14.3 Male Infertility: Evaluation & Surgical Management

Male Infertility: Evaluation & Surgical Management

Infertility affects approximately 15% of couples attempting conception globally, with a male causative factor identified in 30% to 50% of couples (either as sole factor or combined with female factors). The urological workup must systematically delineate treatable etiologies, unmask underlying systemic or genetic pathologies, and optimize outcomes for natural conception or assisted reproductive technologies (ART).

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1. Semen Analysis & WHO 2021 Guidelines (6th Edition)

Semen analysis remains the cornerstone of the laboratory evaluation of the infertile male. The World Health Organization (WHO) published its 6th Edition Laboratory Manual for the Examination of Human Semen in 2021, establishing updated lower reference limits based on the 5th centile of fertile men whose partners achieved pregnancy within 12 months.

Pre-Analytical Standardization

• Abstinence Interval: Strictly 2 to 7 days of sexual abstinence prior to collection.
• Collection Technique: Sample obtained by masturbation into a sterile, wide-mouthed container; delivered to the laboratory within 60 minutes while kept between 20°C and 37°C.
• Confirmation: Because semen parameters exhibit profound intra-individual biological variability, a single abnormal test is never definitive; perform at least two semen analyses if the baseline result is abnormal, with repeat timing guided by clinical circumstances.

+-------------------------------------------------------------------------------------------------+
|                        WHO 2021 (6TH EDITION) SEMEN REFERENCE VALUES                            |
|                                                                                                 |
|  Parameter                               Reference Value (see note below)                      |
|  ---------------------------------------------------------------------------------------------- |
|  Semen Volume                            >= 1.4 mL                                              |
|  Sperm Concentration                     >= 16 million / mL  (16 x 10^6 / mL)                   |
|  Total Sperm Count                       >= 39 million per ejaculate                            |
|  Progressive Motility (PR)               >= 30%                                                 |
|  Total Motility (PR + NP)                >= 42%                                                 |
|  Vitality (Membrane-Intact Cells)        >= 54%                                                 |
|  Normal Forms (Strict Kruger Criteria)   >= 4.0%                                                |
|  Semen pH                                >= 7.2                                                 |
|  Leukocytes (Peroxidase-Positive)        < 1.0 million / mL  (1.0 x 10^6 / mL)                  |
+-------------------------------------------------------------------------------------------------+

The numerical semen reference limits above describe a fertile reference population, not a diagnostic boundary for fertility. pH and leukocyte values are separate consensus thresholds, not fifth-centile reference limits.

Standardized Descriptive Nomenclature

• Normozoospermia: All ejaculate parameters (number, motility, morphology) equal to or above reference limits.
• Oligozoospermia: Sperm concentration < 16 x 10^6 / mL (severe oligozoospermia: < 5 x 10^6 / mL).
• Asthenozoospermia: Progressive motility < 30%.
• Teratozoospermia: Normal morphological forms < 4%.
• Oligoasthenoteratozoospermia (OAT) Syndrome: Simultaneous impairment across all three sperm variables.
• Azoospermia: Total absence of spermatozoa in the ejaculate following centrifugation (3000 x g for 15 minutes) and microscopic pellet examination.
• Aspermia: Complete absence of ejaculate fluid (retrograde ejaculation or anejaculation).
• Necrozoospermia: Reduced sperm vitality; in complete necrozoospermia, no viable sperm are identified. Assess vitality with eosin-nigrosin staining or the hypoosmotic swelling test.
• Leukocytospermia: Presence of >= 1.0 x 10^6 / mL peroxidase-positive white blood cells, indicating inflammation, which does not by itself establish infection or a benefit from antibiotics.

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2. Endocrine Evaluation & Diagnostic Algorithm

Endocrine evaluation is indicated in all men with oligozoospermia or azoospermia, in the presence of erectile or ejaculatory dysfunction, or when physical examination reveals clinical signs of hypogonadism (e.g., gynecomastia, decreased secondary sexual hair, testicular atrophy).

