Eduovisual
Female Reproductive & Breast
Amenorrhea: primary and secondary workup
— Primary amenorrhea: no menses by age 15 with normal secondary sexual characteristics, OR no menses by age 13 with absent secondary sexual characteristics, OR no menses within 3 years of thelarche
— Secondary amenorrhea: absence of menses for ≥3 months in a previously regular cycler, or ≥6 months in a previously irregular cycler
— Oligomenorrhea: cycles >35 days (often managed on same workup pathway)
— Pregnancy (always the first test — urine or serum β-hCG)
— Lactation, menopause (age-appropriate), recent hormonal contraception use
— Compartment I: outflow tract/uterus (imperforate hymen, Asherman, Müllerian agenesis)
— Compartment II: ovary (POI, gonadal dysgenesis, PCOS)
— Compartment III: pituitary (prolactinoma, Sheehan, empty sella)
— Compartment IV: hypothalamus (functional hypothalamic amenorrhea, anorexia, exercise, stress)
— Adolescent presenting with delayed menarche + short stature → think Turner
— Cyclic pelvic pain without menses → outflow obstruction
— Galactorrhea + headaches/visual changes → prolactinoma
— Hot flashes + amenorrhea before age 40 → primary ovarian insufficiency (POI)
— Athlete/dancer with low BMI → functional hypothalamic amenorrhea (female athlete triad/RED-S)
— Hirsutism, acne, obesity → PCOS
Board pearl: Müllerian agenesis (MRKH) and complete androgen insensitivity both present with primary amenorrhea + normal breasts + absent uterus — distinguish by karyotype and testosterone level.
— Never menstruated → primary amenorrhea pathway
— Stopped menstruating → secondary amenorrhea pathway
— Acute cessation after delivery/PPH → Sheehan syndrome (failure to lactate is a classic clue)
— Cessation after D&C or uterine instrumentation → Asherman syndrome
— Sexual activity, contraception, last menstrual period, prior pregnancies
— Weight changes, dietary restriction, exercise intensity (>10 hrs/week aerobic)
— Stress, sleep, mood, eating disorder screen (SCOFF)
— Galactorrhea, headache, visual field changes, anosmia (Kallmann)
— Hot flashes, night sweats, vaginal dryness, dyspareunia → hypoestrogenism
— Hirsutism, acne, voice deepening, clitoromegaly → androgen excess
— Medications: antipsychotics (risperidone, haloperidol → hyperprolactinemia), metoclopramide, opioids, GnRH agonists, chemotherapy, hormonal contraception, glucocorticoids
— Chronic illness: celiac, IBD, type 1 DM, thyroid disease, CKD
— Family history: age of maternal menopause (POI clusters in families), fragile X premutation, autoimmune disease
— Tanner staging at presentation guides workup
— Breast development present + uterus present → outflow obstruction or chronic anovulation
— Breast development present + uterus absent → MRKH or androgen insensitivity
— Breast development absent → hypogonadism (check FSH to localize)
— Cyclic pelvic pain with primary amenorrhea (hematocolpos)
— Headache + bitemporal visual loss (pituitary macroadenoma)
— Severe weight loss, bradycardia, orthostasis (anorexia nervosa)
— Virilization of rapid onset (androgen-secreting tumor)
Key distinction: Functional hypothalamic amenorrhea is a diagnosis of exclusion — you must rule out structural pituitary disease, thyroid dysfunction, hyperprolactinemia, and pregnancy before assigning it, even when the history screams stress/exercise/low BMI.
Step 3 management: Document a complete medication reconciliation at the first visit; iatrogenic hyperprolactinemia from second-generation antipsychotics is one of the most commonly missed causes of secondary amenorrhea and is correctable.
— BMI <18.5, bradycardia (HR <50), orthostatic hypotension → anorexia nervosa (admission criteria)
— Hypertension + central obesity + striae → Cushing
— Short stature (<150 cm), webbed neck, shield chest, widely spaced nipples → Turner syndrome (45,XO)
— Hirsutism (Ferriman-Gallwey ≥8), acne, male-pattern balding → PCOS or androgen excess
— Acanthosis nigricans → insulin resistance (PCOS)
— Striae, buffalo hump, moon facies → Cushing
— Vitiligo → autoimmune polyglandular syndrome (think POI, Addison, thyroid)
— Clitoromegaly, voice deepening, temporal balding → virilizing tumor or NCAH
— Bitemporal hemianopsia → pituitary macroadenoma
— Anosmia + delayed puberty → Kallmann syndrome (GnRH deficiency)
— Goiter, tremor, lid lag → thyroid disease
— Tanner staging (essential in primary amenorrhea)
— Galactorrhea → hyperprolactinemia (compress all quadrants)
— Absent breast development → hypoestrogenism
— Imperforate hymen: bulging bluish membrane, hematocolpos
— Transverse vaginal septum: blind vaginal pouch
— Müllerian agenesis (MRKH): blind vaginal pouch, absent uterus, normal breasts, 46,XX, normal testosterone
— Complete androgen insensitivity: blind vaginal pouch, absent uterus, scant pubic/axillary hair, 46,XY, testosterone in male range
— Estrogen status assessment: pale/thin vaginal mucosa, absent rugae → hypoestrogenic
Board pearl: In a phenotypic female with primary amenorrhea, absent uterus on exam/ultrasound narrows the differential to two diagnoses — MRKH vs. CAIS — and the next test is karyotype + serum testosterone.
