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Amenorrhea: Types, Pathogenesis, Features, and Management

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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 characteristics.
• Secondary amenorrhea: Absence of menstruation for 3 months (or 6-9 months in women with oligomenorrhea) after previously established menses.

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Normal Menstrual Physiology (Basis for Understanding Pathogenesis)

1. Hypothalamus - pulsatile GnRH secretion
2. Anterior pituitary - FSH and LH secretion in response to GnRH
3. Ovaries - follicular development, ovulation, estrogen/progesterone production
4. Uterus/Outflow tract - functioning endometrium and patent outflow

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WHO Classification

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Types and Pathogenesis

A. Outflow Tract / Uterine Causes (Anatomic)

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B. Ovarian (Gonadal) Causes

1. Hypergonadotropic Hypogonadism (High FSH)

• Accelerated follicular atresia in utero → streak ovaries by puberty
• No estrogen → absent secondary sexual characteristics
• Associated stigmata: short stature, webbed neck, shield chest, cubitus valgus, coarctation of aorta (30%), horseshoe kidney
• Gonadectomy if Y-cell line present (risk of gonadoblastoma)

• 46,XX gonadal dysgenesis, 46,XY (Swyer syndrome), mosaic karyotypes
• Partial deletions may allow some estrogen → secondary sexual characteristics then secondary amenorrhea

• Defined as FSH in menopausal range + amenorrhea ≥4 months in women <40 years
• Causes: autoimmune (20-40% of cases), chemotherapy, radiation, galactosemia, FMR1 premutation, idiopathic
• Mechanism: decreased follicular endowment, accelerated atresia, or follicle dysfunction
• 5-10% may still conceive spontaneously

2. Polycystic Ovary Syndrome (PCOS)

• Most common cause of secondary amenorrhea after pregnancy
• Pathophysiology: relatively low FSH with disproportionately high LH → multiple small follicles, androgen excess, chronic anovulation
• Insulin resistance plays a central role; high LH stimulates excess thecal androgen → peripheral aromatization to estrogen → chronic unopposed estrogen
• Rotterdam Criteria: 2 of 3 - hyperandrogenism, oligomenorrhea/amenorrhea, polycystic ovaries on US
• Clinical features: hirsutism (65%), infertility (50%), obesity (35%), amenorrhea (35%), oligomenorrhea (40%), acne (25%)
• Risk of endometrial hyperplasia/cancer from unopposed estrogen

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C. Pituitary Causes

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D. Hypothalamic Causes

• Deficiency of GnRH neurons (failed migration from olfactory placode)
• Characterized by: hypogonadotropic hypogonadism + anosmia
• Low FSH, LH, estrogen; lack of secondary sexual characteristics

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E. Thyroid / Adrenal Causes

• Hypothyroidism: Elevated TRH stimulates prolactin → hyperprolactinemia → amenorrhea; treat hypothyroidism first
• Hyperthyroidism: Alters sex hormone binding globulin and estrogen metabolism
• Congenital adrenal hyperplasia (late-onset): Excess androgens suppress GnRH
• Cushing syndrome: Excess cortisol inhibits GnRH pulsatility
• Virilizing adrenal tumors: Androgen excess

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F. Drug-Induced Amenorrhea

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Diagnostic Evaluation - Decision Tree

Key Investigations

1. Serum/urine beta-hCG - exclude pregnancy first
2. TSH - thyroid dysfunction
3. Serum prolactin - hyperprolactinemia (fasting sample, early follicular phase)
4. Serum FSH + estradiol - differentiate hypergonadotropic vs hypogonadotropic
5. Karyotype - if primary amenorrhea with gonadal failure <25 years or height <5 ft
6. Pelvic ultrasound - antral follicle count, uterine/ovarian morphology
7. MRI pituitary - if elevated prolactin, hypothalamic amenorrhea, or CNS symptoms
8. AMH - correlates with follicular pool; aids POI diagnosis
9. DEXA scan - bone mineral density if long-term hypoestrogenism suspected
10. Progestogen challenge test - limited utility (false positives/negatives common)

