Female Reproductive & Breast

Infertility: female workup and treatment overview

Clinical Overview and When to Suspect Female Infertility

— Earlier evaluation (immediate) is warranted for known risk factors: oligo/amenorrhea, stage III–IV endometriosis, prior pelvic inflammatory disease (PID), pelvic surgery, chemotherapy/radiation, age ≥40, or known male factor.

— Ovulatory dysfunction (~25%) — PCOS most common, hypothalamic amenorrhea, hyperprolactinemia, thyroid disease, primary ovarian insufficiency (POI).

— Tubal/peritoneal factor (~20%) — prior PID (chlamydia/gonorrhea), endometriosis, prior ectopic, tubal ligation.

— Uterine/cervical factor — fibroids (submucosal), polyps, Asherman syndrome, congenital müllerian anomalies.

— Diminished ovarian reserve / age-related decline.

— Unexplained (~15–20%).

— A 32-year-old with regular menses TTC ×14 months → begin full workup of both partners simultaneously.

— A 38-year-old TTC ×7 months → begin workup now (don't wait the full year).

— Irregular cycles + hirsutism + BMI 32 → think PCOS-driven anovulation.

— Severe dysmenorrhea + dyspareunia → endometriosis.

— Prior chlamydia or appendiceal rupture → tubal factor.

Definition: Failure to conceive after 12 months of regular, unprotected intercourse in women <35 years, or after 6 months in women ≥35 years.

Epidemiology: ~12–15% of US couples; causes split roughly into thirds — female factor (~35%), male factor (~30%), combined or unexplained (~35%).

Primary categories of female-factor infertility:

When to suspect on Step 3 stem:

Step 3 management: Always evaluate the couple simultaneously — order a semen analysis at the very first visit. Delaying male workup while pursuing female studies is a classic distractor and a real-world inefficiency.

Board pearl: Age is the single strongest predictor of female fertility; fecundability drops sharply after 35 and precipitously after 40, independent of all other testing. Counsel on this before ordering ovarian reserve labs.

Presentation Patterns and Key History

— Regular 25–35-day cycles with molimina (breast tenderness, mittelschmerz, predictable PMS) → ovulatory in >95% of cases.

— Oligomenorrhea (cycles >35 days) or amenorrhea → anovulation; trigger PCOS, thyroid, prolactin, hypothalamic workup.

— Shortened follicular phase / cycles <24 days → diminished ovarian reserve.

— Gravidity/parity, prior live births, miscarriages, ectopics, terminations (helps distinguish primary vs secondary infertility).

— Duration of unprotected intercourse, coital frequency (optimal every 1–2 days around ovulation), use of lubricants (many are spermicidal).

— Contraceptive history and time since discontinuation.

— STIs (chlamydia/gonorrhea → tubal scarring), prior PID, abnormal Pap/LEEP (cervical stenosis), prior pelvic surgery, D&C (Asherman), fibroids, endometriosis, dysmenorrhea, dyspareunia.

— Galactorrhea (prolactinoma), heat/cold intolerance (thyroid), hirsutism/acne (PCOS, CAH), hot flashes/vaginal dryness in <40 (POI), visual changes/headaches (pituitary mass).

— BMI extremes (both low and high impair ovulation), eating disorders, excessive exercise, tobacco (accelerates ovarian aging by ~10 years), alcohol, cannabis, caffeine >500 mg/d, occupational toxins, chemotherapy/radiation.

Cycle history — the single most informative element:

Targeted reproductive history:

Gynecologic history:

Endocrine/systemic red flags:

Lifestyle and exposures:

Family history: Early menopause (<40 in mother/sister → consider fragile X premutation/FMR1 testing), recurrent pregnancy loss, congenital anomalies.

Partner history: prior paternity, varicocele, mumps orchitis, hernia repair, anabolic steroids, environmental heat exposure.

Key distinction: Primary infertility = never conceived; secondary infertility = prior conception (live birth, loss, or ectopic) — secondary still requires full workup, as tubal damage from a prior ectopic or postpartum infection is the classic cause.

Board pearl: Regular cycles with molimina effectively rule out ovulatory dysfunction; do not over-test ovulation in such a patient — pivot directly to tubal and uterine evaluation.

Physical Exam Findings

— BMI — both obesity (PCOS, insulin resistance) and very low BMI (hypothalamic amenorrhea, functional anovulation) impair fertility.

— Vital signs typically normal; orthostasis or bradycardia raise concern for eating disorder.

— Hirsutism (Ferriman-Gallwey ≥8), acne, acanthosis nigricans, male-pattern alopecia → PCOS or, less commonly, nonclassic CAH, Cushing, androgen-secreting tumor.

— Striae, moon facies, central obesity → Cushing syndrome.

— Vitiligo, hyperpigmentation → autoimmune polyglandular syndrome with POI.

— Visual field deficits (bitemporal hemianopsia) → pituitary macroadenoma.

— Goiter, thyroid nodules, eye signs → thyroid dysfunction.

— Galactorrhea on breast exam → hyperprolactinemia.

— Palpable adnexal masses → endometrioma, ovarian neoplasm, hydrosalpinx.

— Uterine enlargement, irregular contour → fibroids.

