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

Further causes of hypogonadotropic hypogonadism

• Iron deposition — hemochromatosis or repeated transfusion
• Morbid obesity, chronic malnutrition, type 2 diabetes
• Congenital adrenal hyperplasia, especially milder forms presenting in adolescence or adult life
• Prolactinoma — treat with a dopamine agonist, or radiotherapy. A mild elevation of 20–50 µg/L does not warrant further evaluation; if prolactin is significantly elevated, get a cranial MRI

Isolated gonadotropin deficiencies

• Isolated LH deficiency — "fertile eunuch syndrome": features of hypoandrogenism from low LH, but sperm are produced because FSH is adequate
• Isolated FSH deficiency: suppressed spermatogenesis with adequate androgenization
• Both are treated by replacing the appropriate gonadotropin

Genetic Causes

• Klinefelter (47,XXY): most common known genetic cause of male infertility; few non-mosaic men have ejaculated sperm; micro-TESE possible
  • Tall stature in only 30% · small firm testes · gynecomastia · azoospermia
  • Mosaic disease behaves better than non-mosaic, but is only 10–20% of cases
  • Screen for the associated conditions: breast cancer · mediastinal germ cell tumour · leukemia · non-Hodgkin lymphoma · mitral valve prolapse · ischemic heart disease · diabetes
• Y-chromosome microdeletion (AZF): 2nd most common known genetic cause; found in 10–15% of men with azoospermia or severe oligospermia
  • AZFa or AZFb complete deletion → do NOT attempt TESE (no sperm)
  • AZFc deletion → TESE may succeed (sperm may/may not be found)
  • If deletions are MIXED (AZFc plus AZFa or AZFb) there is no role for micro-TESE
  • In AZFc the son has a 100% chance of inheriting it — offer preimplantation genetic diagnosis and selection of a female embryo
• 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)
• Examine in a warm room with privacy — a cold room retracts the cord and masks a varicocele
• Stretched penile length 8–9 cm; erect ~13 cm
• Testis volume (orchidometer): <15 mL small · 15–20 mL equivocal · >20 mL normal
• Also record: syndromic appearance, obesity, height, gynecomastia, hair distribution, scars (penile/inguinal/scrotal), external urethral meatus, plaques, scrotal development, testicular consistency and masses, vas, varicocele, DRE
• History additions: previous IVF attempts — which, why they failed, and whether embryo transfer occurred · previous marriages or pregnancies · contraceptive history · intercourse frequency
• 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); varicocele repair does not improve it — the defect is structural
• Secondary tests (NOT first-line): DNA fragmentation (recurrent abortion/recurrent IVF failure), anti-sperm antibodies (only if changes mgmt; not before ICSI)

Semen leukocytes

• Round cells are either leukocytes or immature sperm — they are not interchangeable, and high leukocytes impair sperm function and motility
• If >5/HPF or >1 million/mL, do one of: immunohistochemistry (expensive) or the Endtz test (detects peroxidase inside leukocytes)
• Leukocytes >1 million/mL → evaluate for genitourinary infection — urethral, urine and semen cultures plus expressed prostatic secretions

Vitality testing

• Do a vitality test when motility is below 5–10%. Normal viability is 58%; necrospermia = no motility with reduced viability

Test	Use	Principle
Eosin Y / nigrosin stain	Diagnosis only — NOT for sperm destined for IVF	A live sperm excludes the dye because its membrane is intact
Hypo-osmotic swelling test	Use when the sperm will be used for IVF	Dead sperm do not swell

• Normal viability with severe asthenospermia → electron microscopy for ultrastructural defects

Antisperm antibodies

• IgG and IgA — IgM is not present in the genital tract
• Suspect with a history of genital duct obstruction, testicular trauma or surgery, or genital infection
• Test when: impaired motility with a normal count · unexplained infertility · sperm agglutination · abnormal post-coital test · sperm shaking · increased leukocytes

Method	What it tests	Note
Direct — immunobead, MAR	Antibody on the sperm itself	The preferred test
Indirect	Antibody in the serum	Less useful

• Treatment: steroids, or — more definitively — ICSI
• Risk factors: varicocele · testicular cancer · biopsy or testicular surgery · cryptorchidism · torsion · genitourinary infection (mumps, epididymitis) · ductal obstruction — vasectomy leads to antisperm antibodies in 60–80%, and CBAVD in about one third · genitourinary trauma · receptive anal intercourse