Hormone Pattern Summary in Secondary Amenorrhea

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Management

Principle: Treat the underlying cause

1. Outflow Tract Obstruction

• Imperforate hymen / vaginal septum: Surgical incision/excision
• MRKH syndrome: Progressive vaginal dilation (Frank's method) or surgical neovaginoplasty; uterus absent so no fertility with own uterus (uterine transplant remains experimental)
• Asherman syndrome: Hysteroscopic lysis of adhesions; barrier (Foley catheter or IUD) + cyclic estrogen-progestin postoperatively

2. PCOS

• Not wanting pregnancy: Combined OCP to regulate cycles and protect endometrium from unopposed estrogen; cyclic progestogens (medroxyprogesterone acetate 10 mg for 12-14 days/month) as alternative
• Insulin resistance: Metformin; weight loss (even 5-10% improves cycles, reduces androgens)
• Wanting pregnancy: Ovulation induction with clomiphene citrate or letrozole (first-line); gonadotropins if clomiphene fails; laparoscopic ovarian drilling
• Screen periodically for diabetes and dyslipidemia

3. Hyperprolactinemia / Prolactinoma

• Dopamine agonists: Cabergoline (preferred) or bromocriptine - reduces prolactin, shrinks tumor, restores ovulation
• Treat hypothyroidism first if both elevated TSH and prolactin are present
• Surgical resection for large macroadenomas not responding to medical therapy

4. Hypothalamic / Functional Amenorrhea

• Exercise-induced: Reduce exercise intensity, increase caloric intake; if hypoestrogenism persists - hormone therapy; calcium 1200-1500 mg/day + Vitamin D 400-800 IU/day
• Anorexia nervosa: Multidisciplinary team; family-based therapy (first-line in adolescents); hospitalization for severe cases; target weight restoration
• Stress-induced: Psychotherapy, stress reduction
• Chronic disease / obesity / Cushing / acromegaly: Specific treatment of underlying disorder
• Note: Bisphosphonates are NOT recommended in amenorrheic athletes (mechanism is decreased bone formation, not increased resorption; also concern about teratogenicity)

5. Primary Ovarian Insufficiency (POI)

• Hormone replacement therapy: Estrogen + progestogen until natural age of menopause (~50 years); doses often higher than standard menopausal HRT
• Bone protection: HRT + calcium + Vitamin D
• Fertility: Oocyte donation is the most reliable option; spontaneous pregnancy possible in 5-10%
• Screen for autoimmune comorbidities: thyroid (TPO antibodies), adrenal (21-hydroxylase antibodies), and screen annually

6. Turner Syndrome

• Estrogen therapy from expected age of puberty (~12-13 years) to initiate secondary sexual characteristics, followed by cyclic estrogen-progestogen
• Growth hormone therapy for short stature
• Cardiac surveillance (coarctation of aorta, bicuspid aortic valve)
• Fertility via donor egg IVF

7. Hypopituitarism / Sheehan Syndrome

• Replace all deficient hormones: estrogen-progestogen, thyroid hormone, glucocorticoids, DDAVP as needed
• MRI pituitary to assess extent of damage

8. Kalllmann Syndrome (wanting pregnancy)

• Pulsatile GnRH therapy via infusion pump, OR
• Gonadotropin injections (FSH + hCG) for ovulation induction

9. Drug-Induced

• Discontinue or substitute offending drug where possible; amenorrhea typically resolves

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Key Clinical Pearls

• Always exclude pregnancy before any workup
• When gonadal failure occurs with primary amenorrhea, there is a high incidence of abnormal karyotype - always karyotype
• Bone health must be addressed in all hypoestrogenic patients (osteoporosis risk)
• The distinction between primary and secondary amenorrhea can be misleading - the causes substantially overlap; do not overemphasize the distinction
• FSH >25-40 mIU/mL on two separate samples = hypergonadotropic amenorrhea
• In PCOS: protect endometrium from unopposed estrogen (risk of endometrial hyperplasia/cancer)
• In Asherman syndrome: the patient is hormonally normal but does not menstruate

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Clinical Cases on Amenorrhea: Differential Diagnosis, Investigations & Management

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Case 1 - 15-year-old girl: Primary amenorrhea + monthly lower abdominal pain

Clinical Interpretation

Most Likely Diagnosis

• Blood accumulates behind the obstruction: hematocolpos (in vagina) → hematometra (in uterus) → hemoperitoneum if reflux through tubes
• If longstanding, can cause endometriosis