— Fixed/retroverted uterus, uterosacral nodularity, posterior cul-de-sac tenderness → endometriosis (classic triad).

— Cervical motion or adnexal tenderness → chronic PID sequelae.

— Vaginal atrophy in young patient → POI or hypoestrogenic state.

General/vitals and habitus:

Skin and androgen excess findings:

Head/neck:

Breast exam: Tanner staging in adolescent presentations; absent breast development with primary amenorrhea suggests estrogen deficiency.

Abdominal/pelvic exam:

Tanner-discordant findings in primary amenorrhea workup raise müllerian agenesis (MRKH) vs androgen insensitivity — examine for presence of pubic hair and a vaginal canal.

Step 3 management: A normal pelvic exam does not rule out tubal disease or endometriosis — proceed with imaging (HSG) and labs regardless.

Board pearl: Uterosacral nodularity + cul-de-sac tenderness on bimanual exam is highly specific for endometriosis; this finding alone justifies referral for diagnostic laparoscopy in an infertile patient.

Key distinction: Galactorrhea + amenorrhea + headache = think prolactinoma; order prolactin first, then MRI pituitary if elevated and not drug-induced.

Diagnostic Workup — Initial Labs and Imaging

— Semen analysis for the male partner — order at visit 1, repeat in 2–3 months if abnormal.

— Confirm rubella, varicella immunity; HIV, hepatitis B/C, syphilis; blood type/Rh; Pap up to date; cervical chlamydia/gonorrhea NAAT.

— Mid-luteal (cycle day 21–23) serum progesterone — >3 ng/mL confirms ovulation (>10 suggests robust ovulation).

— Urinary LH kits, basal body temperature, and menstrual diary support but don't replace progesterone.

— AMH (anti-müllerian hormone) — cycle-independent; low values (<1.0 ng/mL) suggest diminished reserve.

— Cycle day 2–4 FSH and estradiol — FSH >10 IU/L with normal estradiol suggests diminished reserve; high estradiol can falsely normalize FSH.

— Antral follicle count by transvaginal ultrasound (<5–7 total = low reserve).

— TSH (target <2.5 mIU/L preconception), prolactin (fasting, no recent breast exam/intercourse), testosterone and DHEAS if hyperandrogenic, 17-OH progesterone if NC-CAH suspected.

— Hemoglobin A1c, fasting glucose, lipid panel in suspected PCOS.

— Transvaginal ultrasound — uterine cavity, fibroids, polyps, ovarian morphology (PCO-appearance: ≥20 follicles per ovary or volume >10 mL), antral follicle count, hydrosalpinx.

— Hysterosalpingogram (HSG) in early follicular phase (cycle day 5–10, after menses, before ovulation) — assesses tubal patency and uterine cavity.

First-visit basics (both partners):

Ovulation assessment:

Ovarian reserve testing — indicated if ≥35, family history of early menopause, prior ovarian surgery/chemo, single ovary, or unexplained infertility:

Endocrine screen:

Imaging:

CCS pearl: Order semen analysis, mid-luteal progesterone, TSH, prolactin, and HSG as the core opening battery — these five tests cover the majority of correctable causes.

Board pearl: Day-3 FSH plus estradiol must be interpreted together; an "isolated normal" FSH with estradiol >80 pg/mL still indicates diminished reserve.

Diagnostic Workup — Advanced or Confirmatory Studies

— Saline-infusion sonohysterography (SIS) — best for polyps, submucosal fibroids, synechiae; higher sensitivity than HSG for intracavitary lesions.

— Hysteroscopy — gold standard, both diagnostic and therapeutic (resect polyp, lyse adhesions, septum resection).

— MRI pelvis — characterize fibroids, adenomyosis, complex müllerian anomalies (e.g., distinguishing septate from bicornuate uterus before surgery).

— Laparoscopy with chromopertubation — direct visualization of tubes, peritoneum, ovaries; diagnostic and therapeutic for endometriosis, adhesions, hydrosalpinx.

— Hydrosalpinx on imaging → salpingectomy before IVF (hydrosalpinx fluid is embryotoxic and halves implantation rates).

— MRI pituitary if prolactin elevated and not drug-induced, or if visual symptoms.

— Karyotype + FMR1 premutation in women <40 with elevated FSH/low AMH → rule out Turner mosaic, fragile X-associated POI.

— Adrenal imaging if DHEAS markedly elevated (>700 µg/dL).

— Dexamethasone suppression if Cushing suspected.

— Antiphospholipid antibody panel (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein-I), TSH, parental karyotype, hysteroscopy, consider thrombophilia evaluation selectively.

Uterine cavity evaluation when HSG is equivocal or recurrent loss is present:

Tubal evaluation when HSG abnormal or endometriosis suspected:

Endocrine and genetic studies:

Recurrent pregnancy loss workup (≥2 losses):

Cervical factor: Postcoital testing is no longer recommended — poor reproducibility.

Key distinction: SIS detects intracavitary lesions; HSG detects tubal patency. They answer different questions — SIS is not a substitute for HSG when tubal status is unknown.

Step 3 management: Don't repeat AMH frequently — it's a snapshot of reserve, not a treatment marker. Repeat only if clinical picture changes meaningfully or before IVF planning.

