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Classification, Pathogenesis, Investigations & Management of Amenorrhea

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Definition

• Primary amenorrhea: No spontaneous uterine bleeding by age 13 with no secondary sexual characteristics, OR by age 15 with normal secondary sexual characteristics present.
• Secondary amenorrhea: Cessation of previously regular menses for >=3 months, or irregular menses for >=6 months.
• Physiologic amenorrhea: Pregnancy, lactation, menopause - these are normal states.

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Classification Overview

• WHO Class I: Hypogonadotropic hypogonadism (hypothalamic/pituitary failure)
• WHO Class II: Normogonadotropic (PCOS, outflow obstruction)
• WHO Class III: Hypergonadotropic hypogonadism (ovarian failure)

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PRIMARY AMENORRHEA

A. Hypergonadotropic Hypogonadism (High FSH/LH, Low Estrogen) - NO Secondary Sexual Characteristics

1. Turner Syndrome (45,X)

• Initially normal ovarian development in utero, but accelerated atresia of follicles occurs due to loss of the second X chromosome. Result: fibrotic "streak ovaries" with no estrogen production. Elevated gonadotropins due to loss of negative feedback. Associated stigmata: short stature, webbed neck, shield chest, cubitus valgus, low hairline, high-arched palate, multiple pigmented nevi, short 4th metacarpals. A Y cell line must be excluded because of gonadoblastoma risk.

• Karyotype (45,X confirms; mosaicism 45,X/46,XX possible)
• FSH/LH: elevated
• Estradiol: low
• Pelvic ultrasound: streak ovaries, infantile uterus
• Bone age X-ray: delayed
• Echocardiogram (bicuspid aortic valve, coarctation)
• Renal ultrasound (horseshoe kidney)
• FISH/DNA analysis if Y material suspected
• Thyroid antibodies (autoimmune thyroiditis association)

• Estrogen replacement therapy: start with low-dose estrogen (0.3-0.625 mg/day conjugated estrogens or 0.5-1 mg/day estradiol) - avoid high doses in short-stature patients to prevent premature epiphyseal closure
• Add progestogen once breakthrough bleeding occurs or after 2 years: medroxyprogesterone acetate 5-10 mg for 12-14 days/month or continuous 2.5 mg/day
• Growth hormone therapy for short stature
• Gonadectomy if Y cell line detected (gonadoblastoma risk)
• Fertility: requires donor egg IVF; spontaneous pregnancy rare (mosaic forms only)

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2. Pure Gonadal Dysgenesis (46,XX or 46,XY)

• Bilateral streak gonads in chromosomally normal individuals. In 46,XY (Swyer syndrome): SRY gene mutation causes failure of testicular development; gonads are streaks but the patient has a female phenotype (Mullerian structures present). High malignancy risk in the dysgenetic gonad.

• Karyotype (46,XX or 46,XY)
• FSH/LH: elevated
• Testosterone: low (unlike androgen insensitivity)
• Pelvic ultrasound: streak gonads

• In 46,XY: immediate gonadectomy (30% risk of gonadoblastoma)
• Estrogen + progestogen replacement (same as Turner)
• IVF with donor egg for fertility

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3. 17α-Hydroxylase Deficiency

• Enzyme deficiency in both ovaries and adrenal glands prevents conversion of pregnenolone to sex steroids and cortisol. Results in accumulation of mineralocorticoids (hypertension, hypokalemia), low cortisol, low sex steroids. Patients have 46,XX karyotype but no secondary sexual characteristics, and elevated gonadotropins.

• Karyotype: 46,XX
• FSH/LH: elevated
• Progesterone, 17-OH progesterone: elevated
• Cortisol: low; ACTH: elevated
• Serum K+: low, BP elevated
• 24-hour urine steroids

• Glucocorticoid replacement (corrects ACTH excess)
• Estrogen + progestogen replacement for feminization
• Antihypertensives if needed

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B. Hypogonadotropic Hypogonadism (Low FSH/LH, Low Estrogen) - NO Secondary Sexual Characteristics

4. Kallmann Syndrome

• Failure of GnRH neurons to migrate from the olfactory placode to the hypothalamus (KAL1 gene mutation or FGFR1 mutation). Results in isolated GnRH deficiency + anosmia/hyposmia. X-linked (KAL1) or autosomal forms exist.

