Diagnosis:
Secondary amenorrhea and hyperprolactinemia
• Secondary amenorrhea is defined as the absence of menstruation for more than three cycles or six months in a woman who previously has had menses.
• Excluding pregnancy, the causes of secondary amenorrhea can be classified into five main groups:
• Hypogonadotropic hypogonadism (low/normal follicle-stimulating hormone [FSH]; about 46% of the cases);for example, malnutrition, anorexia, depression, chronic anovulation, hypothyroidism, Cushing’s syndrome, and hypothalamic and pituitary lesions.
• Hypergonadotropic hypogonadism (high FSH; about 12%); for example, premature ovarian failure, autoimmune oophoritis, 46, XY karyotype, and fragile X syndrome.
• Hyperprolactinemia (13%).
• Anatomic (Asherman’s syndrome, 7%).
• Hyperandrogenic states (22%); for example, polycystic ovarian syndrome (PCOS), ovarian tumors, and late-onset congenital adrenal hyperplasia.
• The initial laboratory tests for evaluation of secondary amenorrhea should include FSH, luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin levels.
• Hyperprolactinemia can usually be explained by one of these mechanisms:
1. Physiologic stimulation of prolactin secretion; for example, pregnancy, high estrogen, stress, meals, sleep, sexual intercourse, nipple stimulation
2. Decreased dopaminergic inhibition of prolactin secretion:
a. Damage to hypothalamus or pituitary (e.g., tumors, neurosarcoidosis, trauma, surgery, non-lactotroph adenomas).
b. Drugs interfering with dopaminergic pathways (e.g., antipsychotics, metoclopramide, methyldopa, reserpine, verapamil, selective serotonin uptake inhibitors).
3. Prolactin-secreting tumor: pituitary lactotroph adenomas.
4. Miscellaneous pathologic causes: hypothyroidism, chest wall injury, chronic renal failure.
5. Macroprolactinemia: prolactin complexed with immunoglobulins (or rarely polymers of prolactin ranging up to 500 kDa) causes decreased renal clearance and elevated concentrations of nonfunctional prolactin.
• Because a large number of physiologic variables and medications can raise prolactin levels, it is recommended that prolactin testing be repeated to confirm of the increased level. It is also recommended to treat the serum with a method that removes macroprolactin (either gel-filtration or polyethylene glycol precipitation) in samples with prolactin levels higher than 90 to 100 ng/mL.
• In women with persistent hyperprolactinemia, the prevalence of a pituitary tumor is approximately 50% to 60%, justifying follow-up with imaging. Microadenomas (<1cm) usually have levels below 200 ng/mL, whereas macroadenomas (>2cm) typically present with levels above 1000 ng/mL.
• The hook effect occurs when very high levels of prolactin overwhelm the binding capacity of the reagent antibodies in the immunoassay, causing single antibody-antigen complexes instead of the required “sandwich” (capture antibody-antigen-detection antibody) and a falsely low result. Serial dilution of the antigen before adding the reagents is required to accurately determine the antigen concentration.