Board pearl: A unilateral hydrosalpinx visible on TVUS reduces IVF success by ~50%; prophylactic salpingectomy before IVF restores pregnancy rates.

Risk Stratification and First-Line Management Logic

— Ovulatory dysfunction (PCOS, hypothalamic, hyperprolactinemia, thyroid): treat root cause → induce ovulation.

— Tubal factor: IVF is first-line for bilateral occlusion; tubal surgery only in carefully selected young patients with focal distal disease.

— Endometriosis (mild/moderate): laparoscopic ablation/resection improves spontaneous conception; severe → IVF.

— Uterine factor: hysteroscopic resection of submucosal fibroids/polyps/septum/synechiae.

— Male factor: IUI for mild; ICSI for severe oligospermia or azoospermia (with surgical sperm retrieval).

— Unexplained infertility: stepwise — lifestyle optimization → 3 cycles ovulation induction + IUI → IVF.

— Folic acid 400–800 µg/d (4 mg if prior NTD or on antiepileptics); start 3 months pre-conception.

— Smoking cessation, alcohol limit, caffeine <200 mg/d, BMI optimization (weight loss of 5–10% in obese PCOS often restores ovulation).

— Update vaccinations (MMR, varicella, Tdap, influenza, COVID, HPV).

— Optimize chronic disease (HbA1c <6.5%, BP control, switch teratogenic meds: ACEi/ARB, statins, isotretinoin, warfarin, valproate, methotrexate).

— <35: can pursue conservative measures 6–12 months.

— 35–39: more aggressive; consider IUI early, IVF if no success in 3–6 cycles of lower-intensity therapy.

— ≥40: counsel that IVF success per cycle is ~10–15%; donor oocyte may be discussed early.

Stepwise framework after workup — match treatment to diagnosis:

Pre-treatment optimization (always):

Age-based decision tree:

Step 3 management: Lifestyle modification — particularly weight loss in obese PCOS — restores ovulation in ~50–60% and is the single highest-yield first intervention before any pharmacotherapy.

Board pearl: Bilateral tubal occlusion = go straight to IVF, do not waste time on ovulation induction with IUI.

Pharmacotherapy — Ovulation Induction Regimens

— Aromatase inhibitor, 2.5–7.5 mg daily on cycle days 3–7.

— PPCOS II trial: higher live birth rates than clomiphene in PCOS (27.5% vs 19.1%).

— Lower multiple-gestation risk than clomiphene, no thinning of endometrium.

— Off-label for infertility but standard of care.

— Selective estrogen receptor modulator, 50–150 mg days 3–7 or 5–9.

— Antiestrogen effect on endometrium/cervical mucus (downside).

— Multiple pregnancy risk ~7–10%; ovarian hyperstimulation rare.

— Maximum 6 ovulatory cycles — if no pregnancy, escalate.

— Adjunct in PCOS with insulin resistance/obesity; restores ovulation modestly.

— Combined with clomiphene/letrozole if monotherapy fails.

— Continue or stop in pregnancy per individual case (generally safe; often continued through first trimester in GDM-prone patients).

— Injectable, used when oral agents fail or with IUI/IVF.

— High risk of ovarian hyperstimulation syndrome (OHSS) and multiple gestation — requires monitoring with TVUS and estradiol.

Letrozole (first-line for PCOS-associated anovulation):

Clomiphene citrate:

Metformin:

Gonadotropins (FSH ± LH):

GnRH agonists/antagonists: Used in IVF cycles to prevent premature LH surge (leuprolide, ganirelix, cetrorelix).

hCG trigger: Mimics LH surge to induce final oocyte maturation 36 hours before retrieval/IUI.

Bromocriptine or cabergoline: First-line for hyperprolactinemia-driven anovulation; cabergoline preferred (better tolerated, twice-weekly). Stop once pregnant in microadenoma.

Levothyroxine: Target TSH <2.5 mIU/L preconception in hypothyroidism.

Pulsatile GnRH (rare): for hypothalamic amenorrhea unresponsive to weight restoration.

Step 3 management: PCOS anovulation → letrozole first, not clomiphene. This is a relatively recent guideline shift and is heavily tested.

Board pearl: Monitor all gonadotropin cycles with TVUS; cancel the cycle if >3 mature follicles to avoid high-order multiples and OHSS.

Procedures — IUI, IVF, and Surgical Interventions

— Washed sperm placed in uterine cavity around ovulation.

— Indications: mild male factor, cervical factor, unexplained infertility, same-sex couples, donor sperm.

— Often combined with letrozole/clomiphene; ~10–15% pregnancy per cycle in good-prognosis patients.

— Typically 3 cycles attempted before progressing to IVF.

— Controlled ovarian stimulation (gonadotropins) + GnRH antagonist → hCG trigger → transvaginal oocyte retrieval → fertilization (conventional vs ICSI) → embryo culture 3–5 days → fresh or frozen embryo transfer.

— Indications: tubal factor, severe male factor, advanced age, failed IUI cycles, endometriosis, genetic testing (PGT) needs, fertility preservation.

— Per-cycle live birth: ~40% under 35, ~30% at 35–37, ~20% at 38–40, ~10% at 41–42, <5% at ≥43 (own oocytes).

— Hysteroscopic — polypectomy, myomectomy (submucosal), septum resection, lysis of synechiae (Asherman).

