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Summary Table

Category	Details
Risk Factors	Varicocele, cryptorchidism (history of undescended testis), prior chemotherapy or radiation, anabolic steroid use, Klinefelter syndrome (47,XXY), cystic fibrosis (congenital bilateral absence of vas deferens), tobacco/alcohol use, obesity, advanced paternal age, occupational heat exposure
Etiology	Pre-testicular (hormonal/hypothalamic-pituitary axis dysfunction), testicular (primary gonadal failure), or post-testicular (obstructive or ejaculatory dysfunction)
Patient Presentation	Couple unable to conceive after 12 months of regular unprotected intercourse; male partner may be asymptomatic or report decreased libido, erectile dysfunction, or small testicular volume
Classic Physical Exam	Varicocele ("bag of worms" on standing, disappears when supine), small/atrophic testes, gynecomastia (suggests hyperestrogenism or Klinefelter), absent vas deferens on palpation (suggests CFTR mutation)
Key Diagnostic Results	Semen analysis is the cornerstone: oligospermia, asthenospermia, teratospermia, or azoospermia; hormonal panel (FSH, LH, testosterone); scrotal ultrasound for varicocele or obstruction; karyotype if indicated
Management	Varicocelectomy for clinical varicocele with abnormal semen; gonadotropin therapy (hCG + FSH) for hypogonadotropic hypogonadism; clomiphene citrate for idiopathic cases; assisted reproductive technology (IUI, IVF, ICSI) when surgical or medical therapy fails
Keywords	"Bag of worms," "infertile couple," "absent vas deferens," "small soft testes," "azoospermia," "oligospermia," "elevated FSH"

1. Pathophysiology

Male infertility accounts for roughly 40-50% of all infertility cases and can originate from disruption at any level of the hypothalamic-pituitary-gonadal (HPG) axis or the reproductive tract itself.

Pre-testicular causes involve failure of the hypothalamus or pituitary to provide adequate gonadotropin stimulation. The hypothalamus secretes GnRH in a pulsatile fashion, which drives anterior pituitary release of LH and FSH. LH stimulates Leydig cells to produce testosterone, while FSH acts on Sertoli cells to support spermatogenesis. Any disruption to this axis, whether from a pituitary adenoma (notably prolactinoma), Kallmann syndrome (GnRH deficiency + anosmia), exogenous androgen use, or chronic opioid therapy, leads to hypogonadotropic hypogonadism. Without adequate LH and FSH drive, both testosterone production and sperm output decline. This is why patients on exogenous testosterone or anabolic steroids become infertile: exogenous androgens suppress GnRH through negative feedback, collapsing intratesticular testosterone to levels insufficient for spermatogenesis.

Testicular causes represent primary gonadal failure. The most common correctable testicular cause is varicocele, present in approximately 35-40% of men with primary infertility. The mechanism involves retrograde venous flow through the internal spermatic vein (predominantly left-sided due to the left gonadal vein draining into the left renal vein at a right angle), leading to elevated scrotal temperature, oxidative stress, and impaired spermatogenesis. Other testicular causes include Klinefelter syndrome (47,XXY), where seminiferous tubule dysgenesis leads to small, firm testes and azoospermia; cryptorchidism, where prolonged exposure of the gonad to core body temperature damages germ cells irreversibly; and gonadotoxic injury from chemotherapy (particularly alkylating agents like cyclophosphamide) or radiation. In primary testicular failure, the pituitary recognizes low testosterone and absent inhibin B feedback from Sertoli cells, resulting in elevated FSH and LH (hypergonadotropic hypogonadism). This hormonal pattern is the hallmark of irreversible spermatogenic failure.