Core Hormonal Axis Testing

• Initial Morning Panel: Fasting morning serum Total Testosterone (measured between 08:00 and 10:00 AM due to circadian rhythms) with FSH and LH.
• Reflex Hormonal Testing: If testosterone is subnormal, repeat fasting morning testosterone. Use LH to classify hypogonadism; measure prolactin for suspected secondary hypogonadism, calculate free testosterone when indicated by SHBG, and request estradiol selectively.

+---------------------------------------------------------------------------------------------------+
|                             DIAGNOSTIC ENDOCRINE ALGORITHM IN INFERTILITY                         |
|                                                                                                   |
|                    +------------------------------------------+                                   |
|                    | Morning Testosterone, FSH and LH        |                                    |
|                    +------------------------------------------+                                   |
|                                          |                                                        |
|           +------------------------------+------------------------------+                         |
|           |                                                             |                         |
|           v                                                             v                         |
|  +--------------------------------+                    +--------------------------------+         |
|  | HIGH FSH & LH                  |                    | LOW / NORMAL FSH & LH          |         |
|  | LOW TESTOSTERONE               |                    | LOW TESTOSTERONE               |         |
|  +--------------------------------+                    +--------------------------------+         |
|           |                                                             |                         |
|           v                                                             v                         |
|  PRIMARY HYPOGONADISM                                  SECONDARY HYPOGONADISM                     |
|  (Hypergonadotropic Hypogonadism)                      (Hypogonadotropic Hypogonadism)            |
|  --> Intrinsic testicular failure                      --> Hypothalamic / Pituitary failure       |
|  --> Causes: Klinefelter (47,XXY),                     --> Causes: Kallmann syndrome, pituitary   |
|      bilateral cryptorchidism, mumps                       adenoma / hyperprolactinemia,          |
|      orchitis, prior chemo/radiotherapy                    anabolic steroid (AAS) abuse           |
|  --> TESE / micro-TESE for ICSI                        --> MEDICAL THERAPY EFFECTIVE:             |
|                                                            hCG + recombinant FSH                  |
|                                                            (Exogenous T is CONTRAINDICATED)       |
|                                                                                                   |
|  *NOTE ON ISOLATED ELEVATED FSH WITH NORMAL TESTOSTERONE & LH:                                    |
|   Suggests impaired spermatogenesis with preserved Leydig function; it does not specify histology |
|   (loss of negative feedback inhibition from Sertoli-derived Inhibin B).                          |
+---------------------------------------------------------------------------------------------------+

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3. Genetic Testing Indications & Findings

Genetic anomalies account for approximately 15% of cases of non-obstructive azoospermia and severe oligozoospermia. Offer karyotyping for azoospermia or sperm concentration < 5 million/mL. Perform Y-microdeletion testing at ≤ 1 million/mL and consider it below 5 million/mL; select other tests according to the phenotype and provide genetic counseling.

1. Karyotype Analysis (Chromosomal G-Banding)

• Klinefelter Syndrome (47,XXY): The most frequent chromosomal cause of male infertility (present in 10–15% of men with non-obstructive azoospermia). Patients present with eunuchoid body habitus, tall stature, sparse facial/body hair, gynecomastia, small firm testes (< 4 mL), and hypergonadotropic hypogonadism. While naturally infertile, focal islands of active spermatogenesis persist in up to 50% of patients, yielding a 45% to 50% sperm retrieval rate on micro-TESE for ICSI.
• Robertsonian & Reciprocal Translocations: Associated with recurrent pregnancy loss, embryopathy, and severe oligozoospermia.
• 46,XX Male Syndrome: Translocation of the SRY gene onto the X chromosome; phenotypically male with azoospermia and zero sperm retrieval potential.

2. Y-Chromosome Microdeletions (AZF Regions)

Microdeletions occur within the Azoospermia Factor (AZF) locus on the long arm of the Y chromosome (Yq11), assessed in three principal regions: AZFa, AZFb, and AZFc.

