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
  • NOA (small testes, ↑FSH) → the wife's age and fertility best predict the chance of a biologic child
    • Since most such men have testicular sperm retrievable for IVF
  • Before ductal reconstruction or TESE + ICSI → evaluate the female partner
    • Maternal age is the most significant predictor of any reproductive intervention
    • Exam answer: fecundity falls precipitously after 37
• 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)

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Reproductive Physiology (high-yield)

GnRH, LH, FSH and testosterone

• GnRH (hypothalamus) pulsatile q90–120 min → anterior pituitary LH + FSH
• LH → Leydig cells → testosterone (most important regulator of T); hCG is an LH analog
• FSH → Sertoli cells → seminiferous tubule growth/spermatogenesis; essential to initiate spermatogenesis at puberty
• Inhibin-B (Sertoli) inhibits FSH; activin (Leydig) stimulates FSH
• Fetal testis:
  • Sertoli cells secrete Müllerian inhibiting substance (MIS/AMH) → Müllerian ducts regress at 9–10 weeks
    • MIS failure → persistent Müllerian duct syndrome: genetic male who retains a uterus and fallopian tubes despite otherwise normal virilization
  • Leydig-cell testosterone preserves and virilizes the Wolffian system
• Intratesticular T is 50–100× serum
  • Required for spermatogenesis
  • Level sustained by androgen-binding protein (ABP), secreted by Sertoli cells under FSH stimulation
  • Exogenous T suppresses LH/FSH → ↓ intratesticular T → impaired spermatogenesis
    • Paradox: exogenous T raises serum T even as intratesticular T falls
• Testosterone: 98% bound (SHBG 44%, albumin 50%, CBG 4%), 2% free; <300 ng/dL = low

Spermatogenesis

• Scrotal temperature is 2–4°C below core
  • Vascular heat-exchange mechanism + muscular control of the testis's proximity to the body
• Sperm production timeline: ~42–76 days total (45–60 d testis, 2–12 d epididymis)
  • Classic figure (exam answer): spermatogenesis ~64 days + 2–12 d epididymal transit → SA needs ~3 months to reflect any intervention
  • Three phases — proliferative → meiotic → spermiogenesis
    • Overlapping cycles coexist in a helical arrangement → production is continuous, not pulsatile
• Spermatogonia → spermatocyte → spermatid → spermatozoa
  • Same order runs spatially, basement membrane → lumen
  • Primary spermatocytes
    • Made by mitosis of type B spermatogonia
    • Cross the Sertoli tight junctions (blood–testis barrier)
    • First germ cells to undergo meiosis
  • Meiosis: primary spermatocyte → secondary spermatocytes (haploid, 2N DNA) → round spermatids (haploid, 1N DNA) → spermiogenesis
  • Spermiogenesis = metamorphosis of spermatids into spermatozoa in the adluminal compartment
    • Nuclear compaction but no cell division or cytokinesis
• Cell cycle: G0 → G1 → S → G2 → M
  • DNA is replicated in S (synthesis) phase — the diploid genome is copied once and only once
  • No S-phase checkpoint (unlike the G1/S and G2/M transitions), though ATM-mediated mechanisms can still pause the cell to repair DNA damage

Sperm structure and exit route

• Sperm structure:
  • Head = nucleus + acrosome
  • Neck = proximal centriole
  • Tail = midpiece, principal piece, endpiece
    • Midpiece, inside → out: 9+2 axoneme → outer dense fibers → mitochondrial sheath (helical; outermost layer, excluding the plasma membrane)
• Exit route: seminiferous tubules → straight tubules (tubuli recti) → rete testis (mediastinum testis) → 12–20 efferent ductules → caput epididymis
• Sperm mature (motility) in the cauda (tail) — target for retrieval in CBAVD/post-vasectomy
  • Motility is acquired as sperm mature along the epididymis
    • They are stored in the cauda → motile sperm most likely obtained there
  • After ejaculation, vas contents are propelled back toward the cauda
    • The distal vas contracts with greater amplitude, frequency and duration than the proximal vas

Seminal vesicles and prostate

• Seminal vesicles secrete 70–80% of ejaculate, alkaline + fructose
  • → acidic ejaculate (pH <7.2) suggests SV/ejaculatory duct obstruction or absence
  • SV fluid also:
    • Coagulates semen
    • Promotes sperm motility
    • Stabilizes sperm chromatin
    • Suppresses immune activity in the female tract
    • Antioxidant protection
  • Fructose (mean 2–3 mg/mL) = principal sperm energy substrate
    • → low/absent fructose (with a low-volume, acidic ejaculate) suggests ejaculatory duct obstruction or CBAVD
• Prostate — citrate: high zinc inhibits mitochondrial aconitase
  • → prostatic citrate >100 mM vs 0.1 mM in plasma → maintains seminal pH, aids liquefaction
  • Prostate cancer: intracellular zinc falls → aconitase disinhibited → citrate consumed for ATP → citrate depletion underlies prostate MR spectroscopy
• Liquefaction:
  • Prostatic kallikrein proteases — most abundantly PSA (KLK3) — degrade SV semenogelins in the coagulum
  • Citrate aids liquefaction, zinc inhibits it
• Prostate is the main site of T → DHT conversion (5α-reductase)
  • 46,XY infants with 5α-reductase deficiency develop only rudimentary prostates
  • Type II 5α-reductase predominates in BPH tissue
    • Prostatic DHT ↓ ~80% with finasteride, ~94% with dutasteride → gland shrinks 15–25% at 6 months

