Review Article Ann C/in Biochem 1990; 27: 532-541

Sex hormone binding globulin: origin, function and

clinical significance
Colin Selby
From the Department of Clinical Chemistry, City Hospital, Hucknall Road, Nottingham NG5 lPB, UK

SUMMARY. Sex hormone binding globulin (SHBG) is a glycoprotein possessing high

affinity binding for 17 P-hydroxysteriod hormones such as testosterone and
oestradiol. It is probably synthesized in the liver, plasma concentrations being
regulated by, amongst other things, androgen/oestrogen balance, thyroid hormones,
isulin and dietary factors. it is involved in transport of sex steroids in plasma and its
concentration is a major factor regulating their distribution between the protein-
bound and free states. Its detailed role in the delivery of hormones to target tissues
is not yet clear.
Plasma SHBG concentrations are affected by a number of different diseases, high
values being found in hyperthyroidism, hypogonadism, androgen insensitivity and
hepatic cirrhosis in men. Low concentrations are found in myxoedema, hyperprolac-
tinaemia and syndromes of excessive androgen activity. Concentrations are also
affected by drugs such as androgens, oestrogens, thyroid hormones and anti-convul-
sants.
Measurement of SHBG is useful in the evaluation of mild disorders of androgen
metabolism and enables identification of those women with hirsutism who are more
likely to respond to oestrogen therapy. Testosterone: SHBG ratios correlate well with
both measured and calculated values of free testosterone and help to discriminate
subjects with excessive androgen activity from normal individuals.
Additional key phrases: dihydrotestosterone; testostyerone; oestradiol; sex steriod
transport

Although the presence of a specific plasma ISOLATION, PURIFICATION AND

androgen binding protein was postulated in
19581 it was not isolated until 1965.2 The same
year an oestradiol binding protein was indepen-
dently isolated' and by competitive steroid
binding studies the two proteins were shown to
be identical." It consequently became known as
Testosterone-estradiol Binding Globulin (TeBG)
but has since been shown to bind many other
steroids and drugs. It is now more commonly
known as Sex Hormone Binding Globulin
(SHBG) but has also been called SBP (Sex
Steroid Binding Protein) and SSBG (Sex Steroid
Binding Globulin). The protein is present in the
plasma of primates, rabbits, goats, cows, sheep,
reptiles and amphibians.!
This paper was prepared at the invitation of the Clinical
Laboratory Investigation Sub Committee of the Scientific
Committee of the Association of Clinical Biochemists, but does
not necessarily reftect their views.
CHARACTERIZATION
SHBG is most readily isolated from late preg-
nancy plasma by affinity chromatography fol-
lowed by further purification steps."" Monomer-
ic SHBG is a glycoprotein containing 373 amino
acid residues and three carbohydrate side
chains." The total carbohydrate content is 28-
34%6,7.9 and consists largely of sialic acid (36%)
and N-acetylglucosamine (33%). The molecular
structure of circulating SHBG is in dispute, a
variety of monomeric to four unit structures
being suggested.Y'" The most obvious property
of SHBG is its high affinity for steroids,
SHBG binds most readily to planar steroids
which have 18 or 19 carbon atoms and a 17P-
hydroxyl group." Binding occurs by Van der
Waals forces and polar attraction and one mole
of dime ric SHBG binds approximately one mole
of steroid. 6,7,9 Steroid binding depends on both
temperature and pH, being some 2·5 times higher

532

at 4°C than at 37°C but is irreversibly destroyed
above 60°C and below pH 5. The three most
avidly bound naturally occurring steroids are
dihydrotestosterone (DHT), testosterone (T) and
oestradiol (E 2 ) .
BIOSYNTHESIS AND HOMEOSTATIC
CONTROL
SHBG has been localized in the hepatocytes of
adult monkeys" and is secreted along with cor-
tisol binding globulin by cultures of the human
hepatoma cell line HepG2. 13 Concentrations are
higher in hepatic venous than arterial blood."
Plasma concentrations are increased by
oestrogen" and thyroid hormones" and reduced
Sex hormone binding globulin 533
by androgens," possibly by regulation of hepatic
synthesis.
Recently, growth hormone, somatomedin-C,
other growth factors and nutritional status have
been suggested" as the primary homeostatic
mechanism for control of SHBG concentrations.
In vivo growth hormone" and prolactin" reduce
SHBG concentration whilst in vitro, insulin
decreases SHBG production inhibiting the
stimulatory effect of thyroxine and oestradiol."
Dietary lipids affect SHBG concentration,
which falls significantly in men after 2 weeks on
a high fat diet." SHBG concentrations are lower
in obese subjects of both sexes23,24 and rise follow-
ing weight reduction. Congenital absence of
SHBG has been described in two sisters."