Sperm DNA fragmentation

• Test in men with repeatedly failed IVF plus male accessory gland infection, smoking, or varicocele
• Infertile men show higher fragmentation. Sperm harvested from the testis has LOWER fragmentation than ejaculated sperm — so where infertility is driven by high fragmentation, consider TESE with ICSI
• Risk factors — "Infertility FACTS": Fever · Air pollution · Cancer or chemotherapy · Toxic industrial exposure · Smoking · male infertility

Post-coital test

• Indicated when the couple's infertility workup is otherwise normal
• Intercourse immediately before ovulation; cervical mucus collected 9–14 hours later with a non-lubricated speculum. Rapid progressive motility means sperm–mucus interaction is normal
• Causes of an abnormal test: poor timing · antisperm antibodies (shaking sperm) · abnormal semen placement · abnormal semen · abnormal cervical mucus · abnormal vaginal environment
• In unexplained infertility: post-coital test → if abnormal, IUI · sperm penetration assay → IVF/ICSI · acrosome reaction test → IVF/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

• Normal FSH 1.5–12.4 IU/L (the value separating obstructive from non-obstructive is 7.6); normal LH 1.8–8.6 IU/L

• An FSH at the UPPER limit of normal is itself an indication of impaired spermatogenesis — do not read it as normal

• Primary testicular failure is present when FSH exceeds twice the upper normal limit

• High prolactin suppresses both LH and FSH; causes of a mildly elevated prolactin — ESRD · medications · stress · thyroid dysfunction · chest wall irritation

Pattern	Testosterone	LH	FSH	Prolactin
Hypogonadotropic hypogonadism	↓	↓ or N	↓ or N	N
Hypergonadotropic hypogonadism (primary testicular failure)	↓ or N	↑	↑	N
Prolactinoma	↓	N or ↓	N or ↓	↑
Germ cell failure (Sertoli-cell-only)	N	N	↑	N
Androgen resistance	↑	↑	N or ↑	N

• Obstructive azoospermia: LH, FSH and testosterone all normal

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

• Indicated when the ejaculate volume is <1.5 mL AND there is no CBAVD or hypogonadism to explain it
• In azoospermia, ANY sperm in the post-ejaculate urine diagnoses retrograde ejaculation
• In low volume with oligospermia, >5–10 sperm/HPF is taken as retrograde ejaculation — the exact number is unsettled
• Do post-ejaculate urinalysis BEFORE TRUS — TRUS is more invasive and should not come first

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

• Azoospermia affects 10–15% of infertile men
• Confirm with two semen analyses, centrifuged at 3000 g for 15 minutes, each pellet examined under the microscope, before workup
• Differential for LOW-VOLUME azoospermia: ejaculatory duct obstruction · vasal agenesis · testicular failure · hypogonadism · ejaculatory failure
• Semen fructose — if low, the problem is the ejaculatory duct or seminal vesicle (obstruction, agenesis, hypoplasia). Normal is >13 µmol (>120 mg/dL)
• Hypergonadotropic hypogonadism (primary testicular failure) = low testosterone DESPITE a high LH — Klinefelter, Noonan, absent testis, poorly formed testis
• Sertoli-cell-only — azoospermia with everything normal except a high FSH
• Maturation arrest — usually at the primary spermatocyte or late spermatid stage; oligospermia or azoospermia

Vasography — indications

1. Normal-volume azoospermia with normal hormones, normal spermatogenesis, normal testis size and normal histopathology — this combination means proximal obstruction
2. Azoospermia or severe oligospermia with a positive testicular biopsy or epididymal aspiration

• If the obstruction is DISTAL the volume will be low and the pH under 7.2 (seminal vesicle outflow obstruction)
• Vasography does not diagnose epididymal obstruction — that is an intra-operative diagnosis
• Do not perform vasography on an oligospermic man without a history or examination suggesting unilateral obstruction