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Etiology — Pre / Testicular / Post-testicular

• 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)
  • Anabolic steroids = most common cause of profound hypogonadism in young men
    • Testosterone + aromatized estradiol suppress LH/FSH → severe oligozoospermia or azoospermia
  • hCG ± FSH speeds recovery after stopping
  • Exam answer for exogenous T: ~two-thirds recover sperm within 6 mo of stopping, 10% only in the second year, and some never recover
• 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
  • Low-volume + acidic almost always — the seminal vesicles (source of alkalinity) are hypoplastic or absent
  • Semen:
    • Azoospermia
    • Volume <1.0 mL
    • pH <7.0
    • Low fructose
    • No coagulum
    • Prolonged liquefaction
    • Only acidic prostatic + periurethral fluid remains
  • Exam answer: CF gene mutations in 85% · vasal agenesis in ~7% of brothers · unilateral renal agenesis in only 10–15% (mostly CF-mutation-negative) · no Y-microdeletion association
• Acidic low-volume azoospermia → think obstruction
• Normal-pH low-volume azoospermia → incomplete collection, retrograde, or partial obstruction
  • pH cutoff: >7.2 = normal · <7.2 = acidic
• Chronic upper respiratory infections → think CBAVD (CF mutations) and Young's syndrome (both azoospermic)
  • Or immotile cilia syndrome (= Kartagener when situs inversus is present)
• von Hippel-Lindau: infertility most likely from epididymal cystadenomas
  • Usually bilateral in VHL
  • ~1/3 of all epididymal cystadenomas occur in VHL
  • Papillary cystadenoma of the epididymis = the VHL-specific genital lesion (female counterpart: broad ligament cystadenoma)
    • A multicystic solid lesion, unlike a simple epididymal cyst

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
  • Testicular adrenal rest tumors (TARTs): cause infertility by displacing seminiferous tissue
    • Track with poor hormonal control
    • 2.6-fold more likely when CAH diagnosis is delayed >1 year
  • TARTs are benign and ACTH-driven → observe with intensified glucocorticoid suppression, ultrasound surveillance and sperm cryopreservation
    • Surgery only for large or symptomatic non-responders
• 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
  • Holds in hypergonadotropic azoospermia too: mild rise (20–50 ng/mL, same as µg/L) → no pituitary MRI
    • Pituitary tumors typically show prolactin >80 ng/mL with suppressed FSH and LH

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

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Genetic Causes

• CFTR mutations → CBAVD
  • ΔF508 most common
  • Test the 5T allele
  • Test female partner before ART
• Karyotype abnormal in ~6% of infertile men

Klinefelter (47,XXY)

• Most common known genetic cause of male infertility; few non-mosaic men have ejaculated sperm; micro-TESE possible
• 1 in 500–1000 live births
• Also the most common genetic cause of azoospermia — azoospermic in >95% of affected adults
• ~8% have sperm in the ejaculate; ~50% have enough intratesticular sperm for surgical retrieval with IVF/ICSI → paternity remains possible
• Tall stature in only 30% · small firm testes · gynecomastia · azoospermia
  • Also sparse facial hair
• Seminiferous tubule hyalinization → small firm testes + ↑FSH
  • Leydig cells present but testosterone low, with ↑LH and ↑estradiol
• Mosaic disease behaves better than non-mosaic, but is only 10–20% of cases
  • Very tall + gynecomastia + firm 3 mL testes + sperm 0.5 million/mL → most likely mosaic 46,XY/47,XXY
    • Classic 47,XXY is almost always azoospermic
• Screen for the associated conditions:
  • Breast cancer
    • Breast cancer — 20–50-fold ↑ risk, the classic malignancy; driven by the shifted estrogen-to-androgen ratio that also causes the gynecomastia
  • Mediastinal germ cell tumor
    • Mediastinal mass in a Klinefelter patient → consider a mediastinal germ cell tumor
  • Leukemia
  • Non-Hodgkin lymphoma
  • Mitral valve prolapse
  • Ischemic heart disease
  • Diabetes
  • Also ↑ non-germ cell testicular tumors (Leydig and Sertoli cell) and extragonadal germ cell tumors
• Origin & offspring:
  • Usually parental meiotic nondisjunction
  • Most ICSI offspring of 47,XXY men have normal karyotypes, but genetic counseling before ICSI is still needed
  • 0% risk of a daughter with Klinefelter (requires a Y)
    • A daughter inheriting an extra X would be 47,XXX (triple X)