• FSH/LH: very low/undetectable
• Estradiol: low
• GnRH stimulation test: absent or blunted LH/FSH response (pituitary function intact, hypothalamic defect)
• MRI brain: absent/hypoplastic olfactory bulbs
• Smell testing (anosmia)
• Karyotype: 46,XX

• Pulsatile GnRH therapy (via pump) to induce puberty and fertility - most physiologic approach
• Alternative: exogenous gonadotropins (FSH + LH/hCG) for ovulation induction
• Hormone replacement therapy for feminization if fertility not desired

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5. Constitutional Delay of Puberty (Physiologic)

• Delayed maturation of the hypothalamic-pituitary-gonadal axis. Diagnosis of exclusion. Positive family history common.

• Bone age X-ray: delayed (key finding)
• FSH/LH: low-normal
• MRI brain: normal
• Karyotype: normal

• Reassurance and observation (most resolve spontaneously by age 18)
• Low-dose estrogen for 6 months if psychosocial impact severe

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6. CNS Tumors (Craniopharyngioma, Pituitary Adenoma)

• Mass effect compresses hypothalamus/pituitary stalk, disrupting GnRH pulse generation or gonadotropin secretion. Craniopharyngioma arises from Rathke's pouch remnants and is the most common suprasellar tumor in children.

• FSH/LH: low
• MRI brain with contrast (pituitary/hypothalamic region)
• Visual field testing (bitemporal hemianopia)
• Full pituitary hormone panel (GH, TSH, ACTH, prolactin)

• Craniopharyngioma: transsphenoidal resection or craniotomy depending on size; radiotherapy
• Pituitary adenoma: dopamine agonists (prolactinoma), transsphenoidal surgery, or radiotherapy
• Hormone replacement as needed post-treatment

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C. Outflow Tract Defects - Secondary Sexual Characteristics PRESENT

7. Imperforate Hymen / Transverse Vaginal Septum

• Obstruction at the level of the hymen or vagina prevents egress of menstrual blood. Blood accumulates: hematocolpos (vagina), hematometra (uterus), hematosalpinx (tubes). Cyclical pelvic pain with no visible menses is characteristic.

• Clinical exam: bulging bluish hymen
• Pelvic ultrasound: fluid-filled vagina/uterus (hematocolpos)
• MRI pelvis: better delineation of anatomy

• Surgical incision and drainage (hymenotomy)
• For vaginal septum: surgical resection
• Avoid delay - risk of endometriosis and infertility from retrograde menstruation

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8. Mullerian Agenesis (Mayer-Rokitansky-Kuster-Hauser Syndrome - MRKH)

• Failure of Mullerian duct development leads to absent or rudimentary uterus and upper vagina. Ovaries are normal (normal sex steroids, normal secondary sexual characteristics). Karyotype: 46,XX. Associated renal anomalies (horseshoe kidney, renal agenesis) in 30-40% and skeletal abnormalities. Distinction from androgen insensitivity syndrome (AIS): in MRKH, testosterone is female range; in AIS, testosterone is male range.

• FSH/LH: normal
• Testosterone: normal female range (distinguishes from AIS)
• Karyotype: 46,XX
• Pelvic ultrasound / MRI: absent uterus, normal ovaries
• Renal ultrasound

• Vaginal dilation (Frank technique - progressive dilators) - first-line, non-surgical
• Surgical vaginoplasty (McIndoe procedure) if dilation fails
• Fertility: surrogacy using patient's own eggs

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9. Androgen Insensitivity Syndrome (AIS) - 46,XY

• Mutation in the androgen receptor gene (Xq11-12) - X-linked. Testes are present (may be intra-abdominal) and produce testosterone, but tissues cannot respond. Mullerian regression factor (AMH) from testes causes regression of Mullerian structures - so no uterus/fallopian tubes. High estrogen (from peripheral conversion of testosterone) causes breast development but sparse/absent axillary and pubic hair.

• Testosterone: male range (key distinction from MRKH)
• Karyotype: 46,XY
• FSH/LH: normal to elevated
• Pelvic ultrasound / MRI: absent uterus, testes in inguinal canal or labia
• Androgen receptor gene mutation analysis

• Gonadectomy after puberty is complete (testes are malignant risk ~3-22%, mostly in adulthood)
• Estrogen replacement post-gonadectomy
• Vaginal dilation or surgery for vaginal lengthening
• Psychological counseling (disclosure and identity issues)

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SECONDARY AMENORRHEA

D. Pregnancy / Physiologic

• Investigations: serum/urine beta-hCG (most sensitive first test)

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E. Hypothalamic Causes (Low/Normal FSH, Low Estrogen)

10. Functional Hypothalamic Amenorrhea (FHA)

• Reversible suppression of GnRH pulse generator by metabolic/psychological stressors: weight loss, excessive exercise, caloric restriction, psychological stress. The "female athlete triad" is a classic example (energy deficiency + FHA + low bone density). Elevated cortisol and CRH suppress GnRH. Low leptin levels (from fat loss) remove a permissive signal for GnRH.

