Residency · Residency · Urology

Male Infertility: Evaluation and Hormonal Assessment

Epidemiology

Infertility is defined as the failure to conceive after 12 months of unprotected intercourse. It affects approximately 15% of couples, with male factors contributing to about half of these cases. Isolated male factor infertility accounts for roughly 20-30% of cases, while combined male and female factors contribute to another 20%. Because male and female factors often coexist, evaluation of the male partner should be conducted concurrently with the female partner’s assessment to optimize diagnosis and management.

Etiology Classification

Pre-testicular (Hormonal) -- ~2%

Pre-testicular causes of male infertility, which account for about 2% of cases, primarily involve hormonal abnormalities. Hypogonadotropic hypogonadism, characterized by low levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), is a key example. Kallmann syndrome, a condition involving gonadotropin-releasing hormone (GnRH) deficiency combined with anosmia, also falls into this category. Pituitary tumors such as prolactinomas can disrupt hormonal regulation. Exogenous testosterone or anabolic steroid use suppresses the hypothalamic-pituitary-gonadal (HPG) axis, leading to infertility. Certain medications, including opioids and 5-alpha reductase inhibitors, may also impair hormonal function and fertility.

Testicular -- ~30-40%

Testicular causes represent 30-40% of male infertility cases and include structural and genetic abnormalities. Varicocele is the most common correctable cause and involves dilated veins in the scrotum. Cryptorchidism, whether current or historical, can impair testicular function. Genetic conditions such as Klinefelter syndrome (47,XXY) and Y-chromosome microdeletions disrupt spermatogenesis. Sertoli cell-only syndrome, mumps orchitis, prior testicular torsion, chemotherapy, and radiation exposure are additional testicular causes. Some cases remain idiopathic despite thorough evaluation.

Post-testicular -- ~10-20%

Post-testicular causes, accounting for 10-20% of cases, involve obstruction or dysfunction after sperm production. Obstructive azoospermia can result from congenital bilateral absence of the vas deferens (CBAVD), often linked to CFTR mutations, ejaculatory duct obstruction, vasectomy, or post-infectious epididymal obstruction. Ejaculatory dysfunctions such as retrograde ejaculation or anejaculation, as well as coital factors, also contribute to infertility in this category.

Idiopathic -- ~30-40%

Idiopathic infertility refers to cases where physical examination and hormonal profiles are normal, but semen parameters are abnormal. This group comprises 30-40% of male infertility cases and remains a diagnostic challenge.

<image>Flowchart of male infertility etiologies organized by pre-testicular, testicular, and post-testicular causes with relative frequencies</image>

Initial Evaluation

History

A thorough history is essential in evaluating male infertility. Important details include the duration of infertility and any prior pregnancies with the current or other partners. Information about coital frequency and timing helps assess potential behavioral factors. Sexual function should be explored, focusing on erectile and ejaculatory dysfunction. Developmental history, including cryptorchidism and pubertal onset or progression, provides clues to underlying causes. Medical history should cover diabetes, cystic fibrosis (CF), cancer treatments, and prior surgeries such as hernia repair, orchiopexy, or bladder neck procedures. Medication use, including testosterone, finasteride, alpha-blockers, selective serotonin reuptake inhibitors (SSRIs), opioids, and chemotherapy agents, must be reviewed. Lifestyle factors like tobacco, alcohol, marijuana use, heat exposure (from hot tubs, saunas, or laptops), and occupational hazards are relevant. Finally, family history of infertility, CF, or genetic conditions should be documented.

Physical Examination

The physical examination begins with a general assessment of body habitus, presence of gynecomastia, and secondary sexual characteristics such as virilization and hair distribution. Testicular examination involves measuring size with an orchidometer (Prader beads), where normal testes exceed 4 cm in length and 20 mL in volume. Small, firm testes suggest primary testicular failure, while soft testes indicate atrophy. The epididymis is evaluated for fullness, induration, or absence, the latter suggesting CBAVD. The vas deferens should be palpated bilaterally; absence of the vas deferens warrants CFTR genetic testing. Varicoceles are examined with the patient standing, both with and without Valsalva maneuver. Varicoceles are graded from I (palpable only with Valsalva) to III (visible). They are more common on the left side (85%), with isolated right-sided varicoceles prompting evaluation for retroperitoneal pathology. Penile abnormalities such as hypospadias or phimosis should be noted. Digital rectal examination (DRE) assesses prostate size and detects midline cysts that may indicate ejaculatory duct obstruction.