Post-testicular causes involve obstruction or dysfunction of sperm transport. The classic example is congenital bilateral absence of the vas deferens (CBAVD), which is strongly associated with CFTR gene mutations and is considered a forme fruste of cystic fibrosis. These patients produce sperm normally (normal FSH, normal testicular volume) but have obstructive azoospermia because sperm cannot reach the ejaculate. Other post-testicular causes include prior vasectomy, epididymal obstruction from infection (Chlamydia, gonorrhea), and ejaculatory duct obstruction. Retrograde ejaculation (common in diabetic autonomic neuropathy or post-TURP) diverts semen into the bladder instead of antegrade through the urethra; post-ejaculatory urinalysis showing abundant sperm confirms this diagnosis.

2. Classification and Clinical Manifestation

Classification	Mechanism	Hormonal Pattern	Testicular Exam	Semen Analysis	Classic Example
Pre-testicular (Hypogonadotropic hypogonadism)	Deficient GnRH, LH, or FSH	Low FSH, low LH, low testosterone	Normal to small testes (from disuse atrophy)	Oligospermia or azoospermia	Kallmann syndrome (anosmia + delayed puberty), prolactinoma, exogenous androgen use
Testicular (Hypergonadotropic hypogonadism / Primary gonadal failure)	Germ cell or Sertoli/Leydig cell damage	High FSH, high LH, low testosterone	Small, soft, or atrophic testes	Severe oligospermia or azoospermia	Klinefelter (47,XXY), cryptorchidism, post-chemotherapy, mumps orchitis
Testicular (Varicocele)	Venous stasis causing thermal and oxidative damage	Usually normal; mild FSH elevation possible	"Bag of worms" above left testis, worsens with Valsalva	Stress pattern: low count, poor motility, abnormal morphology	Grade II-III left varicocele
Post-testicular (Obstructive)	Physical blockage of sperm transport	Normal FSH, normal LH, normal testosterone	Normal testicular volume; vas deferens may be absent on palpation	Azoospermia with normal volume (if obstruction is distal) or low volume (if ejaculatory duct obstruction or CBAVD)	CBAVD (CFTR mutation), post-vasectomy, epididymal scarring
Post-testicular (Ejaculatory dysfunction)	Failure of antegrade ejaculation	Normal hormones	Normal exam	Low volume or absent ejaculate; sperm found in post-ejaculatory urine	Retrograde ejaculation (diabetes, post-TURP), anejaculation (spinal cord injury)

The clinical classification directly determines the hormonal profile you expect, which is the single most tested concept in exam vignettes. The critical reasoning chain is:

Azoospermia + elevated FSH = primary testicular failure (non-obstructive) = poor prognosis for natural conception.

Azoospermia + normal FSH + normal testicular volume = obstructive azoospermia = potentially correctable.

Azoospermia + low FSH/LH = hypogonadotropic hypogonadism = potentially reversible with gonadotropin therapy.

3. Diagnostic Workup

Test	Purpose	When to Order	Key Findings
Semen analysis (x2)	Best initial test; cornerstone of evaluation	First-line for all infertile males	See reference values below
Serum FSH, LH, testosterone	Distinguish pre-testicular vs. testicular vs. post-testicular	Abnormal semen analysis, or clinical suspicion of hormonal etiology	Elevated FSH = testicular failure; low FSH/LH = hypogonadotropic cause
Serum prolactin	Screen for prolactinoma	Low testosterone with low/normal FSH and LH	Elevated prolactin suggests pituitary adenoma
Scrotal ultrasound with Doppler	Confirm varicocele; assess testicular volume and structural abnormalities	Clinical varicocele, discrepant testicular size, or suspected obstruction	Retrograde venous flow >3 mm during Valsalva confirms varicocele
Transrectal ultrasound (TRUS)	Evaluate ejaculatory duct obstruction	Low ejaculate volume + azoospermia + normal FSH	Dilated seminal vesicles or ejaculatory duct cysts
Karyotype	Diagnose chromosomal abnormalities	Severe oligospermia (<5 million/mL) or non-obstructive azoospermia	47,XXY (Klinefelter)
Y-chromosome microdeletion	Identify AZF deletions (AZFa, AZFb, AZFc)	Non-obstructive azoospermia or severe oligospermia after karyotype	AZFa/AZFb deletion = no sperm retrieval expected; AZFc = may find sperm with micro-TESE
CFTR mutation testing	Screen for cystic fibrosis carrier status	CBAVD on physical exam	Positive CFTR mutation; partner should also be tested before ART
Post-ejaculatory urinalysis	Diagnose retrograde ejaculation	Low ejaculate volume (<1.0 mL) with absent or near-absent sperm	Presence of sperm in post-void urine specimen
Testicular biopsy / micro-TESE	Distinguish obstructive from non-obstructive azoospermia; retrieve sperm for ICSI	Azoospermia when hormonal workup is inconclusive	Normal spermatogenesis on biopsy = obstructive; maturation arrest or Sertoli-cell-only = non-obstructive