100 1 P:Z:=:I:I:l .....1'TTTT1.,..., ._. '--1KIl iiiiiiii f-U..LLLLLLJ..1

75

~
°
u
'0
...
~
11l
0 50
E
11l
0
a.

.....0
~

25

a
DHT T E2 DHT T E2 DHT T E2
Men Women Third trimester
(Foil iculcr ) pregnancy

FIGURE I. The distribution of plasma dihydrotestosterone, testosterone and oestradiol between the free. albumin.
SHBG and CBG bound states in normal subjects in different physiological situations. Results are expressed as the
percentage of the total steroid concentrations circulating in each fraction. Data from Ref 28. • Albumin bound; 0
SHBG bound; • CBG bound; • free.
534 Selby
In human beings the biological half life of
SHBG calculated from the rate of decline post
partum is about 7 days." Little is known of the
biological degradation although evidence" from
rats injected with bovine SHBG suggests the
sialic acid moiety is important in preventing
rapid hepatic disposal.
ROLE OF SHBG AND ALBUMIN IN
STEROID TRANSPORT AND DELIVERY
Less than 2% of biologically active steroids are
free in the circulation, the remainder being
bound to transport proteins, mostly SHBG and
albumin. The bound and free fractions appear to
exist in a state of dynamic equilibrium, governed
overall by the Law of Mass Action; thus the size
ofthe free fraction of a given steroid is dependent
on:
(i) Its total plasma concentration
(ii) The avidity ofbinding to transport proteins
(iii) The concentration of each binding protein
(iv) The concentration and avidity of compet-
ing steriods
Computer simulation of the distribution of some
steroids between the free and protein bound
states is summarized in Fig. 1.28 In normal men
about 44%, and in normal women over 80% of
the available SHBG binding sites remain unoc-
cupied. Over 99% of the available steroid
binding sites on albumin always remain unoc-
cupied. This large excess of steroid binding sites
means that changes in total hormone concentra-
tion produce relatively small changes in the size
of the free hormone fractions. However, changes
in SHBG concentration produce dramatic
changes in both free and albumin bound
hormone. Thus, the large increase in SHBG in
pregnancy results in a rise in total testosterone
(despite a fall in albumin concentration) and a
fall in the percentage of free testosterone. Con-
versely, a reduction in SHBG concentration
results in an increase of both albumin-bound and
of percentage free testosterone. It follows that
both absolute and relative protein concentrations
play an important role in controlling the
distribution of steroids between the bound and
free states. A major metabolic role for both
albumin and SHBG is thought to be that of a
buffer store modulating fluctuations in steroid
concentration and providing a reservoir of
bioavailable hormone.
Hitherto it has been assumed that it is only the
lipid-soluble readily-diffusible free steroid which
is metabolically active. However, it has been
argued that the concentration of some free
steroids (e.g. oestradiol) is too low to generate a
significant biological response" and it is possible
that protein-bound steroid may also be available
---either dissociating in the immediate vicinity of
the target tissue surface or entering the cell intact.
A number of models'"?' depicting hormone
delivery by dissociation have been proposed but
the factors governing the kinetics of dissociation
and tissue uptake remain contentious.P:"
However in all situations studied to date, spon-
taneous dissociation of the protein-hormone
complex is sufficiently rapid to account for the
observed tissue uptake."
Evidence is also accumulating that the intact
SHBG-steroid complex interacts directly with
certain target tissues. Prostatic" and decidual
endometrial cell membranes" possess SHBG
binding sites having characteristics typical of
other membrane receptors, and SHBG and CBG
have been located within the cytosol of a number
of human and animal cells." These proteins may
have a role in the specific transport of steroid to
intra-cellular locations."
Other roles for SHBG have been proposed: the
metabolic clearance rate of steroids with a high
affinity for SHBG is reduced.":" and it seems
likely that SHBG protects such steroids from
hepatic disposal. SHBG may also modify the rate
of conversion of androstenedione to testosterone
as this is higher in individuals with a low
SHBG. 4 1 Finally, it has been suggested that dif-
ferences in association characteristics of testos-
terone and oestradiol for SHBG may mean that
increases in SHBG produce a more oestrogenic
environment, i.e. oestrogen amplification."
SHBG CONCENTRATIONS IN HEALTHY
SUBJECTS
In cord blood SHBG concentrations are low
(approximately 30-40 nmol DHT bound/L)
mean concentrations being higher in boys than
girls." In male (but not female) infants SHBG
concentrations are reported" to increase sharply
from birth to 3 months before declining to
normal pre-pubertal concentrations. Peak pre-
pubertal concentrations (80-l00nmol DHT
bound/L) are reached in both sexes between the
ages of 5-7 years thereafter declining with
approaching puberty, possibly as a result of
increasing secretions of adrenal and gonadal
androgens." However this pre-pubertal decline
in SHBG still occurs in individuals with complete
androgen insensitivity" and the prepubertal

