Bioavailable testosterone

bioavailable testosterone

Test ID: TTBS Testosterone, Total and Bioavailable, Serum

Recommended second-level test for suspected increases or decreases in physiologically active testosterone:

-Assessment of androgen status in cases with suspected or known sex hormone-binding globulin binding abnormalities

-Assessment of functional circulating testosterone in early pubertal boys and older men

-Assessment of functional circulating testosterone in women with symptoms or signs of hyperandrogenism but normal total testosterone levels

-Monitoring of testosterone therapy or antiandrogen therapy in older men and in females

Clinical Information

Testosterone is the major androgenic hormone. It is responsible for the development of the male external genitalia and secondary sexual characteristics. In female patients, its main role is as an estrogen precursor. In both sexes, it also exerts anabolic effects and influences behavior.

In men, testosterone is secreted by the testicular Leydig cells and, to a minor extent, by the adrenal cortex. In premenopausal women, the ovaries are the main source of testosterone, with minor contributions by the adrenals and peripheral tissues. After menopause, ovarian testosterone production is significantly diminished. Testosterone production in testes and ovaries is regulated via pituitary-gonadal feedback involving luteinizing hormone (LH) and, to a lesser degree, inhibins and activins.

Most circulating testosterone is bound to sex hormone-binding globulin (SHBG), which, in men, also is called testosterone-binding globulin. A lesser fraction is albumin bound and a small proportion exists as free hormone. Historically, only free testosterone was thought to be the biologically active component. However, testosterone is weakly bound to serum albumin and dissociates freely in the capillary bed, thereby becoming readily available for tissue uptake. All non-SHBG bound testosterone is therefore considered bioavailable.

During childhood, excessive production of testosterone induces premature puberty in boys and masculinization in girls. In women, excess testosterone production results in varying degrees of virilization, including hirsutism, acne, oligo-amenorrhea, or infertility. Mild-to-moderate testosterone elevations are usually asymptomatic in male individuals but can cause distressing symptoms in female patients. The exact causes for mild-to-moderate elevations in testosterone often remain obscure. Common causes of pronounced elevations of testosterone include genetic conditions (eg, congenital adrenal hyperplasia), adrenal, testicular, and ovarian tumors, and abuse of testosterone or gonadotrophins by athletes.

Decreased testosterone in female individuals causes subtle symptoms. These may include some decline in libido and nonspecific mood changes. In male patients, it results in partial or complete degrees of hypogonadism. This is characterized by changes in male secondary sexual characteristics and reproductive function. The cause is either primary or secondary/tertiary (pituitary/hypothalamic) testicular failure. In men, there also is a gradual, modest but progressive, decline in testosterone production starting between the 4th and 6th decade of life. Since this is associated with a simultaneous increase of SHBG levels, bioavailable testosterone may decline more significantly than apparent total testosterone, causing nonspecific symptoms similar to those observed in testosterone-deficient women. However, severe hypogonadism, consequent to aging, alone is rare.

Measurement of total testosterone (TTST / Testosterone, Total, Mass Spectrometry, Serum) is often sufficient for diagnosis, particularly if it is combined with measurements of LH (LH / Luteinizing Hormone [LH], Serum) and follicle stimulating hormone (FSH / Follicle-Stimulating Hormone [FSH], Serum). However, these tests may be insufficient for diagnosis of mild abnormalities of testosterone homeostasis, particular if abnormalities in SHBG (SHBG1 / Sex Hormone-Binding Globulin [SHBG], Serum) function or levels are present. Additional measurements of bioavailable (this test) or free testosterone (TGRP / Testosterone, Total and Free, Serum) are recommended in this situation. While both bioavailable and free testosterone can be used for the same indications, determination of bioavailable testosterone levels may be superior to free testosterone measurement in most situations.

Interpretation

Total testosterone and general interpretation of testosterone abnormalities:

Decreased testosterone levels indicate partial or complete hypogonadism. In hypogonadism, serum testosterone levels are usually below the reference range. The cause is either primary or secondary/tertiary (pituitary/hypothalamic) testicular failure.

