Infertility — Male and Female

Male causes by anatomic level

• Pre-testicular (endocrine): hypogonadotropic hypogonadism (Kallmann syndrome with anosmia, pituitary adenoma, hyperprolactinemia, opioid or exogenous androgen/anabolic steroid use) — low testosterone with inappropriately low LH/FSH
• Testicular (primary): Klinefelter syndrome (47,XXY), Y-chromosome microdeletions (AZF regions), cryptorchidism, mumps orchitis, varicocele, chemotherapy/radiation, heat exposure — elevated FSH (± elevated LH), with testosterone normal or low depending on whether Leydig cell function is preserved (isolated FSH elevation is typical when germ cell loss occurs with intact Leydig cells)
• Post-testicular (obstructive/ejaculatory): congenital bilateral absence of the vas deferens (CFTR mutations), post-vasectomy or post-herniorrhaphy obstruction, retrograde ejaculation (diabetic autonomic neuropathy, post-TURP, alpha-blockers), erectile dysfunction

Female causes by mechanism

• Ovulatory (roughly a quarter to a third of female factor): PCOS is the single most common cause; also hypothalamic amenorrhea (low energy availability), hyperprolactinemia, thyroid disease, primary ovarian insufficiency
• Tubal/peritoneal: prior Chlamydia trachomatis or gonococcal PID, ruptured appendix, prior tubal or pelvic surgery, endometriosis with adhesions
• Uterine/cervical: submucosal fibroids, Asherman syndrome after instrumentation of a gravid uterus, müllerian anomalies (septate uterus), cervical stenosis after conization
• Age-related diminished ovarian reserve: oocyte aneuploidy from meiotic spindle and cohesin deterioration — the dominant driver after the mid-30s

MALE INFERTILITY MECHANISMS

• Spermatogenesis defects: Impaired testicular germ cell production due to heat exposure, toxins (smoking, alcohol, chemotherapy), infections (mumps orchitis), varicocele (dilated pampiniform plexus causing venous stasis and testicular hyperthermia), or primary testicular failure (Klinefelter syndrome, Y chromosome microdeletions)
• Hormonal dysfunction: Hypogonadism (primary testicular failure with elevated FSH/LH; secondary hypogonadism with low testosterone and low-normal LH/FSH), hyperprolactinemia inhibiting GnRH release, or thyroid disorders affecting spermatogenesis
• Obstruction or dysfunction: Absence of vas deferens (CFTR mutations), ejaculatory duct obstruction, retrograde ejaculation (post-TURP, diabetes, autonomic dysfunction), or erectile dysfunction
• Sperm dysfunction: Impaired motility (flagellar abnormalities, mitochondrial dysfunction), abnormal morphology, or defective capacitation/acrosome reaction
• Immunologic factors: Antisperm antibodies causing agglutination or complement-mediated destruction

FEMALE INFERTILITY MECHANISMS

• Ovulatory dysfunction: Hypothalamic-pituitary-ovarian (HPO) axis disruption (excessive exercise, eating disorders, stress, hyperprolactinemia, thyroid disease), polycystic ovary syndrome (PCOS) causing anovulation with hyperandrogenism, or primary ovarian insufficiency (premature menopause, autoimmune oophoritis, chemotherapy toxicity)
• Anatomic/structural abnormalities: Tubal scarring or obstruction (pelvic inflammatory disease, endometriosis, previous surgery, tubal ligation), uterine abnormalities (fibroids distorting the uterine cavity, intrauterine adhesions, septate uterus), or ovarian masses
• Endometriosis: Ectopic endometrial tissue causing chronic inflammation, altered prostaglandin production, impaired embryo implantation, and reduced oocyte quality
• Luteal phase defect: Inadequate progesterone secretion impairing endometrial development (controversial diagnosis, rarely used)
• Oocyte/embryo dysfunction: Diminished ovarian reserve (age-related aneuploidy, mitochondrial dysfunction), poor embryo quality, or implantation failure (uterine factor, genetic abnormalities)
• Cervical/peritoneal factors: Cervical mucus abnormalities, antisperm antibodies, or peritoneal inflammation

• Chief complaint of infertility: Primary infertility (never achieved pregnancy) versus secondary infertility (previous pregnancy but now unable to conceive); duration and specific timing of coital attempts (timing around ovulation is critical)
• Male-specific findings: Decreased libido or erectile dysfunction (suggesting hypogonadism), history of undescended testis or prior hernia repair, small/firm testes on examination (<4 cm length or <20 mL volume indicates hypogonadism), palpable varicocele (usually left-sided, described as "bag of worms"), absence of vas deferens
• Female-specific findings: Menstrual irregularities (amenorrhea, oligomenorrhea suggesting anovulation; abnormally long or short cycles), dysmenorrhea or dyspareunia (endometriosis), history of pelvic inflammatory disease or sexually transmitted infections, hirsutism/acne/male-pattern baldness (hyperandrogenism in PCOS), galactorrhea (hyperprolactinemia), evidence of thyroid disease
• General history: Age (female fertility declines significantly after age 35), smoking and substance use, occupational exposures (heat, toxins), prior surgeries or infections, medication use (particularly chemotherapy, antipsychotics raising prolactin, or antihypertensives), weight extremes (BMI <18.5 or >30 increasing risk)
• Relationship dynamics: Duration of infertility, frequency and timing of intercourse, stress and mood disorders

