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SHBG
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SHBG
Introduction
Sex hormone-binding globulin (SHBG), also known as sex steroid-binding protein
(SBP) or testosterone-estradiol-binding globuline (TEBG), is the transport plasma
glycoprotein that binds to specific sex hormones, namely testosterone, DHT and
estradiol1. SHBG’s affinity is only for C18 or C19 steroid structures; affinity is
also dependent on the relative orientation of the A- and B- steroid rings and the
presence of a 17β-hydroxyl group1. Other steroid hormones such as
progesterone, cortisol, and other corticosteroids are bound by transcortin.
SHBG (Fig.1) consists of of two identical 373 amino acid chains and three
oligosaccharide chains. Its molecular weight is 93 kDa. There is only one steroidbinding site per SHBG molecule.
Fig.1: Sex hormone binding globulin with testosterone molecule
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Biosynthesis
SHBG is produced mainly in the liver (Fig.2) by hepatocytes
and then released into the bloodstream. Small amounts are produced
in the brain. In women, production sites include the uterus, placenta, ovaries and
adrenal glands as well.
In men, androgen binding protein (ABP) is produced by Sertoli cells in the testes.
ABP has the same amino acid sequence as SHBG, but differs in its site of
production and sugar moiety.
SHBG synthesis is influenced by a number of hormonal and metabolic factors.
Estrogens and thyroid hormones stimulate its synthesis, whereas androgens act
as inhibitors. Other factors are mentioned in the paragraph “Levels”.
Fig.2: Human liver
Metabolism
The biological half-life of SHBG is seven days. Its metabolic clearance is biphasic,
with a fast initial distribution from the vascular compartment into extracellular
space (half-life of a few hours), followed by a slower degradation phase (half-life
of several days).
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Physiological Function
SHBG serves two roles: transporting and regulating
the bioavailability of sex hormones. As a transport
glycoprotein, SHBG binds to sex hormones such as testosterone,
dihydrotestosterone (DHT), estradiol, estriol, estrone and
dihydroepiandrosterone (DHEA), carrying them to target tissues via the
bloodstream. These hormones are biologically inactive when bound, so SHBG
also controls the amount of active sex hormones in circulation, while at the same
time maintaining a reservoir of inactive hormones that are protected from
degradation. Thus the bioavailability of these hormones is dependent on SHBG
levels.
Due to its greater affinity for DHT and testosterone than for estrone/estradiol,
SHBG also greatly affects the balance of bioavailable androgens and estrogens.
In the bloodstream, sex hormones circulate bound mostly to SHBG and to some
degree to serum albumin. Only a small fraction is unbound/free (1-2%). The
exact proportion of biologically active sex steroid hormones is a subject of
ongoing research. It was previously believed that only the free fraction was
biologically active; however, it has been confirmed that nearly all albumin-bound
sex hormones are also available for tissue uptake. Thus the combined free and
weakly-bound (i.e., albumin-bound) sex hormones are sometimes referred to as
the bioavailable11 hormones. As mentioned above, sex steroid hormones bound
to SHBG are considered biologically unavailable.
It has recently been proved, however, that some tissues have plasma membrane
receptors that can bind to the entire carrier protein-hormone complex. SHBGbound DHT can activate the membrane signaling mechanism in prostate cells, for
instance, increasing cyclic adenosine monophosphate (cAMP) formation and
mitogenesis7. SHBG may also have a function in other tissues that have
receptors for DHT. Thus sex steroid hormones appear to act in tissues via two
distinct receptor structures, steroid receptors and SHBG receptors (RSHBG).
SHBG has very high affinity for dihydrotestosterone (DHT) and somewhat lower
affinity for testosterone and estradiol (in that order) 3. Affinity for these steroids
is on the order of Ka=1x 108-1x109. On the other hand, the capacity of SHBG for
these hormones is low. Although each monomeric subunit contains one steroid
binding site, the dimer tends to bind only to a single sex steroid hormone
molecule. In comparison, albumin has a high capacity for sex steroid hormones,
but its affinity for them is 100 times lower than that for SHBG.
In males, approximately 44-65% of testosterone and 20% of estradiol circulate
bound to SHBG.
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The corresponding proportions in females
are 66-78% and 40-60%, respectively. 1-2%
circulate in free form in both sexes, and the remainder is bound to albumin.
Levels
SHBG levels depend on both sex and age. In fertile women, they are also
affected by the phase of menstrual cycle.
Serum SHBG levels are relatively low at birth, increase to high levels during
infancy, and decrease during puberty1. Sexual dimorphism in serum SHBG levels
becomes apparent during and after puberty due to androgen-mediated
suppression of serum SHBG in males. Thus higher concentrations of SHBG levels
are seen in women than in men.
The highest SHBG serum levels of are found in pregnant women near term.
Levels at the end of pregnancy may reach values five times the average for nonpregnant women.