46,XX male (phenotypic)

• No germ cells or sperm — no Y chromosome to direct sperm production
• Testosterone comes from SRY translocated from the Y short arm to the paternal X

Y-chromosome microdeletion (AZF)

• 2nd most common known genetic cause; found in 10–15% of men with azoospermia or severe oligospermia
• AZF region is on the long arm of Y (Yq) → causes non-obstructive azoospermia
  • AZFa complete → azoospermia with Sertoli cell-only syndrome
  • AZFb → spermatogenic arrest
  • AZFc → milder: drastically reduced counts that may decline progressively
• AZFa or AZFb complete deletion → do NOT attempt TESE (no sperm)
• AZFc deletion → TESE may succeed (sperm may/may not be found)
  • Good retrieval prognosis; causes infertility in male offspring but no congenital anomalies
  • Partial AZFc + azoospermia with normal semen volume and pH and FSH >7 IU/L → non-obstructive
    • → treat as idiopathic NOA with micro-TESE
• 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
  • True of any Y microdeletion → 100% of sons
    • The non-recombining, male-specific Y passes intact father → son, with no homologous copy

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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
  • Why: seminiferous tubules make up most of the testis — interstitium only 20–30%
• OA suspected: normal-size testes + indurated epididymides ± absent vas
• NOA/spermatogenic failure suspected: small soft testes + FSH >7.6 IU/L
• FSH >7.6 IU/L + long axis <4.6 cm → 89% likelihood of spermatogenic dysfunction
• FSH <7.6 IU/L + long axis >4.6 cm → 96% likelihood of obstruction
• Absent vas → check CFTR
  • If CFTR-negative → renal US (Wolffian origin → ipsilateral renal agenesis: ~26% unilateral, ~10% bilateral)
  • Vasal agenesis is a clinical diagnosis
    • → confirm a non-palpable vas by careful re-examination in a warm room with a relaxed cremaster before semen analysis
  • Confirm whether the contralateral vas is present
    • CFTR mutations in up to 80% of bilateral absence but only 20% of unilateral absence
  • A palpable scrotal vas does not exclude CBAVD — the inguinal vas and the seminal vesicles can still be absent
  • Unilateral absent vas → semen analysis next:
    • A patent contralateral side often preserves sperm
    • The result decides hormone testing vs transrectal US vs sperm retrieval
  • Unilateral absent vas (exam answer): CFTR carrier testing (incl. 5T allele) + renal US — vas and ureteric bud share a Wolffian origin → ipsilateral renal agenesis may coexist
• 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
    • Spermatogonia divide ~23 times/year after puberty → new autosomal dominant mutation risk rises from 0.22/1,000 births (paternal age <29) to 3.7/1,000 (>45)
    • Counsel couples with paternal age over 40 even with a normal SA: ↑ risk of Treacher Collins, achondroplasia, Apert and Crouzon syndromes

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Semen Analysis (WHO 5th-percentile cutoffs)

• Obtain ≥2 SAs ~1 month apart (esp. if first abnormal); 2–3 days abstinence; examine within 1 hr
  • Spacing (exam answer): at least two SAs 2–3 weeks apart, because semen parameters vary widely
  • Repeat an abnormal result (EAU, strong), alongside the hormonal work-up
  • After a serious febrile illness, wait ≥3 months (~12 weeks) from recovery before testing, since producing an ejaculated sperm takes 42–76 days

• Low-volume cutoff (exam answer): WHO 5th percentile 1.4 mL → e.g. 0.7 mL with sperm present and normal motility and morphology = likely incomplete collection → check collection technique and repeat the SA
• pH should be 7.2–7.8; total sperm number is the most important parameter
• Liquefaction normally within 20–30 min
  • Delayed if not begun by 30 min
  • Non-liquefaction if still incomplete at 60 min
• Azoospermia = no sperm → centrifuge + examine pellet
  • Repeat SA in 1–2 weeks
  • Up to 35% of NOA men later show sperm on repeat SA
  • Recent febrile illness can cause azoospermia with a transiently raised FSH
    • Spermatogenesis usually recovers in 3–4 months → repeat SA before vasography, TRUS or micro-TESE
• Globozoospermia (round-headed, no acrosome) → infertile, requires ICSI (sperm available, no extraction needed)
  • Varicocele repair does not improve it — the defect is structural
  • Linked to SPATA16, PICK1 and DPY19L2 mutations
  • Without an acrosome the sperm cannot penetrate the oocyte, so observation will not change it either
  • Natural conception, IUI and conventional IVF fail → ICSI with ejaculated sperm, sometimes combined with assisted oocyte activation
• 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
  • Includes 0% motility with a normal count → vital stain to exclude necrospermia

• Normal viability with severe asthenospermia → electron microscopy for ultrastructural defects
  • Ultrastructural flagellar defects: motility <5–10%, normal density, most non-motile sperm viable
  • 0% motility → immunobead antisperm antibody testing is impossible (it needs motile sperm)
  • Bronchitis + sinusitis, normal concentration, 0% motility → primary ciliary dyskinesia
    • Viability testing (mostly viable sperm) comes before invasive TRUS