+-------------------------------------------------------------------------------------------+
|                             Y-CHROMOSOME MICRODELETION REGIONS (Yq11)                     |
|                                                                                           |
|  Complete AZFa Deletion:                                                                  |
|  --> Genes involved: USP9Y, DDX3Y                                                         |
|  --> Histological phenotype: Complete Sertoli-Cell-Only (SCO) syndrome                    |
|  --> Clinical outcome: SPERM RETRIEVAL RATE IS VIRTUALLY 0%                               |
|  --> TESE / micro-TESE is STRONGLY CONTRAINDICATED; counsel on donor sperm / adoption     |
|                                                                                           |
|  Complete AZFb Deletion:                                                                  |
|  --> Genes involved: RBMY gene family                                                     |
|  --> Histological phenotype: Complete meiotic germ cell arrest                            |
|  --> Clinical outcome: SPERM RETRIEVAL RATE IS VIRTUALLY 0%                               |
|  --> TESE / micro-TESE is STRONGLY CONTRAINDICATED; counsel on donor sperm / adoption     |
|                                                                                           |
|  AZFc Deletion (Most Common):                                                             |
|  --> Genes involved: DAZ (Deleted in Azoospermia) gene cluster                            |
|  --> Phenotype: Highly variable (severe oligozoospermia to non-obstructive azoospermia)   |
|  --> Clinical outcome: EXCELLENT PROGNOSIS FOR RETRIEVAL                                  |
|  --> TESE / micro-TESE yields viable sperm in 50% to 70% of cases                         |
|  --> GENETIC COUNSELING MANDATORY: 100% of male offspring conceived via ICSI will INHERIT |
|      the Y-microdeletion, with implications for their reproductive health                 |
+-------------------------------------------------------------------------------------------+

3. CFTR Gene Mutations & CBAVD

• Congenital Bilateral Absence of the Vas Deferens (CBAVD) occurs in 1% to 2% of infertile men and represents approximately 10% of obstructive azoospermia.
• Genetic Etiology: Caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7q31. Over 80% to 90% of men with CBAVD carry identifiable CFTR mutations (most commonly compound heterozygosity: a severe cystic fibrosis mutation such as ΔF508 paired with a mild splicing variant like the 5T allele in intron 8).
• Clinical Presentation: Palpably absent bilateral scrotal vasa deferentia, hypoplastic epididymides, low semen volume (< 1.0 mL), acidic semen pH (< 7.0), and absent seminal fructose (due to concomitant congenital seminal vesicle hypoplasia/agenesis).
• Mandatory Policy: Genetic testing of BOTH the male patient and the female partner must be completed prior to sperm retrieval (MESA/TESE) and ICSI. Counsel from both partners’ specific variants and genotypes: affected-child risks can be 25% when both carry one pathogenic variant or 50% when the male has two and his partner one. The phenotype may be CF or a CFTR-related disorder; severe classic CF is not inevitable.
• Renal Sonography Rule: If a patient presents with vasal agenesis (unilateral or bilateral) and tests negative for CFTR mutations, obtain renal ultrasound to assess associated renal anomalies, including agenesis, which arises from early embryonic disruption of the common mesonephric (Wolffian) duct.

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4. Obstructive vs. Non-Obstructive Azoospermia

Differentiating obstructive from non-obstructive azoospermia is essential because obstructive forms are frequently amenable to surgical reconstruction or direct sperm aspiration, whereas non-obstructive forms need etiological assessment, treatment of reversible endocrine causes and, when appropriate, micro-TESE for ICSI.

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5. Surgical Interventions in Male Infertility