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 mg daily, or 50 mg every other day (up to 100 mg); reassess at 6 months and do not continue beyond one year; 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, acts on Leydig cells — raises T, lowers FSH): FDA-approved for hypogonadotropic hypogonadism; 1,500–5,000 IU twice weekly; treat 3–6 mo, add FSH if inadequate; gynecomastia → add anastrozole
• FSH (acts on Sertoli cells): for hypogonadotropic hypogonadism (off-label, costly); ineffective alone without intratesticular T; 75 IU every other day
• hMG: each vial carries roughly 75 IU FSH plus 75 IU LH activity
• Cabergoline for high prolactin — high prolactin lowers GnRH and therefore LH, FSH and testosterone; it also increases LH receptors on Leydig cells. 0.5 mg three times weekly for 12 weeks
• Hyperprolactinemia/secondary HH → treat underlying cause first, then gonadotropins
• If both LH and FSH are low → hCG plus menotrophin, or clomiphene. If FSH is already high → give hCG alone
• Anastrozole: blocks peripheral aromatization of testosterone to estrogen in adipose tissue — give when estrogen is more than 10× testosterone
• Idiopathic infertility: SERM benefit small → ART (IVF) generally superior

Kallmann syndrome

• KAL-1 mutations cause hypogonadotropic hypogonadism; about 10% of men with Kallmann syndrome carry a GNRHR or KAL1 mutation
• Replace LH with hCG, and FSH with recombinant FSH or hMG (hMG carries both LH and FSH activity)
• Men diagnosed late, who have been on exogenous androgen since adolescence, may need 1–2 years of gonadotropin therapy before sperm appear in the ejaculate
• Clomiphene does NOT work in Kallmann syndrome — the receptor is absent
• Pituitary stimulation with antiestrogens (clomiphene, tamoxifen) or aromatase inhibitors (anastrozole, letrozole) may restore testosterone and possibly improve spermatogenesis

Drugs that impair male fertility

Class	Agents and effect
Antibiotics	Nitrofurantoin (reduced epididymal sperm density and motility) · tetracycline (oxidative stress)
Endocrine	Spironolactone, ketoconazole, cimetidine — impair androgen production; cimetidine also degenerates germ cells
Anti-inflammatory	Sulfasalazine — arrests cell division, causes oligoasthenospermia; substitute mesalazine
Urological	Alpha-blockers (retrograde ejaculation) · anti-androgens (bicalutamide, flutamide, nilutamide) · 5-ARIs (reduced semen volume, ED, ejaculatory dysfunction)
Psychotropic	Suppress the HPG axis, impair ejaculation, cause ED and reduce libido — mainly via dopamine antagonism. SSRIs (anorgasmia, delayed or absent ejaculation) · MAOIs · phenothiazines · lithium · risperidone (raises prolactin)
Hormonal	Exogenous testosterone and anabolic steroids — induce hypogonadotropic hypogonadism and azoospermia that may persist 3–4 months or longer after stopping · corticosteroids, especially in adolescence · exogenous estrogen
Antiretroviral	Protease inhibitors (indinavir) · nucleoside reverse transcriptase inhibitors (stavudine)
Recreational	Marijuana (gynecomastia, low testosterone, decreased counts, raised seminal leukocytes) · cocaine (abnormal morphology, decreased motility, low concentration) · alcohol — long-term abuse suppresses the HPG axis, moderate intake does not
Smoking	Dose-dependent deterioration in seminal parameters, increased oxidative stress, poorer sperm DNA quality
Others	CCBs (may inhibit the mannose-ligand receptor so sperm cannot bind the zona pellucida) · chronic opioids (suppress the HPG axis)

• ACE inhibitors appear to IMPROVE sperm motility
• PDE5 inhibitor effects are animal data and clinically unclear: sildenafil induced a premature acrosome reaction and impaired early embryo development; tadalafil decreased motility; vardenafil increased motility and possibly concentration

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, then every 6 months; azoospermia at 6–18 mo → redo; cryopreserve once motile sperm appear (late stricture risk)

Maneuvers to gain additional vasal length

• Separate the vas from the cord structures
• Blunt finger dissection through the external ring to free the vas to the internal ring
• Dissect the entire convoluted vas off its attachments to the epididymal tunica — gains 4–8 cm
• Dissect the epididymis off the testis — gains a further 4–8 cm
• Cut the floor of the inguinal canal and reroute the vas beneath it
• Transposition of the testis if the vessels cross

Predictors of a successful VV/VE

• Obstructive interval under 3 years · medical and surgical history since vasectomy · prior fertility in both partners · presence of a sperm granuloma · long testicular remnant · good-quality sperm in the vasal fluid · watery fluid at the vasectomy site · female partner under 35

• Do NOT perform varicocelectomy and vasovasostomy at the same sitting. After varicocele repair the venous outflow from the testis depends primarily on the vasal vessels, which are divided during vasectomy or vasovasostomy — doing both risks testicular atrophy