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
  • Breach of the blood–testis barrier (e.g. testicular trauma) + sperm agglutination with otherwise normal semen → test by MAR or immunobead
• Test when:
  • Impaired motility with a normal count
  • Unexplained infertility
  • Sperm agglutination
  • Abnormal post-coital test
  • Sperm shaking
  • Increased leukocytes

• 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

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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
  • Oligozoospermia/azoospermia → hormones next (EAU, strong: total T + FSH/LH)
    • Separates testicular failure (↑FSH) from potentially treatable hypogonadotropic causes
• If T <300 ng/dL → repeat T, free/bioavailable T, LH, estradiol, prolactin
  • Same completion panel when the screening FSH is abnormal
    • The hormone pattern, not a single value, defines the diagnosis (table below)
• 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
  • Prolactin is checked to exclude a prolactinoma
    • It is a labile assay → confirm a moderately raised level on a second sample
    • Reserve MRI for very elevated values

• Obstructive azoospermia: LH, FSH and testosterone all normal
• Exogenous testosterone: Leydig cells cannot make T without LH → with LH suppressed, that T must come from outside
• Hypogonadotropic hypogonadism is pre-testicular, e.g. Kallmann syndrome; severely impaired spermatogenesis instead shows ↑FSH with ↑ or normal LH
  • Azoospermia, soft 3.0 cm testes, low T, LH and FSH both <1.0 IU/L → smell test: anosmia + hypogonadotropic hypogonadism confirms Kallmann syndrome

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
  • Viable sperm recovered from the urine can be used for assisted reproduction
• 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
  • Low-volume azoospermia with palpable vasa, normal-sized testes and normal hormones → PEU first
    • TRUS for ejaculatory duct obstruction only if the urine has no sperm
  • Diabetic man with volume <1.5 mL → PEU separates retrograde ejaculation from failure of emission
    • TRUS only if no sperm in the urine
  • Aspermia / dry ejaculation (orgasm without antegrade ejaculate) → PEU first (retrograde vs failure of emission)
    • Not TRUS — duct obstruction is unlikely with no ejaculate at all

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Genetic Testing — Indications

• Karyotype + Y-microdeletion:
  • Primary infertility AND one of
    • Azoospermia/severe oligospermia (<5 M/mL) with ↑FSH
    • Testicular atrophy
    • Presumed spermatogenic failure
  • Oligospermia with two concordant SAs and no palpable scrotal abnormality → a further repeat SA and scrotal ultrasound add nothing
    • Genetic testing is reserved for density <5 M/mL
• CFTR (incl. 5T allele): vasal agenesis (uni/bilateral) · idiopathic obstructive azoospermia · female partner is a carrier
  • Bilaterally impalpable vasa + low-volume (<1.0 mL), acidic azoospermia = CBAVD
    • CFTR testing of both the man (incl. 5T) and his partner before sperm retrieval
  • Partner testing is essential:
    • Both carriers → 25% risk of cystic fibrosis in each child
    • Partner negative for known mutations → residual carrier risk ~0.4%
  • One non-palpable vas + normal kidneys with low-volume azoospermia → CBAVD variant → CFTR testing
    • No karyotype when azoospermia is obstructive
• Y-microdeletion should be done before surgical extraction to guide counseling (AZFa/b → no TESE)
  • Karyotype also comes before sperm retrieval
  • It is complete AZFa and/or AZFb deletions that preclude TESE, and they characteristically give a Sertoli cell-only picture (hence testing in primary infertility with ↑FSH)

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Imaging

• Renal US: congenital absence of vas (regardless of CFTR status) — screen for renal agenesis
  • CBAVD → CFTR testing for the man AND his partner; renal agenesis in 11%
  • Applies to CBAVD variants too
    • In CF-negative men, CBAVD is thought to arise from mesonephric duct–ureteral bud abnormalities linked to 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
  • Low-volume, acidic azoospermia = absent seminal vesicle contribution
    • TRUS separates CBAVD (SV agenesis or hypoplasia) from bilateral EDO (findings above, plus SV cysts)
• Scrotal US: varicocele = veins >3 mm + reversal of flow on Valsalva
  • But treating non-palpable (subclinical) varicocele has no fertility benefit
• Testis size: US is the most accurate measure
  • More sensitive than the Prader or Takihara orchidometer for left–right asymmetry
  • Volume = length × width × height × 0.71
• 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
    • Both vasa palpable qualifies too — present vasa exclude vasal agenesis — when there is no clinical evidence of obstruction

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Azoospermia — Obstructive vs Non-obstructive