— Laparoscopic — ablation/excision of endometriosis, ovarian cystectomy (endometrioma), salpingectomy for hydrosalpinx, tubal anastomosis in selected post-ligation patients <35.

— Abdominal myomectomy for large intramural fibroids distorting cavity.

Intrauterine insemination (IUI):

In vitro fertilization (IVF):

ICSI (intracytoplasmic sperm injection): Direct sperm injection into oocyte — for severe male factor, prior fertilization failure, surgical sperm retrieval.

Preimplantation genetic testing (PGT): Aneuploidy screening (PGT-A) or single-gene disorders (PGT-M) — relevant for advanced maternal age, recurrent loss, known carrier states.

Surgical interventions:

Fertility preservation: Oocyte/embryo cryopreservation before gonadotoxic chemo; ovarian tissue cryopreservation (now non-experimental).

Board pearl: ICSI does not improve outcomes in non-male-factor infertility and adds cost/risk — use only when indicated.

CCS pearl: Hydrosalpinx → salpingectomy before IVF improves implantation rates by ~50%; do not skip this step.

Special Populations — Advanced Reproductive Age and Comorbidities

— Reduced oocyte quantity and quality; aneuploidy rates climb steeply — 50% of oocytes aneuploid at 40, >75% at 43.

— Don't delay: workup at 6 months of trying (≥35) or immediately (≥40).

— Counsel honestly: per-cycle IVF live birth ≤10% at ≥42 with own oocytes; donor oocyte success ~50% regardless of recipient age.

— Higher rates of miscarriage, gestational diabetes, hypertensive disease, preterm birth, stillbirth, cesarean — preconception optimization is critical.

— Low AMH, high day-3 FSH, low antral follicle count.

— Consider earlier IVF, donor oocyte counseling; avoid prolonged IUI courses.

— Reduced ovulation, lower IVF success, higher miscarriage, OHSS-paradox (poor response yet metabolic risk), higher anesthetic risk for retrieval.

— 5–10% weight loss restores ovulation in many PCOS patients; bariatric surgery candidates should wait 12–24 months postoperatively before conception.

— Restore weight (BMI >18.5–20), reduce exercise; pulsatile GnRH if persistent.

Advanced maternal age (≥35, especially ≥40):

Diminished ovarian reserve (any age):

Obesity (BMI ≥30):

Underweight/hypothalamic amenorrhea:

Thyroid disease: Target TSH <2.5 mIU/L; treat overt and subclinical hypothyroidism with TPO antibodies.

Renal/hepatic impairment: Most fertility drugs minimally affected; metformin contraindicated if eGFR <30; coordinate with nephrology/hepatology for safe pregnancy planning.

Diabetes: HbA1c <6.5% before conception to reduce congenital anomaly risk; switch oral agents to insulin or continue metformin per OB endocrine guidance.

Cancer survivors: Coordinate with oncology — fertility preservation before gonadotoxic therapy; avoid pregnancy 6–24 months post-treatment depending on regimen.

Step 3 management: A 41-year-old with low AMH and 8 months of trying → refer directly to reproductive endocrinology for IVF; do not start IUI cycles.

Board pearl: Donor oocyte success depends on oocyte (donor) age, not recipient age — a 47-year-old recipient has the same per-transfer success as the donor's age cohort.

Special Populations — Cancer Survivors, Same-Sex Couples, Genetic Carriers

— Refer to reproductive endocrinology before chemo/radiation when feasible.

— Oocyte/embryo cryopreservation — gold standard for postpubertal females; takes ~2 weeks with random-start protocols.

— Ovarian tissue cryopreservation — option for prepubertal girls or when treatment can't be delayed.

— GnRH agonist co-treatment during chemo (e.g., breast cancer) may reduce premature ovarian insufficiency — modest evidence; not a substitute for cryopreservation.

— Post-treatment counseling: pregnancy generally safe after 2 years for most cancers (longer for some); coordinate with oncology.

— Donor sperm + IUI or IVF; reciprocal IVF (one partner provides oocyte, other carries pregnancy) increasingly common.

— Address legal parentage early — varies by state.

— Discontinue testosterone before stimulation; ovulation typically resumes within 6 months.

— Multidisciplinary care; sensitive language and informed consent paramount.

— Offer expanded carrier screening (CF, SMA, fragile X, hemoglobinopathies, ethnicity-based panels) to both partners.

— PGT-M for known single-gene disorders (BRCA, Huntington, sickle cell).

— PGT-A for advanced maternal age or recurrent loss with euploid uncertainty.

— Balanced translocation carriers (parental karyotype abnormalities) → IVF with PGT-SR.

— Low-dose aspirin + prophylactic LMWH through pregnancy.

— Sperm washing + IUI/IVF; partner on suppressive ART with undetectable viral load (U=U) allows natural conception in many cases.

Oncofertility:

Same-sex female couples and single women:

Transgender men with retained ovaries/uterus:

Genetic carriers and recurrent loss:

Recurrent pregnancy loss with antiphospholipid syndrome:

HIV-discordant couples:

Board pearl: For BRCA carriers, PGT-M can prevent transmission — but is an ethical/personal choice, not mandated. Discuss neutrally.

