Infertility

Reproductive Physiology

This tab covers the male reproductive axis and the biology that underlies fertility: the hypothalamic–pituitary–testis axis, testosterone metabolism, spermatogenesis, the role of the epididymis, vas, and seminal vesicles, sperm structure, and the effects of aging.

Hypothalamic–Pituitary–Testis Axis

• GnRH (from the hypothalamus) stimulates LH and FSH release from the anterior pituitary. Its secretion is seasonal (peaks in spring), circadian (testosterone highest in the morning), and pulsatile (every 90–120 min); pulsatility begins at puberty (~age 12).
• The anterior pituitary produces LH, FSH, GH, TSH, ACTH, and prolactin — only LH and FSH act on the gonads.
• LH stimulates Leydig-cell steroidogenesis and is the most important regulator of testosterone production (so LH-deficient infertility is treated with hCG, an LH analogue). It is suppressed by negative feedback from estrogens (primary) and androgens — estradiol acting mainly at the pituitary, testosterone mainly at the hypothalamus — so exogenous testosterone lowers both LH and FSH.
• FSH stimulates Sertoli cells and seminiferous-tubule growth. It is essential to initiate spermatogenesis at puberty but not for spermatogenesis in acquired (post-pubertal) infertility — so hCG monotherapy can suffice without recombinant FSH. FSH is stimulated by estrogen and activin (a Leydig-cell product) and inhibited by inhibin-B (a Sertoli-cell product, stimulated by FSH, acting by negative feedback at the pituitary).
• Prolactin at normal levels supports Leydig-cell LH receptors and intratesticular testosterone, but hyperprolactinemia abolishes GnRH pulsatility and causes infertility.
• In the testis, Leydig cells make testosterone (drives the internal genitalia — seminal vesicles, epididymis, vas, ejaculatory ducts), DHT (drives the external genitalia and prostate), insulin-like growth factor-3 (transabdominal testicular descent), and activin; Sertoli cells make inhibin, Müllerian-inhibiting substance (regresses the Müllerian ducts), and androgen-binding protein (maintains high intratubular androgen). The SRY gene is critical for sex determination.

Testosterone and Androgens

Testosterone peaks at three life stages: ~13 weeks' gestation, ~2 months of age, and puberty. It is the most important circulating androgen — 90% from the testes, 10% from the adrenals, with normal production of ~5 mg/day.

• Circulation — testosterone is 98% bound (albumin ~50%, loosely; SHBG ~44%, tightly; corticosteroid-binding globulin ~4%, loosely) and 2% free. The free plus loosely-bound fractions are bioavailable testosterone — the only fraction that enters cells. Equilibrium dialysis is the most accurate assay. Total testosterone <300 ng/dL and calculated free testosterone <6.5 ng/dL are considered low; intratesticular testosterone is 50–100× serum levels and is required for spermatogenesis.

↓ SHBG (→ more bioavailable T)	↑ SHBG (→ less bioavailable T)
Obesity, nephrotic syndrome, hypothyroidism, glucocorticoids/progestins/androgens, acromegaly, diabetes	Aging, cirrhosis/hepatitis, hyperthyroidism, anticonvulsants, estrogens, HIV

• Metabolism (mainly hepatic) — aromatase converts testosterone to estradiol (the most potent regulator of the male HPG axis; inhibits LH; supports bone and libido), and 5α-reductase converts it to DHT in target organs. Testosterone and DHT are of similar potency, but if 5α-reductase is blocked, ~13× more testosterone is needed for the same effect; DHT is concentrated in the prostate and hair follicles. The plasma half-life of testosterone is ~12 minutes.

5α-reductase	Location	Inhibited by
Type 1	Non-genital skin, liver, brain	Dutasteride
Type 2	Androgen-dependent tissue (epididymis, genitalia, seminal vesicle, prostate), hair follicles	Finasteride and dutasteride

• Adrenal androgens (androstenedione — more potent than DHEA) are ACTH-driven, albumin-bound, weak, and remain normal after orchiectomy (but cannot maintain prostatic epithelium).
• Cardiovascular — androgen-deprivation therapy raises CV risk, and testosterone deficiency correlates inversely with CAD severity, but a 3-year RCT of testosterone gel in older men (TEAAM, 2015) found no benefit on carotid intima-media thickness, coronary calcium, or sexual function (with greater rises in hematocrit and PSA). Guidelines do not recommend testosterone screening or supplementation to improve cardiovascular outcomes.

Spermatogenesis

There are 13 recognisable germ-cell types, from dark/pale type A and type B spermatogonia → primary spermatocytes (preleptotene → leptotene → zygotene → pachytene) → secondary spermatocytes → spermatids (Sa–Sd2). Only type A spermatogonia are true stem cells (self-renew or differentiate). Producing an ejaculated sperm takes 42–76 days — ~45–60 days in the testis and 2–12 days in the epididymis (seconds in the ducts during ejaculation).

The three phases are proliferative (spermatogonial division), meiotic (crossing-over and halving of chromosomes — mature primary spermatocytes are the first to undergo meiosis; faulty recombination causes azoospermia), and spermiogenesis (remodelling and nuclear compaction of spermatids into spermatozoa). The sequence runs spermatOGONIA → spermatOCYTE → spermatID → spermatOZOA.

