Step 2 CK · Obstetrics & Gynecology

Infertility & Reproductive Endocrinology

Name: Infertility & Reproductive Endocrinology
Creator: Veli Bakalov, MD

A logical workup, PCOS ovulation induction, and the causes of recurrent loss

Obstetrics & Gynecology·Reproductive Endocrinology & Family Planning·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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High-yield

Evaluate infertility after 12 months of unprotected intercourse, or after 6 months if the woman is ≥35 (at once if >40 or an obvious cause); evaluate both partners together.
Semen analysis is the first test (male factor ~35%); WHO 2021 lower limits: volume ≥1.4 mL, ≥16 million/mL, total motility ≥42%, normal morphology ≥4%.
Midluteal (day ~21) progesterone >3 ng/mL confirms ovulation; a high day-3 FSH or low AMH/antral follicle count means diminished reserve (AMH is stable across the cycle).
HSG is the first-line test for tubal patency; laparoscopy with chromopertubation is most accurate and can also treat endometriosis.
PCOS = 2 of 3 Rotterdam criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries) after excluding thyroid disease, hyperprolactinemia, and nonclassic CAH.
PCOS wanting pregnancy → letrozole (beats clomiphene for live birth, especially with obesity); not wanting pregnancy → combined OCPs to protect the endometrium from unopposed estrogen.
Anovulation with low FSH/LH → hypothalamic amenorrhea or hyperprolactinemia; high FSH before 40 → primary ovarian insufficiency; always check TSH and prolactin.
Varicocele is the most common correctable male cause; azoospermia with absent vas → CFTR; small firm testes with high FSH/LH → Klinefelter; anosmia with low GnRH → Kallmann.
Recurrent loss: antiphospholipid antibodies (low-dose aspirin + heparin), cavity imaging (septum → hysteroscopic resection), and parental karyotypes (balanced translocation).

Definition and when to evaluate

Infertility is failure to conceive after 12 months of regular unprotected intercourse, or after 6 months if the woman is 35 or older, because fecundity and ovarian reserve decline with age. Women over 40 and couples with an obvious problem (amenorrhea, known tubal disease or endometriosis, a known male factor) are evaluated at presentation.

12 monthsunprotected intercourse before a workup

6 monthsif the woman is 35 or older

~35%of infertility involves a male factor

Causes. Roughly, male factor accounts for 35%, ovulatory or ovarian dysfunction 25%, tubal and pelvic disease 20%, and uterine or unexplained causes the rest. Factors often coexist, so both partners are evaluated at the same time.

The ordered workup

Start with the cheapest test. Semen analysis is inexpensive and noninvasive, and evaluating only the woman misses the largest single category. Then confirm ovulation, estimate ovarian reserve, and check the tubes and cavity.

Semen analysisFirst test: cheap, noninvasive, and male factor is common.
Confirm ovulationMidluteal progesterone >3 ng/mL.
Ovarian reserveDay-3 FSH, AMH, antral follicle count.
Tubal patencyHysterosalpingography.

Infertility workup order

Semen analysis. WHO (2021) lower reference limits are volume ≥1.4 mL, concentration ≥16 million/mL, total motility ≥42%, and normal morphology ≥4%. Counts fluctuate, so an abnormal result is repeated and followed by FSH, LH, and testosterone levels and a scrotal exam.

Ovulation. Regular cycles with molimina (premenstrual breast tenderness, bloating) usually mean ovulation is occurring. Proof is a midluteal serum progesterone >3 ng/mL, drawn around day 21 of a 28-day cycle, which reflects a functioning corpus luteum.

Ovarian reserve. A high day-3 FSH signals diminished reserve because the pituitary must push harder to recruit a follicle. Anti-Müllerian hormone (AMH), made by granulosa cells of small follicles, reflects the remaining follicle pool and, unlike FSH, is stable across the cycle. Antral follicle count on transvaginal ultrasound completes the picture.

Tubes and cavity. Hysterosalpingography (HSG), timed after menses and before ovulation, is the first-line test for tubal patency and also outlines the cavity. Laparoscopy with chromopertubation is the most accurate test and can treat endometriosis and adhesions. Suspect tubal disease after PID (chlamydia, gonorrhea), ectopic pregnancy, or pelvic surgery.

Anovulation: PCOS and its mimics

PCOS (Rotterdam: 2 of 3). The criteria are oligo- or anovulation; clinical or biochemical hyperandrogenism (hirsutism, acne, high testosterone); and polycystic ovaries on ultrasound. Any two suffice, but mimics must be excluded with TSH, prolactin, and 17-hydroxyprogesterone (nonclassic congenital adrenal hyperplasia). PCOS is the most common cause of anovulatory infertility and is associated with insulin resistance (acanthosis nigricans), obesity, and a high LH:FSH ratio; screen for type 2 diabetes and dyslipidemia.

Unopposed estrogen. Without ovulation there is no corpus luteum and no progesterone, so unopposed estrogen raises the risk of endometrial hyperplasia and cancer. Every PCOS plan must either induce ovulation or supply a progestin.