Step 3 management: Adolescents may decline pelvic exam; transabdominal pelvic ultrasound is an acceptable, less invasive first-line anatomic assessment and is often preferred in this age group for both comfort and yield.
— β-hCG — always first
— TSH — hypothyroidism causes amenorrhea via TRH-mediated prolactin rise
— Prolactin — fasting, non-stressed, repeat if mildly elevated
— FSH (± LH, estradiol) — localizes the axis
— High FSH (>25–40), low estradiol → primary ovarian failure (POI if <40, menopause if age-appropriate) — repeat in 4–6 weeks to confirm
— Low/normal FSH, low estradiol → hypothalamic or pituitary cause → MRI brain
— Normal FSH, normal estradiol → outflow tract or anovulation (PCOS) → progestin challenge or ultrasound
— Hirsutism/acne: total testosterone, DHEAS, 17-hydroxyprogesterone (morning, follicular phase if cycling)
— Suspected Cushing: 24-hr urine free cortisol, late-night salivary cortisol, low-dose dex suppression
— Suspected POI <40: karyotype, FMR1 premutation (fragile X), adrenal antibodies, fasting glucose, TPO antibodies
— Suspected eating disorder: CBC, CMP (hypokalemia, hypophosphatemia on refeeding), ECG (QT)
— Pelvic ultrasound — confirm uterus presence, assess endometrial thickness, identify polycystic morphology (≥20 follicles or volume >10 mL per ovary in adults)
— MRI pituitary with contrast — if prolactin elevated, FSH/LH low, or visual/neuro symptoms
— DEXA — in any patient with ≥6 months of hypoestrogenic amenorrhea (osteoporosis risk)
— Withdrawal bleed → adequate estrogen, intact outflow → anovulation (PCOS)
— No bleed → either hypoestrogenism or outflow obstruction → estrogen-progestin challenge to distinguish
CCS pearl: Order β-hCG, TSH, prolactin, FSH as a single initial panel in the CCS amenorrhea case; advancing the clock without these four will cost you points. Repeat a borderline-elevated prolactin fasting and without recent breast exam or exercise before ordering MRI.
— Confirm with repeat fasting prolactin (avoid post-exercise, post-coitus, post-breast exam)
— If persistently >25 ng/mL → MRI pituitary with contrast
— Macroadenoma (≥10 mm) → formal visual field testing (Humphrey perimetry)
— Consider macroprolactin assay if prolactin elevated but asymptomatic (big-big prolactin artifact)
— Karyotype (Turner mosaic, 46,XY gonadal dysgenesis with risk of gonadoblastoma)
— FMR1 premutation testing — most common identifiable genetic cause
— Adrenal antibodies (21-hydroxylase Ab) — risk for autoimmune Addison; if positive, ACTH stim test
— TPO antibodies, fasting glucose, vitamin D, DEXA
— Exclude mimics: 17-OHP (CAH), DHEAS (adrenal tumor), testosterone (if >150–200 ng/dL, image for ovarian tumor)
— Metabolic workup: fasting glucose + HbA1c or OGTT, lipid panel, BP, BMI
— Endometrial biopsy if amenorrhea >1 year and unopposed estrogen exposure (risk of endometrial hyperplasia/cancer)
— History of D&C, retained products, endometritis, or uterine surgery
— Saline infusion sonohysterography or hysteroscopy (gold standard, diagnostic and therapeutic)
— Failure to bleed after sequential estrogen + progestin challenge supports diagnosis
— Pelvic ultrasound → MRI pelvis for complex Müllerian anomalies (septate uterus, OHVIRA)
— Renal ultrasound (40% of Müllerian anomalies have renal anomalies)
— Diagnosis of exclusion: normal MRI, low/normal FSH/LH, low estradiol, no other cause
— Assess bone density (DEXA), vitamin D, lipid panel
Board pearl: Testosterone >150–200 ng/dL or DHEAS >700 µg/dL with rapid-onset virilization mandates imaging for an androgen-secreting ovarian or adrenal tumor — do not anchor on PCOS.
Step 3 management: Document a DEXA scan in any patient with ≥6 months hypoestrogenic amenorrhea; this is a frequently missed quality metric and a real Step 3 stem.