Sperm Transport and Accessory Glands

• Epididymis — provides sperm transport (rhythmic contractions), storage (in the cauda/tail), and maturation (improved membrane integrity, fertilising ability, motility, and glycolysis). Maturation completes at the distal corpus/proximal cauda, so in CAVD or post-vasectomy obstruction, sperm retrieval targets the cauda for better motility.
• Vas deferens — has absorptive and secretory functions, converts testosterone to DHT, and does not store sperm; sympathetic stimulation propels sperm to the ejaculatory duct before emission.
• Seminal vesicles — secrete 70–80% of the ejaculate and provide fructose; functions include coagulating semen, promoting motility, stabilising chromatin, immune suppression, and antioxidant protection. Their alkaline secretions make semen mildly alkaline, so an acidic ejaculate (pH <7.2) suggests seminal-vesicle obstruction or absence.

Spermatozoa

The spermatozoon has a head (nucleus and acrosome — needed for capacitation/fertilisation; its absence gives infertile round-headed sperm), a neck, and a tail (the midpiece holds the mitochondria, with a 9+2 axoneme for motility, using glucose and fructose for energy). Fertilisation requires four steps: motility, the acrosome reaction, capacitation, and zona pellucida binding.

Aging

Testosterone falls with age (fewer Leydig cells, more SHBG, loss of diurnal variation, blunted HPG feedback, irregular GnRH pulses), while FSH rises. Sperm production declines (from reduced germ-cell proliferation), and paternal age increases the fraction of sperm with sex-chromosomal aneuploidies (though evidence for aneuploid births is limited, except possibly trisomy 21).

Epidemiology & Etiology

Infertility is the failure to achieve a clinical pregnancy after ≥12 months of regular unprotected intercourse. Cumulative pregnancy rates among couples who do conceive are ~75% by 6 months, ~85% by 12 months, and >90% by 24 months.

Definitions and Classification

• Idiopathic infertility — no identifiable cause for an abnormal semen analysis; unexplained infertility — a normal semen analysis and normal partner evaluation with no clear reason.
• Primary male infertility — the man has never initiated a clinical pregnancy; secondary — he has previously initiated one but now cannot.

Epidemiology

Prevalence is ~11% in Canada. Semen parameters peak after 1–2 days of abstinence, so a single day of abstinence is optimal for assessing bulk parameters, while daily intercourse around ovulation maximises the chance of pregnancy. The female partner's age is the single most important predictor of conception — fecundity falls almost 50% in the late 30s, so the infertility "clock" is 12 months under age 35 but 6 months over 35. A male factor is solely responsible in ~20% of couples and contributes in ~30–40%.

Etiology

The most common causes of male infertility are idiopathic (33%), varicocele (27%), obstruction (15%), and endocrinopathy (10%, usually hypogonadism). Causes are classified as pre-testicular, testicular, or post-testicular.

Pre-testicular (hypogonadotropic hypogonadism)

• Congenital — Kallmann syndrome (X-linked recessive, deficient pituitary hormones, anosmia; treated by replacing LH with hCG, then FSH with recombinant FSH/hMG once testosterone normalises) and Prader-Willi syndrome (hypogonadism, small testes, dysmorphic facies, short stature, cognitive impairment).
• Acquired — hyperprolactinemia, pituitary/suprasellar tumours or infiltrative disease, pituitary apoplexy (Sheehan's), pituitary surgery, head trauma, and exogenous androgens.

Testicular

• Congenital primary hypogonadism (DUNKY XX): Down syndrome, Undescended testis, Noonan's, Klinefelter, Y-microdeletions, and XX-male.
  • Klinefelter syndrome — the most common known genetic cause of male infertility and the most common abnormality of sexual differentiation; few non-mosaic 47,XXY men have ejaculated sperm.
  • Y-chromosome microdeletion — the second most common genetic cause; the AZF region (long arm) has three subregions: AZFa or complete AZFb deletions abolish spermatogenesis (AZFa → Sertoli-cell-only; AZFb → maturation arrest), whereas AZFc deletions impair but do not necessarily abolish it (sperm may still be retrievable).
  • Cryptorchidism — after orchidopexy, paternity is ~96% if unilateral and ~70% if bilateral (repair ideally before age 10).
  • Sertoli-cell-only syndrome — normal LH/testosterone with low inhibin-B and therefore elevated FSH.
  • Androgen-receptor resistance — markedly elevated testosterone with impaired fertility, mildly elevated LH, and normal FSH.
• Acquired — medications/toxins (finasteride 5 mg/day reduces semen volume; opioids suppress LH; antipsychotics/SSRIs affect libido/ejaculation), chemotherapy (sperm DNA damage detectable ≥2 years later — bank sperm early in testicular cancer), radiation >7.5 Gy, infections (viral orchitis → bilateral atrophy), increased scrotal temperature (normally 2–4 °C below body), and obesity (adipose aromatase raises estradiol, lowering the T:E2 ratio).
  • Exogenous testosterone/anabolic steroids cause an acquired hypogonadotropic hypogonadism (suppressed FSH/LH, atrophic testes, oligo-/azoospermia) and are the most frequent cause of profound hypogonadism in young men. Cease them first: recovery begins at 4–5 months (up to 2 years), with recovery probabilities of 67%, 90%, 96%, and 100% at 6, 12, 16, and 24 months, and can be accelerated with hCG ± FSH.