Semen Analysis

Collection

Semen analysis requires 2-5 days of abstinence with consistent intervals between samples. Specimens are collected by masturbation into a sterile container and analyzed within one hour to ensure accuracy. At least two abnormal samples, collected 2-4 weeks apart, are necessary before diagnosing a semen abnormality.

WHO Reference Values (6th Edition, 2021)

The World Health Organization (WHO) provides reference values for semen parameters based on the 5th percentile in fertile men. The lower reference limits include a volume of 1.4 mL, total sperm count of 39 million per ejaculate, concentration of 16 million per mL, total motility of 42%, progressive motility of 30%, morphology with at least 4% normal forms by strict (Kruger) criteria, vitality of 54% live sperm, and pH of 7.2.

Terminology

Oligozoospermia refers to low sperm concentration below 16 million per mL. Asthenozoospermia denotes poor motility with total motility under 42%. Teratozoospermia indicates abnormal morphology with fewer than 4% normal forms. Oligoasthenoteratozoospermia (OAT) is a combination of these abnormalities and is the most common abnormal pattern. Azoospermia is the complete absence of sperm in the ejaculate, while cryptozoospermia describes sperm found only after centrifugation.

Semen Analysis Red Flags

Low semen volume below 1.4 mL suggests ejaculatory duct obstruction, retrograde ejaculation, CBAVD, or insufficient abstinence. Azoospermia requires further diagnostic workup. Complete asthenozoospermia, with 0% motility, raises suspicion for immotile cilia syndrome or primary ciliary dyskinesia.

<image>Microscopic images of normal sperm morphology versus common abnormal forms (head defects, midpiece defects, tail defects) used in Kruger strict criteria assessment</image>

Hormonal Assessment

Indications

Hormonal evaluation is indicated in all men with abnormal semen analysis, especially those with oligozoospermia or azoospermia. It is also warranted in cases of suspected endocrinopathy, such as low libido, erectile dysfunction, or decreased virilization, and in men with small testes.

Initial Panel

The initial hormonal panel includes FSH, LH, total testosterone, prolactin, and sometimes estradiol. FSH is the most informative single test; elevated FSH above 7.6 IU/L suggests primary testicular failure due to Sertoli cell damage and impaired spermatogenesis. Markedly elevated FSH, more than twice the upper limit, indicates severe spermatogenic failure. Normal or low FSH in the presence of azoospermia points toward an obstructive cause. LH is elevated in primary hypogonadism and low in secondary hypogonadism. Total testosterone should be measured in the morning while fasting; levels below 300 ng/dL require confirmation with repeat testing and free testosterone measurement. Low testosterone combined with low FSH and LH indicates hypogonadotropic hypogonadism (pre-testicular), whereas low testosterone with elevated FSH and LH suggests primary testicular failure. Prolactin measurement is recommended if testosterone is low or hypogonadotropic hypogonadism is suspected; elevated prolactin warrants pituitary MRI to exclude prolactinoma. Estradiol should be assessed in men with gynecomastia or elevated body mass index, as high estradiol suppresses the HPG axis.

Hormonal Patterns in Male Infertility

In normal men, FSH, LH, and testosterone levels are within normal ranges. Primary testicular failure is characterized by high FSH and LH with low or normal testosterone. Hypogonadotropic hypogonadism shows low FSH, LH, and testosterone. Obstructive azoospermia presents with normal hormone levels. Exogenous testosterone use results in low or undetectable FSH and LH, with high testosterone if the patient is currently using testosterone. Prolactinoma causes low FSH, LH, and testosterone.

Genetic Testing

Karyotype

Karyotype analysis is indicated for men with azoospermia or severe oligozoospermia (sperm concentration below 5 million per mL) and for those with clinical features suggestive of Klinefelter syndrome. Klinefelter syndrome (47,XXY) is the most common genetic cause of male infertility, occurring in approximately 1 in 500 to 1,000 males and accounting for about 10% of azoospermic men. These patients often have tall stature, small firm testes, gynecomastia, low testosterone, and elevated FSH and LH. Although spermatogenesis is severely impaired, microdissection testicular sperm extraction (micro-TESE) can retrieve sperm in 40-60% of cases.