— Hypoestrogenic (low estradiol, regardless of FSH): bone, cardiovascular, and genitourinary risks — needs estrogen replacement unless contraindicated
— Normoestrogenic anovulation (PCOS): unopposed estrogen → endometrial cancer risk — needs cyclic progestin or combined hormonal contraception
— Outflow obstruction: surgical correction; risk of endometriosis from retrograde menstruation if delayed
— Pregnancy-related: prenatal care pathway
— PCOS + not desiring pregnancy → combined OCP (first-line) + lifestyle modification
— PCOS + desiring pregnancy → letrozole (first-line ovulation induction, superior to clomiphene)
— Hyperprolactinemia (prolactinoma) → cabergoline (preferred over bromocriptine)
— Hypothyroidism → levothyroxine; menses typically resume with euthyroid state
— POI → estrogen + progestin replacement until average age of menopause (~51); fertility counseling, egg donation
— Functional hypothalamic amenorrhea → nutritional rehabilitation, reduce exercise, CBT; hormone therapy only if menses don't resume after 6–12 months of lifestyle correction
— Asherman → hysteroscopic lysis of adhesions + estrogen post-op
— Outflow obstruction → surgical correction (hymenotomy, septum resection)
— Annual BP, lipid screening, diabetes screening (OGTT preferred q3 years if normal, more often if obese)
— Sleep apnea screening if obese
— Depression/anxiety screening (increased prevalence)
Key distinction: In functional hypothalamic amenorrhea, the first-line treatment is behavioral, not pharmacologic. Estrogen replacement does not restore bone density as effectively as weight restoration and is reserved for patients failing 6–12 months of lifestyle intervention. This contrasts with POI, where hormone replacement is the immediate first-line therapy.
Step 3 management: For PCOS patients started on OCPs, schedule a 3-month follow-up to reassess cycles, BP, and side effects, then annual cardiometabolic monitoring.
— Combined oral contraceptive (COC) — first-line for menstrual regulation, hirsutism, acne; any low-dose COC works, but those with non-androgenic progestins (drospirenone, norgestimate, desogestrel) are preferred for hyperandrogenism
— Metformin — add if impaired glucose tolerance, T2DM, or for weight/metabolic benefit; not first-line for menstrual regulation alone
— Spironolactone 50–100 mg BID — adjunct for hirsutism; requires reliable contraception (teratogenic, feminization of male fetus)
— Letrozole 2.5–7.5 mg days 3–7 — first-line ovulation induction for fertility (PPCOS II trial: superior live birth vs clomiphene)
— Eflornithine cream — topical for facial hirsutism
— Cabergoline 0.25 mg twice weekly, titrate to normalize prolactin — preferred (better tolerability, more effective tumor shrinkage)
— Bromocriptine — preferred in pregnancy (more safety data) and in patients planning conception
— Monitor prolactin q1 month initially, then q3–6 months; MRI at 1 year or with symptom change
— Transdermal estradiol 100 µg/day patch + cyclic micronized progesterone 200 mg × 12 days/month (preferred regimen — physiologic dosing, lower VTE risk than oral)
— Continue until age ~51 (average menopause)
— Calcium 1000–1200 mg/day, vitamin D 800–1000 IU/day
— Combined OCP acceptable if contraception also needed, but lower estrogen exposure than full HRT
— Medroxyprogesterone 10 mg × 10–14 days every 1–3 months — induces withdrawal bleed and protects endometrium when COC contraindicated
— Levothyroxine, titrate to TSH 0.5–2.5; menses usually resume within months
Board pearl: Cabergoline shrinks macroprolactinomas and is first-line even for tumors causing visual field defects — surgery is reserved for medication failure, intolerance, or apoplexy. This is a high-yield switch from older bromocriptine-first teaching.
Step 3 management: Before prescribing spironolactone for hirsutism, document contraception and obtain baseline potassium and creatinine; recheck potassium at 1 month.
— Imperforate hymen: cruciate or elliptical hymenotomy, ideally after pubertal estrogenization for tissue pliability
— Transverse vaginal septum: resection with Z-plasty; refer to specialized center
— MRKH: vaginal dilation (first-line, Frank dilators successful in 90–95%) before surgical neovagina creation
— OHVIRA (obstructed hemivagina + ipsilateral renal anomaly): hemivaginal septum resection
— Hysteroscopic adhesiolysis under direct visualization
— Post-op estrogen therapy (high-dose for 1–2 months) to promote endometrial regrowth
— Adjuncts: intrauterine balloon, hyaluronic acid gel, second-look hysteroscopy
— Indications: dopamine agonist intolerance/failure, pituitary apoplexy, CSF leak from tumor shrinkage, persistent visual compromise despite medical therapy
— Cushing disease — surgery is first-line (not medical management)
— Complete androgen insensitivity (46,XY, intra-abdominal testes): gonadectomy after puberty completion (allows estrogenization from peripheral aromatization), then estrogen replacement; ~2% malignancy risk
— 46,XY gonadal dysgenesis (Swyer): gonadectomy promptly at diagnosis — up to 30% gonadoblastoma risk
— Turner mosaic with Y chromosome material: prophylactic gonadectomy
— Failed letrozole/clomiphene → gonadotropin therapy with cycle monitoring
— Laparoscopic ovarian drilling — second-line; declining use
— IVF for refractory cases
Key distinction: CAIS gonadectomy is deferred until after puberty; Swyer syndrome gonadectomy is immediate. The difference: CAIS gonads produce estrogen via aromatization and have low malignancy risk pre-puberty; Swyer gonads are streak, hormonally inert, and have high tumor risk.
