Infertility

Definitions & Epidemiology

• Infertility: failure to achieve clinical pregnancy after ≥12 months of regular unprotected intercourse (≥6 months if female partner >35)
• Primary = man has never initiated a pregnancy; secondary = previously initiated a pregnancy (any partner)
• Idiopathic = abnormal SA, no identifiable cause; unexplained = normal SA + normal partner evaluation
• Cumulative pregnancy (fertile couples): 6 mo ≈75% → 12 mo ≈85% → 24 mo >90%
• Female age is the single most important predictor of a couple's conception chances; fecundity falls sharply after 35
• Male factor: sole cause ≈20%, contributory ≈30–40% of infertile couples
• Most common male causes: Idiopathic 33% · Varicocele 27% · Obstruction 15% · Endocrinopathy 10% (hypogonadism most common)

Reproductive Physiology (high-yield)

• GnRH (hypothalamus) pulsatile q90–120 min ➡ anterior pituitary LH + FSH
• LH ➡ Leydig cells ➡ testosterone (most important regulator of T); hCG is an LH analogue
• FSH ➡ Sertoli cells ➡ seminiferous tubule growth/spermatogenesis; essential to initiate spermatogenesis at puberty
• Inhibin-B (Sertoli) inhibits FSH; activin (Leydig) stimulates FSH
• Intratesticular T is 50–100× serum — required for spermatogenesis; exogenous T suppresses LH/FSH ➡ ↓ intratesticular T ➡ impaired spermatogenesis
• Testosterone: 98% bound (SHBG 44%, albumin 50%, CBG 4%), 2% free; <300 ng/dL = low
• Sperm production timeline: ~42–76 days total (45–60 d testis, 2–12 d epididymis)
• Spermatogonia ➡ spermatocyte ➡ spermatid ➡ spermatozoa
• Sperm mature (motility) in the cauda (tail) — target for retrieval in CBAVD/post-vasectomy
• Seminal vesicles secrete 70–80% of ejaculate, alkaline + fructose ➡ acidic ejaculate (pH <7.2) suggests SV/ejaculatory duct obstruction or absence

Etiology — Pre / Testicular / Post-testicular

Category	Mechanism	Examples
Pre-testicular	Hypogonadotropic hypogonadism (↓LH/FSH)	Kallmann (X-linked, anosmia), hyperprolactinemia, pituitary tumor/infiltration, exogenous testosterone, opioids
Testicular	Primary spermatogenic failure	Klinefelter, Y-microdeletion, cryptorchidism, varicocele, orchitis, chemo/XRT, Sertoli-cell-only
Post-testicular	Obstruction / ejaculatory failure	CBAVD, vasectomy, EDO, retrograde ejaculation, anejaculation

• Exogenous testosterone: acquired hypogonadotropic hypogonadism ➡ ↓↓FSH/LH, atrophic testes, oligo/azoospermia ➡ stop first; recovery ~4–5 mo, up to 2 yr (67/90/96/100% at 6/12/16/24 mo)
• Gonadotoxin exposure ➡ stop agent, recheck SA in 3–6 months
• CBAVD: low-volume, acidic, azoospermic ejaculate; test CFTR (present in up to 80% CBAVD); acquired vs congenital obstruction
• Acidic low-volume azoospermia ➡ think obstruction
• Normal-pH low-volume azoospermia ➡ incomplete collection, retrograde, or partial obstruction

Genetic Causes

• Klinefelter (47,XXY): most common known genetic cause of male infertility; few non-mosaic men have ejaculated sperm; micro-TESE possible
• Y-chromosome microdeletion (AZF): 2nd most common known genetic cause
  • AZFa or AZFb complete deletion ➡ do NOT attempt TESE (no sperm)
  • AZFc deletion ➡ TESE may succeed (sperm may/may not be found)
• CFTR mutations ➡ CBAVD; ΔF508 most common; test the 5T allele; test female partner before ART
• Karyotype abnormal in ~6% of infertile men

Evaluation — History & Physical

• Obtain full hx including TICS [Toxin · Inflammation · Childhood hx · Sexual hx]
• Testis size correlates with sperm production: long axis <4.6 cm or volume <20 mL = impaired spermatogenesis
• OA suspected: normal-size testes + indurated epididymides ± absent vas
• NOA/spermatogenic failure suspected: small soft testes + FSH >7.6 IU/L
• Absent vas ➡ check CFTR; if CFTR-negative ➡ renal US (Wolffian origin ➡ ipsilateral renal agenesis: ~26% unilateral, ~10% bilateral)
• Counsel: 1–6% of infertile men have undiagnosed medical disease; abnormal SA ➡ ↑ testicular cancer & mortality risk; advanced paternal age (≥40) ➡ offspring risk