PCOS management by goal

Feature	Wants pregnancy	Not seeking pregnancy
First line	Letrozole (aromatase inhibitor) for ovulation induction	Combined oral contraceptives
Rationale	Higher live-birth rate than clomiphene, especially in obese women (PPCOS II)	Regulate cycles, lower androgens, protect the endometrium
Alternatives	Clomiphene; gonadotropins or IVF if refractory	Cyclic progestin or levonorgestrel IUD if estrogen is contraindicated
Adjuncts	Weight loss; metformin	Weight loss; metformin for metabolic risk

Pharmacology. Letrozole blocks aromatase, lowering estrogen and removing negative feedback so FSH rises and a follicle is recruited. Clomiphene, a SERM, blocks hypothalamic estrogen receptors, raising GnRH, FSH, and LH; letrozole avoids its antiestrogenic effects on the endometrium and cervical mucus. Both raise the risk of multiple gestation, and metformin is only an adjunct.

Sorting anovulation by FSH and prolactin

Cause	Clues	Labs	Fertility approach
PCOS	Hirsutism, acne, obesity	Normal FSH, high LH:FSH, high androgens	Letrozole
Functional hypothalamic amenorrhea	Low BMI, heavy exercise, stress	Low FSH/LH, low estradiol	Restore energy balance; pulsatile GnRH or gonadotropins
Hyperprolactinemia	Galactorrhea; prolactinoma; dopamine-blocking drugs	Prolactin suppresses GnRH → low FSH/LH	Dopamine agonist (cabergoline, bromocriptine)
Thyroid disease	Hypo- or hyperthyroid symptoms	Abnormal TSH; hypothyroidism can raise prolactin	Correct thyroid function
Primary ovarian insufficiency	Before age 40; Turner mosaicism, FMR1 premutation, autoimmunity, chemotherapy	High FSH, low estradiol	Donor oocytes; hormone replacement for bone health

Check TSH and prolactin in every anovulatory woman.

Male factor infertility

Obstructive vs nonobstructive. In azoospermia, normal testes with a normal FSH suggest obstruction, whereas small testes with a high FSH suggest testicular failure, which warrants a karyotype and Y-chromosome microdeletion testing.

Key male-factor causes

Cause	Clues	Hormones	Management
Varicocele	"Bag of worms" scrotal veins, usually left, larger when standing	Usually normal	Most common correctable cause; repair if palpable with abnormal semen
Klinefelter (47,XXY)	Small firm testes, tall stature, gynecomastia, azoospermia	High FSH/LH, low testosterone	Testicular sperm extraction + ICSI
Congenital bilateral absence of the vas	Nonpalpable vasa, azoospermia, low-volume ejaculate	Normal (obstructive)	CFTR testing of both partners; sperm retrieval + ICSI
Kallmann syndrome	Anosmia, delayed or absent puberty	Low GnRH → low FSH/LH and testosterone	Gonadotropins or pulsatile GnRH
Exogenous androgens	Testosterone or anabolic steroid use, small testes	Low FSH/LH (feedback suppression)	Stop the drug

Varicocele anatomy. The left gonadal vein enters the left renal vein at a right angle, so most varicoceles are left-sided; pooled blood warms the testis and impairs spermatogenesis. An isolated right-sided varicocele, or one that persists when supine, calls for imaging to exclude a retroperitoneal mass.

Azoospermia with absent vasa deferentia means a CFTR mutation until proven otherwise, even without lung disease; test the partner for carrier status before assisted reproduction.

Assisted reproduction

Escalation. Treatment steps up from intrauterine insemination (IUI: washed sperm placed in the uterus near ovulation) to in vitro fertilization (IVF). Unexplained infertility usually starts with letrozole or clomiphene plus IUI for a few cycles, moving to IVF if that fails. IVF bypasses the tubes, so it treats tubal factor and unexplained infertility that persists after IUI; with intracytoplasmic sperm injection (ICSI, one sperm injected into each egg) it overcomes severe male factor. A hydrosalpinx is removed before IVF because its fluid lowers success rates.

Ovarian hyperstimulation syndrome (OHSS) complicates gonadotropin stimulation, especially after an hCG trigger in women with PCOS: enlarged ovaries and capillary leak cause ascites, hemoconcentration, oliguria, and thrombosis. ART also raises the risk of multiple gestation and ectopic pregnancy.

Recurrent pregnancy loss

Definition. Recurrent pregnancy loss (RPL) means ≥2–3 losses. Most sporadic losses reflect fetal aneuploidy and do not recur; repeated loss prompts a search for treatable causes.

Antiphospholipid syndrome: lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I antibodies, positive twice at least 12 weeks apart. Treat the next pregnancy with low-dose aspirin plus heparin (warfarin is teratogenic).
Uterine septum: the most common structural anomaly linked to RPL; hysteroscopic septum resection improves outcomes. Image the cavity with sonohysterography or hysteroscopy.
Parental balanced translocation: found on parental karyotypes; offer genetic counseling and IVF with preimplantation genetic testing.
Endocrine: correct thyroid disease and poorly controlled diabetes before conception.