin production, testosterone replacement increases the
hematocrit in aging men, and it may in fact reduce the risk of cardiovascular events.
Epidemiological data indicates that, in general, hypogonadal men have a greater
incidence of
myocardial infarction than eugonadal men. This may be explained by the positive
effects of
testosterone in lowering body and visceral fat, and by the relatively favorable effects of
androgens on clotting factors and coronary vasodilatation. In contrast, androgens are
also
known to lower HDL-cholesterol, which would suggest that androgen supplementation
might
in fact increase cardiovascular risk. Thus, the use of androgen replacement specifically
for the
purpose of reducing cardiovascular risk is currently premature and unjustifiable without
further research.
Decreased sexual drive is usually improved by testosterone. However, it is important
to recognize that erectile dysfunction in older men is usually the net effect of decreased
libido
and impaired penile vascular smooth muscle dilation. The latter is best treated more
specifically, such as with selective vasodilatory agents like Sildenafil (Viagra).
Androgens
also have an important role in cognitive function and androgen administration to aging
men
has definitely been shown to enhance visual-spatial skills of treated individuals.
How Should Androgen Supplementation be Given?
Hormonal replacement may be given for a variety of indications but treatment is
normally for life. Monitoring of the patient on supplementation is also a lifetime
commitment
on the part of the clinician as it may involve constant tailoring of treatment to meet the
individual patient needs. Evaluation of potential candidates for testosterone replacement
therapy should include a complete medical history, physical examination and hormonal
profile. Digital rectal examination and serum PSA determination are mandatory before
starting replacement therapy. For the first year of therapy, patients should be followed
quarterly to assess clinical and biochemical response, with serial digital rectal
examinations
and PSA determinations if they are > 40 years old. After the first year, patients who
remain
stable may subsequently be followed annually. Annual evaluations should include
hemoglobin, liver functions, lipid profile and serum calcium measurements. Bone
density and
psychological evaluation should be performed depending on the initial indications for
androgen supplementation. As serum testosterone levels can fluctuate, particularly after
intramuscular administration, clinical indicators may be a better guide for adjusting
medication dosages.
Androgen Therapy- What are the Risks?
Most obvious among the risks of androgen replacement is the potential to exacerbate
preexisting prostate cancer. There is no obvious association between testosterone
replacement
and the development of prostate cancer, however the concurrent presence of prostate
or breast
cancer is a contraindication for testosterone replacement. Furthermore, it may be
inappropriate for men with severe bladder outlet obstruction due to benign prostatic
hyperplasia. Other potential risks and adverse effects of androgen replacement are:
1. Water retention and electrolyte disturbances
2. Polycythemia (due to the stimulatory effect on erythropoietin)
3. Suppression of blood clotting factors
4. Liver toxicity (not with transdermal application)
5. Infertility due to low or no sperm count (azoospermia)
6. Lipid abnormalities
7. Exacerbation of pre-existing sleep apnea
8. Gynecomastia
Conclusions
There is clear evidence that advancing age is associated with a decrease in
testosterone
production in men. The clinical syndrome of ADAM includes a wide variety of clinical
manifestations, some of which are fairly silent and non-specific. Evaluation of potential
candidates for testosterone replacement therapy should include a complete medical
history,
physical examination and hormonal profile. Generally hormonal findings should
accompany
clinical symptoms to warrant treatment. It behooves the physician to not only recognize
the
signs of symptoms of this largely understudied condition, but to also be familiar with the
benefits, risks and consequences of androgen replacement therapy and to
knowledgeably
monitor patients who receive such care.
Reading
Center JR Nguyen TV, Schneider D, et al. Mortality after all major types of osteoporotic
fracture in men and women: an observational study. Lancet. 86: 878, 1999.
Cherrier MM, Craft S, Matsumoto AH. Cognitive changes associated with
supplementation of
testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report. J
Androl. 24, 568-76, 2003.
Harman SM, Metter EJ, Tobin JD et al. Longitudinal effects of aging on serum total and
free
testosterone levels in healthy men. Baltimore Longitudinal Stud of Aging. JCEM.
86:724-
31, 2001.
Institute of Medicine Statement. http://www.nia.nih.gov/news/pr/2003.
Moffat SD, Zonderman AB, Metter EJ et al. Free testosterone and risk for Alzheimer
disease
in older men. Neurol. 62:188-93, 2004.
Rhoden EL and Morgantaler A. Risks of testosterone-replacement therapy and
recommendations for monitoring. N Engl J Med. 350:482-92, 2004.
Wang C, Eyre DR, Clark R et al. Sublingual testosterone replacement improves muscle
mass
and strength, decreases bone resorption, and increases bone formation markers in
hypogonadal men--a clinical research center study. J Clin Endocr Metab. 81: 3654,
1996.
Whitsel EA, Boyko EJ, Matsumoto AM et al. Intramuscular testosterone esters and
plasma
lipids in hypogonadal men: a meta-analysis.Am. Med. J. 111: 261-9, 2001.
PTurek M.D. 2/2005