Semen Analysis (WHO 5th-percentile cutoffs)

• Obtain ≥2 SAs ~1 month apart (esp. if first abnormal); 2–3 days abstinence; examine within 1 hr

Parameter	Lower cutoff	Term if below
Volume	<1.5 mL	low volume → obstruction/SV issue, retrograde
Total sperm number	<39 million/ejaculate	—
Concentration	<15 million/mL	oligospermia
Total motility	<40%	asthenospermia
Progressive motility	<32%	asthenospermia
Normal morphology (strict)	<4%	teratospermia
Vitality	<58%	necrospermia

• pH should be 7.2–7.8; total sperm number is the most important parameter
• Azoospermia = no sperm ➡ centrifuge + examine pellet; repeat SA in 1–2 weeks; up to 35% of NOA men later show sperm on repeat SA
• Globozoospermia (round-headed, no acrosome) ➡ infertile, requires ICSI (sperm available, no extraction needed)
• Secondary tests (NOT first-line): DNA fragmentation (recurrent abortion/recurrent IVF failure), anti-sperm antibodies (only if changes mgmt; not before ICSI)

Hormonal Evaluation

• FSH + morning total T NOT first-line; obtain if (6): azoospermia · oligospermia (esp. <10 M/mL) · ↓libido · ED · atrophic testes · exam signs of endocrinopathy
• If T <300 ng/dL ➡ repeat T, free/bioavailable T, LH, estradiol, prolactin
• T:E2 ratio <10:1 indicates reproductive dysfunction

	Severe spermatogenic failure	Obstructive azoospermia	Hypogonadotropic hypogonadism
LH	↑ or normal	normal	↓
FSH	↑	normal	↓
Testosterone	↓ or normal	normal	↓

• Post-ejaculate urinalysis ➡ diagnoses retrograde ejaculation (low-volume/aspermia, normal pH)

Genetic Testing — Indications

• Karyotype + Y-microdeletion: primary infertility AND one of — azoospermia/severe oligospermia (<5 M/mL) with ↑FSH · testicular atrophy · presumed spermatogenic failure
• CFTR (incl. 5T allele): vasal agenesis (uni/bilateral) · idiopathic obstructive azoospermia · female partner is a carrier
• Y-microdeletion should be done before surgical extraction to guide counselling (AZFa/b ➡ no TESE)

Imaging

• Renal US: congenital absence of vas (regardless of CFTR status) — screen for renal agenesis
• TRUS (not routine): low-volume azoospermia with palpable vasa, or low volume + significant asthenospermia, or painful ejaculation ➡ EDO findings: SV AP diameter >1.5 cm, ejaculatory duct >2.3 mm, dilated vasal ampulla >6 mm, midline cyst
• Scrotal US: varicocele = veins >3 mm + reversal of flow on Valsalva — but treating non-palpable (subclinical) varicocele has no fertility benefit
• Testis biopsy NOT routine to distinguish OA vs NOA — predicted by FSH + testis size: FSH <7.6 & axis >4.6 cm ➡ 96% obstruction; FSH >7.6 & axis <4.6 cm ➡ 89% spermatogenic failure; indication for biopsy = azoospermia with normal testes, normal FSH, and at least one palpable vas

Azoospermia — Obstructive vs Non-obstructive

Feature	Obstructive (OA)	Non-obstructive (NOA)
Testis size	Normal	Small/soft (<4.6 cm)
FSH	Normal	Elevated (>7.6)
Epididymis	Indurated/full	Normal
Retrieval	TESA/PESA/MESA/TESE (testis = epididymis success)	micro-TESE (1.5× better than conventional)
Reconstruction	Possible (VV/VE)	Contraindicated

• Confirm with second SA + pellet analysis before workup

Medical Management

• Testosterone monotherapy is contraindicated if fertility desired (suppresses HPG ➡ azoospermia)
• SERMs (clomiphene, tamoxifen): block estrogen feedback ➡ ↑GnRH/LH/FSH ➡ ↑T & sperm; clomiphene 25–50 mg (up to 100 mg) every other day; off-label, best for low T + low/normal LH
• Aromatase inhibitors (anastrozole, letrozole): ↓E2 ➡ ↑gonadotropins; for low T + elevated E2 (obesity, Klinefelter); risk ↓BMD
• hCG (LH analogue): FDA-approved for hypogonadotropic hypogonadism; 1,500–5,000 IU twice weekly; treat 3–6 mo, add FSH if inadequate; gynecomastia ➡ add anastrozole
• FSH: for hypogonadotropic hypogonadism (off-label, costly); ineffective alone without intratesticular T; 75 IU every other day
• Hyperprolactinemia/secondary HH ➡ treat underlying cause first, then gonadotropins
• Idiopathic infertility: SERM benefit small ➡ ART (IVF) generally superior

