• Primary: menses does not begin by age 16 yr (or if patient misses important pubertal milestones, e.g., no breast development by age 14 yr)
  • Most common causes
    • Gonadal dysgenesis resulting from chromosome abnormality
    • Physiologic delay of puberty
    • Müan agenesis
    • Obstructed outflow
    • Absence of GnRH secretion
  • Secondary (adult onset): previously menstruating woman has no menses for > 3 cycles or for 6 mo
    • In nonpregnant women, most common causes of secondary amenorrhea
      • Hypothalamic dysfunction (low GnRH secretion associated with stress, intensive exercise, low body mass index (BMI), low-fat diet, or combination of these)
      • Pituitary dysfunction (prolactin-secreting pituitary tumor, empty sella syndrome, Sheehan syndrome, Cushing disease, or GH-secreting tumor)
      • Loss of ovarian follicles (premature ovarian failure)
      • Polycystic ovary syndrome
      • Asherman syndrome (intrauterine adhesions)
      • Thyroid disease

Primary Amenorrhea

• Serum FSH
• Breast exam
• Pelvic ultrasound or MRI to determine presence of cervix and uterus
  • Elevated FSH level indicates gonadal dysgenesis; obtain karyotype for presence of Y chromosome
  • Normal FSH level, no breast development, normal uterus: consider hypothalamic and pituitary causes of amenorrhea (see Low GnRH Secretion and Pituitary Dysfunction, below); refer to endocrinologist
  • Normal FSH level, normal breast development, normal uterus: workup for secondary amenorrhea (see Secondary Amenorrhea, below)
  • Normal FSH level, normal breast development, but blood present in uterus or vagina indicate obstructed outflow
  • Normal FSH level, normal breast development, but no uterus
    • Measure testosterone level
      • Testosterone in female range indicates Müan agenesis
      • Testosterone in male range indicates androgen insensitivity

Secondary Amenorrhea

• Serum human chorionic gonadotropin (hCG)
• Serum prolactin
• Serum FSH
• Serum testosterone
• Calculate BMI
  • Negative hCG, abnormal BMI: evaluate diet and nutritional status
  • Negative hCG, elevated prolactin: rule out hypothyroidism, drug reactions, renal failure (see Pituitary Dysfunction, below)
  • Negative hCG, elevated FSH: evaluate for premature ovarian failure (see Premature Ovarian Failure, below)
  • Negative hCG, elevated testosterone: evaluate for hyperandrogenism/polycystic ovary syndrome (see Hyperandrogenism and Polycystic Ovary Syndrome (PCOS), below)
  • Normal hCG, prolactin, FSH levels plus history of D&C: evaluate for Asherman syndrome (see Asherman syndrome (Intrauterine Adhesions), below)

Clinical Pearls

• Rule out pregnancy in sexually active women
• Reassure women that workup not necessary before 6 mo of amenorrhea, once pregnancy has been excluded

Low GnRH Secretion

• Perform progestin withdrawal test to determine severity of hypoestrogenism
  • Administer medroxyprogesterone acetate, one 10 mg tablet/day for 5 days
  • Test is positive if menses starts within 10 days of completing therapy; patient is producing sufficient estrogen to cause some endometrial growth
  • Test is negative if menses does not start within 10 days; patient produces no estrogen or has Asherman syndrome

Pituitary Dysfunction

Prolactin-Secreting Pituitary Tumors

• MRI scan of hypothalamus and pituitary to confirm prolactinoma
• If pituitary tumor is present, measure serum insulin-like growth factor-1 (IGF-1)

Empty Sella Syndrome (can cause hypopituitarism and amenorrhea by compression of pituitary

• High-resolution MRI or CT of pituitary

Sheehan Syndrome (hypothalamic and pituitary dysfunction following obstetric hemorrhage and hypotension at delivery)