CCS pearl: When a CCS amenorrhea case reveals an absent uterus + 46,XY karyotype + intra-abdominal testes (CAIS), advance the clock to after Tanner V, then order bilateral gonadectomy and begin estrogen replacement at that visit. Premature gonadectomy costs points.
— In women >45, amenorrhea is usually physiologic menopause — workup limited unless atypical features
— Postmenopausal bleeding (PMB) after established amenorrhea: always pathologic until proven otherwise — transvaginal ultrasound (endometrial stripe >4 mm → endometrial biopsy)
— POI patients reaching natural menopause age (~51) → discontinue HRT, reassess cardiovascular risk
— Lowest effective dose, shortest duration for vasomotor symptoms
— Avoid initiation >10 years post-menopause or age >60 (increased CV/stroke risk)
— Transdermal preferred in women with VTE risk, migraines with aura, hypertriglyceridemia, hepatic impairment
— CKD itself causes hypothalamic-pituitary dysfunction → amenorrhea common in advanced CKD/dialysis
— Prolactin clearance reduced → mildly elevated levels expected; correlate with symptoms
— Spironolactone — contraindicated/use with caution if eGFR <30 or hyperkalemia
— Metformin — contraindicated if eGFR <30; reduce dose if 30–45
— Dose-adjust gonadotropin therapy carefully
— Avoid oral estrogen (hepatic first-pass) — use transdermal estradiol
— Cabergoline — hepatically metabolized; use cautiously
— Combined OCPs contraindicated in active liver disease, hepatic adenoma, decompensated cirrhosis
— Acute hepatitis or cholestasis can transiently disrupt menstruation
— DEXA at diagnosis and q1–2 years
— Treat osteoporosis with bisphosphonates if HRT contraindicated; avoid bisphosphonates in women planning future pregnancy (long skeletal half-life, theoretical fetal risk)
Board pearl: Endometrial stripe ≤4 mm on TVUS in a postmenopausal woman with bleeding has a high negative predictive value for endometrial cancer; >4 mm or persistent bleeding → endometrial biopsy regardless of stripe.
Step 3 management: In a CKD patient on dialysis with secondary amenorrhea, the elevated prolactin you find is often physiologic from reduced clearance — don't reflexively order pituitary MRI without correlating symptoms and excluding medications.
— Evaluate at age 13 if no secondary sexual characteristics, age 15 if normal secondary characteristics, or earlier with red flags (cyclic pain, growth failure, neurologic symptoms)
— Confidentiality: state-dependent rules for adolescent reproductive health; document HEEADSSS assessment
— Karyotype results require multidisciplinary disclosure (genetic counselor, psychologist) — particularly for DSD diagnoses
— Bone accrual peaks late adolescence; hypoestrogenic amenorrhea during this window has lifelong skeletal consequences
— Triad: low energy availability ± eating disorder, menstrual dysfunction, low bone density
— Highest risk: distance runners, ballet, gymnastics, figure skating, wrestling
— Treatment: increase caloric intake, reduce training volume, multidisciplinary team (sports medicine, nutrition, psychology)
— Hormonal contraception masks the underlying problem and does not restore bone — counsel athletes accordingly
— β-hCG first, always — including in patients on contraception, with tubal ligation history, or denying sexual activity
— Sheehan syndrome: peripartum pituitary necrosis after PPH → panhypopituitarism → secondary amenorrhea + failure to lactate + adrenal insufficiency; treat with cortisol BEFORE thyroid replacement
— Lymphocytic hypophysitis: pregnancy/postpartum autoimmune pituitary inflammation; mimics adenoma on MRI
— Premature thelarche/adrenarche without progression — generally benign
— Central precocious puberty (girls <8) — GnRH agonist
— Turner syndrome — growth hormone for stature, estrogen for puberty induction (start low-dose age ~11–12, gradually increase), then add progestin after breakthrough bleeding or 2 years
— POI, pre-chemotherapy, gender-affirming care: oocyte cryopreservation, ovarian tissue cryopreservation, GnRH agonist co-treatment during chemo (debated)
Key distinction: In female athlete triad, resuming menses through nutritional rehabilitation improves bone density; giving OCPs does not — and may falsely reassure the patient and clinician. This is a frequently tested counseling point.
Step 3 management: In any adolescent with hypoestrogenic amenorrhea, screen for eating disorders (SCOFF), depression (PHQ-9), and substance use; refer to multidisciplinary care.