Semen Analysis (WHO 2021, 6th Edition)

This is the best initial test for evaluating male infertility. Two specimens collected at least 7 days but no more than approximately 4 weeks apart are recommended to account for physiologic variation. The patient should abstain from ejaculation for 2-7 days before collection.

Parameter	WHO Lower Reference Limit
Volume	$\geq$ 1.4 mL
Sperm concentration	$\geq$ 16 million/mL
Total sperm count	$\geq$ 39 million per ejaculate
Progressive motility	$\geq$ 30%
Total motility (progressive + non-progressive)	$\geq$ 42%
Morphology (strict Kruger criteria)	$\geq$ 4% normal forms
Vitality (live sperm)	$\geq$ 54%
pH	$\geq$ 7.2
Leukocytes (WBC)	< 1.0 million/mL (if elevated, consider leukocytospermia / infection)

Terminology

Term	Definition
Oligospermia	Sperm concentration < 16 million/mL
Asthenospermia	Progressive motility < 30%
Teratospermia	Normal morphology < 4%
Oligoasthenoteratospermia (OAT)	Combined deficiency in count, motility, and morphology (the most common pattern in varicocele)
Azoospermia	Complete absence of sperm in the ejaculate
Aspermia	Absence of ejaculate entirely

Interpreting the semen analysis in context is what the exam tests. A low-volume azoospermic sample with normal FSH and absent vas deferens on exam points directly to CBAVD, not testicular failure. Conversely, azoospermia with markedly elevated FSH and bilateral small testes indicates non-obstructive azoospermia from primary testicular failure.

The hormonal panel is ordered after an abnormal semen analysis to categorize the etiology. The critical branching point is FSH level: elevated FSH reflects loss of negative feedback from inhibin B (produced by Sertoli cells), signaling that the seminiferous tubule compartment is damaged. Normal FSH in the setting of azoospermia suggests the testis is producing sperm but the sperm cannot exit, pointing to an obstructive cause.

For patients with severe oligospermia or non-obstructive azoospermia, genetic testing is indicated. Karyotype identifies Klinefelter syndrome, which accounts for roughly two-thirds of chromosomal causes of male infertility. Y-chromosome microdeletion testing identifies deletions in the AZF (azoospermia factor) region of the long arm of the Y chromosome. This is prognostically important: AZFa and AZFb complete deletions predict no sperm will be found even with surgical retrieval, making sperm donation the only path to biological offspring via the male partner. AZFc deletions carry a more favorable prognosis, with approximately 50-70% chance of sperm retrieval via micro-TESE.