Y-Chromosome Microdeletion

Y-chromosome microdeletion testing is recommended for men with azoospermia or severe oligozoospermia. Three clinically relevant regions on the long arm of the Y chromosome (Yq) are associated with infertility: AZFa, AZFb, and AZFc. Complete deletion of AZFa results in Sertoli cell-only syndrome and virtually no chance of sperm retrieval. Complete deletion of AZFb causes maturation arrest with similarly poor prognosis for sperm retrieval. AZFc deletion is the most common and has a variable phenotype; sperm retrieval is possible in 50-70% of cases with micro-TESE. Complete deletions of AZFa or AZFb should prompt counseling against sperm retrieval attempts due to futility. Importantly, AZFc deletions are transmitted to all male offspring, necessitating genetic counseling.

CFTR Mutation Testing

CFTR mutation analysis is indicated in men with CBAVD or low semen volume with azoospermia. CBAVD is a genital form of cystic fibrosis, with about 80% of affected men carrying at least one CFTR mutation. Because of the risk of cystic fibrosis in offspring, the female partner must also be tested for CFTR mutations.

Scrotal Ultrasound

Scrotal ultrasound is indicated when physical examination reveals abnormalities such as masses or asymmetry, to confirm or characterize varicoceles, to evaluate non-palpable epididymal findings, or to assess for testicular tumors, as men with infertility have a higher risk of testicular cancer. Ultrasound assesses testicular size and volume, echogenicity, presence of varicocele, epididymal pathology, and masses.

Azoospermia Workup

Classification

Azoospermia is classified into obstructive azoospermia (OA) and non-obstructive azoospermia (NOA). OA results from normal spermatogenesis with blocked sperm outflow, characterized by normal testicular volume and normal FSH. Causes include CBAVD, vasectomy, epididymal obstruction, and ejaculatory duct obstruction. NOA involves impaired or absent spermatogenesis, often with small testes and elevated FSH. Causes include Klinefelter syndrome, Y-chromosome microdeletions, Sertoli cell-only syndrome, maturation arrest, and cryptorchidism.

Workup

The workup begins by confirming azoospermia on two centrifuged semen samples. Hormonal studies including FSH, LH, and testosterone are performed. Genetic testing with karyotype and Y-chromosome microdeletion analysis is essential. Scrotal ultrasound evaluates testicular anatomy. Transrectal ultrasound (TRUS) is used if ejaculatory duct obstruction is suspected, especially when semen volume is low, FSH is normal, and vasa deferentia are palpable. Testicular biopsy may be diagnostic to distinguish OA from NOA or therapeutic during micro-TESE for sperm retrieval.

<image>Diagnostic algorithm for azoospermia showing differentiation between obstructive and non-obstructive causes based on testicular exam, FSH level, and further workup steps</image>

Varicocele in Infertility

Varicocele is the most common identifiable and correctable cause of male infertility. It is present in 15% of the general male population, 35-40% of men with primary infertility, and 75-80% of men with secondary infertility. The pathophysiology involves elevated scrotal temperature, reflux of adrenal and renal metabolites, and oxidative stress, all of which impair spermatogenesis. Repair is indicated for palpable varicoceles in men with abnormal semen parameters and infertility, according to AUA/ASRM guidelines. Surgical management techniques are covered in dedicated topics.

Clinical Pearls

Evaluation of infertility must always include both partners simultaneously, as male factors contribute to half of infertile couples. Exogenous testosterone acts as a male contraceptive by suppressing FSH and LH, thereby halting spermatogenesis; it is crucial to inquire about testosterone or anabolic steroid use in the history. FSH is the single most informative hormone in the male infertility workup: elevated FSH indicates spermatogenic failure, whereas normal FSH with azoospermia suggests obstruction. CBAVD is a genital form of cystic fibrosis, so CFTR testing is mandatory for both the patient and his partner. Y-chromosome microdeletion testing is essential before attempting sperm retrieval; complete AZFa or AZFb deletions make retrieval futile. Patients with Klinefelter syndrome (47,XXY) can have sperm retrieved by micro-TESE in 40-60% of cases despite azoospermia, so they should not be counseled as irreversibly infertile. Finally, a single semen analysis is insufficient for diagnosis; abnormal results must be confirmed with a second sample collected 2-4 weeks later.

References

• AUA/ASRM Guideline on Male Infertility, 2020 (amended 2024)
• EAU Guidelines on Male Infertility, 2024 Update
• WHO Laboratory Manual for the Examination of Human Semen, 6th Edition, 2021
• Schlegel PN, et al. "Diagnosis and treatment of infertility in men: AUA/ASRM guideline." J Urol. 2021;205(1):36-43.
• Krausz C, et al. "Y-chromosome microdeletions in infertile men." Hum Reprod. 2014.
• Campbell-Walsh-Wein Urology, 12th Edition, Chapter on Male Infertility

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