• Serum FSH/LH: low or normal but with reduced pulsatility
• Estradiol: low
• Prolactin: normal
• TSH: normal
• Progesterone challenge: may or may not bleed (depending on estrogen levels)
• BMI, nutritional assessment
• DEXA scan (bone density - often reduced)
• MRI brain if no obvious cause (to exclude CNS lesion)

• Treat underlying cause: weight restoration, reduced exercise, stress management, nutritional rehabilitation
• Cognitive behavioral therapy (CBT) - evidence-based for FHA
• Estrogen-progestogen replacement to protect bone density if recovery is delayed
• Transdermal estradiol preferred over oral contraceptives (OCP does not restore bone density as well)
• Avoid clomiphene/gonadotropins until metabolic deficit corrected

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11. Anorexia Nervosa

• Severe caloric restriction -> marked reduction in leptin, IGF-1, and kisspeptin -> suppression of hypothalamic GnRH -> hypogonadotropic hypogonadism. FSH/LH/estradiol all low. Cortisol elevated. T3 syndrome. Bone loss is severe.

• FSH/LH: low
• Estradiol: very low
• Complete metabolic panel, albumin (nutritional status)
• ECG (QTc prolongation, arrhythmias)
• DEXA scan
• Thyroid function: low T3 ("sick euthyroid")

• Multidisciplinary (psychiatry, nutrition, endocrinology, medical)
• Nutritional rehabilitation - primary treatment
• Menses usually return with weight restoration to BMI >18.5
• Estrogen replacement + calcium/vitamin D for bone protection
• No fertility treatment until nutritional recovery achieved

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F. Pituitary Causes

12. Hyperprolactinemia (Prolactinoma)

• Excess prolactin (from prolactinoma or drugs) suppresses hypothalamic GnRH pulsatility via short-loop feedback, decreasing LH/FSH pulses. Results in anovulation and amenorrhea. Galactorrhea may coexist. Dopamine normally inhibits prolactin; anything reducing dopamine (dopamine antagonist drugs, stalk compression) raises prolactin.

• Serum prolactin: elevated (>20 ng/mL pathologic; >200 ng/mL usually prolactinoma)
• TSH (hypothyroidism causes TRH-driven prolactin rise)
• MRI pituitary with gadolinium (microadenoma <10 mm vs macroadenoma >=10 mm)
• FSH/LH: low-normal
• Pregnancy test: rule out (physiologic hyperprolactinemia)
• Drug history: antipsychotics, metoclopramide, methyldopa, etc.

• Dopamine agonists: cabergoline (first-line, once or twice weekly; better tolerated) or bromocriptine (twice daily; preferred in women wanting pregnancy due to more safety data)
• Surgical: transsphenoidal surgery for drug-resistant/intolerant cases or large tumors with visual compromise
• Radiotherapy: reserved for persistent disease post-surgery
• Monitor: prolactin levels, MRI at 6-12 months, visual fields for macroadenomas
• Fertility: menses and ovulation usually return with dopamine agonist treatment

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13. Sheehan Syndrome (Panhypopituitarism)

• Ischemic necrosis of the anterior pituitary following massive postpartum hemorrhage. Enlarged pituitary during pregnancy is highly vulnerable to hypotension. Loss of all anterior pituitary hormones - amenorrhea is the first manifestation (failure to lactate + failure to resume menses post-delivery).

• All anterior pituitary hormones low: FSH/LH, TSH, ACTH, GH, prolactin
• MRI pituitary: empty sella or small necrotic pituitary
• ACTH stimulation test (cortisol response)
• Water deprivation test (rule out diabetes insipidus - posterior pituitary)

• Hormone replacement: hydrocortisone (most urgent - adrenal crisis risk), levothyroxine, estrogen/progesterone
• GH replacement in selected patients
• Desmopressin if central diabetes insipidus present
• Fertility possible with gonadotropin induction

