I. Normal menstrual endocrinology:

  1. Hypothalamus secretes GnRH in a pulsatile fashion
  2. Which stimulates ant. pit to secrete LH & FSH
  1. n.b. if pituitary is exposed to GnRH in a constant, nonpulsatile fashion, secretion of FSH/LH goes DOWN!
  1. Which causes follicles to mature, secreting estrogen & progesterone
  2. Ovulation follows, and if no fertilization, drop in progesterone & menses
  3. Normal menstruation requires
  1. Normally functioning hypothalamic-pituitary-ovarian ("HPO") axis
  2. Responsive endometrium
  3. Unobstructed outflow tract

II. Definition of amenorrhea requiring w/u:

  1. No secondary sexual characteristics or menses by 14yo ("primary" amenorrhea)
  2. No menses by 16 yo ("primary" amenorrhea)
  3. No period x 3 cycles or 6 mos, whichever sooner, in a woman with previous menses ("secondary" amenorrhea)

III. Epidemiology

  1. Primary amenorrhea: 0.3% prevalence
  2. Secondary amenorrhea: 1-3% prevalence

IV. Etiology

  1. Hypothalamic causes (disordered GnRH secretion)
  1. Hyperprolactinemia (inhibits pulsatile GnRH release)
  2. Prolonged intense exercise
  3. Eating disorders
  4. Physiologic stress e.g. from chronic illness including Celiac Disease
  5. Weight loss
  6. Kallman's syndrome (congenital hyogonadotrophic hypogonadism ass'd with anosmiawith absent olfactory sulci; very rare)
  1. Pituitary causes
    1. Sheehan's syndrome (panhypopituitarism from acute necrosis of pituitary us. due to postpartum hemorrhage)
    2. Pituitary tumors
  1. Outflow tract causes
  1. Asherman's (endometrial adhesions from instrumentation, spontaneous abortion, schistosomiasis, or infection)
  2. Mullerian anomaly (e.g. transverse septum in the vagina, Mayer-Rokitansky-Kuster-Hause Sd.-congenital absence of the vagina)
  3. Imperforate hymen
  4. Cervical stenosis
  5. Androgen insensitivity (aka "testicular feminization")
  1. Ovarian causes
    1. Premature ovarian failure from gonadal dysgenesis (46XF, Turner's--46X, Swyer's)
    2. "Resistant ovary syndrome"--resistant to LH/FSH--very rare
    3. Hyperandrogenism with chronic anovulation (aka Polycystic Ovary Syndrome)
  1. Medications
  1. OCP's: if occurs, consider change to different contraceptive method or adding more estrogen, e.g. Premarin 0.625 QD for last 5-7 days of pill cycle
  2. Antipsychotics, inc. all phenothiazines
  3. Antidepressants, inc. tricyclics and MAOIs
  4. Antihypertensives inc. Ca-blockers, Aldomet, Reserpine
  5. Digoxin
  6. Flavenoids
  7. Ovarian toxins (cytoxan, fluorouracin, cisplatin, etc.)
  8. Marijuana

V. Hx

  1. Menstrual Hx: age at menarche, pattern of menses
  1. Events associated with onset of amenorrhea, esp. psychosocial, weigh change, athletics
  1. GYN Hx
  1. STD's
  2. GYN surgery
  3. Pregnancies
  1. Sx of pituitary tumor (galactorrhea, HA, diplopia)
  2. Any endocrine disorders?
  3. Sx of thyroid dysfunction?
  4. Any h/o radiation or chemotherapy?
  5. Meds
  6. Family h/o congenital abnormalities, autoimmune disorders, endocrinopathies, menstrual dysfunction
  7. Sx of hypestrogenemia:
  1. Dyspareunia (from decreased mucus production)
  2. Vasomotor instability
  3. Mood swings

VI. Px

  1. Obesity?
  2. Hyperandrogenism signs: acne, hirsutism, male pattern alopecia, truncal obesity (waist:hip ration > 0.85)
  3. Thyroid exam
  4. Breast Px for galactorrhea
  5. BP
  6. Tanner staging
  7. Striae for hypercortisolism
  8. Pelvic for:
  1. Presence (!) of uterus and ovaries
  2. Vag. walls for estrogen level
  3. Clitoromegaly (>1cm) for hyperandrogenism