— Osteoporosis and fragility fractures — bone loss begins within months; vertebral and hip fracture risk lifelong
— Cardiovascular disease — premature menopause/POI raises CHD risk; estrogen deprivation accelerates atherosclerosis
— Genitourinary syndrome of menopause — vaginal atrophy, dyspareunia, recurrent UTI
— Cognitive and mood effects — depression, anxiety, possible cognitive decline
— Infertility — central concern; counseling and reproductive options
— Endometrial hyperplasia and endometrial cancer — 2–6× increased risk; protect endometrium with cyclic progestin or COC
— Type 2 diabetes — screen with OGTT or HbA1c
— Dyslipidemia, hypertension, NAFLD, OSA, metabolic syndrome
— Infertility and increased pregnancy complications (GDM, preeclampsia, preterm birth)
— Mood disorders — depression, anxiety, eating disorders
— Macroadenoma mass effect: bitemporal hemianopsia, cranial nerve palsies, hypopituitarism
— Pituitary apoplexy — sudden headache, vision loss, ophthalmoplegia, hypotension — endocrine emergency
— Galactorrhea, decreased libido, infertility
— Hematocolpos, hematometra, hematosalpinx → endometriosis from retrograde menstruation, adhesions, infertility
— Post-surgical re-stenosis
— Infertility, recurrent pregnancy loss, placenta accreta spectrum in future pregnancies
— VTE from oral estrogen (especially with smoking, obesity, thrombophilia)
— Endometrial cancer from unopposed estrogen
— Hyperkalemia from spironolactone
— OHSS from gonadotropin ovulation induction
Board pearl: Any PCOS patient with amenorrhea >12 months or postmenopausal-style bleeding warrants endometrial biopsy before initiating fertility treatment — undiagnosed hyperplasia/cancer changes the management plan entirely.
Step 3 management: Co-prescribe calcium, vitamin D, and weight-bearing exercise in every hypoestrogenic patient, regardless of whether you are treating with hormones — these adjuncts are guideline-recommended and frequently omitted.
— Anorexia nervosa with medical instability: HR <50 awake or <45 asleep, SBP <90, orthostatic HR rise >20, temp <36°C, BMI <14, electrolyte derangement, ECG abnormalities — admit for refeeding under monitoring (phosphate, potassium, magnesium daily)
— Pituitary apoplexy: sudden severe headache + visual loss + ophthalmoplegia → emergent neurosurgical evaluation, stress-dose hydrocortisone immediately, MRI
— Sheehan syndrome with adrenal crisis: hypotension, hyponatremia, hypoglycemia — IV hydrocortisone, fluids; thyroid replacement only AFTER cortisol
— Severe symptomatic hyperprolactinemia with visual compromise — admit if rapidly progressive
— Severe ovarian hyperstimulation syndrome from fertility treatment — third-spacing, hemoconcentration, VTE, ascites
— Reproductive endocrinology: POI, recurrent pregnancy loss, fertility evaluation, complex anovulation
— Endocrinology: macroadenoma, Cushing, congenital adrenal hyperplasia, panhypopituitarism
— Neurosurgery: macroadenoma with vision changes, apoplexy, surgical candidates
— Genetics: Turner, fragile X premutation, DSD, familial POI
— Adolescent medicine / Eating disorders: female athlete triad, anorexia, RED-S
— Gynecologic surgery: outflow obstruction, Asherman, Müllerian anomalies
— Psychiatry: eating disorders, depression, adjustment to fertility loss
— Genetic counseling: prior to and after karyotyping, FMR1 testing
— DSD care teams: pediatric endocrinology, gynecology, urology, psychology, genetics
— Eating disorder programs: medicine, nutrition, psychiatry, family therapy
CCS pearl: In a CCS case of suspected pituitary apoplexy, the order set is: IV hydrocortisone 100 mg → IV normal saline → STAT MRI pituitary → neurosurgery consult → ophthalmology consult. Do not delay hydrocortisone for imaging or labs; secondary adrenal insufficiency is the immediate killer.
Step 3 management: For anorexia nervosa with bradycardia <40 or refeeding electrolyte derangement, transfer to a specialized eating disorder unit rather than general medicine — outcomes are markedly better.
— Functional hypothalamic amenorrhea: stress, weight loss, exercise — diagnosis of exclusion
— Kallmann syndrome: GnRH deficiency + anosmia (KAL1, FGFR1 mutations); often primary amenorrhea
— Isolated congenital hypogonadotropic hypogonadism: GnRH deficiency without anosmia
— Infiltrative disease: sarcoidosis, hemochromatosis, Langerhans histiocytosis
— Craniopharyngioma, hypothalamic tumors, radiation
— Drugs: opioids (chronic use → opioid-induced hypogonadism), GnRH agonists, glucocorticoids
— Prolactinoma (most common pituitary adenoma)
— Non-functioning pituitary adenoma with stalk effect
— Sheehan syndrome (postpartum pituitary necrosis after PPH)
— Lymphocytic hypophysitis (autoimmune; pregnancy/postpartum-associated, also from immune checkpoint inhibitors)
— Empty sella syndrome
— Drug-induced hyperprolactinemia: antipsychotics (risperidone, haloperidol), metoclopramide, methyldopa, verapamil, TCAs, opioids, estrogens
— Pituitary apoplexy
— Primary ovarian insufficiency (POI): idiopathic (most common), autoimmune, fragile X premutation, post-chemotherapy/radiation, galactosemia
— Turner syndrome (45,XO and mosaics) — gonadal dysgenesis, streak gonads
— 46,XY gonadal dysgenesis (Swyer syndrome) — phenotypic female, streak gonads, high gonadoblastoma risk
— Resistant ovary syndrome (Savage syndrome)
— Surgical oophorectomy
— Rotterdam criteria; exclude mimics (CAH, Cushing, androgen-secreting tumor, hyperprolactinemia, thyroid disease)
Key distinction: Hypothalamic vs pituitary localization is challenging without imaging; both produce low FSH/LH and low estradiol. The GnRH stimulation test can localize but is rarely used clinically — MRI pituitary is the practical next step in low-FSH amenorrhea after excluding eating disorder and medications.
