Clinical Tests> Endocrine>

DESCRIPTION

• Testosterone (T) and estradiol (E2) have important metabolic actions which are gender-specific (sex-dimorphic).
• Most T and E2 circulate bound to sex hormone-binding globulin (SHBG), a glycoprotein that regulates the amount of sex steroids available for biological action.
• Of total T, 54% weakly bound to albumin and other proteins, 44% bound to SHBG, 2% unbound (free T) (Dunn).
• In reproductive age women, one third of T is secreted by the ovary, whereas two thirds arise from the peripheral conversion of androstenedione to T.
• Androstenedione directly produced by the ovary but also from peripheral conversion of adrenal dehydroepiandrosterone sulfate (DHEA-S).
• Male Hypogonadism (for example, with androgen deprivation therapy for prostate cancer) is linked to the metabolic syndrome, type 2 diabetes and an increased risk for cardiovascular disease (Basari).
• Hyperandrogenism in women (for example, with polycystic ovarian syndrome) is linked to the metabolic syndrome, type 2 diabetes and cardiovascular disease (Moran). High T in postmenopausal women is also linked to an increased risk of type 2 diabetes (Ding, Kalyani).
• High endogenous E2 is associated with an increased risk for type 2 diabetes in males and postmenopausal women (Ding, Kalyani).
• Low SHBG is a risk factor for type 2 diabetes in both males and females (Ding).

ASSAYS

• Total testosterone: commonly measured using chemiluminescence immunoassay or radioimmunoassay; gold standard is liquid chromatography tandem mass spectrometry (LC-MS). LC-MS is especially helpful in cases of low T concentration, for example in females and pre-pubertal individuals, as the immunoassays perform poorly at low T concentrations (Wang).
• Bioavailable testosterone: represents biologically active T, includes both free T and albumin-bound T. Calculated based on the binding of T to SHBG and albumin. Also, measured directly by the ammonium sulfate precipitation method, which precipitates SHBG and SHBG-bound T.
• Free testosterone: gold standard is direct measurement by equilibrium dialysis. Can also be calculated based on total T and SHBG using method validated by Vermeulen (Vermeulen).
• Estradiol: commonly measured using chemiluminescence immunoassay or radioimmunoassay, but gold standard also LC-MS (Kushnir).
• SHBG: chemiluminescence immunoassay, radioimmunassay, ammonium sulfate precipitation method
• DHEA-S: biologically inert steroid produced by the adrenals that becomes active after being converted to androstenedione and then T in the periphery. Measured with chemiluminescence immunoassay, radioimmunassay, or LC-MS.
• LH and FSH: measured using chemiluminescence immunoassay or radioimmunoassay

INDICATIONS

• Male hypogonadism: sexual dysfunction (including erectile dysfunction), muscle weakness, depression, cognitive decline, osteoporosis. Measure morning total (and free) T, on two different occasions. LH and FSH should be checked to differentiate primary versus secondary hypogonadism.
• Female menstrual cycle disturbances: irregular menses or amenorrhea, subfertility, and signs of hyperandrogenism (as in suspected PCOS). Measure total T, DHEA-S, LH, FSH, prolactin, E2 and thyroid function tests.
• Moderate to severe hirsutism: measure total T, free T, and DHEA-S.
• Postmenopausal status: measure FSH
• May check T in the workup of ED if hypogonadism is a consideration.

DIFFERENTIAL DIAGNOSIS

• SHBG decreased in: obesity, hyperinsulinemia (i.e. type 2 diabetes), liver disease, androgen excess, hypothyroidism, glucocorticoid use, nephrotic syndrome
• SHBG increased in: aging, hyperthyroidism, estrogen use, chronic inflammatory states
• T increased in: ovarian tumors, hyperthecosis, adrenocortical carcinoma, nonclassical congenital adrenal hyperplasia
• T decreased in: aging, androgen deprivation therapy, type 2 diabetes (Dhindsa)
• E2 increased in: pregnancy, ovarian sex-cord stromal tumor
• E2 decreased in: menopause, amenorrhea
• LH and FSH increased in: primary hypogonadism, menopause
• LH and FSH decreased in: secondary hypogonadism
• DHEA-S increased in: PCOS, adrenocortical carcinoma

INTERPRETATION

• High T or DHEA-S, low FSH/LH: androgen producing tumor
• High T and DHEA-S, elevated LH/FSH ratio: Consistent with PCOS but not a requirement for the diagnosis.
• Low T, high FSH/LH: primary male hypogonadism, which can be in seen in the setting of type 2 diabetes
• Low T, low FSH/LH: secondary male hypogonadism, more commonly seen in type 2 diabetes
• Low E2, high FSH/LH: primary female hypogonadism, menopause
• Low E2, low FSH/LH: secondary female hypogonadism
• High E2, low FSH/LH: pregnancy, ovarian sex-cord stromal tumor

LIMITATIONS OR CONFOUNDERS

• T levels should be obtained at about 8 am, since there is diurnal variation and the highest levels occurring in the morning.
• In women of childbearing age, E2 is lowest in the early follicular phase and highest in the mid cycle.

EXPERT COMMENTS

• Total T (by immunoassay or LC-MS) is an adequate test to evaluate male hypogonadism in individuals with type 2 diabetes who are not overweight.
• In the setting of overweight/obesity, check free and total T and SHBG levels when considering male hypogonadism. Free T to be checked by equilibrium dialysis or by the Vermeulen method.
• Although male hypogonadism is common in type 2 diabetes, T replacement is not generally recommended, unless symptoms are present, and treatment needs to be individualized.
• Measurement of sex hormones for the assessment of diabetes risk in postmenopausal women is still reserved for research.  

REFERENCES