Post-testicular

• Ejaculatory dysfunction — retrograde ejaculation (pharmacologic: α-blockers/psychotropics; neurogenic: SCI, RPLND, diabetic autonomic neuropathy, MS; anatomic: bladder-neck surgery/TURP) is confirmed on post-ejaculatory urinalysis and managed with sympathomimetics plus urine alkalinisation, induced ejaculation, or surgical sperm retrieval. Anejaculation follows SCI, MS, diabetes, or RPLND.
• Lubricants impair sperm motility (Pre-seed does not), and saliva is toxic to sperm.
• Cystic fibrosis (CFTR) — CFTR mutations are found in up to 80% of congenital bilateral absence of the vas (CBAVD), 20% of unilateral absence, and 21% of idiopathic epididymal obstruction (CFTR testing may follow surgical diagnosis). Kartagener syndrome (primary ciliary dyskinesia) causes infertility from absent ciliary/flagellar motility.

Evaluation: Initial Work-up

This tab covers the initial approach to the infertile male — the goals of evaluation, timing and counselling, the 2020 AUA testing algorithm, and the history and physical examination.

General Principles

Both partners should be assessed concurrently (maternal age is the strongest predictor of outcome in couples undergoing therapy, and many couples have more than one issue). The male work-up is a reproductive history, physical examination, and basic tests, with referral to a male-reproduction specialist for abnormal results. The goals are to identify: (1) potentially correctable conditions; (2) irreversible conditions amenable to ART with the partner's sperm; (3) irreversible conditions needing donor sperm/adoption; (4) life- or health-threatening conditions underlying the infertility (e.g. testicular cancer, pituitary tumour); and (5) genetic or lifestyle/age factors affecting the patient or offspring. After failed ART or recurrent pregnancy loss (≥2), evaluate the male and consider sperm DNA fragmentation and karyotype testing.

Timing and Counselling

Evaluate after 6 months of trying if the female partner is over 35 (otherwise 12 months). Counsel that abnormal semen parameters carry an increased risk of testicular cancer and mortality (1–6% of men have an undiagnosed medical disease at evaluation), and that advanced paternal age (≥40) raises the risk of adverse offspring outcomes (sperm aneuploidy, miscarriage, pre-eclampsia, preterm birth) — genetic counselling may be appropriate.

2020 AUA Testing Algorithm

After history, examination, and at least two semen analyses a month apart (parameters are highly variable — up to 35% of non-obstructive azoospermia men have sperm on a repeat SA without intervention):

• Serum FSH + morning total testosterone if there is azoospermia, oligozoospermia (concentration <10 million/mL), impaired libido, ED, atrophic testes, or a hormonal abnormality on exam. If testosterone is <300 ng/dL, add repeat total/bioavailable testosterone, free testosterone, LH, estradiol, and prolactin.
• Karyotype + Y-microdeletion if primary infertility and one of: azoospermia/severe oligozoospermia (<5 million/mL) with elevated FSH, testicular atrophy, or presumed impaired sperm production.
• CFTR testing (including the 5T allele) if there is vasal agenesis, idiopathic obstructive azoospermia, or a carrier female partner.
• Renal ultrasound if vasal agenesis; TRUS if low semen volume with azoospermia and palpable vasa, low volume with significant asthenospermia (total motility <40% or progressive <32%), or painful ejaculation.

History

Document the duration of infertility and whether it is primary or secondary (secondary infertility focuses on exposures since the last pregnancy), prior treatments, and risk factors (pre-/testicular/post-testicular). Stop any gonadotoxic agent and retest semen in 3–6 months, and retest at least 3 months after recovery from a serious illness or reproductive-tract infection. Review the sexual history (libido, function, lubricants), comorbidities, prior reproductive-tract surgery (vasectomy reversal may be more cost-effective than IVF), and family genetic history.

Physical Examination

• General — body habitus (obesity raises estradiol via adipose aromatase, lowering testosterone and SHBG), virilisation, and gynecomastia (a possible marker of endocrine disorder).
• Testis — size correlates with sperm production (a long axis <4.6 cm or volume <20 mL is low). Normal-sized testes with indurated epididymides ± absent vas suggest obstructive azoospermia, whereas soft, atrophic testes with FSH >7.6 IU/L suggest spermatogenic failure. Examine for masses (testicular cancer).
• Vas deferens — confirm presence to exclude agenesis. Unilateral absence implies failed Wolffian-duct development on that side (with possible ipsilateral renal agenesis, since the vas and ureteral bud share a Wolffian origin). Bilateral absence (CBAVD) warrants CFTR testing (mutations in up to 80% of CBAVD, most commonly ΔF508); both partners should be tested, and a CBAVD man is assumed to be a CFTR carrier even with a negative test. CBAVD semen is typically low-volume and acidic (seminal-vesicle hypoplasia); CAVD men without a CF mutation need renal US (absent ipsilateral kidney in 26% of unilateral and 11% of bilateral cases).
• Epididymides — induration/dilation or cysts/spermatoceles suggest obstruction.
• Varicocele — contributes to infertility via hyperthermia, hormonal imbalance, reactive oxygen species, and hypoperfusion; large varicoceles impair semen quality more than small ones.
• DRE — midline prostatic cysts or dilated seminal vesicles suggest ejaculatory-duct obstruction.

(Embryologic recall: the Wolffian (mesonephric) ducts form the epididymal body/tail, vas, seminal vesicles, and ejaculatory ducts; the Müllerian remnants are the appendix testis and prostatic utricle; the urogenital sinus forms the prostate and bulbourethral glands.)

Evaluation: Semen Analysis & Labs

This tab covers the cornerstone of the male work-up — the semen analysis — along with secondary semen tests, serum hormones, and post-ejaculate urinalysis.

