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Amenorrhea

Definition

• Primary amenorrhea: No menses by age 13 in the absence of secondary sexual characteristics, or no menses by age 15 with normal secondary sexual development
• Secondary amenorrhea: Absence of menses for 3 or more months in a woman who was previously menstruating regularly, or 6 months in a woman with irregular cycles

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Classification by Anatomy (Physiologic Framework)

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Primary Amenorrhea

A. Without Secondary Sexual Characteristics (No breast development)

1. Hypergonadotropic Hypogonadism (High FSH, High LH)

• Initially normal ovarian development in utero, but accelerated follicular atresia produces fibrotic "streak ovaries"
• Stigmata: short stature, webbed neck, shield chest, cubitus valgus, low hairline, high-arched palate, short 4th metacarpals, multiple pigmented nevi
• Y cell line must be excluded (risk of gonadoblastoma - gonadectomy indicated if Y present)

• Structural X chromosome abnormalities; mosaicism (45,X/46,XX)
• Pure gonadal dysgenesis (46,XX or 46,XY with streak gonads)
• 17α-hydroxylase deficiency (enzyme defect preventing estrogen synthesis; also causes hypertension due to mineralocorticoid excess)
• Gonadotropin receptor-inactivating mutations
• Autoimmune oophoritis; galactosemia

2. Hypogonadotropic Hypogonadism (Low FSH, Low LH)

• Kallmann syndrome: GnRH neuron migration failure + anosmia (absent sense of smell); X-linked (KAL1/ANOS1 gene)
• Constitutional delay: diagnosis of exclusion; supported by delayed bone age, normal MRI, and family history
• Nutritional disorders (anorexia nervosa, malnutrition)
• CNS lesions (craniopharyngioma, germinoma, infiltrative disease)
• Hypopituitarism

1. FSH level - if high, suspect gonadal failure; karyotype
2. If low/normal FSH - CNS MRI to exclude lesion
3. Bone age X-ray to support constitutional delay

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B. With Secondary Sexual Characteristics + Pelvic Anatomy Abnormalities

• Congenital absence of the uterus and upper vagina
• 46,XX karyotype, normal ovarian function (normal FSH, LH, estrogen)
• Cause: failure of Mullerian duct development
• Management: vaginal dilators (Frank technique) or surgical vaginoplasty

• 46,XY with non-functional androgen receptor
• Phenotypically female; testes present intra-abdominally
• Absent uterus (Mullerian inhibiting substance from testes present)
• Short, blind-ending vagina; absent or sparse pubic/axillary hair
• High risk of gonadal malignancy - gonadectomy after puberty

• Outflow obstruction - blood accumulates (hematocolpos, hematometra)
• Cyclic pelvic pain; bluish bulge at introitus (imperforate hymen)
• Treatment: surgical incision/excision

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C. With Secondary Sexual Characteristics + Normal Pelvic Anatomy

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Secondary Amenorrhea

Causes by Compartment

• Excessive exercise ("athletic amenorrhea") - part of the Female Athlete Triad (low energy availability + menstrual dysfunction + low bone density)
• Weight loss / low body fat
• Psychological stress
• Anorexia nervosa (severe form - FSH and LH both markedly low)

• Antipsychotics (phenothiazines, haloperidol, clozapine, pimozide)
• Antidepressants (TCAs, MAOIs)
• Antihypertensives (calcium channel blockers, methyldopa, reserpine)
• Estrogenic drugs (digitalis, flavonoids, marijuana, oral contraceptives)
• Ovarian toxins (busulfan, chlorambucil, cisplatin, cyclophosphamide, fluorouracil)

• Hyperprolactinemia: prolactinoma most common (>80% of sellar lesions); prolactin inhibits GnRH pulsatility and directly suppresses gonadotropin release. Presents with galactorrhea + amenorrhea
• Sheehan syndrome: postpartum pituitary necrosis from obstetric hemorrhage - panhypopituitarism
• Pituitary apoplexy: sudden infarction or hemorrhage of a pituitary adenoma
• Empty sella syndrome: reported in 4-16% of patients with amenorrhea + galactorrhea
• Acquired hypopituitarism: trauma, tumor, lymphocytic hypophysitis

• Defined as ovarian failure at any age from menarche to 40 years
• FSH >25-40 IU/L (single measurement >50 IU/L suggestive)
• Causes:
  • Idiopathic (30-90% of cases)
  • FMR1 premutation (fragile X premutation, 55-200 CGG repeats): accounts for 0.8-7.5% sporadic, up to 13% familial POI
  • Chromosomal (partial X deletion - Xq21-28 region critical)
  • Autoimmune (20-40% of cases; associated with thyroid, adrenal insufficiency)
  • Iatrogenic: radiation, alkylating chemotherapy (cyclophosphamide), surgery affecting ovarian blood supply
  • Galactosemia, infections (autoimmune-lymphocytic oophoritis), Perrault syndrome