Differential Diagnosis

Investigations

1. Physical examination - inspection of introitus: bluish bulging membrane at vaginal opening confirms imperforate hymen
2. Pelvic ultrasound - hematocolpos (fluid-filled vagina), hematometra; normal ovaries
3. MRI pelvis - gold standard for defining anatomy (level of obstruction, uterine/cervical anatomy)
4. Beta-hCG - always rule out pregnancy
5. Karyotype if anatomy unclear or uterus absent

Management

• Surgical: Cruciate incision of the hymen (hymenotomy) under general anaesthesia with drainage of retained blood (hematocolpos)
• Post-op: spontaneous menstruation establishes; fertility is preserved
• Monitor for endometriosis as a long-term sequela of retrograde menstruation
• Do NOT needle aspirate without surgical backup (risk of infection)

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Case 2 - 16-year-old girl: No menarche attained (Primary amenorrhea, no other details given)

Clinical Interpretation

Differential Diagnosis

Investigations Algorithm

• Serum FSH, LH, estradiol
  • High FSH → Karyotype (Turner, gonadal dysgenesis)
  • Low FSH/LH + no uterus on US → Kallmann, physiologic delay

• Pelvic exam + ultrasound - uterus present or absent?
  • Absent uterus → Karyotype (46,XX = MRKH; 46,XY = CAIS)
  • Uterus present, no anatomic obstruction → TSH, prolactin, FSH

• If FSH elevated → karyotype, AMH, autoimmune screen (POI)
• If FSH low/normal + low estrogen → MRI brain (Kallmann, pituitary tumour)
• If FSH normal, estrogen normal → rule out PCOS (testosterone, LH:FSH ratio, pelvic US)

Management (depends on diagnosis)

• Turner syndrome: Estrogen therapy to induce puberty → combined HRT; GH therapy for stature; fertility via oocyte donation; cardiac surveillance
• MRKH: Vaginal dilators (Frank's method) or surgical neovaginoplasty; uterus absent so surrogacy
• CAIS: Gonadectomy (gonadoblastoma risk with intra-abdominal testes); estrogen replacement; vaginal dilation
• Kallmann: Pulsatile GnRH or gonadotropin therapy if pregnancy desired; HRT otherwise
• Constitutional delay: Watchful waiting; low-dose estrogen may be considered if distressing

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Case 3 - 24-year-old married woman: 3 months absent menses, previously regular cycles

Clinical Interpretation

Differential Diagnosis (in order of probability)

Investigations Algorithm

• TSH - hypothyroidism/hyperthyroidism
• Serum prolactin (fasting, early morning)
• Serum FSH + estradiol

• Progestogen challenge (medroxyprogesterone 10 mg x 5-10 days)
  • Withdrawal bleed = adequate estrogen, patent outflow (likely anovulation/PCOS)
  • No withdrawal bleed = either hypoestrogenic state OR outflow tract problem (Asherman)
  • If no bleed: give estrogen + progestogen - if still no bleed → outflow problem → hysteroscopy

• Testosterone, DHEA-S (PCOS, adrenal causes)
• Pelvic ultrasound (PCOS morphology, ovarian follicle count)
• Saline infusion sonography or hysteroscopy (Asherman suspected)

Management

• Pregnancy: Obstetric care; contraception counselling
• Hypothyroidism: Levothyroxine → cycles resume
• PCOS: OCP for cycle regulation + endometrial protection; metformin for insulin resistance; weight loss; clomiphene/letrozole if fertility desired
• FHA (stress/weight): Address underlying cause; nutrition, psychological support; HRT if hypoestrogenic
• Asherman syndrome: Hysteroscopic adhesiolysis + postoperative estrogen
• POI: HRT (estrogen-progestogen) until age 50; oocyte donation for fertility

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Case 4 - 30-year-old woman: Amenorrhea 7 months + galactorrhea + headache

Clinical Interpretation

Pathophysiology

• Prolactinoma secretes excess prolactin
• Prolactin inhibits pulsatile GnRH secretion → reduced FSH/LH → anovulation → amenorrhea
• Prolactin stimulates breast tissue → galactorrhea (even without pregnancy/breastfeeding)
• Tumor mass effect → headache (compression of surrounding structures); if large → bitemporal hemianopia (compression of optic chiasm)