Step 3 management: Cancer diagnosis in a 28-year-old woman desiring future fertility → urgent reproductive endocrinology referral the same week for cryopreservation before chemo starts.

Complications and Adverse Outcomes

— Triggered by hCG (endogenous or exogenous); risk factors: young age, PCOS, high AMH, prior OHSS, multiple follicles.

— Mild: abdominal distension, nausea, ovarian enlargement <8 cm.

— Moderate: ascites on ultrasound, weight gain, vomiting.

— Severe: tense ascites, hemoconcentration (Hct >45%), oliguria, electrolyte derangement, pleural effusion, AKI, thromboembolism.

— Critical: ARDS, anuria, VTE, hepatorenal failure.

— Prevention: GnRH antagonist protocols, GnRH agonist trigger instead of hCG, freeze-all embryos, cabergoline prophylaxis, individualized dosing.

— Treatment: supportive — fluids, paracentesis for tense ascites, VTE prophylaxis (LMWH), hospital admission for severe cases.

— IUI with gonadotropins: ~20–30% multiples; IVF (single embryo transfer): ~1–2%.

— Twin pregnancies carry higher risk of preterm birth, preeclampsia, GDM, cesarean, NICU admission.

— Elective single embryo transfer (eSET) is now standard in good-prognosis patients.

Ovarian hyperstimulation syndrome (OHSS):

Multiple gestation:

Ectopic pregnancy: Higher baseline in IVF (~2–4%) and tubal disease patients; heterotopic pregnancy (intrauterine + ectopic) occurs in ~1/100 IVF pregnancies — always image both adnexa.

Miscarriage: Background rate elevated with age; ~50% at age 42.

Procedural complications: Oocyte retrieval — bleeding, infection, ovarian torsion, bowel/bladder injury (~<1%).

Long-term: No consistent increase in breast/ovarian/endometrial cancer with fertility drugs in pooled data; ongoing surveillance.

Psychological: Depression, anxiety, relationship strain — universal screening and counseling resources.

CCS pearl: Severe OHSS → admit, IV fluids cautiously, albumin if needed, daily weights/labs, thromboprophylaxis with LMWH, paracentesis for symptomatic ascites.

Board pearl: Persistent abdominal pain after embryo transfer with positive β-hCG → rule out heterotopic pregnancy with TVUS even if intrauterine gestation seen.

When to Escalate Care — Referral and Inpatient Triage

— Any patient meeting infertility criteria (12 months <35, 6 months ≥35).

— Age ≥40 — refer immediately at first visit.

— Known anatomic abnormality (uterine septum, fibroids, hydrosalpinx).

— Abnormal semen analysis after repeat testing.

— Failed oral ovulation induction × 3–6 cycles.

— Recurrent pregnancy loss (≥2 losses).

— Suspected diminished ovarian reserve (AMH <1, FSH >10).

— Endometriosis with significant disease burden.

— Same-sex couples or single women desiring conception.

— Cancer diagnosis requiring fertility preservation — same-week urgent referral.

— Endocrinology — uncontrolled thyroid, prolactinoma macroadenoma, suspected Cushing, CAH, type 1 diabetes preconception.

— Genetics counseling — abnormal karyotype, family history of inherited disease, recurrent loss, consanguinity.

— Urology — male partner with abnormal semen analysis, varicocele, azoospermia.

— Gyn oncology — suspicious ovarian mass.

— Mental health — depression/anxiety screening positive, eating disorder.

— Severe OHSS with hemoconcentration, oliguria, dyspnea, thromboembolism → admit.

— Ovarian torsion (stimulated ovary at risk) → emergent surgical consult.

— Ectopic pregnancy with hemodynamic instability → OR.

— Pelvic infection post-procedure with sepsis → admit, IV antibiotics.

When to refer to reproductive endocrinology/infertility (REI) specialist:

When to refer to other specialists:

Inpatient triage:

Step 3 management: A patient post-retrieval presents with rapid weight gain, abdominal pain, Hct 49%, creatinine 1.5 → admit for severe OHSS with IV crystalloid (cautious), thromboprophylaxis, daily monitoring.

Board pearl: Sudden unilateral pelvic pain in a stimulated ovary cycle — think torsion, get TVUS with Doppler, consult gyn surgery — torsion is a surgical emergency regardless of pregnancy status.

Key Differentials — Within Female Infertility Categories

— PCOS (Rotterdam: 2 of 3 — oligo/anovulation, hyperandrogenism, polycystic ovaries on US) — most common cause; obesity, insulin resistance, hyperandrogenism.

— Hypothalamic amenorrhea — low BMI, excessive exercise, stress; low FSH, low LH, low estradiol.

— Hyperprolactinemia — prolactin >25 ng/mL; medications (antipsychotics, metoclopramide), prolactinoma, hypothyroidism.

— Thyroid dysfunction — hypo or hyper; correct first.

— Primary ovarian insufficiency (POI) — amenorrhea <40, FSH >25 IU/L on 2 occasions; karyotype, FMR1, adrenal antibodies, thyroid antibodies.

— Nonclassic CAH — 17-OH progesterone elevated; hirsutism, mild virilization.

— Cushing syndrome — central obesity, striae, hypertension; dexamethasone suppression.