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G. Ovarian Causes

14. Primary Ovarian Insufficiency (POI) / Premature Ovarian Failure

• Loss of ovarian function before age 40. Causes include:
  • Chromosomal: Partial X deletion (Xq21-28 critical), mosaicism, FMR1 premutation (13-26% of FMR1 premutation carriers develop POI)
  • Autoimmune: Lymphocytic oophoritis; associated with autoimmune thyroid disease, adrenal insufficiency, type 1 DM (screen for adrenal antibodies - 21-hydroxylase antibodies)
  • Iatrogenic: Chemotherapy (alkylating agents - cyclophosphamide), radiotherapy, bilateral oophorectomy, ovarian surgery
  • Infections: Mumps oophoritis
  • Galactosemia
  • Idiopathic: 30-90% of cases
• FSH >25-40 IU/L on two occasions 4 weeks apart (single FSH >50 IU/L strongly suggestive)

• FSH: elevated (>25-40 IU/L x2, 4 weeks apart)
• Estradiol: low
• AMH: low/undetectable
• Karyotype (if age <35)
• FMR1 premutation testing
• Thyroid antibodies (anti-TPO)
• Adrenal antibodies (21-hydroxylase / adrenal cortex antibodies)
• ACTH stimulation test if adrenal antibodies positive
• Pelvic ultrasound: small ovaries, reduced antral follicle count
• DEXA scan

• Hormone replacement therapy (HRT): estrogen-progestogen - essential to protect bone and cardiovascular health; continue until age 50 (natural menopause age)
• Emotional support / counseling (diagnosis is psychologically devastating in young women)
• Fertility counseling: ~5-10% chance of spontaneous conception; otherwise requires egg donation IVF
• Screen and treat autoimmune comorbidities (especially adrenal - risk of Addisonian crisis)
• Calcium 1000-1200 mg/day + Vitamin D

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15. Polycystic Ovary Syndrome (PCOS)

• Chronic anovulation due to disordered gonadotropin secretion: increased LH pulse frequency and amplitude (from insulin resistance / hyperinsulinism lowering SHBG and increasing LH sensitivity) stimulates excess androgen production from theca cells. FSH is relatively suppressed, preventing dominant follicle selection. Result: multiple small arrested follicles (antral follicles 2-9 mm - the "polycystic" appearance). Peripheral adipose tissue converts androgens to estrone, maintaining estrogen stimulation of the endometrium without progesterone withdrawal - increasing endometrial cancer risk with long-term anovulation.
• Rotterdam criteria (2 of 3): oligo/anovulation, clinical/biochemical hyperandrogenism, polycystic ovarian morphology (PCO) on ultrasound.

• FSH: normal or slightly low; LH: elevated (LH:FSH ratio >2-3, though not used routinely for diagnosis)
• Total and free testosterone: elevated
• DHEA-S, 17-OH progesterone (to exclude late-onset CAH)
• SHBG: low
• Fasting glucose + insulin; HOMA-IR (insulin resistance)
• HbA1c / OGTT
• Lipid profile
• AMH: often elevated (>35 pmol/L / 5 ng/mL suggests PCO morphology)
• Pelvic ultrasound: >=20 follicles per ovary (2-9 mm) OR ovarian volume >10 mL
• Endometrial biopsy if prolonged anovulation (endometrial hyperplasia/cancer risk)

• Lifestyle modification (first-line): weight loss (even 5-10% improves menstrual cyclicity and insulin resistance), exercise
• Menstrual regulation: Combined OCP (regulates menses, treats hyperandrogenism, protects endometrium) - preferred in women not seeking pregnancy
• Progestogen withdrawal (medroxyprogesterone acetate 10 mg for 10-14 days every 1-3 months) to induce withdrawal bleed and protect endometrium if OCP contraindicated
• Metformin: improves insulin resistance, restores menstrual cyclicity, adjunct to ovulation induction
• Ovulation induction (for fertility): letrozole (first-line aromatase inhibitor) > clomiphene citrate; gonadotropins if both fail; laparoscopic ovarian drilling if gonadotropin-resistant
• Hirsutism: anti-androgens (spironolactone, finasteride) combined with OCP
• Long-term monitoring for metabolic syndrome, type 2 DM, cardiovascular risk, endometrial cancer

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H. Uterine / Outflow Causes (Normogonadotropic)

16. Asherman Syndrome (Intrauterine Synechiae)

• Endometrial destruction and formation of intrauterine adhesions (synechiae) following uterine instrumentation (most commonly dilatation & curettage, especially post-abortion or post-partum D&C) or endometritis. The adhesions obliterate the endometrial cavity, preventing menstruation. Hormonal levels are normal - the uterus does not respond.