Board pearl: Fragile X premutation (FMR1) is the most common identifiable genetic cause of POI — test all women with POI before age 40, especially with family history of intellectual disability or tremor/ataxia.
— Asherman syndrome: intrauterine adhesions after D&C, endometritis, retained products, uterine surgery
— Cervical stenosis: post-LEEP/cone biopsy, post-radiation, post-infection
— Imperforate hymen (primary amenorrhea, cyclic pain, hematocolpos)
— Transverse vaginal septum
— Müllerian agenesis (MRKH syndrome): 46,XX, absent uterus/upper vagina, normal ovaries, normal breasts, normal hair pattern; 40% renal anomalies, vertebral anomalies (MURCS)
— Complete androgen insensitivity (CAIS): 46,XY, absent uterus, normal breasts, scant pubic/axillary hair, intra-abdominal testes, testosterone in male range
— Hypothyroidism: TRH stimulates prolactin → secondary hyperprolactinemia + direct effects on cycle
— Hyperthyroidism: oligomenorrhea more common than amenorrhea
— Cushing syndrome: cortisol excess suppresses GnRH
— Congenital adrenal hyperplasia (non-classic 21-hydroxylase deficiency): elevated 17-OHP, hyperandrogenism mimicking PCOS
— Adrenal or ovarian androgen-secreting tumor: rapid-onset virilization, very high testosterone or DHEAS
— Acromegaly: GH excess → menstrual disturbance
— Intrauterine pregnancy, ectopic, molar pregnancy
— Recent miscarriage, retained products
— Lactational amenorrhea
— Celiac disease, IBD, chronic kidney disease, cirrhosis, HIV, malignancy
— Severe stress, depression, opioid use
— Hormonal contraception (post-pill amenorrhea — usually <6 months; if >6 months, workup as secondary amenorrhea)
— Depot medroxyprogesterone, levonorgestrel IUD (often desired effect)
— Chemotherapy (especially alkylators), pelvic radiation
— Antipsychotics, antidepressants, opioids, glucocorticoids
Board pearl: In PCOS workup, always check 17-hydroxyprogesterone in the early morning, follicular phase — non-classic congenital adrenal hyperplasia (NCAH) is a common PCOS mimic, treated with low-dose glucocorticoids, with implications for offspring genetic counseling.
Step 3 management: Post-pill amenorrhea beyond 6 months is not "normal" — initiate the standard secondary amenorrhea workup; do not attribute to contraception history.
— Estrogen + progestin until age ~51 (transdermal estradiol 100 µg + cyclic progesterone preferred)
— Annual: BP, lipid panel, fasting glucose, TSH (autoimmune cluster), DEXA q1–2 years
— Calcium 1000–1200 mg/day, vitamin D 800–1000 IU/day, weight-bearing exercise
— Cardiovascular risk reduction: smoking cessation, statin if indicated
— Fertility counseling: egg donation, adoption, embryo donation; spontaneous pregnancy rate 5–10%
— Mental health support and patient advocacy resources
— Annual BP, weight/BMI, depression screening
— Lipid panel at baseline, repeat q2 years (more often if abnormal)
— Diabetes screening: OGTT or HbA1c at baseline, repeat q3 years (more often if obese, family history, prior GDM)
— Endometrial protection: COC, cyclic progestin, or levonorgestrel IUD if amenorrhea persists
— Lifestyle: 5–10% weight loss restores ovulation in many; Mediterranean diet, 150 min/week moderate exercise
— Hirsutism: COC ± spironolactone; counsel that response takes 6 months
— Preconception counseling: folate, weight optimization, glucose control, letrozole for ovulation induction
— Microadenoma: cabergoline, prolactin q3–6 months once stable, MRI q1–2 years initially then less frequent
— Macroadenoma: closer monitoring, visual fields, MRI q1 year
— Attempt drug holiday after 2+ years of normal prolactin and tumor shrinkage; recurrence ~50%
— Nutrition, weight restoration, stress reduction, CBT
— If menses don't resume in 6–12 months → consider transdermal estradiol + cyclic progesterone for bone protection
— Repeat DEXA q1–2 years
— Contraception needs (return of fertility can be unpredictable)
— Bone health and calcium/vitamin D
— Cardiovascular risk factor management
— Mental health screening at each visit
Step 3 management: For a PCOS patient on metformin and COC, schedule return visits at 3 months then annually; check LFTs, lipids, glucose, and BP, and ask explicitly about hirsutism response and mood.
Board pearl: POI patients should continue HRT until average age of menopause (~51) — this is replacement, not treatment — and the cardiovascular and bone benefits outweigh risks at physiologic doses.