• 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
  • Low volume = <1.5 mL → also seminal vesicle or prostatic hypoplasia → investigate with TRUS
  • Low-volume ejaculate in general also: incomplete collection · short abstinence · retrograde ejaculation or failure of emission
• Normal volume (>1.5 mL) → TRUS unnecessary; this is the setting where diagnostic testis biopsy is most appropriate
• Semen fructose
  • If low, the problem is the ejaculatory duct or seminal vesicle (obstruction, agenesis, hypoplasia).
  • Normal is >13 µmol (>120 mg/dL)
  • Seminal vesicles make the fructose and 70–80% of the ejaculate → low volume + absent fructose = absent/hypoplastic SVs or EDO
• 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
  • Biopsy shows no germ cells; low Sertoli-cell inhibin B → FSH rises, while Leydig cells are spared (normal LH and testosterone)
• 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
• Small testes + elevated FSH → vasography of no benefit; diagnostic testis biopsy not indicated

Azoospermia — next step

• Normal volume and pH (excludes EDO and CBAVD) + low-normal FSH → obstruction with intact spermatogenesis → testis biopsy with sperm retrieval and cryopreservation
  • Biopsy shows normal spermatogenesis → obstruction is post-testicular → vasovasostomy or epididymovasostomy at the same sitting as the biopsy
• Normal volume + FSH >7.6 IU/L + testis long axes ≤4.6 cm → 89% spermatogenic dysfunction → next step micro-TESE
• Obstructive azoospermia:
  • Varicocelectomy does not help
  • Donor insemination only for uncorrectable obstruction when the couple refuses ICSI

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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
  • Clomiphene blocks estrogen receptors at the hypothalamus and pituitary
    • Removes estradiol negative feedback → GnRH rises → pituitary secretes more LH and FSH
  • Azoospermia with low T (280 ng/dL) and FSH not low (8.5 IU/L) → clomiphene, not recombinant FSH
    • Titrate to mid-normal serum testosterone to raise intratesticular T
• Aromatase inhibitors (anastrozole, letrozole): ↓E2 → ↑gonadotropins
  • For low T + elevated E2 (obesity, Klinefelter)
  • Risk ↓BMD
• hCG (LH analog, 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)
  • Kallmann responds to treatment: hCG first, add FSH/hMG once testosterone normalizes
    • Sperm appear but no pregnancy → assisted reproduction
  • Azoospermic on exogenous testosterone → stop testosterone (suppresses gonadotropins) and start hCG + recombinant FSH
    • Induce spermatogenesis before any sperm retrieval
• 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
  • hCG-driven intratesticular testosterone is essential — FSH fails to induce spermatogenesis even when given with exogenous testosterone
• Semen volume and sperm production are often limited (small prostate, seminal vesicles and testes), but sperm quality is typically normal and EDO is not a feature
• 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

• 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

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Surgical Sperm Retrieval

• Indications: azoospermia (OA or NOA), ejaculatory dysfunction
• Epididymal: MESA (microsurgical, highest yield + cryo), PESA (percutaneous)
  • Low-volume azoospermia with distal obstruction → MESA preferred for IVF/ICSI:
    • Fewer complications, sperm more motile than testicular sperm, enough to freeze multiple vials
  • In obstructed systems the most motile sperm lie more proximally (often the efferent ductules) → move the aspiration toward the caput until motile sperm appear
• 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

Testis biopsy

• Done mainly to identify and retrieve sperm for ART
  • Biopsy, including fine-needle aspiration, is not recommended without simultaneous sperm retrieval
• Spermatogenesis may be highly focal → a random biopsy can miss sperm; cryopreserve sperm from a diagnostic biopsy when ART is an option
  • Focal even in Sertoli-cell-only → retrieval rates up to 50% reported across NOA overall, so biopsy before TESE is not recommended
• Sertoli-cell-only histology → micro-TESE is still next (sperm found in a minority, rate in the table above)
  • hCG and clomiphene not indicated with normal testosterone
  • PESA is for obstructive azoospermia
• Open technique: incise the tunica albuginea at the upper medial aspect
  • Avascular, farthest from the posterolateral epididymis and the vascular arcade at the mediastinum testis
• Fix in Bouin's (or Zenker's, buffered glutaraldehyde)
  • Never formalin, which causes shrinkage and tubular artifact that distort histology
• Complications: bleeding is the most common; accidental biopsy of the epididymis is the most serious

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Vasectomy Reversal (VV / VE)