Post-operative instructions

• Scrotal supporter at all times for 6 weeks (except showering, including sleeping), then during athletic activity until pregnancy
• Light work resumes in ~72 hours · reduce activity for 2 weeks · delay ejaculation for 3 weeks (reduces anastomotic sperm leak, granuloma and stricture)
• Azoospermia persisting at 6 months → redo vasovasostomy or vasoepididymostomy

Ejaculatory Duct Obstruction (EDO)

• EDO accounts for under 5% of obstructive azoospermia
• Congenital = most common; presents low-volume, acidic, low/absent fructose, normal FSH, normal spermatogenesis on biopsy, palpable vas
• Presentation: hematospermia · low-volume ejaculate (<1 cc) · infertility · painful ejaculation · a history of epididymitis or prostatitis
• Evaluate when the semen volume is under 1 mL; causes include infection, inflammation, prior surgery, and compression by a congenital cyst
• Semen findings: low volume (mostly seminal vesicle fluid) · low fructose (<13 µmol) · watery semen — there is no semenogelin to make it coagulate · low sperm concentration
• CBAVD vs EDO: they produce a nearly identical semen analysis. CBAVD has an atrophied or absent seminal vesicle and NO palpable vas; EDO patients have a vas
• Dx: TRUS ± aspiration (motile sperm → cryopreserve)
• If TRUS is negative but EDO is still suspected, aspirate the seminal vesicle — more than 3 sperm/HPF confirms it
• Tx: TURED (resect verumontanum / unroof Müllerian cyst) → 63–83% semen improvement, ~25% pregnancy; or surgical sperm extraction
• TURED complications: retrograde ejaculation, restenosis, reflux of urine → watery ejaculate/chemical epididymitis, urinary incontinence, stricture, rectal injury, bladder-neck injury

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)

• Symptomatic varicocele (pain) is a separate indication in its own right, independent of fertility
• Adolescent indications: ≥20% size discrepancy, bilateral hypotrophy, abnormal SA (Tanner 5), pain
• Unilateral varicocele can cause BILATERAL testicular damage
• If the examination is normal, do not order an ultrasound — finding a subclinical varicocele will not help
• If the semen analysis is normal and there are no symptoms, repeat the semen analysis every 1–2 years
• The semen analysis typically shows a "stress pattern": oligospermia · asthenospermia (commonest) · teratospermia
• After repair, do a semen analysis every 3 months until one year has passed or pregnancy occurs
• Average time to pregnancy after repair is 8 months; count corrects before motility
• Tie the gubernacular vessels in a recurrent varicocele

Favour inguinal (external oblique opened)	Favour subinguinal (fascia intact)
Prepubertal children	Prior inguinal surgery
Solitary testis	Obesity
Tight, low external ring	Lax, capacious external ring; high external ring
Short cord, high-lying testis	Long cord with low-lying testis
Less experienced with microsurgical repair	Very experienced with microsurgical repair

• In children with a hernia, use the inguinal approach
• 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 devascularization and testicular gangrene, scrotal hematoma, 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 hematoma
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%), hematoma, 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%), hematoma, wound infection	Technical failure 7–27%, pain due to thrombophlebitis, reaction to contrast media, misplacement or migration of coils, retroperitoneal hemorrhage, 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

	Transferred	Fertilization	Minimum sperm	Motile sperm needed	Pregnancy rate
IUI	Sperm → uterus, transcervical	In vivo	≥5 million/mL	Yes	7–19% per cycle
GIFT	Oocytes + sperm → fallopian tube, laparoscopic	In vivo	—	Yes	36% per cycle
IVF (incubation)	Embryo(s) → uterus, transcervical	In vitro	25–50,000/oocyte normal men; 0.5–1.0 million/oocyte infertile men	Yes	39% per cycle
ICSI	Embryo(s) → uterus, transcervical	In vitro	1 sperm/oocyte	No	—

• IUI involves no manipulation of the female gametes; ideal where semen deposition into the vagina is mechanically impaired — hypospadias, penile curvature — or for abnormal cervical mucus or sperm–mucus interaction
• ICSI indications: severe oligospermia or azoospermia (obstructive or non-obstructive) · immotile or poorly motile sperm · prior failure of IVF with gamete incubation

