Reproductive · PANCE / PANRE

Secondary Amenorrhea

Absence of menses for ≥3 months (regular cycles) or ≥6 months (irregular cycles) in a previously menstruating woman.

Also known as: secondary amenorrhea, missed menses, absent menses

Overview

Cessation of menstruation for at least 3 consecutive months in a woman with previously regular cycles, or 6 months in a woman with previously irregular cycles.

Epidemiology

Affects ~3-4% of reproductive-age women. Pregnancy is by far the most common cause; pathologic causes include PCOS (most common pathologic), hypothalamic amenorrhea, hyperprolactinemia, thyroid disease, and primary ovarian insufficiency.

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Risk factors

  • Recent pregnancy or breastfeeding
  • Significant weight loss, low BMI, eating disorder
  • Excessive exercise (endurance athletes, dancers)
  • Major psychological stress
  • Antipsychotics, opioids, hormonal contraceptives
  • Intrauterine instrumentation (Asherman syndrome)
  • Family history of premature ovarian insufficiency

Pathophysiology

Menstruation requires cyclic ovarian estrogen/progesterone production with intact endometrial responsiveness and patent outflow. Common pathways: hypothalamic suppression (energy deficit, stress), pituitary lesions (prolactinoma), ovarian failure (POI, chemo/radiation), endometrial damage (Asherman from D&C, infection), and androgen excess (PCOS) producing anovulation.

Clinical presentation

Symptoms

  • Cessation of menses
  • Symptoms of underlying cause: galactorrhea (prolactinoma), hot flashes (POI/menopause), hirsutism (PCOS), heat/cold intolerance (thyroid), weight changes
  • Cyclic pelvic pain may suggest outflow obstruction (cervical stenosis post-procedure)

Signs / physical exam

  • BMI, vital signs
  • Visual field testing if pituitary lesion suspected
  • Thyroid exam, breast exam (galactorrhea)
  • Pelvic exam: vaginal atrophy (low estrogen), uterine size, adnexal masses
  • Skin: acanthosis nigricans, hirsutism, acne, striae

Differential diagnosis

  • Pregnancy — Most common cause; always check hCG
  • PCOS — Hyperandrogenism + chronic anovulation
  • Functional hypothalamic amenorrhea — Low weight, exercise, stress; low FSH/LH/estradiol
  • Hyperprolactinemia — Galactorrhea; check medications, pregnancy, TSH; pituitary MRI
  • Thyroid disease — Hypo- or hyperthyroid symptoms; abnormal TSH
  • Primary ovarian insufficiency — Hot flashes, vaginal dryness <40 yo; elevated FSH on two occasions
  • Asherman syndrome — Amenorrhea or hypomenorrhea after D&C, endometritis, or uterine surgery; absent withdrawal bleed; hysteroscopy diagnostic
  • Cushing syndrome / hyperandrogenism (CAH, tumor) — Virilization, central obesity, striae; specific endocrine testing

Diagnostic workup

Diagnostic criteria

Progesterone challenge test (medroxyprogesterone 10 mg × 10 days) can assess estrogen status: bleeding suggests adequate estrogen + patent outflow (anovulation pattern); no bleeding suggests low estrogen OR outflow obstruction OR endometrial unresponsiveness — confirm with estrogen-progestin challenge.

Labs

  • Pregnancy test (urine or serum hCG) — always first
  • TSH and prolactin
  • FSH (high → POI; low/normal → central or PCOS)
  • If hyperandrogenism: total testosterone, DHEAS, 17-OHP
  • Estradiol if FSH abnormal

Imaging

  • Pelvic ultrasound if structural cause suspected
  • Brain MRI (pituitary protocol) for elevated prolactin or hypogonadotropic hypogonadism
  • Hysteroscopy or saline sonohysterography if Asherman suspected (history of D&C, endometritis)

Diagnostic algorithm

flowchart TD
  A[Secondary amenorrhea] --> B[hCG]
  B -->|Positive| C[Pregnancy]
  B -->|Negative| D[TSH, prolactin]
  D -->|High prolactin| E[Pituitary MRI<br/>Dopamine agonist]
  D -->|Abnormal TSH| F[Thyroid treatment]
  D -->|Normal| G[FSH, estradiol]
  G -->|High FSH| H[Primary ovarian<br/>insufficiency<br/>repeat in 1 month]
  G -->|Low/normal FSH| I{Hyperandrogenism?}
  I -->|Yes| J[PCOS workup]
  I -->|No| K[Progesterone challenge]
  K -->|Withdrawal bleed| L[Anovulation:<br/>functional HA, PCOS]
  K -->|No bleed| M[E+P challenge:<br/>bleed = outflow OK<br/>no bleed = Asherman]
Algorithm for secondary amenorrhea — pregnancy first, then TSH/prolactin/FSH stratify.

Treatment

First-line

  • Treat the underlying cause
  • Pregnancy: prenatal care
  • PCOS: see PCOS entry — COCP or cyclic progestin
  • Functional hypothalamic amenorrhea: nutritional restoration, reduce exercise, address stress; CBT for those with eating disorder
  • Hyperprolactinemia: dopamine agonists (cabergoline preferred, bromocriptine alternative)
  • Thyroid disease: levothyroxine or antithyroid therapy
  • POI: hormone therapy (estrogen + progestin) until average age of menopause

Asherman syndrome

  • Hysteroscopic lysis of adhesions
  • Postoperative estrogen to promote endometrial regrowth
  • Intrauterine device or balloon to prevent re-adhesion

Premature ovarian insufficiency

  • Hormone replacement until ~age 51 (mean menopause age)
  • Calcium and vitamin D
  • Fertility counseling — pregnancy possible with donor oocytes
  • Screen for autoimmune comorbidities (adrenal, thyroid)

Complications

  • Infertility
  • Osteoporosis from prolonged hypoestrogenism
  • Endometrial hyperplasia from unopposed estrogen (PCOS, obesity)
  • Cardiovascular risk in untreated POI
  • Psychological distress

PANCE pearls

  • Always rule out pregnancy first — even with denied sexual activity, contraception use, or recent menses.
  • Functional hypothalamic amenorrhea is a diagnosis of exclusion; first restore energy availability before starting hormone therapy.
  • Hyperprolactinemia from medications (antipsychotics, metoclopramide, opioids) usually causes prolactin <100 ng/mL; tumors cause higher levels.
  • POI is diagnosed with two FSH levels >25-40 IU/L drawn at least 1 month apart in a woman under 40.
  • A withdrawal bleed after progesterone challenge implies adequate endogenous estrogen — proceed with workup for anovulation, not POI.

References

  • ACOG CO 605 — ACOG Committee Opinion 605: Primary Ovarian Insufficiency in Adolescents and Young Women
  • Endocrine Society 2017 — Functional Hypothalamic Amenorrhea: Endocrine Society Clinical Practice Guideline (Gordon et al., JCEM 2017)
  • Endocrine Society 2011 — Diagnosis and Treatment of Hyperprolactinemia: Endocrine Society Clinical Practice Guideline (Melmed et al., JCEM 2011)

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