• Progesterone challenge test: no withdrawal bleed (despite adequate estrogen)
• Estrogen + progestogen test: still no bleed (confirms outflow obstruction or endometrial unresponsiveness)
• Hysteroscopy: gold standard - direct visualization of adhesions
• Hysterosalpingography (HSG): "irregular filling defects" in uterine cavity
• Sonohysterography (saline infusion sonography): useful screening
• FSH/LH/Estradiol: normal

• Hysteroscopic adhesiolysis (division of adhesions under direct vision)
• Post-operative estrogen therapy (high-dose conjugated estrogens 1.25-2.5 mg/day for 30-60 days) + progestogen to stimulate endometrial regeneration
• Intra-uterine device or balloon/stent may be placed temporarily to prevent re-adhesion
• Prognosis for fertility depends on severity of adhesions (American Fertility Society classification I-IV)

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I. Thyroid Disorders

17. Hypothyroidism

• Hypothyroidism causes elevated TRH, which stimulates both TSH and prolactin secretion -> secondary hyperprolactinemia -> GnRH suppression -> amenorrhea. Also: direct effect on gonadotropin pulsatility.

• TSH: elevated (primary hypothyroidism)
• Free T4: low
• Prolactin: may be mildly elevated
• Anti-TPO antibodies (Hashimoto's)

• Levothyroxine replacement - menses almost always resume with euthyroid state restoration

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18. Hyperthyroidism

• Excess thyroid hormones increase SHBG, decrease free androgens, alter LH pulsatility. Less commonly causes amenorrhea than hypothyroidism.

• TSH: suppressed
• Free T4/T3: elevated
• TSH receptor antibodies (Graves)

• Antithyroid drugs (propylthiouracil, methimazole), radioiodine, or thyroidectomy depending on cause

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Investigation Algorithm Summary

1. Rule out pregnancy (beta-hCG)
2. TSH, Prolactin (exclude thyroid disease and hyperprolactinemia)
3. FSH / LH
   - Elevated: Ovarian failure (POI/Turner) -> karyotype, FMR1, autoimmune screen
   - Normal: PCOS screen (testosterone, ultrasound), or outflow tract
   - Low: Hypothalamic/pituitary cause -> MRI brain/pituitary
4. Progesterone challenge test
   - Bleeds: Anovulation with intact outflow (PCOS/FHA likely)
   - No bleed + normal hormones: Outflow obstruction -> hysteroscopy
5. If no bleed + low estrogen + low/normal gonadotropins: MRI pituitary/hypothalamus
6. Estrogen + progesterone challenge (if progesterone challenge fails)
   - Bleeds: Confirms outflow intact, hypogonadism
   - No bleed: Confirms outflow obstruction (Asherman, Mullerian anomaly)

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Differential Diagnosis Table (Secondary Amenorrhea by Hormonal Pattern)

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Key Points

• Always exclude pregnancy first with beta-hCG.
• The four most common causes of secondary amenorrhea are: pregnancy, hyperprolactinemia, thyroid disorders, and iatrogenic (OCPs, antipsychotics).
• Elevated FSH = ovarian cause; Low FSH = hypothalamic or pituitary cause; Normal FSH + no bleed to progestins = outflow obstruction.
• FMR1 premutation carriers have a 13-26% lifetime risk of POI - genetic counseling is important.
• Bone density loss is a major complication of long-standing hypoestrogen from any cause - estrogen replacement or HRT is essential.
• In POI, adrenal antibody testing is mandatory - autoimmune adrenal insufficiency coexists in 20-40% and poses an Addisonian crisis risk.

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Clinical Case Analysis: Amenorrhea - Differential Diagnosis, Investigation Algorithm & Management

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CASE 1: 15-Year-Old Girl - Primary Amenorrhea WITH Cyclical Lower Abdominal Pain

Clinical Reasoning

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Differential Diagnosis

"Transverse blockage of the outflow tract with an intact endometrium frequently causes cyclic pain without menstrual bleeding in adolescents. The blockage of blood flow can cause hematocolpos, hematometra, hemoperitoneum, and endometriosis." - Berek & Novak's Gynecology

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Investigation Algorithm

• Inspect the introitus: imperforate hymen shows a bluish, bulging, tense membrane (from trapped blood = hematocolpos)
• Transverse septum: no bulge visible but foreshortened vagina
• Check for secondary sexual characteristics (present - confirms HPO axis intact)

• Pelvic ultrasound (transabdominal): first-line imaging
  • Hematocolpos: fluid-distended vagina
  • Hematometra: blood-filled uterus
  • Normal ovaries bilaterally (confirms normal gonadal function)
• MRI pelvis: gold standard for anatomical delineation
  • Precisely maps the level and thickness of obstruction
  • Rules out uterine anomalies (didelphys, bicornuate)
  • Essential for surgical planning