Primary testicular failure is associated with increased luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and decreased total, bioavailable, and free testosterone levels. Causes include:

-Genetic causes (eg, Klinefelter syndrome, XXY males)

-Developmental causes (eg, testicular maldescent)

-Testicular trauma or ischemia (eg, testicular torsion, surgical mishap during hernia operations)

-Autoimmune diseases (eg, autoimmune polyglandular endocrine failure)

-Metabolic disorders (eg, hemochromatosis, liver failure)

Secondary/tertiary hypogonadism, also known as hypogonadotrophic hypogonadism, shows low testosterone and low, or inappropriately “normal,” LH/FSH levels. Causes include:

-Inherited or developmental disorders of hypothalamus and pituitary (eg, Kallmann syndrome, congenital hypopituitarism)

-Medical or recreational drugs (eg, estrogens, gonadotropin releasing hormone [GnRH] analogs, cannabis)

-In prepubertal boys, increased levels of testosterone are seen in precocious puberty. Further work-up is necessary to determine the cause of precocious puberty.

-In men, testicular or adrenal tumors or androgen abuse might be suspected if testosterone levels exceed the upper limit of the normal range by more than 50%.

Monitoring of testosterone replacement therapy:

Aim of treatment is normalization of serum testosterone and LH. During treatment with depot-testosterone preparations, trough levels of serum testosterone should still be within the normal range, while peak levels should not be significantly above the normal young adult range.

Aim is usually to suppress testosterone levels to castrate levels or below (no more than 25% of the lower reference range value).

Decreased testosterone levels may be observed in primary or secondary ovarian failure, analogous to the situation in men, alongside the more prominent changes in female hormone levels. Most women with oophorectomy have a significant decrease in testosterone levels.

Increased testosterone levels may be seen in:

-Congenital adrenal hyperplasia: Non-classical (mild) variants may not present in childhood but during or after puberty. In addition to testosterone, multiple other androgens or androgen precursors, such as 17 hydroxyprogesterone (OHPG / 17-Hydroxyprogesterone, Serum), are elevated, often to a greater degree than testosterone.

– Prepubertal girls: analogous to boys, but at lower levels, increased levels of testosterone are seen in precocious puberty.

-Ovarian or adrenal neoplasms: High estrogen values also may be observed and LH and FSH are low or “normal.” Testosterone-producing ovarian or adrenal neoplasms often produce total testosterone values above 200 ng/dL.

-Polycystic ovarian syndrome: Hirsutism, acne, menstrual disturbances, insulin resistance, and, frequently, obesity form part of this syndrome. Total testosterone levels may be normal or mildly elevated and uncommonly exceed 200 ng/dL.

Monitoring of testosterone replacement therapy:

The efficacy of testosterone replacement in females is under study. If it is used, then levels should always be kept within the normal female range. Bioavailable (this test) or free testosterone (TGRP / Testosterone, Total and Free, Serum) levels should also be monitored to avoid overtreatment.

Antiandrogen therapy is most frequently employed in the management of mild-to-moderate idiopathic female hyperandrogenism, as seen in polycystic ovarian syndrome. Total testosterone levels are a relatively crude guideline for therapy and can be misleading. Therefore, bioavailable (this test) or free testosterone (TGRP / Testosterone, Total and Free, Serum) also should be monitored to ensure treatment adequacy. However, there are no universally agreed biochemical end points and the primary treatment end point is the clinical response.

Usually, bioavailable (and free testosterone) levels parallel the total testosterone levels. However, a number of conditions and medications are known to increase or decrease the sex hormone-binding globulin (SHBG) concentration, which may cause total testosterone concentration to change without necessarily influencing the bioavailable or free testosterone concentration, or vice versa:

-Treatment with corticosteroids and sex steroids (particularly oral conjugated estrogen) can result in changes in SHBG levels and availability of sex-steroid binding sites on SHBG. This may make diagnosis of subtle testosterone abnormalities difficult.

-Inherited abnormalities in SHBG binding.

-Liver disease and severe systemic illness.

-In pubertal boys and adult men, mild decreases of total testosterone without LH abnormalities can be associated with delayed puberty or mild hypogonadism. In this case, either bioavailable or free testosterone measurements are better indicators of mild hypogonadism than determination of total testosterone levels.

-In polycystic ovarian syndrome and related conditions, there is often significant insulin resistance, which is associated with low SHBG levels. Consequently, bioavailable or free testosterone levels may be more significantly elevated.

Either bioavailable (this test) or free testosterone (TGRP / Testosterone, Total and Free, Serum) should be used as supplemental tests to total testosterone in the above situations. The correlation coefficient between bioavailable and free testosterone (by equilibrium dialysis) is 0.9606. However, bioavailable testosterone is usually the preferred test, as it more closely reflects total bioactive testosterone, particularly in older men. Men at this agehave elevated SHBG levels and may also have varying albumin levels due to coexisting illnesses.

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