G5. Secondary Amenorrhea

I. Definition and Etiology

Definition

• Secondary amenorrhea: cessation of menses for ≥ 3 months in women with previously regular menses.
• Also: cessation of menses for ≥ 6 months in women with previously irregular menses.

Etiologic Groups

• Physiologic: pregnancy, lactation, menopause.
• Hypothalamus: weight loss, anorexia nervosa, intense exercise, stress/anxiety, chronic disease.
• Pituitary: hyperprolactinemia/prolactinoma, Sheehan syndrome, pituitary apoplexy/tumor.
• Ovary: premature ovarian insufficiency/failure, PCOS.
• Uterus/outflow tract: Asherman syndrome, endometrial ablation, cervical stenosis.
• Other endocrine/systemic: hypo/hyperthyroidism, adrenal disease.
• Medication: dopamine antagonists, antipsychotics/metoclopramide, chemotherapy, hormonal contraception, GnRH analogues.

II. Diagnostic Workup

Initial Evaluation

1. Pregnancy test: beta-hCG first in every patient.
2. History: cycle pattern, contraception, weight change, exercise, stress/eating disorder, drugs, galactorrhea, headache/visual symptoms, hot flushes, postpartum hemorrhage, uterine instrumentation.
3. Physical examination: BMI, thyroid signs, galactorrhea, acne/hirsutism/virilization, estrogen deficiency and pelvic exam if indicated.
4. Basic labs: TSH, prolactin, FSH, LH, estradiol.
5. Androgens if hyperandrogenism/virilization; pelvic US for ovaries/endometrium/uterine cavity.
6. Brain MRI if high prolactin persists, headache/visual symptoms or suspected pituitary lesion.

Hormonal Pattern

• High FSH/LH + low estradiol: ovarian failure → primary ovarian insufficiency / menopause / gonadal damage.
• Low or normal FSH/LH + low estradiol: hypothalamic-pituitary cause → functional hypothalamic amenorrhea, pituitary disease.
• Normal estrogen + no progesterone effect: chronic anovulation → PCOS, thyroid disease, hyperprolactinemia.
• Normal hormones + no bleeding: uterine/endometrial/outflow cause → Asherman syndrome, cervical stenosis, ablation.

Withdrawal Tests

• Progestin challenge: give progestin → withdraw it → wait for bleeding.
• Withdrawal bleeding positive:
  • Meaning: estrogenized endometrium + patent outflow tract.
  • Likely diagnosis: anovulation, especially PCOS or other chronic anovulation.
• Withdrawal bleeding negative:
  • Possibilities: low estrogen, damaged endometrium, or outflow obstruction.
  • Next: estrogen-progestin challenge.
• Estrogen-progestin challenge positive: uterus/outflow can bleed → low endogenous estrogen from hypothalamic/pituitary/ovarian cause.
• Estrogen-progestin challenge negative: uterine/outflow cause → Asherman syndrome or cervical stenosis.

III. Main Causes

Functional Hypothalamic Amenorrhea

• Pathomechanism: weight loss, anorexia nervosa, intense exercise or stress → disrupted pulsatile GnRH → low/normal FSH/LH → low estradiol → anovulation.
• Clinical context: heavy sport, rapid weight loss, eating disorder, chronic stress.
• Diagnosis: low estradiol, low/normal FSH/LH, normal TSH/PRL after excluding pregnancy and organic disease.
• Risk: hypoestrogenism → low bone mineral density, infertility.
• Treatment: nutritional rehabilitation, weight restoration, reduce excessive exercise, stress treatment.
• Hormone therapy: estrogen + progestin if prolonged hypoestrogenism.

Hyperprolactinemia and Prolactinoma

• Pathomechanism: high prolactin → inhibits GnRH → low FSH/LH → anovulation and amenorrhea.
• Causes: prolactinoma, dopamine-antagonist drugs, primary hypothyroidism via ↑ TRH, renal disease, pregnancy/lactation.
• Clinical features: amenorrhea/oligomenorrhea, galactorrhea, infertility, headache or visual field defects if macroadenoma.
• Diagnosis: serum prolactin, TSH; pituitary MRI if persistent unexplained elevation or mass symptoms.
• Treatment: remove causative drug if possible; levothyroxine for hypothyroidism; dopamine agonist for prolactinoma (cabergoline/bromocriptine).