INITIAL EVALUATION (BOTH PARTNERS)

• Detailed history and physical examination: Assess duration of infertility, menstrual/sexual history, medical/surgical history, medication/substance use, family history of genetic or reproductive disorders, and occupational/environmental exposures
• Semen analysis (male evaluation): Assess volume (≥1.5 mL), concentration (≥15 million/mL = normozoospermia; oligozoospermia if <15 million/mL), motility (≥40% total motility or ≥32% progressive; asthenozoospermia if reduced), morphology (≥4% normal forms by strict Kruger criteria; teratozoospermia if <4%), vitality, and presence of white blood cells (suggesting infection). Repeat semen analysis is essential if abnormal, as parameters vary significantly between samples. Semen culture if WBCs elevated.

MALE FACTOR WORKUP (IF ABNORMAL SEMEN ANALYSIS)

• Serum testosterone and LH/FSH: Low testosterone with normal/elevated LH suggests primary hypogonadism (testicular failure); low testosterone with low/normal LH/FSH suggests secondary hypogonadism (pituitary/hypothalamic dysfunction)
• Prolactin level: Elevated prolactin causing hypogonadism; if markedly elevated (>200 ng/mL), obtain MRI pituitary to exclude adenoma
• Thyroid function (TSH): Thyroid disease impairs spermatogenesis
• Post-ejaculation urinalysis: Presence of >5-10 sperm suggests retrograde ejaculation
• Testicular ultrasound and color Doppler: Assess for varicocele, testicular masses, or structural abnormalities; consider if abnormal semen analysis or clinical suspicion
• Genetic testing: Karyotype and Y chromosome microdeletion analysis if severe oligozoospermia/azoospermia; CFTR mutations if absent vas deferens

FEMALE FACTOR WORKUP

• Ovulation assessment: Serum progesterone in luteal phase (day 21 of 28-day cycle, or 7 days before expected menses) showing ≥3 ng/mL suggests ovulation; alternatively, luteinizing hormone (LH) surge detected by home urine testing or serum LH on day 10-14; basal body temperature charting (less reliable)
• Ovarian reserve testing: Serum follicle-stimulating hormone (FSH), anti-mullerian hormone (AMH), and antral follicle count (AFC) on ultrasound; FSH >10 mIU/mL on day 3 suggests diminished reserve; AMH <1.0 ng/mL indicates poor reserve; AFC <5-6 suggests low reserve
• Thyroid function (TSH) and prolactin level: Screen for ovulatory dysfunction
• Pelvic ultrasound: Assess uterine morphology (fibroids, septate uterus, adhesions), endometrial thickness, ovarian pathology (cysts, PCOS findings), and antral follicle count
• Hysterosalpingography (HSG): Gold standard for tubal patency; demonstrates spill of contrast into peritoneal cavity if tubes patent; identifies hydrosalpinx, strictures, or uterine cavity abnormalities
• Diagnostic laparoscopy: Direct visualization for endometriosis, adhesions, or other peritoneal pathology; reserved for specific clinical indications (severe endometriosis suspected, recurrent pregnancy loss, or failed IVF) and not routine screening
• Karyotype and fragile X testing: If recurrent pregnancy loss or family history of genetic disorders

SPECIAL DIAGNOSTIC CONSIDERATIONS

Foundational steps for every couple (ASRM)

• Lifestyle and timing: smoking/alcohol cessation, weight optimization toward normal BMI, intercourse every 1–2 days in the fertile window, preconception folic acid; treat identified thyroid disease with levothyroxine and hyperprolactinemia with a dopamine agonist per Endocrine Society recommendations — cabergoline is preferred for efficacy, though bromocriptine has more accumulated pregnancy safety data; the agonist is generally discontinued once pregnancy is confirmed

First-line for anovulatory infertility

• Aromatase inhibitor — letrozole: now preferred first-line for ovulation induction in PCOS (ASRM/ACOG), based on the PPCOS II trial showing higher live-birth rates than clomiphene; blocks estrogen negative feedback, raising endogenous FSH
• SERM — clomiphene citrate: alternative ovulation induction agent; antiestrogenic effect on cervical mucus and endometrium is its drawback
• Metformin: adjunct in PCOS with insulin resistance; not a substitute for letrozole for live birth
• Gonadotropins (FSH ± LH): escalation after oral agents fail — requires ultrasound and estradiol monitoring because of OHSS and multiple-gestation risk. Pulsatile GnRH or hCG/FSH is used for hypogonadotropic hypogonadism in either sex