— Androgen-secreting tumor — testosterone >150 ng/dL or DHEAS >700 µg/dL with rapid virilization.

— Post-PID tubal scarring (chlamydia is leading culprit).

— Endometriosis with adhesions.

— Prior ectopic pregnancy or tubal surgery/ligation.

— Pelvic tuberculosis (consider in immigrants from endemic areas).

— Post-appendiceal rupture adhesions.

— Submucosal fibroids — distort cavity; resect hysteroscopically.

— Endometrial polyps — resect.

— Asherman syndrome — intrauterine adhesions after D&C, infection.

— Müllerian anomalies — septate (most treatable), bicornuate, unicornuate, didelphys.

— Cervical stenosis (post-LEEP/cone).

Within ovulatory dysfunction (the most common female factor):

Within tubal/peritoneal:

Within uterine/cervical:

Key distinction: Septate uterus (resect hysteroscopically) vs bicornuate uterus (generally not resected) — both can cause loss, but management diverges sharply; MRI or 3D US distinguishes.

Board pearl: Day-3 FSH >25 + amenorrhea <40 = POI. Don't anchor on early menopause without confirming with repeat labs 4–6 weeks apart.

Key Differentials — Beyond Female Reproductive Tract

— Oligospermia/azoospermia — varicocele, testicular failure, cryptorchidism, Klinefelter, post-chemo, Y-microdeletions.

— Obstructive azoospermia — CBAVD (often CFTR mutations), prior vasectomy, infection.

— Endocrine — hypogonadotropic hypogonadism (Kallmann), exogenous testosterone, anabolic steroid use (common, under-disclosed).

— Functional/lifestyle — heat exposure, marijuana, tobacco, opioids, obesity.

— Erectile dysfunction, retrograde ejaculation (diabetes, alpha-blockers, post-prostate surgery), vaginismus, dyspareunia, infrequent intercourse.

— Lubricant use — many commercial lubricants (KY, Astroglide) are spermicidal; recommend mineral oil, canola oil, or "fertility-friendly" lubricants (Pre-Seed).

— Celiac disease — undiagnosed celiac linked to unexplained infertility and recurrent loss; screen with TTG-IgA.

— Inflammatory bowel disease — active disease impairs fertility; well-controlled disease usually does not.

— Autoimmune (lupus, antiphospholipid) — recurrent loss more than infertility per se.

— Chronic kidney disease, severe liver disease, HIV — endocrine dysregulation.

— Eating disorders — anorexia, bulimia; functional hypothalamic amenorrhea.

— Chemotherapy (alkylators worst), pelvic radiation, recent depot contraceptive (Depo can suppress ovulation for up to 18 months).

— Medications: NSAIDs (LUFS — luteinized unruptured follicle), antiepileptics, opioids.

Male factor (~30% of infertility) — always evaluate:

Coital/sexual factors:

Systemic disease impacting fertility:

Iatrogenic:

Unexplained infertility (~15–20%): Diagnosis of exclusion after normal complete workup; manage stepwise with letrozole/IUI then IVF.

Step 3 management: Don't anchor on female factor alone — a comprehensive evaluation requires concurrent male workup. Up to 30% of "female infertility" stems consults reveal abnormal semen analyses missed by primary care.

Board pearl: Recurrent miscarriage + iron-deficiency anemia + diarrhea → screen for celiac; treatment with gluten-free diet can restore fertility.

Long-Term Plan, Preconception, and Maintenance

— Folic acid 400–800 µg/d (4 mg if prior NTD, valproate, MTX, or diabetes); start ≥3 months before conception.

— Optimize chronic disease: diabetes (HbA1c <6.5%), hypertension (switch ACEi/ARB to labetalol/nifedipine), thyroid (TSH <2.5), epilepsy (switch valproate/topiramate), depression (continue SSRI if needed — risk/benefit).

— Vaccinations updated: MMR, varicella (live — 1 month before conception), Tdap, influenza, COVID, HPV.

— Stop teratogens: isotretinoin, methotrexate, warfarin, statins, ACEi/ARB, valproate, lithium (relative), mycophenolate.

— Avoid alcohol, tobacco, recreational drugs; limit caffeine <200 mg/d.

— Weight optimization toward BMI 20–25 if feasible.

— Continue prenatal vitamin with folate through conception.

— Monitor for treatment-related complications (OHSS, ectopic, multiples).

— Mental health support; infertility-specific counseling resources.

— Early TVUS at 6–7 weeks to confirm intrauterine pregnancy, rule out ectopic/heterotopic, count gestational sacs.

— Standard prenatal care with attention to ART-specific risks: ectopic, heterotopic, preterm birth, preeclampsia, GDM, vanishing twin.

— Continue progesterone supplementation through 10–12 weeks if part of frozen embryo transfer or IVF protocol.

— Discuss adoption, gestational carrier, donor gametes early to allow processing.

— Address grief; continued mental health support.

— Address underlying conditions (PCOS metabolic risk, endometriosis pain management) regardless of fertility outcome.

Preconception checklist (continue throughout treatment):

During fertility treatment:

Once pregnant via ART:

Long-term reproductive health if treatment unsuccessful:

Step 3 management: Switch ACEi/ARB to labetalol or nifedipine before attempting conception — fetal renal/skull defects are second/third trimester risks; first-trimester exposure is also linked to cardiac/CNS anomalies.