Vasectomy

• 4th most common contraceptive method; more cost-effective/safer than tubal ligation; not linked to prostate cancer, CHD, dementia, or ↓testosterone
• On counselling, ask about fertility, sexual and past surgical history, and check for scars so the vas is not approached through scarred tissue
• Send the vas to histopathology to document that it was actually resected — a medicolegal safeguard
• 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
• Testosterone production is maintained if the testicular radiation dose is under 24 Gy — but monitor, since treatment may become necessary at any point
• 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

Hypogonadism & Testosterone Replacement

Control of GnRH and testosterone

Rhythm	Detail
Seasonal	Peaks in spring; regulated by the pineal gland
Circadian	Testosterone peaks in the early morning; regulated by neural connections from the suprachiasmatic nucleus
Pulsatile	Peaks every 90–120 minutes

• Evening testosterone is 40% lower than morning testosterone — this is why the sample must be a morning one
• A fatty meal lowers testosterone by 25%
• DHT is 2–10× more potent than testosterone
• Bioavailable testosterone = free + albumin-bound (the albumin-bound fraction exerts some effect; the SHBG-bound fraction does not)
• Free T is measured by ultracentrifugal ultrafiltration or dialysis; bioavailable T by ammonium sulfate precipitation
• Measure free or bioavailable testosterone when the total sits at the lower limit of normal, or when SHBG is likely to be altered
• Also assess LH and prolactin to exclude secondary hypogonadism; if the HPG axis looks abnormal, get an MRI of the central nervous system

SHBG decreased	SHBG increased
Obesity · nephrotic syndrome · hypothyroidism · glucocorticoids, progestins and androgenic steroids · acromegaly · diabetes mellitus	Aging · hepatic cirrhosis and hepatitis · hyperthyroidism · anticonvulsants · estrogen therapy · HIV disease

Definition and thresholds

Hypogonadism is either: low testosterone with symptoms, or symptoms with a normal testosterone that respond to a treatment trial.

• The testosterone corresponding to the lower limit of normal for young men — approximately 300 ng/dL (10.4 nmol/L) — is the level below which clinical symptoms become more likely

Testosterone	Action
< 8 nmol/L	Treat
8–12 nmol/L	Short-term testosterone trial
> 12 nmol/L	Normal

• Systemic illness associated with androgen deficiency — burn injury · surgical stress · HIV · myocardial infarction · CKD · traumatic brain injury · chronic opioid exposure · diabetes · sepsis · rheumatoid arthritis · obesity · respiratory illness · chronic liver disease · stroke · cancer · COPD

Symptoms

Physical	Cognitive	Sexual
Reduced energy and endurance · diminished work and physical performance · loss of body hair, reduced beard growth · fatigue · reduced lean muscle mass · obesity	Depressive symptoms · cognitive dysfunction · reduced motivation · poor concentration and memory · irritability	Reduced sex drive · reduced erectile function

• Young patient with ED and symptomatic low testosterone → start with testosterone, with or without a PDE5 inhibitor
• Elderly patient with ED → start with a PDE5 inhibitor. If there is no response and the laboratory confirms low testosterone, then give replacement

Testosterone replacement therapy

Indications — delayed puberty (idiopathic, Kallmann) · Klinefelter with hypogonadism · sexual dysfunction with low testosterone · low bone mass in hypogonadism · adult men with consistent and preferably multiple signs and symptoms · hypopituitarism · testicular dysgenesis with hypogonadism

Contraindications

Prostate cancer · PSA > 4 ng/mL · male breast cancer	Any man wishing to father children · hematocrit > 50%
Severe sleep apnea · severe LUTS due to BPH	Congestive heart failure · severe hepatic failure

Options — lifestyle modification (the essential first step) · topical gels and patches · short-acting injectables · pellets · oral buccal patch · intranasal gel · alternative medical strategies · oral testosterone undecanoate (not for age-related low testosterone)

• In a man who wants to preserve fertility, use an aromatase inhibitor, hCG, a SERM, or a combination — NOT testosterone
• Give a short trial of about 3 months; if there is no response, stop
• Follow-up — baseline DRE and PSA, plus hemoglobin/hematocrit, liver function, cholesterol and lipid profile. Reassess efficacy and adverse events at 3–6 months, then annually
• In Klinefelter with breast cancer and low testosterone, give an aromatase inhibitor, not testosterone — some testosterone converts to estrogen and can flare the cancer. Only in complete remission can he take testosterone