Procedural and surgical management

• Intrauterine insemination (IUI) ± ovarian stimulation for mild male factor, cervical factor, or unexplained infertility
• Hysteroscopic myomectomy for cavity-distorting submucosal fibroids, septum resection, adhesiolysis; laparoscopic ablation/excision of endometriosis; salpingectomy for hydrosalpinx before IVF, which improves implantation
• Varicocelectomy for a palpable varicocele with abnormal semen parameters (AUA/ASRM)
• IVF for tubal occlusion, advanced maternal age, failed lesser therapy; ICSI for severe oligo-/astheno-/teratozoospermia; surgical sperm retrieval (microTESE) for nonobstructive azoospermia; donor gametes or gestational carrier when indicated

Contraindicated / avoid

• Exogenous testosterone in a man desiring fertility — suppresses LH/FSH and intratesticular testosterone, causing azoospermia; use clomiphene or hCG instead
• Unmonitored gonadotropin cycles; empiric antibiotics or empiric testosterone for idiopathic male infertility; and any ACE inhibitor/ARB, isotretinoin, or warfarin continued into a conception cycle

Complications of treatment

• Ovarian hyperstimulation syndrome (OHSS) — emergency in its severe form: hCG-driven VEGF release increases capillary permeability, causing third-spacing into the peritoneum and pleura. Signs: rapid weight gain, tense ascites, oliguria, hemoconcentration (rising hematocrit), hyponatremia, dyspnea. Severe disease brings venous thromboembolism (including unusual sites such as internal jugular veins), acute kidney injury, and ARDS. Risk is highest in young, lean patients with PCOS and high antral follicle counts; GnRH-antagonist protocols with a GnRH-agonist trigger and "freeze-all" embryo transfer reduce risk
• Multiple gestation: from gonadotropins and multi-embryo transfer; drives preterm birth, preeclampsia, growth restriction, and neonatal morbidity — the rationale for elective single embryo transfer (ASRM/SART)
• Ovarian torsion — surgical emergency: enlarged stimulated ovaries; sudden unilateral pain with nausea and absent venous flow on Doppler
• Oocyte retrieval injury: intraperitoneal hemorrhage, bladder or bowel injury, pelvic abscess — postprocedure pain with falling hematocrit or fever
• HSG-related complications: contrast intravasation, and infectious flare of an undrained hydrosalpinx (ACOG supports periprocedural doxycycline when tubal disease is suspected)
• ICSI/ART offspring risks: modest increase in imprinting disorders (Beckwith-Wiedemann, Angelman) and congenital anomalies, and obligate transmission of Y-chromosome microdeletions to sons — the basis for pretreatment genetic counseling
• Psychological morbidity: depression, anxiety, and relationship strain are common and underscreened

Complications of the underlying disease

• Ectopic and heterotopic pregnancy: damaged tubal cilia from prior PID or endometriosis; after IVF, a positive hCG with pain and an empty uterus mandates urgent evaluation — rupture is an emergency
• Endometrial hyperplasia/carcinoma in chronically anovulatory PCOS from unopposed estrogen; investigate abnormal uterine bleeding
• Untreated primary ovarian insufficiency: hypoestrogenic bone loss and cardiovascular risk, warranting hormone therapy until the average age of menopause

• Semen analysis is the single best first test in any infertile couple — cheap, noninvasive, and abnormal in a large share of cases. Always repeat an abnormal result before acting on it; parameters vary widely between samples.
• Letrozole, not clomiphene, is first-line ovulation induction in PCOS (ASRM/ACOG). The classic distractor is metformin alone — it improves ovulatory frequency but is inferior for live birth.
• Exogenous testosterone causes infertility. A bodybuilder or a man "on testosterone for low T" with azoospermia and suppressed LH/FSH needs the testosterone stopped, not more of it.
• Azoospermia algorithm: azoospermia with low-volume, acidic, fructose-negative ejaculate and non-palpable vasa → CFTR testing (congenital bilateral absence of the vas deferens, a CF variant); low-volume ejaculate with palpable vasa → post-ejaculatory urinalysis for retrograde ejaculation and consider ejaculatory duct obstruction (transrectal ultrasound); normal-volume azoospermia with normal FSH and palpable vasa → obstruction proximal to the ejaculatory duct; normal-volume azoospermia with high FSH and small firm testes → karyotype and Y-microdeletion testing (Klinefelter 47,XXY).
• Anosmia + delayed puberty + low LH/FSH = Kallmann syndrome (failed GnRH neuron migration); treated with pulsatile GnRH or hCG/FSH, and fertility is achievable — distinguish this from primary testicular failure, where gonadotropins are high.
• **Left-sided bag of worms that does not decompress when supine** demands imaging: a new right-sided or non-reducible varicocele suggests retroperitoneal malignancy or renal cell carcinoma with renal vein involvement.
• Hydrosalpinx before IVF → salpingectomy first; retained tubal fluid is embryotoxic and substantially lowers implantation success.
• Sudden abdominal distension, weight gain, and oliguria days after an hCG trigger = OHSS; check hematocrit and address thromboprophylaxis. Any positive hCG after IVF with pain and an empty uterus is an ectopic (or heterotopic) pregnancy until proven otherwise.
• Ovarian reserve testing (day-3 FSH, AMH, antral follicle count) predicts response to stimulation, not the chance of natural conception — a common exam trap.