increase in insulin may be the major controlling
factor." In male subjects adult SHBG concentra-
tions (approximately 20-45 nmol DHT bound/L)
are reached by about 18 years of age, but in
female subjects adult concentrations
(approximately 35-90 nmol DHT bound/L) are
not reached until about 20 years of age. In both
sexes SHBG concentrations slowly increase
throughout life until by the mid-eighties they are
about twice as high as those at 20.4S In healthy
rested men SHBG concentrations have been
reported to show a significant circadian rhythm
characterized by a peak in the early afternoon
and a nadir about midnight," although such a
rhythm is difficult to reconcile with the biological
halflife. SHBG has been shown by some authors
to vary throughout the menstrual cycle being
some 15% higher during the luteal phase" but
this is not a consistent finding."
Plasma concentrations of SHBG rise rapidly
from conception" until the 30th week of gesta-
tion when they are 6-10 fold higher than non-
pregnancy concentrations. 53
SHBG AND DRUGS
Many different drugs modify circulating con-
centrations of SHBG and in such cases care is
required in the interpretation of measurements of
both testosterone and oestradiol. SHBG
synthesis is increased by natural" and synthetic
oestrogens," thyroid hormones, 16 anticonvul-
sants" and rifampicin. 56 In general there is an
increase in SHBG and total plasma steroid con-
centration but a fall in the free fraction. However
synthetic oestrogens produce a fall in total en-
dogenous steroid due to suppression of steroid
biosynthesis and negligible binding to SHBG. 2S
Oestrogens administered orally are a more
powerful stimulant of SHBG synthesis than
those given percutaneously due to their direct
absorption into the portal system." Anti-
oestrogens such as clomiphene" and tamoxifen"
also induce SHBG synthesis presumably as a
result of their inherent weak oestrogenic activity.
Dexamethasone," progesterone" and exogenous
gonadotrophins'? have also been reported to
increase SHBG concentration.
SHBG concentrations are reduced by drugs
with androgenic or progestagenic activity includ-
ing natural and synthetic androgens," synthetic
gestagens 63•64 (but not progesterone) and some
anabolic steroids." Lowering of SHBG is
thought to be due to a reduction in synthesis
rather than increased metabolic clearance. Some
drugs such as danazol" and norgestrel" displace
Sex hormone binding globulin 535
bound testosterone from SHBG and the resulting
increase in free testosterone lowers SHBG
synthesis. Others, such as medroxyprogesterone
acetate do not displace endogenous steroids"
and there is a fall in both total and free testos-
terone concentration." This difference is impor-
tant if these drugs are used in combination with
oestrogens for treating acne, hirsutism or viril-
ism.
SHBG CONCENTRAnONS IN DISEASE
STATES
Changes in SHBG occur in a wide variety of
pathological conditions. Elevated concentrations
are found in hypo gonadal men; both testicular
failure and defective gonadotrophin secretion are
associated with low plasma concentrations of
total and free testosterone/" SHBG concentra-
tions fall with androgen replacement therapy. In
syndromes of androgen insensitivity both total
testosterone and SHBG may be elevated,60,70 the
degree of elevation being dependent on the sever-
ity of the defect and the degree of conversion of
androgen to oestrogen (oestradiol concentra-
tions are usually high). SHBG concentrations are
elevated in a proportion of male diabetics" but
the cause and clinical significance remain to be
clarified. In men" (but not women?") severe
alcoholic liver disease is associated with
increased SHBG (possibly due to increased
oestrone formation) and free androgen con-
centrations are reduced, partly due to high
SHBG concentrations and partly to impaired
gonadal function. In women high concentrations
of SHBG are found in primary biliary cirrhosis."
High concentrations of SHBG are found in
women with anorexia nervosa" despite low
oestradiol concentrations and failure to ovulate.
In men with anorexia nervosa elevated SHBG
concentrations are much less common" and
refeeding has no demonstrable effect. Hyper-
thyroid subjects, including those overtreated
with thyroid hormones, also have elevated
SHBG concentrations":" probably due to
increased hepatic synthesis, whereas those with
myxoedema tend to have reduced levels. In
women with breast cancer SHBG concentrations
have been reported as normal" or low" and a
relationship between tumour oestrogen receptor
status and SHBG concentration has been ob-
served."
Reduced concentrations of SHBG and
elevated androgens are frequently found in