— PCOS on COC: 3 months, then annually
— POI on HRT: 3 months for symptom/dose adjustment, then every 6–12 months
— Prolactinoma on cabergoline: prolactin at 1 month, then q3 months until stable, then q6–12 months; MRI at 1 year (sooner for macroadenoma or visual changes)
— Hypothalamic amenorrhea: monthly during nutritional rehabilitation, then q3 months
— Post-surgical (Asherman, outflow obstruction): 4–6 weeks post-op, then by symptoms
— PCOS: BP, weight, glucose, lipids, depression screen; pelvic ultrasound only for new symptoms (not surveillance)
— POI: estradiol level not routinely needed if symptoms controlled; FSH suppression not a treatment goal; DEXA q1–2 years
— Prolactinoma: prolactin level, visual fields if macroadenoma, MRI as above
— Spironolactone: K+ and creatinine at 1 month, then annually
— Metformin: B12 q1–2 years, renal function annually
— Adolescents: developmentally appropriate, confidential where legal, parental involvement balanced; bone accrual education
— Athletes: explain that OCPs do not fix bone density in RED-S; weight restoration does
— Infertility: timeline expectations, ovulation tracking, when to escalate to ART, emotional support
— POI: bereavement-type counseling; address sexual function, partner communication, family-building options
— DSD diagnoses: developmentally staged disclosure, peer support groups, psychology referral
— Pregnancy excluded? Documented β-hCG?
— DEXA in hypoestrogenic amenorrhea ≥6 months?
— Endometrial protection plan in PCOS with anovulation?
— Contraception plan if spironolactone or letrozole prescribed?
— Mental health screening at each visit?
Key distinction: Estradiol levels are not a treatment target in POI; clinical symptom control and bone protection are. Patients often arrive asking "what's my estrogen number" — counsel that symptom-based dosing is the standard.
Step 3 management: Build a shared decision-making note for HRT in POI documenting bone, cardiovascular, GU, and quality-of-life benefits weighed against (low at physiologic doses) VTE and breast cancer concerns; many patients have read about WHI and need contextualization.
— Most US states allow adolescents to consent to reproductive health services (contraception, STI testing, pregnancy services) without parental notification — know your state
— Karyotyping that reveals DSD (e.g., 46,XY in a phenotypic adolescent female) requires carefully staged, developmentally appropriate disclosure, ideally in a multidisciplinary setting with psychology and genetic counseling
— Avoid disclosing karyotype directly to a young adolescent without parental and team preparation; document the disclosure plan
— Pregnancy in a minor may trigger mandatory reporting of statutory rape depending on state age-of-consent and partner-age differential laws
— Eating disorders in minors with severe medical instability may warrant involuntary treatment evaluation if parents refuse care
— Document suicidality screening; eating disorders carry the highest mortality of psychiatric illnesses
— Gonadectomy in CAIS: historically performed without patient knowledge; current standard is delayed surgery with full informed consent at age of capacity
— Fertility-ending treatments (chemotherapy, radiation, oophorectomy): document fertility preservation discussion before initiation
— Off-label medications (e.g., letrozole for ovulation induction — now standard but technically off-label): document discussion
— POI patients aging out of adolescent gynecology may discontinue HRT during transition — schedule warm handoffs
— Patients leaving fertility clinics for primary care may lose endometrial protection counseling — communicate clearly
— Post-discharge after Sheehan or apoplexy: ensure steroid stress-dose education, MedicAlert bracelet, endocrinology follow-up
— POI and PCOS care disparities by race/ethnicity and insurance
— Fertility treatments often not covered by insurance — counsel on cost upfront
— Eating disorders underdiagnosed in patients of color and in higher-weight patients
— Always document β-hCG before ordering pelvic imaging with contrast, before initiating teratogenic medications (spironolactone, isotretinoin, methotrexate, ACEi)
— Spironolactone requires effective contraception — undocumented contraception is a sentinel event in some systems
Step 3 management: When prescribing spironolactone for PCOS hirsutism, document in the chart: (1) negative β-hCG, (2) contraception method, (3) baseline K+ and creatinine, and (4) teratogenicity counseling. Missing any of these is a real-world safety event.