Surgical Sperm Retrieval

• Indications: azoospermia (OA or NOA), ejaculatory dysfunction
• Epididymal: MESA (microsurgical, highest yield + cryo), PESA (percutaneous)
• Testicular: TESE (open — gold standard; micro-TESE preferred, less ↓T), percutaneous core biopsy, TESA (least invasive, lowest yield)
• OA ➡ retrieve from testis OR epididymis (equal success); NOA ➡ micro-TESE
• Fresh or cryopreserved sperm equally effective for ICSI; always have andrology lab ready to cryopreserve
• Complication: hematoma, ↓T

TESE retrieval rate by diagnosis	Retrieval
Klinefelter syndrome	68%
AZFc deletions	70%
Sertoli-cell-only	30%
Post-chemotherapy	53%
Cryptorchidism (post-orchiopexy)	74%
Maturation arrest	40%
AZFa, AZFb deletions	0

Vasectomy Reversal (VV / VE)

• Vasovasostomy when vasal fluid is clear/thin/watery AND contains sperm
• Vasoepididymostomy when vasal fluid is thick/white/toothpaste-like and spermless (epididymal obstruction) — anastomose only to a tubule containing sperm
• Better outcomes: bilateral VV, more distal VE anastomosis, sperm at reconstruction site, shorter obstructive interval
• Use indigo carmine (methylene blue kills sperm); always sample/cryopreserve vasal fluid first
• VV/VE may be preferred over retrieval+ICSI when female partner has normal fertility; consider sperm cryo at reconstruction if >25 yr post-vasectomy
• Post-op SA at 1, 3, 6 mo; azoospermia at 6–18 mo ➡ redo; cryopreserve once motile sperm appear (late stricture risk)

Ejaculatory Duct Obstruction (EDO)

• Congenital = most common; presents low-volume, acidic, low/absent fructose, normal FSH, normal spermatogenesis on biopsy, palpable vas
• Dx: TRUS ± aspiration (motile sperm ➡ cryopreserve)
• Tx: TURED (resect verumontanum / unroof Müllerian cyst) ➡ 63–83% semen improvement; or surgical sperm extraction
• TURED complications: retrograde ejaculation, restenosis, reflux of urine ➡ watery ejaculate/chemical epididymitis, incontinence, stricture

Ejaculatory Dysfunction / Anejaculation

• Causes: SCI, MS, diabetic neuropathy, RPLND/pelvic surgery (sympathetic T10–L2 injury)
• Retrograde ejaculation ➡ sympathomimetics + urine alkalinization, or sperm from urine for ART
• Ejaculatory stimulation: lesion above T10 ➡ penile vibratory stimulation (intact reflex arc); T10 or below ➡ electroejaculation
• Autonomic dysreflexia risk if SCI ≥T6 ➡ pretreat with sublingual nifedipine 20 mg, monitor BP/pulse
• RPLND aspermia ➡ post-orgasmic urinalysis; recovery up to 12–24 mo; permanent if persists at 24 mo

Varicocele

• Definition: abnormal dilation/tortuosity of pampiniform plexus (gonadal/internal spermatic veins)
• Found in ~15% general population, ~35% primary infertility, 75–81% secondary infertility
• ~85% left (asymmetric anatomy); isolated right or non-reducible/new ➡ image (rule out retroperitoneal mass / nutcracker)
• Mechanism of subfertility: ↑testicular temperature (loss of counter-current heat exchange), oxidative stress, hypoxia, hormonal imbalance
• Grading: 0 subclinical (US only) · 1 palpable on Valsalva only · 2 palpable at rest · 3 visible

Repair indications (infertility): all of — palpable varicocele + infertility + abnormal SA (NOT subclinical/imaging-only)

• Adolescent indications: ≥20% size discrepancy, bilateral hypotrophy, abnormal SA (Tanner 5), pain
• Outcomes: ~70% SA improvement (up to 9 mo) · 30–40% pregnancy post-varicocelectomy · ~50% pain resolution
• Large varicoceles improve more than small; up to 50% of azoospermic men with palpable varicocele return sperm to ejaculate; RCT pregnancy 44% vs 10%; may also ↑testosterone
• Subinguinal microsurgical = most popular (artery/lymphatic-sparing, low recurrence, low hydrocele)
• High recurrence: retroperitoneal, radiographic
• High hydrocele: retroperitoneal, laparoscopic, conventional inguinal
• Artery not preserved: retroperitoneal, conventional inguinal
• Deferential veins spared ➡ as long as one set remains, venous return adequate (keep vasal vein)
• Scrotal approach avoided (atrophy)

