Secondary Amenorrhea

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

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 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]

Treatment

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)