Early morning testosterone levels in young male individuals are, on average, 50% higher than p.m. levels. Reference values were established using specimens collected in the morning.
Testosterone levels can fluctuate substantially between different days, and sometimes even more rapidly. Assessment of androgen status should be based on more than a single measurement.
The low end of the normal reference range for total testosterone in prepubertal subjects is not yet established.
While free testosterone can be used for the same indications as bioavailable testosterone, determination of bioavailable testosterone levels may be superior to free testosterone measurement in most situations.
Total testosterone and general interpretation of testosterone abnormalities:
In male patients:
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, XXY 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)
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
-Medical or recreational drugs (eg, estrogens, gonadotropin releasing hormone [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 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.
Monitoring of antiandrogen therapy:
Aim is usually to suppress testosterone levels to castrate levels or below (no more than 25% of the lower reference range value).
In female patients:
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 are elevated, such as 17 hydroxyprogesterone (OHPG / 17-Hydroxyprogesterone, Serum), often to a greater degree than testosterone.
-Prepubertal girls: analogous to males, 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 greater than 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, greater than 200 ng/dL.
The efficacy of testosterone replacement in females is under study. If it is used, total testosterone levels should be kept within the normal female range at all times. Bioavailable or free testosterone levels also should be monitored to avoid overtreatment.
Antiandrogen therapy is most commonly 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 or free testosterone also should be monitored to ensure treatment adequacy. However, there are no universally agreed biochemical endpoints and the primary treatment end point is the clinical response.
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 or free 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.