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.
• Oligomenorrhea: menstrual interval > 35 days; evaluate similarly if persistent.

Etiologic Groups

• Physiologic: pregnancy, lactation, menopause.
• Hypothalamus: functional hypothalamic amenorrhea, weight loss, anorexia nervosa, intense exercise, stress/anxiety, chronic disease.
• Pituitary: hyperprolactinemia, prolactinoma, Sheehan syndrome, pituitary apoplexy, other tumors/infiltrative disease.
• Ovary: polycystic ovary syndrome (PCOS), primary ovarian insufficiency, resistant ovary syndrome, menopause.
• Uterus/outflow tract: Asherman syndrome, endometrial ablation, cervical stenosis.
• Endocrine/systemic: hypothyroidism, hyperthyroidism, Cushing syndrome, adrenal disease.
• Medication: antipsychotics, metoclopramide, antidepressants, opioids, 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, medications, galactorrhea, headache, visual symptoms, hot flushes, postpartum hemorrhage, uterine instrumentation.
3. Physical examination: BMI, thyroid signs, galactorrhea, acne/hirsutism/virilization, estrogen deficiency, pelvic examination if indicated.
4. Basic labs: TSH, prolactin, FSH, LH, estradiol.
5. Androgens if hyperandrogenism/virilization: total/free testosterone, DHEA-S, 17-OH-progesterone.
6. Pelvic ultrasound: ovaries, follicles, endometrium, uterine cavity clues.
7. Brain MRI: persistent high prolactin, headache/visual symptoms, suspected pituitary tumor, apoplexy, Sheehan syndrome.

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 + normal/low 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 test: give progestin for several days → stop → wait for withdrawal 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 or ultrasound-guided evaluation.
• Estrogen-progestin challenge positive: uterus/outflow tract can bleed → hypoestrogenic HPO-axis cause.
• Estrogen-progestin challenge negative: endometrial scarring or outflow obstruction → hysteroscopy / hysterosalpingography.

III. Main Causes

Functional Hypothalamic Amenorrhea

• Definition: reversible suppression of GnRH pulsatility without organic pituitary/ovarian disease.
• Pathomechanism: low energy availability, weight loss, intense exercise, stress → disrupted pulsatile GnRH → low/normal FSH/LH → low estradiol → anovulation.
• Clinical context: anorexia nervosa, heavy sport, rapid weight loss, chronic stress, female athlete triad / relative energy deficiency.
• Diagnosis: low estradiol, low/normal FSH/LH, normal TSH/prolactin, exclusion of pregnancy and organic disease.
• Risk: hypoestrogenism → low bone mineral density, infertility.
• Treatment: nutritional rehabilitation, weight restoration, reduce excessive exercise, stress treatment.
• Hormone therapy: consider cyclic estrogen/progestin if prolonged hypoestrogenism; treat bone health and fertility according to goal.

Hyperprolactinemia and Prolactinoma

• Pathomechanism: high prolactin → inhibits GnRH → low FSH/LH → anovulation and amenorrhea.
• Causes: prolactinoma, pregnancy/lactation, primary hypothyroidism, dopamine-antagonist drugs, renal disease, chest wall stimulation.
• Hypothyroidism mechanism: low thyroid hormone → high TRH → increased prolactin → GnRH suppression.
• Clinical features: amenorrhea/oligomenorrhea, galactorrhea, infertility, low libido, headache or visual field defects if macroadenoma.
• Diagnosis: serum prolactin; repeat mild elevation; check TSH; pituitary MRI if persistent unexplained elevation or mass symptoms.
• Treatment: remove causative drug if possible; levothyroxine for hypothyroidism; dopamine agonist for prolactinoma.
• Dopamine agonists: cabergoline usually preferred; bromocriptine also used.
• Surgery: transsphenoidal resection if drug resistance/intolerance or compressive urgent problem.

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: FSH/LH, prolactin, TSH with low free T4, ACTH with 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, often in adenoma → sudden severe headache, visual disturbance, ophthalmoplegia, altered mental state, acute hypopituitarism.
• Management of apoplexy: urgent glucocorticoids, MRI/CT, endocrine and neurosurgical assessment.

Primary Ovarian Insufficiency

• Definition: ovarian failure before age 40 years.
• Causes: idiopathic, autoimmune, genetic, chemotherapy, radiotherapy, ovarian surgery.
• Clinical features: amenorrhea/oligomenorrhea, infertility, hot flushes, vaginal dryness, sleep disturbance.
• Diagnosis: low estradiol + elevated FSH on repeated testing; exclude pregnancy, thyroid disease and hyperprolactinemia.
• Ultrasound: few/no follicles in ovarian depletion; follicles may be present in resistant ovary syndrome.
• Treatment: estrogen replacement until average menopause age; add progestin if uterus present.
• Fertility: intermittent ovarian function may occur; donor-oocyte IVF is most effective if pregnancy desired.

PCOS and Chronic Anovulation

• Role: common cause of oligomenorrhea/secondary amenorrhea after pregnancy is excluded.
• 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.
• Labs: androgens may be elevated; LH/FSH ratio may be increased but is not required for diagnosis.
• Treatment principle: cycle protection with combined hormonal contraception or cyclic progestin; weight/metabolic treatment; ovulation induction if fertility desired.

Asherman Syndrome

• Definition: intrauterine adhesions causing reduced/absent endometrial cavity function.
• Causes: dilation and curettage, postpartum curettage, uterine infection, endometrial ablation, intrauterine surgery.
• Pathomechanism: basal endometrium injury → scarring/fibrosis → endometrium cannot proliferate/bleed.
• Clinical features: secondary amenorrhea or hypomenorrhea, infertility, recurrent pregnancy loss; often after uterine instrumentation.
• Hormones: usually normal FSH/LH/estradiol.
• Diagnosis: hysteroscopy is diagnostic and therapeutic; hysterosalpingography or saline sonography may show adhesions.
• Treatment: hysteroscopic adhesiolysis + postoperative estrogen therapy; sometimes intrauterine balloon/IUD to prevent re-adhesion.

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 or 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.