Secondary amenorrhea is defined as the absence of menses for 3 consecutive months in women who have passed menarche. Menopause is defined as the terminal episode of naturally occurring menses; it is a retrospective diagnosis, usually made after 6 months of amenorrhea.
The causes of secondary amenorrhea include pregnancy, hypothalamic-pituitary causes, hyperandrogenism, uterine causes, premature ovarian failure, and menopause.
Pregnancy is the most common cause for secondary amenorrhea in premenopausal women. The differential diagnosis includes rare ectopic secretion of hCG by a choriocarcinoma or bronchogenic carcinoma.
B. Hypothalamic-Pituitary Causes (With Low or Normal FSH)
The hypothalamus must release GnRH in a pulsatile manner for the pituitary to secrete gonadotropins. GnRH pulses occurring more than once per hour favor LH secretion, while less frequent pulses favor FSH secretion. In normal ovulatory cycles, GnRH pulses in the follicular phase are rapid and favor LH synthesis and ovulation; ovarian luteal progesterone is then secreted that slows GnRH pulses, causing FSH secretion during the luteal phase. Most women with hypothalamic amenorrhea have a persistently low frequency of GnRH pulses.
Secondary “hypothalamic” amenorrhea may be caused by stressful life events such as school examinations or leaving home. Such women usually have a history of normal sexual development and irregular menses since menarche. Amenorrhea may also be the result of strict dieting, vigorous exercise, organic illness, or anorexia nervosa. Intrathecal infusion of opioids causes amenorrhea in most women. These conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. Young women in whom the results of evaluation and progestin withdrawal test are normal have noncyclic secretion of gonadotropins resulting in anovulation. Such women typically recover spontaneously but should have regular evaluations and a progestin withdrawal test about every 3 months to detect loss of estrogen effect.
PRL elevation due to any cause may cause amenorrhea. Pituitary tumors or other lesions may cause hypopituitarism. Corticosteroid excess of any cause suppresses gonadotropins.
C. Hyperandrogenism (With Low-Normal FSH)
Elevated serum levels of testosterone can cause hirsutism, virilization, and amenorrhea. In PCOS, GnRH pulses are persistently rapid, favoring LH synthesis with excessive androgen secretion; reduced FSH secretion impairs follicular maturation. Progesterone administration can slow the GnRH pulses, thus favoring FSH secretion that induces follicular maturation. Rare causes of secondary amenorrhea include adrenal P450c21 deficiency, ovarian or adrenal malignancies, and Cushing syndrome. Anabolic steroids also cause amenorrhea.
D. Uterine Causes (With Normal FSH)
Infection of the uterus commonly occurs following delivery or D&C but may occur spontaneously. Endometritis due to tuberculosis or schistosomiasis should be suspected in endemic areas. Endometrial scarring may result, causing amenorrhea (Asherman syndrome). Such women typically continue to have monthly premenstrual symptoms. The vaginal estrogen effect is normal.