women with hyperprolactinaemiar" Prolactin
and growth hormone are structurally and
536 Selby
phylogenetically related and SHBG concentra-
tions tend to be low in acromegaly and subjects
undergoing treatment with growth hormone."
Grossly obese subjects of both sexes have
reduced SHBG and total testosterone concentra-
tions although free testosterone tends to remain
normal." Increased androgen production rates
are found in obese women; increased metabolic
clearance rates are found in obese men and
women possibly due to excessive androgen
metabolism in adipose tissue."
Syndromes of androgen excess
A number of different clinical conditions are
associated with an effective excess of circulating
androgens. They present with acne," hirsutism."
virilism" and features of polycystic ovarian
disease. Biochemically they are a heterogeneous
group characterized by increased androgen
secretion from the adrenal, ovary or both,"
increased peripheral conversion and increased
metabolic clearance rate of androgens'" and pos-
sible variation in target organ sensitivity." Total
testosterone is elevated in only about 50%86,87 of
cases, androstenedione and dehydroepiandro-
sterone and its sulphate may also be elevated" but
SHBG is usually low, often less than 30 nmol
DH T bound/L.
Although there have been no detailed studies it
is generally assumed that women who complain
of acne and hirsutism in whom SHBG is normal
are more likely to be suffering from an abnormal-
ity of the skin, e.g. elevated 511. reductase activity,
than circulating androgen concentration."
Management of hirsutism and acne is usually
directed at reducing free androgen concentration
by suppressing androgen secretion and/or
increasing SHBG synthesis." Most physicians
favour use of oestrogen (adminstered with a suit-
able progestagen to induce withdrawal bleeding)
to increase SHBG synthesis. The powerful pro-
gestagen cyproterone acetate has several clinic-
ally useful effects. It suppresses gonadotrophin
secretion and androgen synthesis and inhibits the
effects of androgen on the target organ."
However, the use of either oestrogen or
cyproterone acetate is inappropriate in those
who wish to conceive.
Reduced concentrations of SHBG are also
found in other conditions of androgen excess
including congenital adrenal hyperplasia and
Cushings syndrome." In women with androgen-
secreting ovarian tumours SHBG concentrations
are variously normal" or low-presumably
depending on the degree of peripheral conversion
of androgens to oestrogens.
INDICATIONS FOR MEASUREMENT OF
SHBG
The diagnosis of hirsutism or virilism is made
essentially on clinical grounds. Biochemical as-
sessment merely helps to establish the aetiology
of the condition. In milder cases of androgen
excess characterized by acne, hirsutism and
menstrual disturbance, total and free testos-
terone concentrations are likely to be normal in
over 50% of cases. In a recent survey in Notting-
ham (Jeffcoate and Selby, unpublished observa-
tion) of 66 untreated women presenting with
hirsutism, SHBG was below 30 nmol/L in 31
(47%) and below 35 nmol/L in 38 (58%) whereas
testosterone was elevated (greater than 2·8 nmolj
L) in only 18 (27%). When SHBG is suppressed
and total testosterone remains normal or slightly
elevated the ratio of testosterone to SHBG
increases. Estimation of this ratio (usually
termed the Free Androgen Index; FAI) and cal-
culated as:
total testosterone
SHBG x 100
is a more sensitive means of identifying subjects
with abnormal androgen status84,93- 9S than by
measurement of either total or measured free
testosterone (Fig. 2). In non-obese, non-hirsute
oligomenorrhoeic women an elevated free
androgen index during the early follicular phase
of a spontaneous menstrual cycle is reported to
be a sensitive and specific indicator of polycystic
overian disease." Knowledge of SHBG con-
centration also enables a calculation of free tes-
tosterone (the 'derived' free testosterone")
another extremely sensitive index of abnormal
androgen status.
The finding of a low SHBG is significant and
has several important implications.
(i) Total testosterone and SHBG concentrations
are partially interdependent. A suppressed
SHBG in the presence of a high normal or
slightly elevated total testosterone infers an
increase in 'bioavailable' androgen with a
consequent increase in peripheral androgen
activity.
(ii) Since the aim of oestrogen therapy is to
elevate plasma SHBG concentrations, those
subjects who have a suppressed SHBG may
be the most likely to respond.
(iii) If SHBG concentrations lie within the refer-
ence range in women with hirsutism it is
 Sex hormone binding globulin 537