SHBG serum levels are affected by a number of factors that regulate SHBG
synthesis and release. High androgen levels decrease SHBG concentrations; high
levels of prolactin, insulin and insulin-like growth factor 1 (IGF-1) have the same
effect. Other factors which decrease SHBG levels include obesity, female aging
and menopause, glucocorticoids3 and administration of androgens.
On the other hand, high estrogen and thyroid hormone levels increase SHBG
concentration. Other factors which may increase SHBG levels include stress,
male aging, high carbohydrate intake and drugs (e.g., antiepilepticum phenytoin,
oral contraceptives).
Circulating SHBG levels follow rhythmic variations . Daily variations in SHBG
concentrations are similar to those of other proteins and albumins in serum, and
are greatly affected by posture9.
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Fig.3: Changes of SHBG levels during
the life cycle
Typical SHBG6 levels of children and adult males and females are given in the
table 1.
For each assay, the relevant reference values are shown in the appropriate
Instructions for Use (IFU).
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Table 1: Typical SHBG levels
Specimen (serum)
Reference interval
(nmol/L)
Puberty Tanner stage:
Stage I
male:
28.0-150
female:
39.0-176
Stage II
male:
44.0-160
female:
7.20-107
Stage III
male:
5.50-163
female:
28.0-171
Stage IV
male:
13.0-88.0
female:
28.0-149
Stage V
male:
10.0-60.0
female:
20.0-130
Adult
male:
10.0-80.0
female:
20.0-130
pregnancy
week 10-15
52-168
week 20-25
172-260
week 35-40
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Diagnostic utility – prospects and possibilities
As an analyte, SHBG is of great informational value due to its role in three
regulatory circuits: the gonadal, thyroid and insular axes.
Gonadal axis: The concentration of bound sex hormones significantly affects
SHBG production. Its production is reduced in the presence of androgens,
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including those administered externally; conversely,
it is increased in the presence of estrogens, including
some estrogen-containing contraceptives.
Therefore even mild imbalances result in complications in both sexes. In cases of
excessive estrogens (e.g., in boys with gynecomasty), SHBG tends to bind to
androgens, rendering estrogens more pronounced. On the other hand,
a predominance of androgens leads to a decrease in SHBG production; as
a consequence, the proportion of free androgen grows in relation to that of
bound androgen. Such a situation may occur in polycystic ovary syndrome
(PCOS).
Thyroid axis: SHBG levels correlate positively with thyroid hormone levels.
Therefore SHBG levels are elevated in cases of hyperthyroidism and dimished in
hypothyroidism. In subclinical situations, in which only TSH levels are outside
normal limits (diminished in hyperthyroidism; increased in hypothyroidism),
measurement of SHBG can serve as independent complementary, laboratory
indicator.
Insular axis: SHBG and insulin levels correlate negatively with one another. This
is why we often find hirsutism in women with impaired insulin sensitivity and
hyperinsulinemia (frequent in obese individuals): increased insulin production
leads to a drop in SHGB levels, causing an elevation of free androgen
concentration and ultimately hirsutism. The above-mentioned PCOS, for instance,
is typically accompanied by a decrease in peripheral insulin sensitivity. SHBG
levels are also diminished in cases of Reaven’s syndrome (hyperglycemia,
hypertension, obesity, decreased HDL cholesterol, elevated triglycerides).
Elevated SHBG levels are associated with the following conditions:
- hyperthyroidism
- excess of estrogens
- gynecomastia in men (development of abnormally large mammary
glands)
- hypogonadism8, particularly in Turner’syndrome
- growth hormone deficiency
- anorexia nervosa
- liver cirrhosis
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SHBG levels are elevated in older men, pregnant
women, postmenopausal women, and during use of
oral contraceptives, hormonal replacement therapy,
and administration of certain antiepileptic drugs.
Decreased SHBG levels are associated with the following conditions:
- hypothyroidism
- acromegaly
- Cushing’s syndrome
- nephrotic syndrome
- excess of androgens
- hirsutism
- polycystic ovary syndrome (PCOS)1,3
- obesity
- hyperprolactemia
- alopecia
- Reaven’s syndrome
SHBG concentrations may decrease during androgen treatment.
Free Androgen Index (FAI):
As previously mentioned, SHBG concentrations are influenced by androgen levels,
primarily testosterone. Serum SHBG levels are inversely related to free,
presumably bioactive testosterone concentrations4,5. There are a number of
conditions and medications which may cause an increase or decrease in SHBG
levels. At the same time, free testosterone levels may be changed without
altering total testosterone levels, or vice versa. Thus, true androgen status can
be assessed either by measuring free testosterone directly or by calculating the
ratio of total testosterone (TT) to SHBG. This ratio is called the Free Androgen
Index (FAI) or the Testosterone Free Index (TFI).