• Vasovasostomy when vasal fluid is clear/thin/watery AND contains sperm
  • Copious crystal-clear, watery fluid with no sperm seen → still VV
    • Clear fluid signals a patent, nonobstructed epididymis upstream
  • Even rare nonmotile sperm with a patent abdominal vas → VV; prognosis for sperm return after VV alone is excellent
  • Sperm in the vasal fluid on at least one side → sperm return to the ejaculate in 99.5%
    • Pregnancy 52% at ≥2 years (63% excluding female factors)
• Vasoepididymostomy when vasal fluid is thick/white/toothpaste-like and spermless (epididymal obstruction)
  • Anastomose only to a tubule containing sperm
  • Such fluid at the testicular vas, copious and water-insoluble = secondary epididymal obstruction → VE, even when saline flows freely down the abdominal vas
  • No vasal fluid → barbotage the testicular vas with 0.1 mL saline through a 24-gauge angiocatheter while milking
    • VE is reserved for a vas still dry and spermless without a sperm granuloma
  • When in doubt, or inexperienced with VE → perform VV
    • But only 15% of men with bilateral absence of vasal sperm after barbotage regain ejaculated sperm
  • Thick, white, sperm-free fluid + EDO on vasography (epididymal and ejaculatory duct obstruction) → abandon reconstruction
    • Aspirate epididymal sperm for cryopreservation + IVF/ICSI
  • Hydrocele found during evaluation for reversal → suggests secondary epididymal obstruction → be prepared to perform VE
• Better outcomes:
  • Bilateral VV
  • More distal VE anastomosis
    • Distal epididymovasostomy site → higher pregnancy rates than proximal (sperm transit more epididymis, where motility and membrane maturation occur)
    • No difference in patency reported
  • 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
  • AUA — sperm retrieval + IVF/ICSI preferred over reversal when:
    • Advanced female age (consider when >37; average time to pregnancy after reversal is 12 months)
    • Female factors requiring IVF
    • Expected ICSI success exceeds surgical success
    • Couple's financial preference
  • Not indications: advanced paternal age · prior nonconception by either partner
• 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)
  • Exam answer: first SA at 6–8 weeks; motile sperm expected within 6 months of VV
• 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
• Crossed (crossover) VV indications:
  • Unilateral inguinal vasal obstruction + contralateral atrophic testis
  • Inguinal vas/ejaculatory duct obstruction or aplasia on one side + epididymal obstruction on the other
    • One high-success crossover VV beats two low-yield operations (e.g. unilateral VE + contralateral TURED)

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
  • Sperm granuloma at the testicular end → the leak vents pressure away from the epididymis → predicts sperm at the testicular vas and a better prognosis regardless of time since vasectomy
  • Its absence most strongly predicts reversal failure
• Long testicular remnant
• Good-quality sperm in the vasal fluid
• Watery fluid at the vasectomy site
• Female partner under 35

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)
  • No intercourse either for 3 weeks — early ejaculation pressurizes the fresh anastomosis
  • No lifting >10 lb or strenuous activity for 4 weeks after VV (6 weeks after VE)
• Azoospermia persisting at 6 months → redo vasovasostomy or vasoepididymostomy

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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
  • Seminal vesicle cysts, congenital or acquired, are thought to result mainly from EDO
• 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
  • Partial EDO → low volume with poor motility; CBAVD or seminal vesicle hypoplasia → low-volume, acidic, azoospermic ejaculate
• Dx: TRUS ± aspiration (motile sperm → cryopreserve)
  • ≥1 palpable vas + low-volume acidic semen + absent fructose + normal FSH → TRUS for correctable EDO:
    • Midline Müllerian cyst or dilated ejaculatory ducts
  • EDO often → seminal vesicles >1.5 cm in diameter, but complete EDO may not dilate them → equivocal TRUS needs SV aspiration or vasography
• If TRUS is negative but EDO is still suspected, aspirate the seminal vesicle
  • More than 3 sperm/HPF confirms it
  • Low-volume azoospermia + FSH <7.5 IU/L + dilated SVs → TRUS-guided SV aspiration
    • Millions of sperm confirm EDO — EDO must be proven before balloon dilation or TUR
  • Low-volume azoospermia, normal exam, low FSH (adequate spermatogenesis likely) + nondilated SVs (0.9–1.1 cm) → EDO unlikely → testis sperm extraction + cryopreservation
• Tx: TURED (resect verumontanum / unroof Müllerian cyst) → 63–83% semen improvement, ~25% pregnancy; or surgical sperm extraction
  • Azoospermia persists after TURED despite normalized ejaculate volume → persistent EDO excluded → scrotal exploration + testis biopsy (epididymal obstruction vs testicular failure)
• TURED complications:
  • Retrograde ejaculation
  • Restenosis
  • Reflux of urine → watery ejaculate/chemical epididymitis
    • TURED is not benign — urine reflux up the excurrent ducts → chemical or bacterial epididymitis, which would destroy a fresh vasoepididymostomy
  • Urinary incontinence
  • Stricture
  • Rectal injury
  • Bladder-neck injury

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Ejaculatory Dysfunction / Anejaculation