VII. Clinical approach (derived from Speroff et al.)

  1. If primary amenorrhea and no secondary sexual characteristics, refer for w/u for congenital abnormalities
  2. INITIAL w/u:
  1. Rule out pregnancy
  2. TSH to r/o hypothyroidism
  3. PRL to r/o hyperprolactinemia (2/3 will have no galactorrhea!)
  1. If PRL > 100 mcg/dL or galactorrhea (by hx or px), MRI to r/o Pituitary Adenoma
  2. If PRL elevated but not > 100 mcg/dL, consider:
    1. Liver failure
    2. Renal failure
    3. Side f/x of antidepressants, antipsychotics, antihypertensives, opiate analgesics, or H-2 blockers
    4. Cocaine abuse
  1. If PRL and TSH are normal and pregnancy ruled out, determine level of endogenous estrogen production with progesterone challenge test
  1. Note-If amenorrhea has been prolonged and/or signs of androgen excess:
  1. Consider possibility of endometrial hyperplasia or dysplasia and consider endometrial biopsy before inducing withdrawal bleed
  2. Consider possibility of "decidualization" of endometrium, with adequate circulating estrogen but not w/d bleed after progesterone challenge-occurs in hyperandrogenic states, e.g. adrenal tumors, PCOS; in this case, won't get a w/d bleed after hormonal manipulation
  1. Progesterone challenge test
  1. A way to determine degree of endogenous estrogen production (simpliy checking random serum levels is not helpful)
  2. Provera 10mg QD x 10d or Progesterone in oil 200mg IM x 1
  3. Any uterine bleeding beyond a few drops between 2 and 7 days after completion indicates adequate estrogen production, responsive endometrium, and patent outflow tract; thus, the problem is inadequate progesterone production, presumably due to anovulation
  1. One common cause is Polycystic Ovary Syndrome
  2. Note that anovulatory women are at increased risk for endometrial Ca and perhaps breast Ca; should cycle with hormones to prevent this (see PCOD section)
  1. Lack of bleeding indicates problem with estrogen production, responsiveness endometrium, or patency of outflow tract
  1. If progesterone challenge test yields no bleeding, follow with combined estrogen/progesterone challenge:
  1. This step is sometimes omitted if the patient has normal physical exam and no h/o pelvic infection, trauma, or instrumentation
  2. Premarin 1.25 QD for 21d then Provera 5-10mg QD on last 5d
  3. Bleeding 2-7 days after last dose confirms responsive endometrium and patent outflow tract
  4. Repeat for another month of no bleed
  1. If don't get bleed with estrogen/progesterone challenge, indicates unresponsive endometrium or nonpatent outflow tract (see above)
  1. Consider hysterosalpingogram and possible hysteroscopic adhesolysis (for Asherman's), MRI (for Mullerian abnormality)
  1. If do get bleed with estrogen/progesterone challenge, dx = estrogen deficiency, and must determine location of problem along HPO axis
  1. Check FSH, LH (do so at least 2 weeks after last exogenous hormone administration to results aren't distorted)
  2. If high (FSH > 20 IU/L or LH > 40 IU/L), suggests ovarian failure or absent ovaries
  1. If > 45yo, probably menopause! (will us. see FSH > LH; can also get this from malignancy, e.g. lung, so ask about sx)
  2. If < 40yo, is "premature ovarian failure" (consider working up with calcium, phosphate, serum glucose, thyroid function testing, CBC, ESR, total protein, and rheumatoid factor & ANA to look for autoimmune cause)
  3. Should follow adrenal function, e.g. with a.m. cortisol, b/c can often get adrenal failure following premature ovarian failure
  4. If < 30yo, consider karyotyping to r/o XY mosaicism b/c of risk of malignancy in undeveloped testicular tissue (extremely rare if > 30yo); can also get gonadal dysgenesis with 46 XF and Turner's (46X)
  1. If low or nl, suggests pituitary or hypothalamic dysfunction (though can see biologically inactive forms if LH/FSH in rare instances)
  1. Consider pituitary MRI to r/o pituitary adenoma (see above), unless a clear cause for hypothalamic dysfunction is present (see above)
  2. If MRI and PRL are normal, probably hypothalamic amenorrhea (see above)
  1. Note that whatever the cause of estrogen deficiency, it must be treated
  1. Prob. increases risk for osteoporosis and perhaps CAD
  2. Consider supplemental estrogen, e.g. oral contraceptives, in all these pts to provide adequate estrogen, though may not improve bone mineral density
    1. In a trial in 24 ballet-dancers with exercise-associated amenorrhea randomized to conjugated equine estrogen 0.625mg/d for 25d/mo + medroxyprogesterone acetate 10mg/d for 10d/mo vs. placebo; all 24 received Ca 1250mg/d.  At 2y, no diff. in BMD between the two groups (Fertil. Steril. 80:398, 2003--JW)
  3. Consider calcium supplementation (1500mg/d) as well

(Source: Karen Jones, M.D. 8/95; AFP 53:1185, 1996)