• FSH, LH: normal
• Estradiol: normal (puberty has occurred)
• Beta-hCG: negative
• No karyotype needed unless examination is atypical

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Management

• Cruciate (X-shaped) incision of the hymen under anesthesia - allows complete drainage of hematocolpos
• Drain the retained blood completely
• Avoid needle aspiration alone - remove the obstruction entirely
• Post-op: check for complete drainage on ultrasound
• Prognosis: excellent fertility if treated promptly

• Surgical excision of the septum
• Level of septum: 46% upper third, 40% middle third (most common locations)
• Post-operatively: vaginal dilators must be used to prevent adhesion and re-obstruction during healing
• Fertility outcomes: good with early surgical repair; upper/middle septa may carry slightly higher infertility risk

• First-line: laparoscopic uterovaginal anastomosis (conservative)
• Hysterectomy if conservative surgery fails
• Ovaries retained regardless to preserve endocrine function and allow future IVF surrogacy options

• May resolve spontaneously once obstruction is relieved
• GnRH agonist therapy if significant disease found

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CASE 2: 16-Year-Old Girl - Primary Amenorrhea, No Secondary Sexual Characteristics Stated

Clinical Reasoning

• No secondary sexual characteristics: indicates failure of estrogen production (either gonadal or hypothalamic/pituitary origin) - hypergonadotropic or hypogonadotropic hypogonadism.
• Secondary sexual characteristics present: outflow obstruction or MRKH or AIS (covered in Case 1 / androgen insensitivity).

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Differential Diagnosis

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Investigation Algorithm

• Height, weight, BMI - short stature suggests Turner
• Smell test (anosmia suggests Kallmann)
• Secondary sexual characteristics (Tanner staging)
• Dysmorphic features (Turner stigmata)
• Visual fields (bitemporal hemianopia = pituitary/suprasellar mass)
• Pelvic examination or imaging

• Karyotype - mandatory
  • 45,X or mosaic: Turner syndrome
  • 46,XX: pure gonadal dysgenesis
  • 46,XY: Swyer syndrome - urgent gonadectomy
• FMR1 premutation testing (if <35 years)
• Thyroid antibodies, adrenal antibodies
• Pelvic ultrasound: streak ovaries, uterine size
• Echocardiogram + renal ultrasound (Turner)
• DEXA scan (bone density)

• MRI brain/pituitary (to exclude craniopharyngioma, other CNS mass)
• Olfactory testing (Kallmann)
• Bone age X-ray (constitutional delay: delayed bone age; diagnosis of exclusion)
• GnRH stimulation test (to differentiate hypothalamic from pituitary cause)
  • Pituitary responds to exogenous GnRH in hypothalamic failure; does not respond in pituitary failure
• Full pituitary panel: GH, IGF-1, cortisol (ACTH stimulation), TFTs

• Pelvic ultrasound or MRI: is a uterus present?
  • No uterus: testosterone level (if male range = AIS; if female range = MRKH)
  • Uterus present but obstructed: imperforate hymen, vaginal septum (see Case 1)

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Management

• Estrogen therapy: start low (0.3-0.625 mg/day conjugated estrogens or 0.5-1 mg/day estradiol) - avoid high doses to prevent premature epiphyseal closure in short-stature patients. Gradually increase over months.
• Add progestogen after 1-2 years or when breakthrough bleeding occurs (MPA 5-10 mg for 12-14 days/month OR oral micronized progesterone 200 mg for 12-14 days/month)
• Growth hormone therapy (under paediatric endocrinology) for height augmentation
• Gonadectomy only if Y cell line detected
• Cardiac and renal follow-up
• Annual thyroid function, bone density monitoring
• Psychological counseling; fertility via donor egg IVF

• Goal is induction of puberty: start low-dose estrogen, gradually increase
• For fertility: pulsatile GnRH pump (most physiologic) or exogenous gonadotropins (FSH + hCG)

• Reassurance; watchful waiting (usually spontaneous menarche by age 17-18)
• Short-course low-dose estrogen if psychosocial distress is significant

• Transsphenoidal surgery or craniotomy depending on size
• Post-surgical hormone replacement (pituitary hypofunction expected)
• Radiotherapy for residual/recurrent disease

• Vaginal dilation (Frank technique - progressive dilators) - first-line, non-surgical
• McIndoe vaginoplasty or Vecchietti procedure if dilation fails
• Fertility via gestational surrogacy using patient's own eggs