• Causes: SCI, MS, diabetic neuropathy, RPLND/pelvic surgery (sympathetic T10–L2 injury)
  • SCI = most common cause of ejaculatory failure; diabetes mellitus and MS are the other frequent neurologic causes
• Neuroanatomy:
  • Erection mainly parasympathetic (S2–4) via cavernosal nerves running behind the prostate
  • Sympathetic outflow T10–12 (exam answer; T10–L2 in the RPLND context)
  • Pudendal nerve (S2–4) → penile sensation + bulbospongiosus contraction
  • Complete T12 SCI:
    • Reflexogenic erections persist
    • Psychogenic and nocturnal erections lost
    • Ejaculation poor — the spinal ejaculation generator lies at T11–12
• Retrograde ejaculation → sympathomimetics + urine alkalinization, or sperm from urine for ART
  • Most common causes: TURP and diabetic autonomic neuropathy
  • Drug culprit alpha-methyldopa (centrally acting antihypertensive → ↓sympathetic outflow → weak alpha-adrenergic bladder neck closure)
    • Causative drug cannot be stopped → pseudoephedrine restores bladder neck closure
  • Confirm with >5–10 sperm/HPF in postejaculatory urine
• Ejaculatory stimulation:
  • Lesion above T10 → penile vibratory stimulation (intact reflex arc)
  • T10 or below → electroejaculation
  • Complete high (C5–6) SCI → vibratory stimulation first (works in up to 70%) → electroejaculation → testicular sperm extraction
• Autonomic dysreflexia risk if SCI ≥T6 → pretreat with sublingual nifedipine 20 mg, monitor BP/pulse
  • Pseudoephedrine alone cannot start emission after SCI; use cautiously in lesions above T6 (autonomic dysreflexia)
• RPLND aspermia → post-orgasmic urinalysis; recovery up to 12–24 mo; permanent if persists at 24 mo
• Premature ejaculation (PE): diagnosed from the history — self-estimated IELT, perceived control, distress — with no routine lab tests
  • Lifelong PE → straight to first-line drugs; acquired PE → treat the cause first (ED, prostatitis, LUTS, anxiety, hyperthyroidism)
  • Thyroxine = hormone most implicated — excess shortens ejaculatory latency

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Varicocele

• Definition: abnormal dilation/tortuosity of pampiniform plexus (gonadal/internal spermatic veins)
• Arterial supply:
  • Testicular artery ← aorta
  • Vasal (deferential) artery ← superior vesical artery
  • Cremasteric (external spermatic) artery ← inferior epigastric artery
• Found in ~15% general population, ~35% primary infertility, 75–81% secondary infertility
  • The rise to ~80% in secondary infertility reflects progressive, duration-dependent damage
• ~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
• Unilateral varicocele can cause BILATERAL testicular damage
• If the examination is normal, do not order an ultrasound
  • Finding a subclinical varicocele will not help
• The semen analysis typically shows a "stress pattern": oligospermia · asthenospermia (commonest) · teratospermia

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)
  • Also required: female partner with normal or potentially correctable fertility → all four criteria
  • The infertility must be documented (couple), and abnormal SA = ≥1 abnormal semen parameter or sperm function test
• Symptomatic varicocele (pain) is a separate indication in its own right, independent of fertility
• Adolescent indications:
  • ≥20% size discrepancy
    • Semen not analyzed → a significant left–right testicular size difference is the main indication
      • Exam answer: hypotrophy thresholds as small as 10–20% or 2–3 mL
  • Bilateral hypotrophy
  • Abnormal SA (Tanner 5)
  • Pain
• If the semen analysis is normal and there are no symptoms, repeat the semen analysis every 1–2 years
  • Applies to adults with a palpable varicocele not attempting conception; if SA is abnormal → offer repair
• Normal SA → even a grade 3 varicocele does not explain the infertility
  • → evaluate the female partner (due after just 6 months of trying if she is >35)
• Grade 2–3 + contralateral grade 1 → bilateral varicocelectomy (more semen improvement than repairing the dominant side alone)
  • Does not apply to subclinical (Doppler-only) varicoceles
• Varicocelectomy is more cost-effective than IUI
  • IUI is unsuitable when sperm concentration is too low
  • Older female partner → consider IVF

After repair

• 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

Approach

• 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
  • The larger-varicocele gain is in semen
  • Overall pregnancy rates are similar (they start worse)
• Up to 50% of azoospermic men with palpable varicocele return sperm to ejaculate
• RCT pregnancy 44% vs 10%
  • Spontaneous pregnancy after repair (palpable varicocele + abnormal semen) ranges 20–60%
  • The RCT comparison is vs no surgery at 1 year, a 34-point absolute increase
• May also ↑testosterone
• Recurrence, testicular artery ligation and postoperative hydrocele predict poor outcomes
• Subinguinal microsurgical = most popular (artery/lymphatic-sparing, low recurrence, low hydrocele)
  • Prior vasectomy → deferential artery may be compromised
    • → microsurgical subinguinal repair (spares testicular artery + lymphatics) best preserves Leydig (hormonal) function
  • At the end of microsurgical inguinal/subinguinal repair only the testicular + cremasteric arteries, lymphatics and the vas with its artery and vein remain
    • Every other vein is ligated
• 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)
  • Vasal (deferential) veins drain to the internal iliac veins, separate from the gonadal system → keep the testis drained after microsurgical repair
• Scrotal approach avoided (atrophy)

Varicocele Treatment — Recurrence & Complications

• Radiographic occlusion recurs more often than microsurgical subinguinal repair
• Laparoscopic and retroperitoneal routes are more invasive than subinguinal, with more potential for serious morbidity