Differential Diagnosis

Investigations

1. Serum prolactin (fasting, no recent breast stimulation) - levels >200 ng/mL are virtually diagnostic of prolactinoma; 100-200 ng/mL highly suggestive; 25-100 ng/mL: drug-induced or small microadenoma
2. TSH - exclude hypothyroidism as cause of elevated prolactin (treat thyroid first if both abnormal)
3. Beta-hCG - rule out pregnancy (physiological hyperprolactinemia)
4. MRI pituitary with contrast - gold standard to visualize adenoma, determine size (micro vs macro), assess suprasellar/cavernous extension
5. Visual field testing (Goldman perimetry) - if macroadenoma suspected; bitemporal hemianopia suggests optic chiasm compression
6. FSH, LH, estradiol, testosterone - assess degree of hypogonadism
7. Full pituitary screen - GH, IGF-1, ACTH, cortisol, free T4 if mass is large (panhypopituitarism?)
8. Drug history - rule out iatrogenic hyperprolactinemia

Management

First-line: Dopamine Agonist Therapy

• Cabergoline (preferred): 0.25-0.5 mg twice weekly; better tolerated, more effective at normalizing prolactin and shrinking tumor
• Bromocriptine: 1.25-2.5 mg daily, titrated up; cheaper; more side effects (nausea, dizziness, orthostatic hypotension); crosses placenta - historically used in pregnancy
• Both normalize prolactin in ~80-90% of patients, restore ovulation, and cause tumor shrinkage
• If TSH also elevated: treat hypothyroidism first - prolactin often normalizes

If wanting pregnancy:

• Dopamine agonist (usually switched to bromocriptine in pregnancy if needed) → ovulation restored
• Cabergoline/bromocriptine generally discontinued once pregnancy confirmed (for microadenomas)
• Macroadenomas: continued monitoring with visual fields; reinstate dopamine agonist if tumor expansion occurs

Second-line: Transsphenoidal surgery

• Indications: resistance/intolerance to dopamine agonists, rapid visual deterioration, apoplexy (sudden tumor hemorrhage/infarction)
• Cure rates ~70-80% for microadenomas, lower for macroadenomas

Radiotherapy

• Third-line; for residual tumor after surgery or when medical/surgical options fail

Monitoring

• Prolactin levels at 1-3 months after starting therapy
• Repeat MRI at 6-12 months
• Visual fields if macroadenoma

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Summary Table

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Clinical Case Analysis: 16-year-old with Primary Amenorrhea

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Clinching the Diagnosis from the History Alone

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Diagnosis: Complete Androgen Insensitivity Syndrome (CAIS)

Genetics and Pathophysiology

• Karyotype: 46,XY (genetically male)
• Mutation in the androgen receptor (AR) gene located on the X chromosome - X-linked recessive inheritance
• Defects include complete absence of the AR gene, or mutations disrupting binding domains of the receptor
• The AR is entirely non-functional, so androgens cannot exert any biological effect at the cellular level

Embryological Mechanism

Clinical Features

• Female external genitalia - unambiguous female appearance
• Well-developed breasts - but with pale areolae and immature nipples
• Absent/very sparse pubic and axillary hair - pathognomonic
• Blind vaginal pouch - vagina present but shortened, ends blindly
• No uterus, no fallopian tubes (müllerian structures absent)
• Testes - located in abdomen, inguinal canal, or labia majora (may be palpable as inguinal lumps; ~1% of all prepubertal girls with inguinal hernia have CAIS)
• Tall stature with eunuchoidal body proportions (long limbs, big hands and feet)
• Serum testosterone in male range - but biologically inert

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Differential Diagnosis

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Investigations Algorithm

Step 1 - Exclude pregnancy

• Beta-hCG (urine or serum) - negative in CAIS (blind vaginal pouch, no uterus)

Step 2 - Confirm secondary sexual characteristics

• Physical examination:
  • Breast development (Tanner stage)
  • Pubic/axillary hair (Tanner stage)
  • Genital examination: blind vaginal pouch, absent cervix, absent uterus
  • Inguinal examination: palpable gonads?