• Most common cause of oligomenorrhea/amenorrhea in reproductive-age women
• Hypothalamic-pituitary dysfunction; elevated LH:FSH ratio, hyperandrogenism

• Most common outflow cause of secondary amenorrhea
• Caused by vigorous curettage (D&C), endometritis
• Endometrium destroyed; normal hormone levels
• Diagnosis: hysteroscopy (gold standard), saline infusion sonography
• Treatment: hysteroscopic lysis of adhesions

• Hypothyroidism: elevated TSH → elevated TRH → stimulates prolactin release → amenorrhea
• Hyperthyroidism: can also disrupt the cycle
• Cushing syndrome: excess cortisol suppresses GnRH
• Chronic illness: renal failure, liver disease, malabsorption

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Evaluation Algorithm

Initial Tests (Both Primary and Secondary)

1. Pregnancy test (urine/serum β-hCG) - always first
2. TSH - exclude thyroid disease
3. Prolactin - exclude hyperprolactinemia
4. FSH, LH - distinguish ovarian from central cause

Progestogen Challenge Test (Secondary amenorrhea, when cause unclear)

• Give medroxyprogesterone acetate 10 mg for 5-10 days
• Positive (withdrawal bleed occurs): estrogen is adequate; uterus is patent; anovulation is present (PCOS likely)
• Negative (no bleed): either hypoestrinism OR outflow obstruction
  • Then give estrogen + progestogen: if bleed occurs → hypoestrinism; if no bleed → outflow obstruction (Asherman syndrome, Mullerian agenesis)

FSH Interpretation

Additional Investigations by Suspicion

• MRI sella turcica: if galactorrhea, headaches, visual field defects, or hypogonadotropic hypogonadism
• Karyotype: primary amenorrhea, POI under age 30
• FMR1 premutation: POI in women <40
• 21-hydroxylase antibodies: spontaneous POI (risk of Addison's disease)
• ACTH stimulation test: if antiadrenal antibodies positive
• Testosterone, DHEAS: if signs of hyperandrogenism
• 24h urinary cortisol or overnight dexamethasone suppression: if Cushing suspected
• Pelvic ultrasound / hysteroscopy: anatomic evaluation

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Differential Diagnosis at a Glance

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Treatment

Depends on Cause

• Cyclic estrogen + progestogen replacement to develop/maintain secondary sexual characteristics and prevent osteoporosis
• Starting dose: oral conjugated estrogens 0.3-0.625 mg/day OR estradiol 0.5-1 mg/day
• Add medroxyprogesterone acetate 2.5 mg daily or 5-10 mg for 12-14 days/month (if uterus present)
• In short patients: avoid high estrogen doses (risk of premature epiphyseal closure)

• Dopamine agonists: cabergoline (first-line), bromocriptine
• Reduce prolactin → restore GnRH pulsatility → menstrual cycles resume

• Address underlying cause: weight restoration, reduce exercise intensity, stress management
• Cognitive behavioral therapy for eating disorders
• No estrogen replacement is sufficient without treating the underlying cause

• OCP for cycle regulation + hyperandrogenism
• Metformin if insulin resistance
• Ovulation induction (clomiphene, letrozole) if fertility desired

• Hysteroscopic adhesiolysis + estrogen supplementation post-procedure to promote endometrial regeneration

• Surgical correction

• Pulsatile GnRH infusion (if fertility desired) or exogenous gonadotropins (FSH + LH/hCG)
• HRT for secondary sexual characteristics if fertility not desired

• No proven treatment to restore ovarian function reliably
• Oocyte donation is the most effective option for pregnancy
• HRT to reduce cardiovascular and bone risks

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Key Points to Remember

• Always exclude pregnancy first in secondary amenorrhea
• Turner syndrome is the most common cause of hypergonadotropic primary amenorrhea
• Mullerian agenesis is the most common cause of primary amenorrhea with normal secondary sexual characteristics
• PCOS is the most common cause of secondary amenorrhea overall
• Asherman syndrome is the most common uterine cause of secondary amenorrhea
• FMR1 premutation testing is indicated in POI under 40 (risk of transmitting fragile X to offspring)
• Women with POI caused by spontaneous gonadal failure should be screened for autoimmune adrenal insufficiency (21-hydroxylase antibodies)
• The Female Athlete Triad (energy deficiency + menstrual dysfunction + low bone density) is an important reversible cause in young athletes

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