1. Varicocelectomy

• Pathophysiology: Retrograde venous pooling in the pampiniform plexus causes testicular hyperthermia, venous stasis, tissue hypoxia, elevated hydrostatic pressure, and oxidative stress with increased Sperm DNA Fragmentation Index (DFI).
• Clinical Indications (EAU Guidelines): The principal infertility indication combines the following features:
  1. The varicocele is clinically palpable (Grade I: palpable on Valsalva; Grade II: palpable at rest; Grade III: visibly apparent at rest).
  2. The couple has documented infertility of >= 12 months.
  3. The semen analysis demonstrates documented abnormal parameters.
  4. The female partner has a good ovarian reserve and the couple can allow time for a response. (Repair of subclinical varicoceles detected solely on Doppler ultrasound is NOT recommended).
• Gold Standard Technique: Microsurgical Subinguinal Varicocelectomy utilizing an operating microscope (8–15x magnification). This technique allows precise identification and ligation of all internal and external spermatic veins while preserving the testicular artery and lymphatics. Compared to open retroperitoneal (Palomo) or inguinal (Ivanissevich) repairs, the microsurgical approach minimizes the postoperative hydrocele formation rate to < 1% (vs. 5–10%) and reduces recurrence rates to < 1–2%.

2. Microsurgical Anastomoses for Obstructive Azoospermia

• Vasovasostomy (VV): Microsurgical two-layer or modified one-layer end-to-end reconstruction for post-vasectomy reversal or iatrogenic vasal injury. Patency rates exceed 90–95%, with natural pregnancy rates around 50–70%.
• Vasoepididymostomy (VE): Consider when examination of vasal fluid from the testicular stump suggests secondary epididymal obstruction: thick, toothpaste-like fluid without sperm or sperm parts favors VE over VV. Assess both fluid character and microscopy. Performed as a microsurgical end-to-side intussusception between the vas lumen and an isolated epididymal tubule.
• Transurethral Resection of Ejaculatory Ducts (TURED): Indicated for ejaculatory duct obstruction (EDO) caused by midline prostatic utricle cysts or post-inflammatory calcifications; unroofing may restore seminal emission and sperm output in appropriately selected obstruction.

3. Testicular Sperm Extraction: Conventional vs. Micro-TESE

• In non-obstructive azoospermia (NOA), spermatogenesis is typically heterogeneous and focal, with tiny isolated "islands" of active spermatogenesis interspersed among sclerotic tubules.
• Microdissection TESE (micro-TESE):
  • Performed through an equatorial incision of the tunica albuginea with operating microscope magnification (15–20x).
  • The surgeon systematically interrogates the testicular parenchyma to selectively identify and excise dilated, opaque, wider seminiferous tubules, which have a high probability of harboring active spermatogenesis, while deliberately avoiding thin, collapsed, translucent tubules.
  • Clinical Selection: EAU favors micro-TESE for NOA because it targets focal spermatogenesis while limiting tissue removal and vascular injury. Reported retrieval rates vary; comparative studies do not establish a universal advantage of a fixed size. Counsel about failed retrieval and postoperative testosterone decline, and follow endocrine function.

Summary Reference Tables: Semen, Endocrine & Genetic Profiles

Table 1: Endocrine & Genetic Diagnostic Patterns in Azoospermia

Symptomatic Androgen Deficiency in the Ageing Male

Diagnose hypogonadism from compatible symptoms or signs plus consistently low testosterone, not age or one isolated result. Obtain fasting morning total testosterone and repeat a low result on a separate occasion. Consider SHBG/calculated free testosterone when indicated; LH/FSH distinguish primary from secondary disease. Investigate the cause and address reversible obesity, illness or medication effects.

EAU uses total testosterone below 12 nmol/L as a diagnostic threshold in symptomatic men; interpret it with repeat testing and the clinical picture. Testosterone therapy is an individual treatment decision for confirmed deficiency, not a general anti-ageing prescription. Explain likely benefits, uncertainties and monitoring.

Assess fertility plans, prostate/breast disease, cardiovascular status and haematocrit before treatment. Exogenous testosterone suppresses gonadotropins and spermatogenesis and is unsuitable when fertility is desired. Monitor clinical response, testosterone and haematocrit at three, six and twelve months, then annually; haematocrit above 54% requires adjustment or withdrawal, with venesection when indicated.

Worked decision: An older man has fatigue and a single afternoon low testosterone during acute illness. Reassess after recovery with appropriate morning measurements and symptom review before labelling permanent deficiency or prescribing testosterone.

Primary references: EAU Male Hypogonadism and Endocrine Society guideline.