Board pearl: Confirm intrauterine pregnancy at 6–7 weeks in every ART pregnancy; heterotopic risk is ~1/100 vs 1/30,000 in spontaneous conception.

Follow-Up, Monitoring, and Counseling

— Baseline TVUS day 2–3 of cycle to rule out cysts.

— Start medication days 3–7.

— Mid-cycle monitoring with TVUS (follicle size — trigger when lead follicle ≥18 mm) and serum estradiol; trigger with hCG or recombinant LH.

— Mid-luteal progesterone to confirm ovulation.

— Pregnancy test 14 days after ovulation if no menses.

— Daily/every-other-day monitoring during stimulation with TVUS + estradiol.

— Trigger criteria: ≥3 follicles ≥17 mm.

— Oocyte retrieval 34–36 hours after trigger.

— Embryo transfer day 3 or 5; β-hCG 9–11 days after transfer; serial β-hCG, then TVUS at 6 weeks.

— Realistic expectations: cumulative live birth across 3 IVF cycles ~50–60% under 35, decreasing with age.

— Financial: most US insurance does not cover IVF universally — discuss costs ($12–20K per cycle plus meds), state mandates vary.

— Emotional support: infertility-related depression ~30%; offer mental health referrals, support groups (RESOLVE).

— Multifetal reduction counseling if high-order multiples occur.

— Reassess after failed IUI × 3 and failed IVF × 1–2.

— Consider PGT-A, donor gametes, gestational carrier, adoption.

— Standard postpartum care plus screening for postpartum depression (elevated risk after infertility).

— Address contraception desires — secondary infertility may recur if more children desired.

During ovulation induction cycles:

During IVF:

Post-treatment counseling:

Cycle failures:

Long-term surveillance after successful pregnancy:

Step 3 management: After 3 failed IUI cycles → move to IVF, don't continue indefinite IUI. Per-cycle yield plateaus after cycle 3–4.

Board pearl: A patient with negative β-hCG after embryo transfer who develops pelvic pain and ascites → think delayed OHSS; pregnancy can prolong/worsen course, but absence of pregnancy doesn't exclude it.

Ethical, Legal, and Patient Safety Considerations

— Risks of stimulation (OHSS, torsion), retrieval (bleeding, infection), pregnancy (multiples, ectopic), and long-term unknowns.

— Disposition of embryos: storage costs, donation to research, donation to another couple, discard, "compassionate transfer" — must be addressed before retrieval and documented.

— Divorce or death of partner — written directives required; jurisdiction-specific.

— Donor gametes/embryos — anonymous vs known; counsel on rising prevalence of direct-to-consumer DNA testing eroding anonymity.

— Gestational carriers — legal contracts, intended-parent rights vary widely by state (some prohibit commercial surrogacy entirely).

— Psychological screening for donors and recipients is standard.

— Reportable infections (HIV, syphilis) discovered during workup — public health notification required.

— Suspected coercion (e.g., intimate partner violence revealed during infertility workup) — counsel privately, offer resources.

— Minors seeking fertility preservation before cancer therapy — parental consent + assent; ethics consult if disagreement.

— Elective single embryo transfer (eSET) preferred to minimize multiples — patient safety priority.

— Multifetal pregnancy reduction must be offered non-directively; respect patient autonomy and religious values.

— Infertility care is inequitably distributed; many states lack insurance mandates. Step 3 vignettes increasingly probe structural barriers (cost, geography, race-based disparities in access and outcomes).

— Patient on gonadotropin stimulation presenting to ED with pain — always notify her REI team; cycles can be cancelled mid-stim if needed and OHSS workup differs from routine pelvic pain.

Informed consent for ART — multidimensional:

Third-party reproduction:

Mandatory reporting and special situations:

Multifetal pregnancy and reduction:

Equity and access:

Transition-of-care safety:

Step 3 management: A patient and her estranged spouse have frozen embryos; she wants to use them after separation — do not proceed without written consent of both gamete providers and review of the original clinic disposition agreement.

Board pearl: eSET is the standard for good-prognosis patients — multiples are a complication, not a treatment success.

High-Yield Associations and Rapid-Fire Facts

— Regular cycles + molimina = ovulatory.

— Mid-luteal progesterone >3 = ovulated.

— Day-3 FSH >10 or AMH <1 = diminished reserve.

— HSG = tubal patency + uterine cavity outline.

— SIS/hysteroscopy = intracavitary lesions.

— Rotterdam: 2 of 3 (oligo-ovulation, hyperandrogenism, PCO morphology).

— Letrozole > clomiphene for live birth (PPCOS II).

— Weight loss 5–10% restores ovulation in many.

— Long-term: T2DM, dyslipidemia, OSA, endometrial cancer (unopposed estrogen).

— Bilateral occlusion → IVF (skip tubal surgery in most).

— Hydrosalpinx → salpingectomy before IVF.

— Endometriosis classic triad: dysmenorrhea, dyspareunia, dyschezia + infertility.

— Galactorrhea + amenorrhea → prolactin → MRI if elevated.

— Hot flashes <40 → POI → karyotype + FMR1.

— Rapid virilization + testosterone >150 → androgen-secreting tumor → imaging.

