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Interpretive Handbook

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Test 9285 :
Sex Hormone-Binding Globulin (SHBG), Serum

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Sex hormone-binding globulin (SHBG), a homodimeric 90,000 to 100,000 molecular weight glycoprotein, is synthesized in the liver. Metabolic clearance of SHBG is biphasic, with a fast initial distribution from vascular compartment into extracellular space (half-life of a few hours), followed by a slower degradation phase (half-life of several days).

 

SHBG binds sex steroids with high affinity (KD approximately 10[-10]M), dihydrotestosterone (DHT) ->testosterone (T) ->estrone/estradiol (E). Although each monomeric subunit contains 1 steroid binding site, the dimer tends to bind only a single sex-steroid molecule. The main function of SHBG is sex-steroid transport within the blood stream and to extravascular target tissues. SHBG also plays a key role in regulating bioavailable sex-steroid concentrations through competition of sex steroids for available binding sites and fluctuations in SHBG concentrations. Because of the higher affinity of SHBG for DHT and T, compared to E, SHBG also has profound effects on the balance between bioavailable androgens and estrogens. Increased SHBG levels may be associated with symptoms and signs of hypogonadism in men, while decreased levels can result in androgenization in women.

 

SHBG levels in prepubertal children are higher than in adults. With the increase in fat mass during early puberty they begin to fall, a process that accelerates as androgen levels rise. Men have lower levels compared with women and nutritional status is inversely correlated with SHBG levels throughout life, possibly mediated by insulin resistance. Insulin resistance, even without obesity, results in lower SHBG levels. This is associated with increased intra-abdominal fat deposition and an unfavorable cardiovascular risk profile. In postmenopausal women, it may also predict the future development of type 2 diabetes mellitus. Androgens and norethisterone-related synthetic progesterones also decrease SHBG in women.

 

Endogenous or exogenous thyroid hormones or estrogens increase SHBG levels. In men, there is also an age-related gradual rise, possibly secondary to the mild age-related fall in testosterone production. This process can result in bioavailable testosterone levels that are much lower than would be expected based on total testosterone measurements alone.

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnosis and follow-up of women with symptoms or signs of androgen excess (eg, polycystic ovarian syndrome and idiopathic hirsutism)

 

An adjunct in monitoring sex-steroid and anti-androgen therapy

 

An adjunct in the diagnosis of disorders of puberty

 

An adjunct in the diagnosis and follow-up of anorexia nervosa

 

An adjunct in the diagnosis of thyrotoxicosis (tissue marker of thyroid hormone excess)

 

A possible adjunct in diagnosis and follow-up of insulin resistance and cardiovascular and type 2 diabetes risk assessment, particularly in women

 

In laboratories without access to bioavailable testosterone or equilibrium dialysis-based "true" free testosterone assays, sex hormone-binding globulin measurement is crucial in cases when assessment of the free testosterone fraction (aka free androgen index or calculated free testosterone) is required. At Mayo Medical Laboratories, both bioavailable testosterone (TTBS / Testosterone, Total and Bioavailable, Serum) and free testosterone (TGRP / Testosterone, Total and Free, Serum) measurements are available. Free testosterone (TGRP) is measured by equilibrium dialysis, obviating the need for sex hormone-binding globulin measurements to calculate free androgen fractions.

Interpretation Provides information to assist in interpretation of the test results

Many conditions of mild-to-moderate androgen excess in women, particularly polycystic ovarian syndrome, are associated with low sex hormone-binding globulin (SHBG) levels. Most of these women are also insulin resistant and many are obese. A defect in SHBG production could lead to bioavailable androgen excess, in turn causing insulin resistance that depresses SHBG levels further. There are rare cases of SHBG mutations that clearly follow this pattern. SHBG levels are typically very low in these individuals. However, in most patients, SHBG levels are mildly depressed or even within the lower part of the normal range. In these patients, the primary problem may be androgen overproduction, insulin resistance, or both. A definitive cause cannot be usually established. Any therapy that either increases SHBG levels (eg, estrogens or weight loss), reduces bioactivity of androgens (eg, androgen receptor antagonists, alpha-reductase inhibitors), or reduces insulin resistance (eg, weight loss, metformin, peroxisome proliferator-activated receptor [PPAR] gamma agonists), can be effective. Improvement is usually associated with a rise in SHBG levels, but bioavailable or free testosterone levels should also be monitored.

