Testosterone, Adult Male (TESTO)

EPIC Test Name

TESTOSTERONE TOTAL MALE

EPIC Code

LAB2562

Clinical Indications

Testosterone, an androgenic hormone and a precursor of estrogen, is biosynthesized and secreted primarily by the Leydig cells located of the testes in men, where it is bound to Androgen Binding Protein (ABP) secreted by the Sertoli cells of the testes to maintain its high concentration that is needed for spermatogenesis and sperm maturation process. Testosterone secretion is regulated via the Hypothalamic-Pituitary-Testicular Axis, in which GnRH stimulates FSH and LH. Both FSH and LH are secreted in pulsatile pattern and with circadian rhythm. LH stimulates Leydig cells to produce testosterone; FSH acts on Sertoli cells regulates production of ABP and inhibin B. A negative feedback of the Axis is achieved via androgens and Inhibin B. Testosterone also functions in the development of external genitalia and secondary sexual characteristics in men.

In the circulation, Testosterone exists in different forms. They are free testosterone accounting for about 2% of total testosterone, tightly bound to Sex Hormone Binding Globulin (SHBG, about 60%), and weakly bound to albumin (remaining fraction). The term of “Bioavailable testosterone” stands for a sum of free and albumin fractions (Free + albumin bound). Both ABP and SHBG share the same amino acid sequence of a gene product at chromosome 17, but there are differences. SHBG is synthesized at the liver, and its concentration is increased by estrogen (during pregnancy) and excess of thyroid hormones (hyperthyroidism), and decreased by exogenous androgens, and glucocorticoids, GH, liver disease, hypothyroidism and is invers-relationship with insulin concentration. Therefore, in these conditions, total testosterone concentrations in the circulation or serum/plasma samples can be affected, but the free testosterone concentration may not.

In evaluation of hirsutism and virilization in women, tests for testosterone and DHEA-S are recommended. Elevated DHEA-S level suggests an adrenal origin of androgens, whereas increased testosterone indicates an adrenal or ovarian origin.

In men, causes of testosterone level abnormalities can occur during embryo phase or before birth, childhood and adulthood, leading to a variety of clinical presentations.
• Hypogonadotropic Hypogonadism occurs when defects in the hypothalamus or pituitary causing lack of normal gonadal stimulation. Causes may include congenital or acquired panhypopituitarism, hypothalamic syndromes, GnRH deficiency, hyperprolactinemia, malnutrition or anorexia, and iatrogenic causes. All are associated with decreased testosterone and gonadotropin concentrations. Kallmann syndrome, for example, is the most common form of hypogonadotropic hypogonadism due do GnRH deficiency. It is inherited as an autosomal dominant trait with characteristics of hypogonadism and anosmia (loss of the sense of smell).
• Hypergonadotropic hypogonadism occur due to defects at the primary gonadal origin, characterized with increase of LH and FSH concentrations and decrease of testosterone concentrations. Its causes can be acquired (e.g., irradiation, castration, mumps orchitis, or cytotoxic drugs), inherited (Klinefelter syndrome), defective in testosterone biosynthesis (20α-hydroxylase deficiency), due to testicular agenesis or seminiferous tubular disease, and other miscellaneous causes (e.g., aging).
• Defects in androgen action or androgen insensitivity syndrome (AIS) are caused by mutations in the androgen receptor gene. Patients with complete AIS have a male karyotype (46,XY) but with female external genitalia (labia, clitoris, and vaginal opening) and testes intraabdominally. Such patients have no uterus, fallopian tubules, or proximal vagina due to effect of anti-Müllerian hormone (AMH) with testosterone concentrations increased or within reference range, and elevated LH.
• Patients with 5α-reductase deficiency have high values of the ratios of testosterone to dihydrotestosterone (DHT) and infant males are born with ambiguous genitalia. Measurements of testosterone after stimulation with hCG can be used to assess if patients with cryptorchidism or ambiguous genitalia have testicular tissue in the body. HCG stimulates Leydig cell if presence to produce testosterone.
• Measurement of morning testosterone together with LH, and thyroid-stimulating hormone (TSH) is recommended for male patients with Erectile dysfunction or impotence after rule out possible causes associated with psychologic factors, neuropathy, or vascular abnormalities, diabetes mellitus, hypertension, uremia, hypogonadism, hyper- and hypothyroidism, neoplasms, and certain medications. Elevated LH and FSH suggest primary hypogonadism, while as testosterone concentration may be within reference intervals, yet still may be subnormal for a given patient with elevated LH or FSH. In rare situations, hyperprolactinemia can be an infrequent cause of erectile dysfunction. Sildenafil, Viagra, or Revatio is FDA approved for treatment for male erectile dysfunction. The drugs are phosphodiesterase 5 (PDE5) inhibitor. Inhibition of PDE5 in the corpus cavernosum of the penis blocks degradation of cGMP resulting in relaxation of vascular smooth muscle and increase inflow of blood.
• Gynecomastia is associated with an increased ratio of estrogen over androgen. Transient gynecomastia occurs to most newborns caused by high estrogen concentrations from mother. Gynecomastia in puberty occurs to most of normally developed boys due to relatively low production of androgens and it is usually self-limited. Gynecomastia in adult occurs most in age of 50 - 80 years, often due to testicular insufficiency or failure, resulting in a rise of estrogen/androgen ratio, or of increased body fat, a peripheral tissue where aromatization of testosterone to estradiol takes place. Pathologically, Gynecomastia can develop as the result of iatrogenic causes, hyperthyroidism, or liver disease. Patients with liver diseases can have impaired estrogen clearance and SHBG production resulting in an increase of bioavailable estrogen. Germinal cell or nonendocrine tumors that produce hCG which stimulates testicular aromatase activity, therefore, estrogen production. Estrogen-producing tumors in adrenal glands, the testes, or the liver, cause gynecomastia. In assisting diagnosis of gynecomastia, testing for testosterone, estradiol, hCG, and LH are recommended. It is worth of notice that elevated prolactin of prolactinoma patients also have gynecomastia, but as a subsequence of galactorrhea.