Semen Analysis

The sample should be examined within 1 hour of collection after 2–3 days of abstinence, with at least two analyses a month apart (and a repeat 1–2 weeks later if azoospermic). The WHO lower limits are the 5th percentile derived from men whose partners conceived within a year — values below them do not by themselves diagnose infertility, but the odds of infertility rise with the number of abnormal parameters. The parameters individually diagnostic of infertility are azoospermia, necrozoospermia, complete asthenozoospermia, and complete globozoospermia.

Parameter	Lower reference limit
Semen volume	1.5 mL
Total sperm number (most important)	39 million/ejaculate
Sperm concentration	15 million/mL (oligospermia below)
Total motility	40%
Progressive motility	32%
Normal morphology	4% (teratozoospermia below)
Vitality	58%

• Low volume (<1.5 mL) — from obstruction/hypoplasia (CBAVD, severe androgen deficiency), α-blockers, retrograde ejaculation (sperm pass backward into the bladder — vs aspermia, a dry ejaculate), or incomplete collection. Hypervolemia (>5 mL) dilutes sperm.
• Asthenospermia (total motility <40% or progressive <32%) — from structural defects, prolonged abstinence, infection, anti-sperm antibodies, partial obstruction, or varicocele.
• Teratozoospermia (<4%) — globozoospermia (no acrosome → small round heads) requires ICSI (ejaculated sperm are available, so no surgical extraction); strict morphology should not be used in isolation for decisions.
• Vitality (<58%) — necrospermia; if motility is 0%, a vital stain distinguishes necrospermia, and electron microscopy can confirm immotile cilia syndrome (managed with IVF).
• Azoospermia — confirm by centrifuging and examining the pellet for rare sperm, then repeat. Normal-volume azoospermia reflects obstruction or a spermatogenic problem; low-volume azoospermia with acidic pH suggests genital-tract obstruction, while normal pH (>7.2) suggests incomplete collection, retrograde ejaculation, or partial obstruction (normal semen pH is 7.2–7.8).

Secondary Semen Analyses

• Sperm DNA fragmentation (TUNEL, Comet assays) — associated with lower pregnancy and higher miscarriage rates; not used in the initial work-up but useful with repeated IVF failure. There is no corrective therapy, but options include testicular (vs ejaculated) sperm with ICSI (higher live-birth rates), antioxidants, varicocele repair, and reduced abstinence.
• Semen leukocytes — round cells >1 million/mL are abnormal; staining (Papanicolaou/immunocytochemistry) distinguishes pyospermia (WBCs — evaluate for infection/STI) from harmless immature germ cells.
• Anti-sperm antibodies — follow disruption of the blood-testis barrier (trauma, mumps orchitis, vasectomy → ASA in 60–80%); IgA and IgG predominate. Test only if it will change management (not before ICSI); ICSI gives higher pregnancy rates than IUI in affected couples.
• Sperm aneuploidy testing (FISH for chromosomes 13, 18, 21, X, Y) — indicated for recurrent pregnancy loss.
• Fructose (from the seminal vesicles) — low semen fructose suggests ejaculatory-duct obstruction.

Serum Hormones

FSH and morning total testosterone are not first-line; obtain them for azoospermia, oligozoospermia (<10 million/mL), impaired libido, ED, atrophic testes, or a hormonal abnormality on exam. FSH indirectly reflects germ-cell mass: a testis <4.6 cm with FSH >7.6 IU/L suggests spermatogenic failure, whereas a larger testis with FSH <7.6 suggests obstruction. If morning testosterone is <300 ng/dL, add free/bioavailable testosterone, LH (distinguishes primary from secondary hypogonadism), estradiol (a total T:E ratio <10:1 indicates reproductive dysfunction), and prolactin (a labile assay — confirm before acting; MRI if very high).

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

Post-ejaculate Urine

A post-ejaculate urinalysis diagnoses retrograde ejaculation; viable sperm recovered from the urine can be used with ART.

Evaluation: Genetics, Imaging & Special

This tab covers genetic testing, imaging, the work-up of recurrent pregnancy loss, and fertility preservation before gonadotoxic therapy.

Genetic Testing

• Karyotype + Y-microdeletion — indicated for primary infertility with azoospermia/severe oligozoospermia (<5 million/mL) and elevated FSH, testicular atrophy, or presumed impaired sperm production.
• CFTR (including the 5T allele) — indicated for vasal agenesis/abnormalities, idiopathic obstructive azoospermia, or a carrier female partner.

Karyotype abnormalities (e.g. Klinefelter) are the most common known genetic cause of male infertility (an abnormal karyotype in ~6% of infertile men). Y-microdeletion is the second most common — perform it in azoospermia before surgical sperm extraction: complete AZFa and/or AZFb deletions should not undergo TESE (no sperm), whereas AZFc (and smaller partial AZFa/AZFb) deletions may or may not yield sperm. For a man with a CFTR mutation, test the female partner: the risk of an affected child is 25% if both are carriers and up to 50% if the man has mutations in both alleles and the partner is a carrier.