4. Management and Treatment

Etiology	First-Line Treatment	Alternative / Adjunct	Key Notes
Varicocele	Varicocelectomy (microsurgical subinguinal approach preferred)	Percutaneous embolization	Indicated when clinical varicocele is present + abnormal semen analysis + female partner has adequate fertility potential
Hypogonadotropic hypogonadism	hCG 1,500-2,000 IU SC 2-3x/week to restore intratesticular testosterone, then add FSH (rFSH 75-150 IU SC 3x/week) if spermatogenesis does not resume within 6 months	Pulsatile GnRH via pump (if hypothalamic origin)	Do NOT treat with exogenous testosterone, as it suppresses spermatogenesis
Exogenous testosterone-induced infertility	Discontinue exogenous testosterone; bridge with clomiphene citrate 25-50 mg daily or hCG to maintain androgen levels while awaiting spermatogenic recovery	Enclomiphene (selective estrogen receptor modulator)	Recovery may take 6-12 months or longer; prior duration of use affects timeline
Prolactinoma	Cabergoline 0.25-0.5 mg twice weekly (dopamine agonist)	Bromocriptine 2.5 mg 2-3x daily	Normalizing prolactin restores GnRH pulsatility and subsequently gonadotropin secretion
Obstructive azoospermia (post-vasectomy)	Vasovasostomy (microsurgical)	Vasoepididymostomy if epididymal obstruction	Success rates decline with increasing time since vasectomy
CBAVD	Sperm retrieval (TESA/micro-TESE) + ICSI	No surgical reconstruction possible (vas deferens is absent)	Both partners need CFTR mutation testing and genetic counseling before ART
Non-obstructive azoospermia	Micro-TESE + ICSI	Hormonal optimization with clomiphene or hCG/FSH prior to micro-TESE may improve retrieval rates	If AZFa or AZFb deletion is present, sperm retrieval is not expected; consider donor sperm
Retrograde ejaculation	Sympathomimetics: pseudoephedrine 60 mg QID or imipramine 25-75 mg daily before ejaculation	Sperm recovery from alkalinized post-ejaculatory urine for IUI	Alkalinize urine with sodium bicarbonate before collection to improve sperm viability
Idiopathic male infertility	Empiric clomiphene citrate 25-50 mg daily (off-label)	Antioxidant supplementation (vitamin E, CoQ10, selenium); lifestyle modifications	Evidence is moderate; trial of 3-6 months before reassessing

Varicocelectomy is the most commonly tested surgical intervention. The microsurgical subinguinal approach offers the best outcomes (improved semen parameters in approximately 60-70% of patients) with the lowest complication rate. Improvement in semen parameters typically takes 3-6 months post-operatively, which corresponds to the duration of a full spermatogenic cycle (approximately 74 days for spermatogenesis + 12-14 days for epididymal transit). The exam tests the indication: a varicocele must be clinically palpable (not merely found on ultrasound) and associated with abnormal semen parameters in a couple with documented infertility.

For hypogonadotropic hypogonadism, the single most important concept is: never give exogenous testosterone to a man who wants fertility. Exogenous testosterone shuts down the HPG axis, collapses intratesticular testosterone (which needs to be 50-100x higher than serum levels to support spermatogenesis), and drives sperm counts to zero. The correct approach is hCG (which mimics LH and stimulates Leydig cells to produce endogenous intratesticular testosterone) with or without recombinant FSH (which directly stimulates Sertoli cells). This distinction between "testosterone for hypogonadism" and "gonadotropins for fertility" is a heavily tested concept.

Clomiphene citrate functions as a selective estrogen receptor modulator (SERM) at the hypothalamus and pituitary. By blocking estrogen-mediated negative feedback, it increases GnRH pulsatility, which raises endogenous LH and FSH secretion, thereby boosting both testosterone and sperm production. It is used off-label for idiopathic male infertility and as a bridge therapy when discontinuing exogenous androgens.