• AIS: gonadectomy after puberty (30%+ risk of gonadoblastoma over lifetime); estrogen replacement; vaginal dilation
• Swyer syndrome: immediate gonadectomy at diagnosis; HRT for feminization

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CASE 3: 24-Year-Old Married Woman - Secondary Amenorrhea for 3 Months, Previously Regular Cycles

Clinical Reasoning

1. Pregnancy / lactation
2. Hyperprolactinemia
3. Thyroid disorders (hypothyroidism > hyperthyroidism)
4. Iatrogenic (OCPs, antipsychotics)
5. PCOS (though usually presents with irregular rather than absent cycles)
6. Functional hypothalamic amenorrhea (stress, weight loss, exercise)
7. POI (less likely at 24 but possible)

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Differential Diagnosis

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Investigation Algorithm

STEP 1: Beta-hCG (urine or serum)
   ├── POSITIVE → Confirm intrauterine pregnancy by USS
   │              Manage accordingly (obstetric care)
   └── NEGATIVE → Proceed to Step 2

STEP 2: TSH + Serum Prolactin
   ├── TSH elevated (hypothyroidism) → Treat with levothyroxine
   │   (menses usually restore within 3-6 months)
   ├── TSH suppressed (hyperthyroidism) → Anti-thyroid drugs / RAI / surgery
   ├── Prolactin elevated → MRI pituitary (see Case 4)
   └── Both normal → Proceed to Step 3

STEP 3: FSH, LH, Estradiol + Testosterone, DHEA-S, 17-OH progesterone
   ├── FSH elevated (>25 IU/L x2, 4 weeks apart) → POI
   │   → Karyotype, FMR1, autoimmune screen
   ├── Testosterone / DHEA-S elevated → PCOS vs. CAH vs. androgen tumor
   │   → Pelvic USS, 17-OH progesterone, OGTT
   └── All normal → Proceed to Step 4

STEP 4: Progestogen Challenge Test
   (Medroxyprogesterone acetate 10 mg/day x 10 days)
   ├── BLEEDS within 2-7 days of stopping
   │   → Confirms adequate estrogen + intact outflow
   │   → Diagnosis: anovulation (PCOS, functional hypothalamic, post-pill)
   │   → Pelvic ultrasound for PCOS; assess BMI/stress/exercise history
   └── NO BLEED → Proceed to Step 5

STEP 5: Estrogen + Progestogen Challenge
   (Conjugated estrogens 1.25 mg/day x 21 days + MPA 10 mg on days 16-21)
   ├── BLEEDS → Confirms outflow intact; hypoestrogen confirmed
   │   → Re-check FSH (if elevated = POI; if low = FHA/pituitary)
   │   → MRI pituitary/hypothalamus
   └── NO BLEED → Outflow obstruction confirmed
       → Hysteroscopy (Asherman syndrome)
       → Pelvic USS / MRI for anatomical cause

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Management by Cause

• Levothyroxine (starting 25-50 mcg/day; titrate to normalize TSH)
• Menses usually resume within 3-6 months of achieving euthyroid state

• Reassurance - resolves spontaneously within 3-6 months in most cases
• No specific treatment needed; investigate only if beyond 6 months

• Lifestyle modification (weight loss 5-10% restores cycles)
• OCP (menstrual regulation, endometrial protection)
• Metformin (insulin resistance)
• Ovulation induction if fertility desired (letrozole first-line)

• Identify and address the stressor (weight restoration, reduce exercise, manage stress)
• CBT (cognitive behavioral therapy) - evidence-based
• Estrogen/progestogen if hypoestrogen persists (bone protection)
• No hormonal induction of ovulation until energy balance is restored

• HRT (estrogen + progestogen) until age 50
• Autoimmune workup; adrenal antibodies
• Fertility counseling: ~5-10% spontaneous conception; donor egg IVF otherwise
• Calcium + Vitamin D; DEXA scan

• Hysteroscopic adhesiolysis
• Post-op high-dose estrogen (conjugated estrogens 1.25-2.5 mg/day x 30-60 days) + progestogen
• IUD or intrauterine balloon post-operatively to prevent re-adhesion

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CASE 4: 30-Year-Old Woman - Amenorrhea 7 Months + Galactorrhea + Headache

Clinical Reasoning

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Differential Diagnosis

"Prolactin levels can be increased by pituitary adenomas that produce prolactin, by other CNS lesions that disrupt the normal transport of dopamine down the pituitary stalk, and by medications that interfere with normal dopamine secretion." - Berek & Novak's Gynecology