Imaging

• Renal ultrasound — indicated for congenital absence of the vas (regardless of CFTR status), because the Wolffian duct forms both the vas and the kidney's connection; ipsilateral renal anomaly/agenesis occurs in ~26–75% of unilateral and ~10% of bilateral vasal agenesis.
• Transrectal ultrasound (TRUS) — not initial; used to assess for ejaculatory-duct obstruction when there is low semen volume with azoospermia and palpable vasa, low volume with significant asthenospermia, or painful ejaculation. (Semen is ~10% testicular, ~20% prostatic, ~70% seminal-vesicle fluid; obstruction of the alkaline SV contribution gives acidic semen (pH <7.0).) EDO findings: seminal-vesicle AP diameter >1.5 cm, ejaculatory-duct caliber >2.3 mm, dilated vasal ampulla >6 mm, or a prostatic cyst. TRUS does not help in CBAVD.
• Scrotal ultrasound — assesses testicular size and varicoceles (US varicocele = veins >3 mm with flow reversal on Valsalva), but is not routine (treating non-palpable varicoceles does not improve outcomes); a routine work-up of an isolated right varicocele is unnecessary unless it is new-onset, non-reducible, or large.
• Brain MRI — for secondary hypogonadotropic hypogonadism (a pituitary tumour); the 2018 AUA testosterone guideline advises MRI if total testosterone <150 ng/dL with low/low-normal LH, regardless of prolactin.
• Testicular biopsy — not routine to distinguish obstructive from non-obstructive azoospermia (predicted clinically: FSH >7.6 IU/L with testis <4.6 cm → 89% spermatogenic failure; FSH <7.6 with testis >4.6 cm → 96% obstruction) — reserve it for intermediate values, and cryopreserve any sperm found (spermatogenesis can be focal).

Recurrent Pregnancy Loss

Defined as ≥2 failed pregnancies and distinct from infertility; most miscarriages reflect fetal abnormalities. Causes include genetic (translocations), uterine anatomic, infectious, immunologic, and endocrine factors, plus a male contribution — the commonest male etiologies being karyotypic abnormalities and sperm DNA fragmentation. The male work-up is karyotype, sperm DNA fragmentation, and sperm aneuploidy testing.

Gonadotoxic Therapy and Fertility Preservation

Discuss the effects on sperm production and encourage sperm banking (multiple specimens) before treatment — recovery depends on spermatogonial stem-cell survival.

• Radiation — recovery takes months to years above 1 Gy, and >10 Gy usually causes permanent azoospermia (fractionated radiation is more harmful than a single dose).
• Chemotherapy — alkylating agents (cyclophosphamide, ifosfamide, procarbazine) and cisplatin target stem cells and most often cause permanent azoospermia; most other agents target differentiating germ cells and cause transient suppression with recovery in 3–6 months.
• Onco-TESE — for an azoospermic man with an intratesticular tumour, cryopreserve testicular tissue at orchiectomy.
• RPLND — counsel about aspermia/retrograde ejaculation (the ejaculatory sympathetic fibres, T10–L2, lie near the dissection) and offer banking; recovery of antegrade ejaculation can take 12–24 months, and aspermia persisting at 24 months is likely permanent.
• After treatment — advise avoiding pregnancy for ≥12 months, and defer a semen analysis until 12 (preferably 24) months afterward; TESE is an option for persistent azoospermia.

Management: Medical & Selection

This tab covers non-surgical (hormonal) therapy for male infertility and how treatment is selected by clinical scenario. The unifying principle: boost endogenous, intratesticular testosterone without exogenous testosterone, which suppresses spermatogenesis.

Medical (Non-Surgical) Therapy

• Selective estrogen receptor modulators (SERMs) — clomiphene, tamoxifen. They antagonise estrogen receptors at the hypothalamus/pituitary, raising GnRH → LH/FSH → testosterone (and sperm counts), with a greater testosterone rise than anastrozole. Clomiphene (25 mg up to 100 mg daily) is the most-used agent for hypogonadism when fertility must be preserved, though it is off-label (not FDA-approved in males); enclomiphene is the side-effect-sparing stereoisomer in development. Consider SERMs for low testosterone with a borderline-high FSH ("lazy pituitary").
• Aromatase inhibitors (anastrozole, letrozole) — block conversion of testosterone to estradiol, useful in men with testosterone deficiency and elevated estradiol (a low T:E ratio <10, as in obesity or Klinefelter); off-label, with a theoretical risk of reduced bone density.
• Gonadotropins — hCG mimics LH to drive Leydig-cell (intratesticular) testosterone; it is FDA-approved for pituitary hypogonadism (e.g. Kallmann) and works best with a pre-treatment testis length >4 cm, often given alone for 3–6 months before adding FSH. FSH alone does not induce spermatogenesis without adequate intratesticular testosterone. hCG can cause gynecomastia in up to one-third (treat with anastrozole); pulsatile GnRH is not approved in the US/Europe.
• Growth hormone (via IGF-1, off-label) and supplements/antioxidants (questionable clinical utility) round out the options.

Treatment Selection

• Do not prescribe testosterone monotherapy to a man interested in current or future fertility — its negative feedback suppresses gonadotropins and spermatogenesis (recovery after stopping takes months, rarely years).
• Hyperprolactinemia — treat the underlying cause.
• Secondary (hypogonadotropic) hypogonadism — deficient LH/FSH. Idiopathic/congenital (Kallmann) responds to exogenous gonadotropins; first-line is hCG (1,500–2,500 IU twice weekly, response proportional to baseline testis size), adding FSH after testosterone normalises. For acquired causes, treat the underlying disorder first; SERMs are an off-label alternative (ineffective if the pituitary itself is damaged, e.g. post-resection).
• Infertile men with low testosterone (low/normal LH) — use AIs, hCG, or SERMs (alone or combined) to raise endogenous testosterone without impairing spermatogenesis: AIs if estradiol is elevated, hCG or SERMs if LH is low/normal; an elevated LH (primary hypogonadism) predicts a limited response.
• Idiopathic infertility — SERMs offer limited benefit relative to ART (IVF gives higher pregnancy rates); an FSH analogue may be considered.
• Non-obstructive azoospermia — optimise spermatogenesis before surgical sperm retrieval, though the data for SERMs/AIs/gonadotropins beforehand are limited.