Sheehan Syndrome and Pituitary Apoplexy

• Sheehan syndrome: postpartum pituitary ischemic necrosis after severe postpartum hemorrhage/hypotension.
• Mechanism: enlarged pregnancy pituitary + hypovolemia → pituitary hypoperfusion → hypopituitarism.
• Clinical features: failure to lactate, amenorrhea, fatigue, weight loss, cold intolerance, hypotension, hypoglycemia, loss of pubic/axillary hair.
• Labs: low pituitary hormones → low FSH/LH/PRL/TSH/ACTH and low cortisol.
• MRI: empty sella or pituitary atrophy later.
• Treatment order: glucocorticoid replacement first → then levothyroxine → then estrogen-progestin if uterus present.
• Pituitary apoplexy: acute hemorrhage/infarction → sudden severe headache, visual symptoms and acute hypopituitarism; needs urgent endocrine/neurosurgical care.

Primary Ovarian Insufficiency

• Definition: depletion/dysfunction of ovarian follicles before age 40 years.
• Causes: idiopathic, autoimmune, genetic, chemotherapy, radiotherapy, ovarian surgery.
• Clinical features: amenorrhea/oligomenorrhea, infertility, hot flushes, vaginal dryness.
• Diagnosis: low estradiol + high FSH/LH on repeated testing.
• Treatment: estrogen replacement until average menopause age; add progestin if uterus present.
• Fertility: donor-oocyte IVF is most effective if pregnancy desired.

PCOS and Chronic Anovulation

• Mechanism: chronic anovulation → no cyclic progesterone withdrawal → irregular bleeding or amenorrhea.
• Clinical features: oligomenorrhea/amenorrhea, acne, hirsutism, obesity or insulin resistance; not all patients are obese.
• Treatment principle: cycle protection with combined hormonal contraception or cyclic progestin; weight/metabolic treatment; ovulation induction if fertility desired.

Asherman Syndrome

• Causes: dilation and curettage, postpartum curettage, uterine infection, endometrial ablation, intrauterine surgery.
• Pathomechanism: endometrial scarring/fibrosis → intrauterine adhesions prevent normal endometrial proliferation/bleeding.
• Clinical features: secondary amenorrhea or hypomenorrhea, infertility, recurrent pregnancy loss after uterine instrumentation/infection.
• Hormones: usually normal FSH/LH/estradiol.
• Diagnosis: hysteroscopy or hysterosalpingography/saline sonography.
• Treatment: hysteroscopic adhesiolysis + postoperative estrogen therapy.

IV. Treatment Principles and Exam Points

Treatment by Category

• Pregnancy/lactation/menopause: physiologic explanation; manage according to reproductive goal and symptoms.
• Hypothalamic: nutrition, weight restoration, reduce exercise load, stress/eating-disorder treatment.
• Prolactin/thyroid: dopamine agonist for prolactinoma; levothyroxine for hypothyroidism.
• Ovarian insufficiency: estrogen-progestin replacement if uterus present; bone and cardiovascular protection; fertility counseling.
• PCOS/anovulation: protect endometrium, treat hyperandrogenism/metabolic risk, induce ovulation if fertility desired.
• Uterine/outflow: hysteroscopic correction/adhesiolysis when indicated.

Exam Algorithm

1. Secondary amenorrhea → beta-hCG.
2. Then TSH + prolactin + FSH/LH + estradiol.
3. High prolactin → repeat/confirm, exclude hypothyroidism/drugs → pituitary MRI if persistent.
4. High FSH + low estradiol → primary ovarian insufficiency / menopause.
5. Low FSH/LH + low estradiol → hypothalamic or pituitary cause.
6. Normal estrogen with chronic anovulation signs → PCOS most likely.
7. No withdrawal bleeding despite estrogen-progestin → Asherman syndrome or outflow obstruction.