— Anosmia + primary amenorrhea → Kallmann syndrome
— Short stature + webbed neck + amenorrhea → Turner (45,XO)
— Failure to lactate + amenorrhea + postpartum hemorrhage → Sheehan syndrome
— Amenorrhea + galactorrhea + bitemporal hemianopsia → prolactinoma (macroadenoma)
— Cyclic pelvic pain + primary amenorrhea + normal secondary characteristics → imperforate hymen or transverse vaginal septum
— Amenorrhea + low BMI + bradycardia + low bone density → female athlete triad / anorexia
— Absent uterus + 46,XX + normal breasts + normal hair → MRKH
— Absent uterus + 46,XY + normal breasts + sparse pubic hair → CAIS
— Hirsutism + obesity + acne + oligomenorrhea → PCOS
— Rapid virilization + very high testosterone → androgen-secreting tumor
— Amenorrhea after D&C → Asherman
— Amenorrhea + autoimmune disease cluster (vitiligo, Hashimoto, type 1 DM, Addison) → autoimmune POI
— High FSH + low estradiol → primary ovarian failure
— Low FSH + low estradiol → hypothalamic or pituitary
— Normal FSH + normal estradiol + anovulation → PCOS or thyroid/prolactin issue
— Elevated prolactin → exclude pregnancy, hypothyroidism, medications before MRI
— Testosterone >150–200 ng/dL → ovarian tumor
— DHEAS >700 µg/dL → adrenal tumor
— 17-OHP elevated → non-classic CAH
— Risperidone causes amenorrhea more than any other antipsychotic (highest prolactin)
— Aripiprazole and quetiapine have lowest prolactin effect — switch options
— Letrozole > clomiphene for PCOS ovulation induction (PPCOS II)
— Cabergoline > bromocriptine for prolactinoma (except in pregnancy planning)
— Transdermal estradiol > oral in VTE risk, liver disease, migraine with aura
— Fragile X premutation → POI + tremor/ataxia in male relatives
— BRCA1/2 → earlier menopause, fertility preservation considerations
— Galactosemia → POI
Board pearl: When the stem mentions an antipsychotic and amenorrhea/galactorrhea, the answer is switch to aripiprazole (or check prolactin and discuss with prescriber) — not order pituitary MRI.
— Normal breast development, no uterus on ultrasound
— Next step: karyotype + serum testosterone
— Answer flow: 46,XX with male-range testosterone is impossible; 46,XX, normal female testosterone → MRKH; 46,XY, male-range testosterone → CAIS
— β-hCG negative, TSH normal, prolactin 85
— Next step: repeat fasting prolactin; if persistently elevated → MRI pituitary
— Trap: skipping straight to MRI without confirming prolactin
— Normal exam, low FSH, low estradiol, normal prolactin/TSH, normal MRI
— Diagnosis: functional hypothalamic amenorrhea
— First-line treatment: nutritional rehabilitation, reduce exercise, CBT — not OCPs
— Negative progestin challenge, no withdrawal bleed after estrogen + progestin
— Diagnosis: Asherman syndrome
— Next step: hysteroscopy
— Repeat FSH in 4+ weeks confirms; estradiol low
— Diagnosis: POI
— Next steps: karyotype, FMR1, adrenal antibodies, TSH, DEXA; start HRT (transdermal estradiol + cyclic progesterone)
— Ultrasound: polycystic morphology; testosterone mildly elevated
— Diagnosis: PCOS (after excluding CAH, Cushing, prolactinoma)
— Not desiring pregnancy → COC; desiring pregnancy → letrozole
— Diagnosis: imperforate hymen with hematocolpos
— Treatment: hymenotomy
— Low TSH, low free T4, low cortisol, low FSH
— Diagnosis: Sheehan syndrome
— Treatment: hydrocortisone first, then levothyroxine, then sex hormone replacement
Board pearl: When a stem describes a postpartum patient with failure to lactate, the diagnosis is almost always Sheehan — and the first medication ordered is hydrocortisone, never thyroxine first.
Amenorrhea workup begins with β-hCG, then TSH, prolactin, and FSH, framed by the four-compartment model (outflow tract, ovary, pituitary, hypothalamus) — with management driven by etiology, estrogen status, fertility goals, and protection of bone and endometrium.
— Regardless of contraception, tubal ligation, or denied sexual activity, pregnancy is the most common cause of secondary amenorrhea and must be excluded before any imaging, medication, or invasive workup — a non-negotiable patient safety step.
— Outflow obstruction (imperforate hymen, MRKH, Asherman) → surgical/anatomic correction
— Ovarian failure (high FSH, POI, Turner) → karyotype, FMR1, autoimmune workup, HRT to age 51
— Pituitary (high prolactin, Sheehan, macroadenoma) → MRI, cabergoline, stress-dose steroids if apoplexy/Sheehan
— Hypothalamic (low FSH, functional, Kallmann) → nutritional rehab first-line, MRI to exclude structural disease
— Hypoestrogenic states (POI, hypothalamic amenorrhea, hyperprolactinemia) → bone, cardiovascular, GU risks → estrogen replacement or treat underlying cause
— Normoestrogenic anovulation (PCOS) → endometrial cancer risk → cyclic progestin or COC, metabolic surveillance
— Confirm pregnancy excluded → localize the axis with targeted labs → image only when indicated → manage by etiology with attention to fertility, bone, endometrium, cardiometabolic risk, and mental health → schedule structured follow-up (3 months then annual) → document teratogenicity counseling and contraception when prescribing spironolactone, letrozole, or other reproductive-age medications → engage multidisciplinary care for DSD, eating disorders, POI, and complex Müllerian anomalies.
Board pearl: If you remember only one sequence: β-hCG → TSH → prolactin → FSH → progestin challenge ± pelvic ultrasound → targeted next step. This single algorithm correctly directs the vast majority of Step 3 amenorrhea stems.