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FIGURE 2. SHBG. total T and SHBG:T ratios (T/SHBG x 100) in normal women and women with evidence of
excessive androgen activity. - - Mean value. A, Normal subjects; B. subjects with clinical evidence of excessive
androgen activity.

likely that the predominant effect is excessive MEASUREMENT OF SHBG

skin responsiveness, so called 'idiopathic hir-
sutism'.
In situations where changes of SHBG con-
centration are likely to occur (male hypogonad-
ism, androgen insensitivity, thyroid disorders,
diabetes mellitus, liver disease and extreme
changes in body weight) interpretation of total
testosterone measurements without knowledge
of the SHBG concentration is difficult. Thus
SHBG measurements in serum are indicated
when investigating gonadal function in such
patients. SHBG measurements are also impor-
tant in the interpretation of changes in oestradiol
and testosterone in subjects taking drugs known
to affect either SHBG synthesis and/or gonadal
steroid production.
Thus SHBG concentrations are good guide to
androgen status and may be regarded as indica-
tive of peripheral circulating androgen activity.
Alternatively, interpretation of measurements of
total testosterone may be improved by expressing
them as a function of SHBG concentration. By
such means abnormalities of androgen status
may be revealed which would remain hidden by
measurement of testosterone alone.
Assays for SHBG have recently been
reviewed.F:" They are generally one of two types,
binding assays in which the quantity of tritium
labelled dihydro-testosterone or testosterone
specifically bound to SHBG is measured, or a
specific immunoassay of the SHBG protein.
Where a liquid scintillation counter is available
there is a choice of relatively inexpensive binding
assays suitable for clinical purposes. In the
absence of a liquid scintillation counter the only
practical alternative is a commercial immunoas-
say (see Appendix)
A National External Quality Assessment
Scheme for SHBG measurement is organized
from this laboratory, some 40 laboratories par-
ticipate, using a variety of methods. Evidence
from this scheme suggests that the Farmos
Immuno-Radiometric assay, and the binding
assays of Rosner," Anderson et al.,26 Fattah and
Chard'?" and Iqbal and Johnson'?' are suitable.
However, the possibility of interference in
binding assays from drugs such as danazol must
be borne in mind.!"
Reagent costs of binding assays are less than
half of those of a commercial immunoassay
(about £3·3D/patient, 1989 prices) assuming com-
538 Selby
plete usage ofa kit for one assay batch. Although
other commercial assays are represented on the
scheme, at the time of writing insufficient data
are available to comment about their perfor-
mance.
PROVISION OF AN SHBG SERVICE
Provision of an SHBG service is dependent on a
number of factors; androgen assay workload,
knowledge of the pathophysiology of androgens,
availability of analytical expertise and equipment
(especially for binding assays) and financial
resources. The service is best provided on a sub-
regional basis, one or two laboratories undertak-
ing to offer the service. If a service is to be
established the relevant recommendations pro-
vided by the Association of Clinical Biochemists
Analytical Working Party Task Force for Testos-
terone!" also apply to SHBG. The laboratory
should:
(i) Assay at least 30-40 samples at least once a
fortnight
(ii) Participate in the SHBG NEQAS
(iii) Use one of the methods recommended above
APPENDIX
UK Supplien of SHBG kits
(I) DPC Immuno Radiometric Assay (IRMA) avail-
able from:
Diagnostic products (UK) Ltd,
22 Blacklands Way,
Abingdon Business Park,
Abingdon,
Oxon OXI4 lDY, UK.
(2) Farmos IRMA and Delfia Immuno Fluorimetric
Assay (IFMA); both available from:
Pharmacia Ltd,
Pharmacia House,
Midsummer Boulevard,
Milton Keynes,
Buckinghamshire MK9 3HP, UK.
(3) Techland RIA available from:
Biogenesis Ltd,
12 Yeomans Park,
Yeomans Way,
Bournemouth,
Dorset BH8 OBJ, UK.
Acknowledgements
I am grateful to Professor V H T James, Drs W
J Jeffcoate and C B Marenah for helpful discus-
sions and comments, and to Mrs L M Selby for
typing the manuscript.
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