Varicocele Treatment — Recurrence & Complications

Treatment	Recurrence/Persistence %	Overall complications	Specific complications
Open approach
Scrotal approach	–	Testicular atrophy, arterial damage with risk of devascularisation and testicular gangrene, scrotal haematoma, post-operative hydrocele
Inguinal approach	2.6–13	Hydrocele (7.3%), testicular atrophy, epididymo-orchitis, wound complications	Post-operative pain due to incision of external oblique fascia, genitofemoral nerve damage
Open retroperitoneal high ligation	15–29	Hydrocele (5–10%), testicular atrophy, scrotal edema	External spermatic vein ligation failure
Microsurgical inguinal or subinguinal	0.4	Hydrocele (0.44%), scrotal haematoma
Laparoscopy	3–6	Hydrocele (7–43%), epididymitis, wound infection, testicular atrophy due to injury of testicular artery, bleeding	External spermatic vein ligation failure; intestinal, vascular and nerve damage; pulmonary embolism; pneumo-scrotum; peritonitis; post-operative pain in right shoulder
Percutaneous approach
Antegrade sclerotherapy	5–9	Hydrocele (5.5%), haematoma, infection, scrotal pain, testicular atrophy, epididymitis	Technical failure 1–9%, left-flank erythema
Retrograde sclerotherapy	6–9.8	Hydrocele (3.3%), wound infection, scrotal pain	Technical failure 6–7.5%, adverse reaction to contrast medium, flank pain, persistent thrombophlebitis, venous perforation
Retrograde embolization	3–11	Hydrocele (10%), haematoma, wound infection	Technical failure 7–27%, pain due to thrombophlebitis, reaction to contrast media, misplacement or migration of coils, retroperitoneal haemorrhage, fibrosis, ureteric obstruction, venous perforation

Assisted Reproductive Technology

• IUI: washed sperm into uterus at ovulation; needs ≥5–10 million total motile sperm post-wash; better with ovulation induction
• IVF: egg + sperm in dish; abnormal motility/morphology ↓ fertilization
• ICSI: single sperm injected into egg ➡ overcomes poor concentration/motility/morphology; needs only few viable sperm; ~33% live birth per cycle; ~19% twins
• Indications for ART: unreconstructable obstruction (CBAVD), NOA, idiopathic infertility, few viable sperm

Vasectomy

• 4th most common contraceptive method; more cost-effective/safer than tubal ligation; not linked to prostate cancer, CHD, dementia, or ↓testosterone
• Counsel: intended permanent; reversal/retrieval+IVF not always successful/expensive; not immediate sterility — use other contraception until PVSA confirms success
• Vas isolation: no-scalpel (NSV) or other minimally-invasive preferred (lower hematoma/pain/infection); conventional not recommended
• Vas occlusion (recommended): mucosal cautery ± fascial interposition; open-ended (testicular end) with cautery + FI on abdominal end; Marie Stopes extended electrocautery
  • Not recommended: folding-back; division+ligation alone (unless surgeon failure rate ≤1%); fascial interposition alone
• Complications: hematoma/infection 1–2%, chronic scrotal pain 1–2%, symptomatic nodule <5%, early failure ≤1%
• Post-vasectomy SA timing: AUA 2–4 mo
• Success (can stop contraception): one sample with azoospermia OR ≤100,000 non-motile sperm/mL
• Pregnancy risk after confirmed success ≈ 1/2000 (late failure/recanalization); repeat vasectomy if motile sperm rise or persist >6 mo

Fertility Preservation & Gonadotoxic Therapy

• Discuss + offer sperm banking BEFORE chemo/XRT (multiple specimens); cancer patients have poorer baseline SA + post-thaw motility
• Radiation: recovery months–years if >1 Gy; >10 Gy ➡ usually permanent azoospermia (testicular dose); fractionated worse than single dose
• Chemo: alkylating agents (cyclophosphamide, ifosfamide, procarbazine) + cisplatin target stem cells ➡ permanent azoospermia at high dose; others ➡ transient, recover 3–6 mo
• Avoid conception ≥12 months after completing treatment (genomic damage to germ cells)
• Recheck SA ≥12 mo (ideally 24 mo) post-treatment; persistent azoospermia ➡ TESE option
• Testis cancer ➡ bank early; azoospermia with intratesticular lesion ➡ onco-TESE at orchiectomy