Additional Information

Testosterone secretion is affected by circadian rhythm, early morning testosterone levels can be about 50% higher than late evening in young males, and such effect is not seen in older males.

Interpretative Information

Decreased testosterone levels, and elevated LH and FSH levels indicate Hypergonadotropic Hypogonadism, or primary testicular failure. The causes may include:
• Acquired conditions (irradiation, mumps orchitis, castration, testicular trauma or ischemia, and cytotoxic drugs)
• Inherited genetic disorders, e.g., Klinefelter syndrome (47,XXY) and mosaics
• Defective androgen biosynthesis, e.g., 17,20-Lyase deficiency
• Testicular agenesis and streak gonads
• Selective seminiferous tubular disease
• Miscellaneous or others

Low testosterone, and low or inappropriately "normal" LH and FSH levels indicate Hypogonadotropic Hypogonadism or secondary/tertiary hypogonadism. Causes may include:
• Panhypopituitarism (congenital or acquired, e.g., cranial irradiation, head trauma)
• Hypothalamic syndrome (acquired or congenital)
• Structural defects (neoplastic, inflammatory, and infiltrative)
• Prader-Willi syndrome
• Laurence-Moon-Biedl syndrome
• GnRH deficiency (Kallmann syndrome)
• Hyperprolactinemia (prolactinoma or drugs)
• Malnutrition and anorexia nervosa
• Drug-induced suppression of luteinizing hormone (androgens, estrogens, tranquilizers, antidepressants, antihypertensives, barbiturates, cimetidine, GnRH analogs, and opiates)

Elevated testosterone levels can be seen in the followings:
• Precocious puberty in prepubertal boys. Further work-up is needed for the cause(s). Elevated testosterone levels are seen in precocious puberty in girls, but at lower levels.
• In men, testosterone levels > upper limit of the reference range by > 50% indicate possible presence of testicular or adrenal tumors, or androgen abuse.
• Congenital adrenal hyperplasia (CAH), where 17-hydroxyprogesterone is elevated more significantly than testosterone. This is usually identified by newborn screening program.
• Testosterone-producing ovarian in women or adrenal neoplasms. Elevated estrogen values may also occur with LH and FSH at low or "normal" range.
• Testosterone levels within reference range or mildly elevated can be seen in patients with polycystic ovarian syndrome.

CPT

84403

LOINC

2986-8

References

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Contact Information

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