Management: Surgical

This tab covers the surgical options for male infertility: sperm retrieval, vasography, vasectomy reversal, ejaculatory-duct obstruction, ejaculatory stimulation, varicocelectomy, and assisted reproductive technology.

Surgical Sperm Retrieval

The efferent ducts coalesce into a single epididymal tubule from the caput onward, so aspiration is safely done at the proximal head (multiple lobules), while any injury distal to the caput obstructs the whole side. Retrieval is indicated for azoospermia (obstructive or non-obstructive) or ejaculatory dysfunction:

• Epididymal — microsurgical (MESA) or percutaneous (PESA) aspiration.
• Testicular — open TESE (the gold standard; preferably micro-TESE, which retrieves the most sperm with less testosterone loss than conventional TESE; contraindicated in Sertoli-cell-only syndrome or maturation arrest), percutaneous core biopsy (blind — risks the epididymis/testicular artery, so target the midsection), or TESA (least invasive). The most common complication is hematoma.

Approach by cause: obstructive azoospermia — sperm from either testis or epididymis (equivalent outcomes); non-obstructive azoospermia — micro-TESE (~1.5× more successful than non-microsurgical extraction).

Vasography

Absolute indications (all three): azoospermia, complete spermatogenesis on biopsy, and at least one palpable vas. Principles: sample vasal fluid first and cryopreserve any motile sperm before injecting dye; use indigo carmine, not methylene blue (which kills sperm); and never inject toward the epididymis under pressure. Large fluid volume with sperm indicates obstruction toward the seminal-vesicle end, whereas a dry, spermless vas after milking indicates epididymal obstruction; a vas ending blindly suggests partial agenesis (test for CFTR).

Vasectomy Reversal

Microsurgical reconstruction anastomoses the vas to the most distal site containing sperm. Higher patency/pregnancy follow bilateral vasovasostomy, intact sperm at the reconstruction site, and a shorter obstructive interval. Counsel couples on reconstruction vs sperm retrieval + ICSI: reconstruction is preferable when the female partner has normal fertility, while IVF/ICSI is favoured with female factors or very remote vasectomy (>25 years). The contraindication is non-obstructive azoospermia.

The vasal fluid appearance guides the anastomosis:

Vasal fluid	Procedure
Clear/thin, watery (± sperm)	Vasovasostomy
Thick, dry, "toothpaste-like," spermless	Vasoepididymostomy (only onto a sperm-containing tubule)

Length for a large vasal gap is gained sequentially (separating the cord, freeing the convoluted vas without unravelling it, rerouting under the inguinal canal, and dissecting the epididymis off the testis — bridging up to 10 cm). Simultaneous vasovasostomies at two sites devascularise the intervening segment, and a crossed vasovasostomy connects a healthy testis to the contralateral unobstructed vas. Postoperatively, use scrotal support, avoid ejaculation for 3 weeks, and obtain semen analyses at 1, 3, and 6 months (redo if azoospermia persists at 6 months); cryopreserve sperm once they appear, as late stricture can occur.

Ejaculatory Duct Obstruction

Congenital EDO is the most common (acquired forms follow prostatitis or cyst compression). It presents as a low-volume, acidic, low-fructose, azoospermic ejaculate with normal FSH and biopsy and a palpable vas; TRUS shows a midline (müllerian) cyst or dilated ducts/seminal vesicles (SV AP >1.5 cm). Management is TURED (improves semen parameters in 63–83%), resecting at the verumontanum while preserving the bladder neck, sphincter, and rectum. Complications include restenosis, reflux of urine causing watery ejaculate and chemical epididymitis, retrograde ejaculation, and stricture.

Ejaculatory Stimulation

Indicated for ejaculatory dysfunction from impaired sympathetic outflow (SCI, MS, diabetes, RPLND/pelvic surgery). The technique depends on the lesion level: above T10, the ejaculatory reflex arc is intact → penile vibratory stimulation; at/below T10 → electroejaculation (then sperm retrieval if both fail). In SCI at/above T6, watch for autonomic dysreflexia (headache, hypertension, bradycardia, diaphoresis — potentially life-threatening) — pretreat with 20 mg sublingual nifedipine and monitor blood pressure.

Varicocelectomy

Not indicated for non-palpable (imaging-only) varicoceles. Consider repair in a man attempting conception who has a palpable varicocele, infertility, AND abnormal semen parameters (but not for azoospermia) — it raises pregnancy rates versus no treatment but defers ART by ≥6 months, and the evidence to repair before ART in NOA is not definitive.

Assisted Reproductive Technology

Indicated for unreconstructable obstruction (CBAVD), few viable sperm, NOA, or idiopathic infertility.

• Intrauterine insemination (IUI) — washed semen placed in the uterus at ovulation, ideally with ovulation induction; natural-cycle IUI is no better than timed intercourse for abnormal semen. A total motile count <5 million after processing predicts lower success (≥5–10 million is usually needed).
• IVF ± ICSI — IVF leaves egg and sperm to fertilise, whereas ICSI injects a single sperm and so overcomes poor sperm quality with only a few viable sperm needed. IVF gives ~33% live delivery per cycle (lower with female age >35) and ~19% twin deliveries; for surgical sperm, fresh and cryopreserved sperm give equivalent ICSI outcomes.