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Investigation Algorithm

STEP 1: Confirm Hyperprolactinemia
   - Serum prolactin (fasting, morning, non-stressful venepuncture)
   - Re-measure if mildly elevated (physiologic factors can raise levels transiently)
   - Note: "Hook effect" - very high prolactin (>10,000 ng/mL) may give falsely low reading
     → Request serial dilution if macroprolactinoma suspected clinically but PRL seemingly low
   - Macroprolactin (IgG-bound prolactin): check if asymptomatic mild elevation - biologically inactive

STEP 2: Rule out secondary causes BEFORE imaging
   ├── Beta-hCG (physiologic lactation from pregnancy!)
   ├── TSH (hypothyroidism → TRH stimulates prolactin)
   ├── Renal function panel (chronic renal failure)
   └── Drug history review (antipsychotics, metoclopramide, etc.)
       → If drug is causative: stop drug if possible (consult prescribing physician)

STEP 3: Prolactin Level Interpretation
   ├── <100 ng/mL with headache → Consider stalk compression, drug cause, hypothyroidism
   ├── 100-250 ng/mL → Microadenoma likely; proceed to MRI
   └── >250 ng/mL → Macroadenoma likely; proceed urgently to MRI + ophthalmology

STEP 4: MRI Pituitary with Gadolinium Contrast (gold standard)
   ├── Microadenoma (<10 mm): hypointense lesion within pituitary
   ├── Macroadenoma (≥10 mm): large pituitary mass ± suprasellar extension
   └── Empty sella, stalk compression, craniopharyngioma: alternative diagnoses

STEP 5: Full Pituitary Hormone Panel
   - FSH, LH (suppressed)
   - Estradiol (low)
   - IGF-1, GH (acromegaly co-secretion?)
   - Cortisol (8 AM) / ACTH stimulation test (pituitary compression → secondary adrenal insufficiency)
   - TSH, free T4

STEP 6: Ophthalmology Assessment
   - Formal visual field testing (Humphrey perimetry)
   - Mandatory if macroadenoma with suprasellar extension
   - Baseline before treatment; monitor during treatment

STEP 7: Bone Density (DEXA scan)
   - Estrogen deficiency + hyperprolactinemia = accelerated bone loss

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Management

First-Line: Dopamine Agonist Therapy

• Dopamine agonists normalize prolactin in ~90% of microadenomas and ~70% of macroadenomas
• Tumor shrinkage occurs in most macroadenomas (median reduction 50-60%)
• Menses and ovulation resume in most women within weeks to months of starting treatment
• Caution: cardiac valvular effects of cabergoline are a concern at high doses used in Parkinson's disease, but the doses used for prolactinoma are much lower and risk is not established

• Prolactin levels at 4-6 weeks, then 3-6 monthly
• MRI pituitary at 6-12 months (macroadenoma) or annually (microadenoma)
• Visual fields re-test at 3 months for macroadenoma (should improve rapidly with dopamine agonist)

Second-Line: Transsphenoidal Surgery

• Drug intolerance or resistance (prolactin fails to normalize or tumor fails to shrink)
• Macroadenoma with visual compromise that does not improve rapidly on medical therapy
• Patient preference
• CSF leak from tumor apoplexy
• Desire to stop medication and attempt remission

• Microadenoma: ~70-80% surgical cure rate
• Macroadenoma: ~30-40% cure rate (higher recurrence)
• Risk: panhypopituitarism, CSF leak, meningitis, visual injury

Third-Line: Radiotherapy

• Stereotactic radiosurgery (gamma knife) for persistent disease after medical + surgical failure
• Effect is slow (years) and risk of hypopituitarism is significant

Specific Considerations for This Case:

• Start cabergoline urgently
• Ophthalmology review for visual fields within 1-2 weeks
• If acute visual loss: emergency transsphenoidal surgery
• Treat secondary adrenal insufficiency first if co-present (hydrocortisone before levothyroxine)

• Menses and fertility typically restore with dopamine agonist treatment
• Bromocriptine preferred if patient wants to conceive (more pregnancy safety data)
• Stop dopamine agonist once pregnancy confirmed (for microadenomas; continue for macroadenomas with prior suprasellar extension under close monitoring)
• Monitor for tumor growth during pregnancy: visual fields monthly; MRI if symptoms recur

• Estrogen supplementation if amenorrhea/hypoestrogen persists despite treatment
• Calcium 1000 mg/day + Vitamin D 800-1000 IU/day
• DEXA follow-up

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Summary Comparison Table