• Administer thyrotropin-releasing hormone, 100 µg I.V., and measure prolactin at 0 and 30 min
• If ratio of prolactin at 30 min to that at 0 min is <3, evaluate for panhypopituitarism

Premature Ovarian Failure

• Measure serum FSH levels three times, 1 mo apart; complete ovarian failure marked by levels > 25 U/L on three tests

Hyperandrogenism and Polycystic Ovary Syndrome (PCOS)

• Androgen-secreting tumors associated with serum testosterone levels > 200 ng/dl
• PCOS associated with serum testosterone levels of 50-150 ng/dl
• Measure 17-hydroxyprogesterone level at 8 A.M.
  • Level > 4 ng/ml diagnostic of nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency
  • Level < 4 ng/ml excludes nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency
• Ultrasound showing multiple small ovarian follicles (> 10 per ovary) supports PCOS diagnosis

Asherman Syndrome (Intrauterine Adhesions)

• Administer conjugated estrogens, 2.5 mg x 35 days, plus medroxyprogesterone acetate, 10 mg/day on days 26-35; absence of withdrawal bleeding after challenge suggests Asherman syndrome, which can be confirmed radiologically or by hysteroscopy

Primary Amenorrhea

• Gonadal dysgenesis: if Y chromosome is present, ovaries should be removed to prevent malignancy
• Müan agenesis: surgical construction of a new vagina
• Androgen insensitivity: surgical removal of gonads after puberty
• Obstructed outflow: surgery

Secondary Amenorrhea

Low GnRH Secretion

• Reduce psychosocial stress, gain weight, lower exercise intensity
• Oral contraceptives
• Low-dose hormone replacement (conjugated estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg/day) or cyclic hormone replacement
• Vitamin D, 400 IU/day, and calcium, 1,200?1,500 mg/day, to slow decline in bone mineral density

Pituitary Dysfunction

Prolactin-Secreting Pituitary Tumors

• Drug comparison
  • Low-dose oral contraceptives (any standard contraceptive dose): can initiate withdrawal bleeding and prevent osteoporosis; not associated with tumor growth
  • Dopamine agonists: for women who wish to become pregnant; measure serum prolactin levels 1 mo after initiation or change in dose or drug; if prolactin level is normal, continue initial dosage (if not, increase dose gradually); GI side effects (nausea/vomiting) most common reason for discontinuing medication; excellent efficacy
    • Bromocriptine
      • Dose: start at 1.25 mg at bedtime; after 1 wk, 1.25 mg b.i.d; then 2.5 mg b.i.d (max, 5 mg b.i.d); use vaginal administration if oral is not tolerated
      • Cost/mo: 2.5 mg b.i.d: $123.98
    • Cabergoline
      • Dose: start at 0.5 mg once a week; then 1 mg once or twice a week (max, 1.5 mg 2-3 times per wk)
      • Cost/mo: 2 mg/wk: $465.95

If medical therapy fails, surgical removal of the tumor is indicated

Empty Sella Syndrome

• Specific replacement of documented hormonal abnormalities

Sheehan Syndrome

• Specific replacement of documented hormonal abnormalities

Premature Ovarian Failure

• No proven therapy
• Estrogen-progestin therapy to prevent osteoporosis

Hyperandrogenism and Polycystic Ovary Syndrome (PCOS)

• PCOS: oral contraceptives to suppress ovarian androgen secretion
• Adrenal hyperplasia: low-dose glucocorticoids to suppress adrenal androgen production

Asherman Syndrome

• Surgical lysis of intrauterine adhesions, then stimulation of endometrial growth with estrogen

Laughlin, et al: J Clin Endocrinol Metab 83:25, 1998

Perkins, et al: Hum Reprod 16:2198, 2001

Perkins, et al: J Clin Endocrinol Metab 84:1905, 1999

Reindollar, et al: Am J Obstet Gynecol 155:531, 1986

Warren: J Clin Endocrinol Metab 75:1393, 1992