Vasectomy

Guideline basis: AUA 2015 and CUA 2022.

Background

Vasectomy is the 4th most commonly used method of contraception (after condoms, oral contraceptives, and tubal ligation). It is simpler, faster, safer, less expensive, and equally effective compared with tubal ligation — and is among the most cost-effective of all contraceptive methods, at roughly one-quarter the cost of tubal ligation.

In Canada there is no specific age of consent; any man with the legal capacity to provide informed consent may undergo vasectomy. Consider offering younger men more time to reflect before proceeding.

Pre-operative Assessment

Obtain a preoperative consultation in person where possible (telephone or electronic communication are acceptable alternatives). In the US there is no requirement for spousal or partner involvement, though patients should be advised that partner involvement is desirable.

History — focus on three areas:

• Reproductive history and reproductive status of the female partner — if the chance of pregnancy in the partner is already poor, the need for vasectomy may be less than the couple expects.
• Whether family planning is complete — if the partner is currently pregnant, consider delaying until after delivery to avoid regret should the pregnancy be lost unexpectedly.
• General medical history, particularly bleeding risk factors (liver disease, bleeding diathesis, anticoagulant medications).

Physical exam — examine the genitalia.

Labs — not required unless indicated by history; consider preoperative coagulation tests if bleeding risk factors are present.

Counselling Points

• Vasectomy is intended as permanent contraception, though it has a high probability of reversibility.
• Alternatives exist — permanent (tubal ligation) and non-permanent (barrier methods, oral or injectable contraception for the partner).
• Options for fertility after vasectomy (reversal, or sperm retrieval with IVF) are not always successful and may be expensive; preoperative sperm banking can be discussed for patients concerned about permanence.
• Impaired fertility from anti-sperm antibodies after vasectomy is infrequent, and serum anti-sperm antibodies should not be considered a deterrent to reversal.
• Vasectomy does not produce immediate sterility — time to azoospermia or rare non-motile sperm (RNMS) varies from weeks to months. Couples must use other contraception until success is confirmed by post-vasectomy semen analysis (PVSA).

Risk of Complications

• Symptomatic hematoma and infection: 1–2% — rates vary with surgeon experience and diagnostic criteria; epididymitis rates are generally low.
• Chronic scrotal pain: 1–2% — negatively affects quality of life; usually (not always) improved with medical or surgical therapy, and few men ultimately require surgery for it.
• Failure (failure to achieve azoospermia/RNMS, or pregnancy):
  • Early failure — motile sperm in the ejaculate at 3–6 months post-vasectomy; repeat vasectomy is needed in ≤1% when a low-failure occlusion technique is used.
  • Late failure — motile sperm after two prior PVSAs documented azoospermia; even confirmed occlusion is not 100% reliable, with pregnancy risk ≈1/2000 after a PVSA showing azoospermia or RNMS.
• Symptomatic nodule: <5% — presumed sperm granuloma (or suture granuloma if a ligature was used); acute pain usually resolves within 2–3 months; treat symptomatically with anti-inflammatories/analgesics; persistent pain is rare and may respond to excision and repeat vasectomy.
• Change in sexual function — frequency or satisfaction increases in half or more of patients and decreases in only ~5%. There is no evidence vasectomy increases erectile dysfunction, orgasmic or ejaculatory changes, reduced libido, or diminished genital sensation; no effect on hormones (testosterone, FSH, LH), lipids, or bone mineral density; and no association with prostate cancer, coronary heart disease, stroke, hypertension, dementia, or testicular cancer.

Procedure

Antibiotic Prophylaxis

Not indicated for routine vasectomy unless the patient is at high infection risk. The AUA Best Practice Policy on antimicrobial prophylaxis recommends prophylaxis for genital surgery that does not enter the urinary tract only when risk factors are present — and even ≥1 risk factor does not necessarily mandate prophylaxis. Risk factors: advanced age, anatomic anomalies of the urinary tract, poor nutritional status, diabetes, smoking, chronic corticosteroid use, immunodeficiency, distant coexistent infection, and prolonged hospitalization.

Anesthesia

Perform under local anesthesia, with or without oral sedation. IV sedation or general anesthesia is reserved for patients who decline local or when local ± oral sedation is judged inadequate. Infiltrate local anesthetic into skin and perivasal tissue using the smallest available needle (25–32G). There are insufficient data that adding buffer, epinephrine, or corticosteroids — or a topical cutaneous spray — reduces pain or postoperative inflammation, so these are not endorsed. Topical anesthetic cream may be used in addition to, but never as the sole source of, local anesthesia.

Vas Isolation

Intraoperative and early postoperative pain, bleeding, and infection relate mainly to the isolation method. Routine histologic examination of excised vas segments is not required.

Method	Recommendation	Notes
No-scalpel vasectomy (NSV)	Recommended	Minimally invasive; two special instruments (vas ring clamp and vas dissector) plus sequential specific steps — altering any step makes it a "minimally-invasive vasectomy," not NSV. Incision usually <10 mm, no skin sutures; dissection kept minimal. Significantly lower hematoma, pain, and infection than conventional.
Other minimally-invasive technique	Recommended	Acceptable alternative to NSV.
Conventional incisional	Not recommended	One midline or bilateral scalpel incisions, usually 1.5–3.0 cm; no special instruments (vas grasped with towel clip or Allis forceps); larger area of dissection.

