Measurement of total testosterone (TTST / Testosterone, Total, Serum) is often sufficient for diagnosis, particularly if it is combined with measurements of LH and follicle-stimulation hormone (FSH) (LH / Luteinizing Hormone [LH], Serum and FSH / Follicle-Stimulating Hormone [FSH], Serum). However, these tests may be insufficient for diagnosis of mild abnormalities of testosterone homeostasis, particularly if abnormalities in SHBG (SHBG / Sex Hormone Binding Globulin [SHBG], Serum) function or levels are present. Additional measurements of free testosterone or bioavailable testosterone are recommended in this situation; bioavailable testosterone (see TTBS / Testosterone, Total and Bioavailable, Serum) is the preferred assay.
Total Testosterone and General Interpretation of Testosterone Abnormalities:
Males:
Decreased testosterone levels indicate partial or complete 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, XX males)
-Developmental causes (eg, testicular maldescent)
-Testicular trauma or ischemia (eg, testicular torsion, surgical mishap during hernia operations)
-Infections (eg, mumps)
-Autoimmune diseases (eg, autoimmune polyglandular endocrine failure)
-Metabolic disorders (eg, hemochromatosis, liver failure)
-Orchidectomy
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)
-Pituitary or hypothalamic tumors
-Hyperprolactinemia of any cause
-Malnutrition or excessive exercise
-Cranial irradiation
-Head trauma
-Medical or recreational drugs (eg, estrogens, GNRH analogs, cannabis)
Increased testosterone levels:
-In prepubertal boys, increased levels of testosterone are seen in precocious puberty. Further workup is necessary to determine the cause(s) of precocious puberty
-In adult 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.
Bioavailable and Free Testosterone:
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 SHBG (SHBG / Sex Hormone Binding Globulin [SHBG], Serum) 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 (TTBS / Testosterone, Total and Bioavailable, Serum) or free (TGRP / Testosterone Total and Free, Serum) testosterone 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. Older men not only have elevated SHBG levels, but albumin levels also may vary due to coexisting illnesses.