When medical and surgical options are exhausted, assisted reproductive technology becomes the pathway. IUI (intrauterine insemination) is appropriate for mild oligospermia or ejaculatory dysfunction when total motile sperm count after processing exceeds approximately 5-10 million. IVF is indicated for moderate male factor. ICSI (intracytoplasmic sperm injection) is the treatment for severe oligospermia, obstructive azoospermia (using surgically retrieved sperm), or non-obstructive azoospermia (using sperm from micro-TESE). ICSI requires only a single viable sperm per oocyte.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It's Similar	Key Discriminator
Female factor infertility	Couple presents with inability to conceive; initial workup may focus on the female partner	Semen analysis is always part of the initial evaluation of any infertile couple, regardless of history; a normal female workup with abnormal semen analysis redirects the diagnosis
Erectile dysfunction	Both present as reproductive failure; may coexist	ED involves inability to achieve/maintain erection; male infertility involves abnormal sperm production/delivery despite adequate erectile function; history and semen analysis distinguish them
Klinefelter syndrome vs. Kallmann syndrome	Both present with small testes and infertility in a young male	Klinefelter: tall stature, gynecomastia, firm small testes, elevated FSH/LH (hypergonadotropic). Kallmann: anosmia, delayed puberty, low FSH/LH (hypogonadotropic)
Obstructive vs. non-obstructive azoospermia	Both present as azoospermia on semen analysis	Obstructive: normal FSH, normal testicular volume, may have absent vas deferens. Non-obstructive: elevated FSH, small/soft testes
Hydrocele vs. varicocele	Both cause scrotal swelling	Hydrocele: transilluminates, non-tender, does not change with position. Varicocele: does not transilluminate, feels like "bag of worms," increases with standing/Valsalva and decompresses when supine
Epididymitis	Scrotal pathology in a reproductive-age male	Epididymitis presents with acute scrotal pain, fever, and tenderness localized to the epididymis with a positive Prehn sign (pain relief with scrotal elevation); infertility is a chronic, painless presentation
Testicular torsion	Acute scrotal pathology, young male	Sudden onset severe pain, absent cremasteric reflex, "bell-clapper" deformity, negative Prehn sign, surgical emergency; not a chronic infertility presentation
Seminal vesicle obstruction vs. retrograde ejaculation	Both present with low ejaculate volume	Retrograde ejaculation: sperm present in post-ejaculatory urine. Ejaculatory duct obstruction: dilated seminal vesicles on TRUS, sperm absent from urine as well

6. Traps and High-Yield Pearls

The most common way students lose points on male infertility questions is by failing to recognize the hormonal pattern that distinguishes the three etiologic categories. The exam will give you a man with azoospermia and expect you to determine the cause based on FSH, LH, and testosterone levels, not the semen analysis alone. A student who sees "azoospermia" and immediately jumps to "testicular failure" without checking whether FSH is normal (suggesting obstruction) or low (suggesting hypogonadotropic hypogonadism) will select the wrong answer.

The second major trap involves exogenous testosterone and fertility. The vignette may describe a man on testosterone replacement therapy for hypogonadism who now presents with infertility. The wrong answer will be "increase testosterone dose." The correct answer is to discontinue testosterone and initiate hCG with or without FSH to restore spermatogenesis. This tests whether the student understands that exogenous testosterone suppresses the HPG axis and eliminates intratesticular testosterone production.

A third tested concept is the CBAVD-CFTR connection. When the exam describes a man with azoospermia, low semen volume, and bilaterally absent vas deferens on examination, the expected next step is CFTR mutation testing, not a testicular biopsy. The partner must also undergo CFTR screening before proceeding with assisted reproduction, because if both partners carry CFTR mutations, the offspring is at risk for cystic fibrosis.

Finally, students frequently confuse when to order genetic testing. Karyotype and Y-chromosome microdeletion analysis are indicated for non-obstructive azoospermia or severe oligospermia (typically < 5 million/mL), not for mild oligospermia or isolated motility defects. The practical implication of Y-microdeletion testing is prognostic: identifying an AZFa or AZFb deletion changes counseling because surgical sperm retrieval is expected to fail, sparing the patient an unnecessary procedure.

The core competency being tested across all male infertility questions is the ability to integrate the semen analysis with the hormonal profile and physical examination to localize the defect, determine reversibility, and select the appropriate intervention. The exam rewards systematic reasoning through the HPG axis, not memorization of isolated facts.

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