The choice between midline and bilateral incisions is left to clinical judgment.

Vas Occlusion

Success and failure rates relate to the occlusion method.

Recommended:

• Mucosal cautery ± fascial interposition.
• Open-ended vasectomy — leave the testicular end unoccluded, apply mucosal cautery to the abdominal end, with fascial interposition. (Hypothetically reduces back-pressure pain and may aid future reversal via sperm granuloma formation; fascial interposition prevents recanalization.)
• Non-divisional extended electrocautery (Marie Stopes technique) — electrocoagulate the full-thickness anterior wall and partial-thickness posterior wall over ~2.5–3 cm without dividing the vas; the only non-divisional technique (all others divide the vas). Developed for easy dissemination, particularly in resource-limited settings.
• Division and ligation (suture or clips, ± fascial interposition, ± excising a short segment) — justified only for surgeons whose training/experience yields consistent failure rates ≤1%.

Defining terms: fascial interposition places a layer of internal spermatic fascia between the two divided ends (over either the testicular or abdominal end); it may raise complication rates and is typically combined with ligation/excision or mucosal cautery. There is no consistent evidence that excising a short segment (<4 cm) is preferable to division alone. Folding-back sutures each divided end on itself so the cut ends do not face each other.

Not recommended: folding-back; division and ligation (unless surgeon experience qualifies, as above); fascial interposition alone.

Special Scenarios

Prior or planned ipsilateral varicocelectomy — isolate the vas carefully and completely exclude the deferential artery and veins to avoid testicular injury. After varicocelectomy the deferential veins may be the sole testicular venous return (in a proper varicocelectomy all spermatic cord veins are ligated except the deferential vein), and the deferential artery may become the principal arterial supply if the testicular artery is damaged.

Post-operative Care

• Remain in clinic 15–20 minutes after the procedure; provide verbal and/or written aftercare instructions.
• Wear supportive undergarments immediately to reduce cord tension, continuing until comfortable without them.
• Mild swelling and pain for a few days are common — manage with oral analgesics.
• Keep the site clean and dry; showers (with gentle soap-and-water washing) are permitted the day after surgery, but avoid swimming or tub bathing for 3–5 days.
• Refrain from ejaculation for ~1 week; most men resume intercourse within 2 weeks.
• Hematospermia in the first month or two is benign and resolves spontaneously.
• Patients may return to non-physical work the same or next day if not limited by discomfort.

Post-vasectomy Semen Analysis

Men and partners must use other contraception until success is confirmed by PVSA.

Timing

• 2012 AUA: 2–4 months after vasectomy; exact timing is left to surgeon judgment — a longer interval improves the chance of azoospermia/RNMS but prolongs the need for interim contraception.
• 2022 CUA: 3 months after vasectomy.
• Sperm clearance is fastest with mucosal cautery + fascial interposition and slowest with ligation, so the occlusion method may inform timing.
• Collect after 2–7 days' abstinence, keep at body temperature, and submit within 30–60 minutes. Examine a fresh, uncentrifuged sample by direct microscopy within 2 hours (centrifugation may impair motility); if no sperm are seen, examine the centrifuged sample for motile and immotile sperm.

Defining Success

• 2012 AUA and 2022 CUA: a single sample showing azoospermia OR only rare non-motile sperm (≤100,000 non-motile sperm/mL).
• 2016 CUA: one azoospermic sample OR two samples showing only rare non-motile sperm.
• Counsel about late failure despite azoospermia/RNMS — usually detected first as pregnancy, then confirmed by motile sperm on semen analysis. Reappearance of (mostly immotile) sperm after two azoospermic samples occurs in up to 10% of patients and has not been associated with pregnancy.
• An FDA-approved home test detects sperm counts >250,000/mL but does not assess motility; two negative tests give a 99.9% negative predictive value. Note the 250,000/mL cutoff is higher than the ≤100,000 non-motile sperm/mL definition of success used in the guideline.

Failure & Recanalization

Causes of failure: technical/surgical error (e.g. occluding one vas twice and missing the other — persistently normal or near-normal motile counts); failure to identify vas duplication (very rare); or recanalization (suspect when motile sperm or rising concentrations appear after a PVSA had shown azoospermia/RNMS; may be transient or persistent).

AUA:

• If <6 months post-vasectomy with ANY motile sperm — continue other contraception and repeat PVSA every 4–6 weeks for up to 6 months. ~30–50% of men with recanalization eventually reach azoospermia/RNMS by 6 months (vas fibrosis occludes the recanalization), so do not judge failure on a single motile-sperm result within 6 months.
• Repeat vasectomy if motile sperm increase on serial analyses or persist >6 months.
• If >6 months with >100,000 non-motile sperm/mL persisting, use serial trends and clinical judgment (plus patient preference and risk tolerance) to decide on failure and repeat vasectomy.

2022 CUA:

• If any motile sperm or substantial immotile counts (>100,000/mL) — continue contraception and repeat the analysis.
• Persistence of any motile sperm or >100,000/mL on two samples indicates failure and is an indication for repeat vasectomy.

2016 CUA: if any motile sperm OR >100,000 non-motile sperm — continue contraception and repeat in 4–8 weeks; if repeat shows azoospermia or <100,000 non-motile sperm, contraception can be abandoned; if motile or >100,000 non-motile sperm persist at 6 months, repeat vasectomy is indicated.

If a man reports his partner is pregnant but his semen analysis is azoospermic, advise that the pregnancy could be due to transient recanalization despite the result.