FAI = TT (nmol/L)/SHBG (nmol/L) x 100
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Diagnostic utility-Practical applications
SHBG levels are determined primarily in order to evaluate
androgen status in men and women. Measurement of SHBG concentration is a
useful tool in the evaluation of mild androgen metabolism disorders, and it
identifies those women with hirsutism whoa are likely to respond to estrogen
therapy. As the ratio of total testosterone to SHBG correlates well to both
measured and calculated values for free testosterone, SHBG measurement helps
to identify subjects with excessive androgen activity.
Diagnosis and follow-up of women with symptoms or signs of
androgen excess (PCOS and idiopathic hirsutism)
Many conditions characterized by mild to moderate androgen excess in
women, particularly PCOS, are associated with low SHBG levels. Most
women with these conditions are also insulin resistant, and many are
obese. A defect in SHBG production can lead to an excess in bioavailable
androgens, which in turn causes an increase in insulin resistance that
depresses SHBG levels even further. The Free Androgen Index (FAI) is
lower than normal, while total testosterone remains normal. Thus an
increase in free testosterone with a simultaneous decrease in SHBG is an
indicator of possible PCOS.
Monitoring sex steroid or anti-androgen therapy
The primary method of monitoring sex steroid or antiandrogen therapy is
direct measurement of the relevant sex steroids and gonadotropins.
However, clinical assays are not available for many synthetic androgens
and estrogens. In these instances, rises in SHBG levels indicate successful
anti-androgen or estrogen therapy, while falls indicate successful androgen
treatment.
Diagnosis of disorders of puberty
Boys with signs of precocious puberty may have elevated levels of SHBG.
Diagnosis and follow up of anorexia nervosa
Patients with anorexia nervosa have elevated SHBG levels. With successful
treatment, levels start to fall and nutritional status improves.
Normalization of SHBG levels precedes and may predict the normalization
of reproductive function.
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Diagnosis of thyrotoxicosis
SHBG levels are elevated in instances of this condition.
There are situations in which assessment of true thyroid
status may be difficult: in patients with thyroid hormone transport
protein abnormalities with suspected thyroid hormone resistance, or with
suspected inappropriate thyroid stimulating hormone (TSH) secretion such
as a TSH-secreting pituitary adenoma. In such cases elevated SHBG levels
suggest tissue thyrotoxicosis, while normal levels indicate euthyroidism. In
patients with gradually worsening thyrotoxicosis, serial SHBG
measurement may assist in the timing of treatment (in addition to clinical
assessment, thyroid hormone and TSH levels measurement).
Diagnosis and follow-up of insulin resistance, and risk assessment of
cardiovascular status and type II diabetes in women
In patients with known insulin resistance, or with a high risk of type II
diabetes, low SHBG levels may predict progressive insulin resistance,
cardiovascular complications, and the progression of type II diabetes.
Increased SHBG levels may indicate successful treatment.
References
1. Hammond G.F.: Molecular properties of corticosteroid binding globulin and the
sex-steroid binding proteins. Endocrin Rev, 1990, 11, 65-79
2. Tietz: Textbook of Clinical Chemistry, 3nd Ed., Burtis C.A., Ashwood E.R., eds.
W.B. Saunders Company, 1999, p. 1603
3. Rosner W.: The functions of corticosteroid-binding globulin and sex hormonebinding globulin: recent advances, Endocrin. Rev., 1990, 11, 80-91
4. Mathur R.S., Moody L.O., Landgrebbe S., Williamson H.O.: Plasma androgens and
sex hormone-binding globulin in the evaluation of hirsute patients, Fertil. Steril.,
1981, 35, 29-35
5. Nanjee M.N., Wheeler M.J.: Plasma free testosterone. Ann. Clin. Biochem., 1985,
22, 387-390
6. Alan H.B. WU, PhD, DABCC, FACB: Tietz Clinical Guide To Laboratory Tests, 4th
edition. W.B. Saunders Company, Philadelphia, 2006, 982-983
7. Rosner W., Hryd D.J., Khan M.s. et al.: Sex hormone binding globulin binding to
cell membranes and generation of a second messenger, J.Androl., 1992, 13, 101106
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8. Griffin J.E., Wilson J.D.: Disorder of testes and male reproductive tract. In
Williams Textbook of Endocrinology, 8th ed. J.D.Wilson and D.W. Foster, Eds.,
Philadelphia, W.B.Saunders Co., 1992, pp. 799-852
9. Valero-Polito J., Fuentes-Arderiu X.: Daily rhythmic and non-rhythmic variations of
follitropin, lutropin, testosterone and sex-hormone-binding globulin in men,
Eur.J.Clin.Biochem., 1996, 34, 455-462
10. Stanczyk F.Z.: Steroid hormones In: Infertility, Contraception and Reproductive
Endocrinology, 3rd ed., D.R.Mishell, V.Davajan and R.A.Lobo, Eds., Boston,
Blackwell Scientifici Publications, 1991, pp. 53-76
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