AMENORRHEA

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 HPO axis
  2. Responsive endometrium
  3. Unobstructed outflow tract

II. Definition of amenorrhea requiring w/u:

  1. No secondary sex. characteristics or menses by 14 yo
  2. No menses by 16 yo
  3. No period x 3 cycles or 6 mos, whichever sooner, in a woman with previous menses

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. Stress, depression
  5. Kallman's syndrome (congenital hyogonadotrophic hypogonadism ass'd with anosmiawith absent olfactory sulci; very rare)
  6. Celiac Disease
  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, SpAb, 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. 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
  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. ALWAYS RULE OUT PREGNANCY!!!
  3. INITIAL w/u:
  1. TSH to r/o hypothyroidism
  2. PRL to r/o hyperprolactinemia (2/3 will have no galactorrhea!)
  3. Imaging study to r/o Pituitary Adenoma if Galactorrhea (by hx or px) or Hyperprolactinemia
  1. Coned-down lateral XR of sella turcica is sufficient if PRL is < 100ng/ml and no visual change or HA; otherwise, MRI
  1. NEXT step: determine level of endogenous estrogen production with progesterone challenge test
  1. Caution! If amenorrhea has been prolonged and/or signs of androgen excess:
  1. May be due to endometrial hyperplasia/dysplasia; may want to do endometrial bx before inducing withdrawal bleed (?)
  2. May be due to "decidualization" of endometrium, with adequate circulating estrogen but not w/d bleed after progesterone challenge-occurs in hyperandrogenic states, e.g. adrenal tumors, PCOD (?); in this case, won't get a w/d bleed after hormonal manipulation
  1. Progesterone challenge test
  1. The best way to check; random estradiol levels are useless
  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 PCOD (see section on PCOD)
  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 one of these
  1. Follow abnormal progesterone challenge test with combined estrogen/progesterone challenge:
  1. May omit this step if pt has nl Px 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
  5. If get bleed, dx = estrogen deficiency
  1. If don't get bleed with estrogen/progesterone challenge, indicates unresponsive endometrium or nonpatent outflow tract (see IV.B. above)
  1. Consider HSP 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 > 30 or LH > 40), indicates ovarian failure or absent ovaries
  1. If > 45y, 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" (check Ca, phosphate, TSH/fT4i, thyroid Ab, CBC, ESR, TP/albumin, RF, ANA to r/o 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, MUST DO 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, indicates pituitary or hypothalamic dysfunction (though can see biologically inactive forms if LH/FSH in rare instances)
  1. Check cone-down x-ray of sella turcica (MRI if abnormal, PRL is >100, or sx of pituitary tumor--see above) to r/o pituitary tumor (can start w/cone-down view on plain films?), unless a clear cause for hypothalamic dysfunction is present (see above)
  1. See above for tx approach to pituitary adenoma
  1. If do MRI and no tumor nor empty sella seen and PRL is normal, prob. 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)