— Letrozole 2.5–7.5 mg days 3–7.

— Clomiphene 50–150 mg days 5–9; max 6 cycles.

— Cabergoline first-line for prolactinoma in infertility.

— Metformin adjunct in PCOS.

— <35: ~40% live birth/cycle.

— 38–40: ~20%.

— ≥43: <5% — consider donor oocyte (~50% regardless of recipient age).

Workup quick recall:

PCOS pearls:

Tubal/peritoneal:

Hormonal red flags:

Drug pearls:

IVF stats (own oocytes):

OHSS: PCOS + young + high AMH = highest risk; trigger with GnRH agonist + freeze-all to prevent.

Heterotopic pregnancy: 1/100 in ART vs 1/30,000 spontaneous — image both adnexa.

Folic acid: 400–800 µg/d standard; 4 mg if prior NTD or on antiepileptics.

Board pearl: Letrozole is the first-line ovulation induction agent in PCOS. Memorize this single fact — it appears repeatedly on Step 3.

Board Question Stem Patterns

— Best next step: lifestyle modification + letrozole (not clomiphene). Distractor: metformin alone.

— Best next step: refer to REI for IVF; don't pursue prolonged IUI.

— Best next step: IVF, not tubal reconstruction.

— Best next step: cabergoline → restores ovulation in most.

— Workup: karyotype + FMR1 premutation + adrenal/thyroid antibodies; counsel on donor oocyte.

— Best step: diagnostic laparoscopy with excision/ablation.

— Best step: hysteroscopic septoplasty.

— Diagnosis: severe OHSS → admit, fluids, LMWH, paracentesis.

— Image again: rule out heterotopic ectopic.

— Answer: semen analysis — must be done at the start.

Stem 1 — PCOS anovulation: "32-year-old, BMI 33, irregular cycles, hirsutism, acne. TTC × 14 months. Normal semen analysis. TSH and prolactin normal."

Stem 2 — Advanced age, low reserve: "39-year-old, regular cycles, TTC × 7 months. AMH 0.6, AFC 5."

Stem 3 — Tubal factor: "29-year-old with prior chlamydia, normal cycles. HSG shows bilateral distal occlusion."

Stem 4 — Hyperprolactinemia: "31-year-old with amenorrhea, galactorrhea, prolactin 145, normal TSH. MRI shows 7 mm pituitary microadenoma."

Stem 5 — POI: "34-year-old with hot flashes, secondary amenorrhea 8 months. FSH 48 (repeated), estradiol low."

Stem 6 — Endometriosis: "28-year-old with severe dysmenorrhea, dyspareunia, dyschezia. Bimanual exam: uterosacral nodularity."

Stem 7 — Uterine factor: "33-year-old with recurrent loss; HSG shows arcuate filling defect; MRI confirms septate uterus."

Stem 8 — OHSS: "Post-retrieval patient, day 7, abdominal distension, dyspnea, Hct 49, Cr 1.4."

Stem 9 — Heterotopic: "ART pregnancy, β-hCG appropriate, IUP seen at 7 weeks. New right pelvic pain."

Stem 10 — Male factor missed: "Couple TTC × 18 months, all female workup normal. Best next step?"

Board pearl: "Best next step" in infertility stems almost always rewards either getting the missing piece of workup (semen analysis, HSG, progesterone) or respecting the time-cost of advanced maternal age (don't delay referral).

One-Line Recap

Female infertility — failure to conceive after 12 months (<35) or 6 months (≥35) — requires simultaneous evaluation of both partners with semen analysis, mid-luteal progesterone, TSH, prolactin, HSG, and ovarian reserve testing, with treatment matched to cause: letrozole for PCOS anovulation, hysteroscopic correction of uterine lesions, salpingectomy before IVF for hydrosalpinx, and IVF for tubal factor, severe male factor, or advanced age.

Workup core: Semen analysis + mid-luteal progesterone + TSH/prolactin + HSG + AMH/AFC = covers >90% of correctable causes; add SIS/hysteroscopy when intracavitary disease suspected.

First-line drugs: Letrozole > clomiphene for PCOS-related anovulation (PPCOS II trial); cabergoline for hyperprolactinemia; metformin adjunctively for insulin-resistant PCOS; gonadotropins reserved for refractory cases with TVUS/estradiol monitoring to prevent OHSS and multiples.

Procedural triggers: Bilateral tubal occlusion → IVF (not surgery); hydrosalpinx → salpingectomy before IVF; submucosal fibroid/polyp/septum → hysteroscopic resection; severe endometriosis or advanced age with low reserve → IVF; severe male factor → ICSI.

Step 3 takeaways: Don't delay workup or referral in women ≥35; always evaluate the male partner at visit 1; always confirm intrauterine pregnancy at 6–7 weeks after ART and screen for heterotopic; counsel honestly on age-related success rates; preconception folate, vaccine updates, teratogen review, and chronic disease optimization (TSH <2.5, HbA1c <6.5%, BP control with safe agents) are non-negotiable before any cycle.

Board pearl: When the stem gives regular cycles with molimina, ovulation is intact — pivot to tubal and uterine evaluation rather than over-testing ovulation, and never forget the semen analysis as the cheapest, highest-yield test in the entire workup.