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Assisted Reproductive Technology

• IUI: washed sperm into uterus at ovulation
  • Needs ≥5–10 million total motile sperm post-wash
  • Better with ovulation induction
  • Total motile sperm count = volume × concentration × % motility
    • IUI is effective when it is >5 million → a Kallmann patient on hCG/FSH who reaches this should try IUI, not IVF/ICSI
• 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

• 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
• Isolated mild oligospermia (normal exam, normal female partner) → IUI first → regular IVF after several failed IUIs
  • ICSI is reserved for severe oligospermia

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Vasectomy

• 4th most common contraceptive method
  • More cost-effective/safer than tubal ligation
  • Not linked to prostate cancer, CHD, dementia, or ↓testosterone
• On counseling, 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
  • Hemoclips on both the abdominal and testicular ends of the divided vas → failure rate <1%
• Complications:
  • Hematoma/infection 1–2%
  • Chronic scrotal pain 1–2%
  • Symptomatic nodule <5%
  • Early failure ≤1%
  • Post-vasectomy pain refractory to conservative treatment, no other identifiable cause → vasectomy reversal (low morbidity)
    • Complete response 34–50%, overall improvement 82–93%
    • Reversal counseling: pain relief may take ≥3 months; a 20% reoperation rate from 1 to 9 years has been reported
• Vasectomy disrupts the blood–testis barrier → detectable serum antisperm antibodies in 60–80% of men
• Post-vasectomy SA timing: AUA 2–4 mo
• Success (can stop contraception): one sample with azoospermia OR ≤100,000 non-motile sperm/mL
  • AUA: one well-mixed, uncentrifuged fresh PVSA showing azoospermia or rare non-motile sperm (RNMS) → e.g. 90,000 non-motile sperm/mL = cleared
    • No repeat PVSA or repeat vasectomy needed
• Pregnancy risk after confirmed success ≈ 1/2000 (late failure/recanalization)
  • Repeat vasectomy if motile sperm rise or persist >6 mo

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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
  • Spermatogonia are the testicular cells most susceptible to ionizing radiation
    • Radiosensitivity follows mitotic activity, and spermatogonia divide rapidly
  • Sperm recovery depends on spermatogonial stem cell survival
  • Exam answer: testicular doses ≥7.5 Gy → irreparable damage to spermatogenesis and a significantly ↓ chance of fatherhood; the testis need not be directly exposed to be harmed (scatter 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)
  • After chemotherapy: contraception for 1–2 years (harmful genetic changes are common in sperm)
    • → conception with ejaculated sperm — natural, IUI or IVF — is contraindicated until then
• Recheck SA ≥12 mo (ideally 24 mo) post-treatment; persistent azoospermia → TESE option
  • Poor semen parameters shortly after chemotherapy → likely the chemotherapy
    • TRUS not warranted (TRUS is for low ejaculate volume <1.0 mL with low motility)
• Testis cancer → bank early; azoospermia with intratesticular lesion → onco-TESE at orchiectomy
• Transgender women on hormone therapy:
  • Up to 70–80% keep some degree of spermatogenesis, but only ~5–10% show normal sperm production
  • Testicular volume = best predictor of preserved spermatogenesis
    • Type of therapy, its duration and pre-orchiectomy hormone levels do not predict it

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Hypogonadism & Testosterone Replacement

Control of GnRH and testosterone

• 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)
  • SHBG-bound (44%, tightly bound) is the only non-bioavailable fraction
    • Free + loosely bound (albumin, corticotropin-binding globulin) = bioavailable → only this can act on the androgen receptor
• Free T is measured by ultracentrifugal ultrafiltration or dialysis; bioavailable T by ammonium sulfate precipitation
  • Equilibrium dialysis measures free and total T most accurately; calculated free T <6.5 ng/dL is low
• Measure free or bioavailable testosterone when the total sits at the lower limit of normal, or when SHBG is likely to be altered
  • Without equilibrium dialysis, free-T assays are unreliable → calculate bioavailable T from total T + SHBG (plus albumin where relevant)
    • In diabetic men, whose SHBG varies, diagnose hypogonadism on a low bioavailable T
• Also assess LH and prolactin to exclude secondary hypogonadism
  • If the HPG axis looks abnormal, get an MRI of the central nervous system

• Hyperthyroidism ↑ SHBG → ↓ bioavailable T even when total T looks normal
  • Low-normal total T + reduced libido → measure SHBG to interpret it

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

• 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
• Primary (hypergonadotropic) hypogonadism — congenital risk factors, DUNKY XX: Down syndrome · Undescended (maldescended) testis · Noonan · Klinefelter · Y-microdeletions · XX-male
• Testicular injury is another risk factor for primary hypogonadism
  • Torsion
  • Trauma
  • Orchitis
  • Atrophy
  • Radiation
  • Chemotherapy
  • Bilateral orchiectomy
  • Autoimmune failure
• Ask about it, plus cryptorchidism or orchiopexy, in every androgen-deficiency history

Symptoms

• 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

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