Step 3 - Imaging

• Pelvic ultrasound (first-line): absent uterus, absent ovaries; may visualize intra-abdominal or inguinal testes
• MRI pelvis (gold standard): confirms absent Müllerian structures, localizes gonads precisely

Step 4 - Hormonal profile

Step 5 - Definitive diagnosis

• Karyotype: 46,XY - confirms the diagnosis
• AR gene sequencing - identifies the specific mutation (not always needed clinically but confirms diagnosis)

Step 6 - Associated evaluation

• Bone mineral density (DEXA scan) - baseline before gonadectomy
• Renal ultrasound - usually normal in CAIS (unlike MRKH)
• Psychological assessment - essential before disclosure of karyotype

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Management

1. Psychological Support and Counselling (FIRST PRIORITY)

• Sensitive, age-appropriate communication
• Ideally a multidisciplinary team: gynecologist, endocrinologist, psychologist/psychiatrist, social worker
• The patient identifies entirely as female and should be treated accordingly
• Long-term psychological support and peer support groups

2. Gonadectomy (Surgical Removal of Testes)

• ~2-5% lifetime risk of testicular malignancy (gonadoblastoma, dysgerminoma) - most commonly seminomatous germ cell tumors
• Malignant transformation generally does not occur until after puberty
• Therefore, gonadectomy is recommended after pubertal development is complete (to allow testosterone → estradiol conversion to complete breast development naturally)
• Timing debate: Some advocate deferring until adulthood to allow the patient to be fully involved in the decision; recent evidence supports this approach given the low pre-pubertal malignancy risk
• Method: Bilateral laparoscopic gonadectomy (preferred, especially for intra-abdominal testes)

3. Hormone Replacement Therapy (HRT) - Post-Gonadectomy

• Estrogen replacement: Conjugated estrogen or transdermal estradiol, continued until the usual age of menopause (~50 years)
  • Maintains secondary sexual characteristics (breasts, skin, vaginal health)
  • Prevents osteoporosis (bone protection)
  • Cardiovascular and metabolic benefits
• No progestogen needed - uterus is absent, so endometrial protection is not required
• Bone mineral density monitoring with DEXA scan

4. Vaginal Management

• Vagina may be short or inadequate in length
• Progressive vaginal dilation (Frank's method): first-line; self-dilation with progressively larger dilators
• If dilation fails: surgical vaginal lengthening:
  • McIndoe procedure (split-thickness skin graft neovaginoplasty)
  • Vecchietti procedure
  • Intestinal vaginoplasty
• Goal: functional vagina for sexual activity

5. Fertility Counselling

• CAIS patients are sterile (no uterus, no ovaries, intra-abdominal testes produce abnormal sperm if any)
• Cannot carry a pregnancy
• Adoption and surrogacy can be discussed in the future
• Genetic counselling for family members (X-linked recessive - mother may be a carrier)

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Summary Flowchart for This Case

16-year-old: Primary amenorrhea
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Secondary sexual characteristics?
  Breasts: PRESENT (Tanner IV-V)
  Pubic/axillary hair: ABSENT/SPARSE
  No cyclic pain
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Uterus absent on ultrasound
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Karyotype → 46,XY
Testosterone → Male range
LH → Elevated
AMH → Elevated
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DIAGNOSIS: Complete Androgen Insensitivity Syndrome (CAIS)
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Management:
1. Psychological counselling (immediate)
2. Reassure female gender identity
3. Gonadectomy (after puberty is complete / when patient consents)
4. Estrogen HRT (post-gonadectomy, lifelong)
5. Vaginal dilation if needed
6. Long-term follow-up: bone density, psychological support

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Key Teaching Points

1. Breast development = estrogen exposure. In CAIS, testosterone is aromatized peripherally to estradiol → normal breasts despite 46,XY karyotype
2. Absent pubic/axillary hair = non-functional androgen receptor. This is the single most distinguishing feature from MRKH (where hair is normal)
3. No uterus = no cyclic pain. Müllerian structures are absent because testes secrete MIS/AMH normally
4. Testosterone is in the male range - but biologically inactive due to non-functional AR
5. The gonads are testes, not ovaries - located in abdomen/inguinal canal/labia
6. AMH is elevated - the most sensitive biochemical marker (active testicular Sertoli cell function)
7. This is an X-linked recessive condition - mother is a carrier; 1 in 2 of her 46,XY offspring will be affected

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