 

The primary method of monitoring sex-steroid or antiandrogen therapy is direct measurement of the relevant sex-steroids and gonadotropins. However, for many synthetic androgens and estrogens (eg, ethinyl-estradiol) clinical assays are not available. In those instances, rises in SHBG levels indicate successful anti-androgen or estrogen therapy, while falls indicate successful androgen treatment.

 

Adult SHBG levels in boys with signs of precocious puberty support that the condition is testosterone driven, rather than representing premature adrenarche.

 

Patients with anorexia nervosa have high SHBG levels. With successful treatment, levels start to fall as nutritional status improves. Normalization of SHBG precedes, and may be predictive of, future normalization of reproductive function.

 

Thyrotoxicosis increases SHBG levels. In situations when assessment of true functional thyroid status may be difficult (eg, patients receiving amiodarone treatment, individuals with thyroid hormone transport-protein abnormalities, patients with suspected thyroid hormone resistance or suspected inappropriate thyroid-stimulating hormone [TSH] secretion such as a TSH-secreting pituitary adenoma), an elevated SHBG level suggests tissue thyrotoxicosis, while a normal level indicates euthyroidism or near-euthyroidism. In patients with gradual worsening of thyrotoxicosis (eg, toxic nodular goiter), serial SHBG measurement, in addition to clinical assessment, thyroid hormone, and TSH measurement, may assist in the timing of treatment decisions. Similarly, SHBG measurement may be of value in fine-tuning suppressive TSH therapy for patients with nodular thyroid disease or treated thyroid cancer. Results are not definitive in the short-term in patients receiving drugs that displace total thyroxine (T4) from albumin.

 

SHBG is also produced by placental tissue and therefore values will be elevated during pregnancy. Reference ranges for pregnant females have not been established in our institution.

 

In patients with known insulin resistance, "metabolic syndrome," or high risk of type 2 diabetes (eg, women with a history of gestational diabetes), low SHBG levels may predict progressive insulin resistance, cardiovascular complications, and progression to type 2 diabetes. An increase in SHBG levels may indicate successful therapeutic intervention.

 

A genetic variant of SHBG (Asp327->Asn) introduces an additional glycosylation site in 10% to 20% of the population, resulting in significantly slower degradation. These individuals tend to have higher SHBG levels for any given level of other factors influencing SHBG.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Human antimouse antibodies may be present in specimens from patients who have received immunotherapy utilizing monoclonal antibodies. Other heterophile antibodies may also be present in patient specimens. This assay has been specifically formulated to minimize the effects of these antibodies on the assay. However, results from patients known to have such antibodies must be carefully evaluated.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

CHILDREN

Males

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

31-167

Stage II

11.5

49-179

Stage III

13.6

5.8-182

Stage IV

15.1

14-98

Stage V

18.0

10-57

*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for boys at a median age of 11.5 (+/-2) years. For boys, there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18.

 

Females

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

43-197

Stage II

10.5

7.7-119

Stage III

11.6

31-191

Stage IV

12.3

31-166

Stage V

14.5

18-144

*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for girls at a median age of 10.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African American girls. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18.

 

ADULTS          

Males: 10-57 nmol/L

Females (non-pregnant): 18-144 nmol/L

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Pugeat M, Crave JC, Tourniare J, Forest MG: Clinical utility of sex hormone-binding globulin measurement. Horm Res 1996;45:148-155

2. Tehernof A, Despres JP: Sex steroid hormone, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 2000;32:526-536

3. Kahn SM, Hryb DJ, Nakhle AM, Romas NA: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol 2002;175:113-120

4. Hammond GL: Access of reproductive steroids to target issues. Obstet Gynecol Clin North Am 2002;29:411-423

5. Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), cortisol and ferritin in neonates, children, and young adults. Clin Chem Lab Med 2002;40(11):1151-1160


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