---

Male Infertility - Complete Details from Gynaecology Textbooks

---

1. EPIDEMIOLOGY & DEFINITION

• Infertility is defined as failure to conceive after 12 months of regular unprotected intercourse.
• Male factor is the sole cause in ~20% of infertile couples and a contributing factor in up to 50% of cases.
• Worldwide, male factor accounts for 51.2% of infertility and subfertility.
• In Europe: male factor 19-57%, combined male and female factors 34.4%.
• Relative prevalence of etiologies (Table 36-1):

---

2. PHYSIOLOGY OF MALE REPRODUCTION

Anatomy

• Testes - site of androgen synthesis (Leydig cells) and spermatogenesis (Sertoli cells lining seminiferous tubules)
• Epididymis
• Vas deferens
• Prostate, seminal vesicles, ejaculatory duct, bulbourethral glands, urethra

Hormonal Axis

• LH (from pituitary) stimulates Leydig cells to synthesize and secrete testosterone
• FSH (from pituitary) acts with testosterone on Sertoli cells to support spermatogenesis

Spermatogenesis

• Spermatogonia undergo mitosis, then meiosis (primary -> secondary spermatocytes -> spermatids), then spermiogenesis to mature spermatozoa
• The full cycle takes approximately 72-74 days

Sperm Transport & Capacitation

• The epididymis stores the equivalent of three ejaculations
• During ejaculation, spermatozoa are released from the vas deferens mixed with prostatic fluid, seminal vesicle secretions, and bulbourethral gland secretions
• Semen initially gelatinous, then liquefaction occurs in 20-30 minutes via prostatic proteolytic enzymes
• Capacitation: Spermatozoa undergo this process within cervical mucus - involves removal of inhibitory mediators (cholesterol) from sperm surface, tyrosine phosphorylation, and calcium ion influx - enables sperm to recognize fertilization cues
• Sperm transport from posterior vaginal fornix to fallopian tubes occurs within 2 minutes during follicular phase

Fertilization

• Capacitated sperm passing through cumulus cells release hydrolytic enzymes via exocytosis = acrosome reaction
• Sperm then binds to and penetrates zona pellucida
• Sperm-oocyte membrane fusion triggers cortical reaction (cortical granule release) - prevents polyspermy

---

3. SEMEN ANALYSIS

Collection

• 2-5 days of abstinence recommended (shorter durations, ≤2 days, may improve IUI pregnancy rates; >5 days is detrimental)
• Two samples obtained 4 weeks apart for reliability

WHO Normal Values (Table 36-3)

Semen Analysis Terminology

Sperm Morphology

• Assessed using Tygerberg strict criteria (Kruger 1986)
• Normal lower limit: ≥4% normal forms (strict criteria)
• Assesses head, midpiece, and tail - even mild abnormalities classified as abnormal
• Low morphology <9% is a better discriminator for infertility than count or motility

Round Cells & Leukocytes

• Round cells include immature germ cells and leukocytes
• Leucocytes distinguished by positive peroxidase staining; normal <1 million/mL
• Bacteriospermia prevalent in ~50% of infertile men; most common pathogens: Chlamydia trachomatis (41.4%), Ureaplasma urealyticum (15.5%), Mycoplasma hominis (10.3%)

Antisperm Antibodies

• Risk factors: ductal obstruction, prior genital infection, testicular trauma, prior vasectomy reversal
• Tested with immunobead test or mixed agglutination reaction
• Management typically with ICSI (though benefit uncertain)

Sperm DNA Integrity

• Sperm DNA fragmentation associated with impaired IVF pregnancy rates and elevated miscarriage risk
• Assessed by: sperm chromatin structure assays, TUNEL assay (best correlation), sperm chromatin dispersion test, single gel electrophoresis
• Elevated fragmentation can be reduced with antioxidant supplementation

Epigenetic Assessment

• Genome-wide alterations in histone modifications and DNA methylation seen in infertile men
• Assessed by Episona test; weight loss may reverse obesity-related epigenetic sperm changes

---

4. DIFFERENTIAL DIAGNOSIS / CLASSIFICATION

A. Pretesticular Causes (Endocrine/Coital)

B. Testicular Causes

C. Posttesticular Causes

Frequency Distribution (Table 36-5)

---

5. MALE AGE AND FERTILITY

• Men have fathered children into their 90s, but pregnancy rates decline with paternal age 40-45 and markedly beyond 50
• Increasing paternal age is associated with higher disomic sex chromosomes and structural chromosomal abnormalities in sperm
• Offspring of older fathers have higher rates of autism, schizophrenia, and other neurodevelopmental disorders (de novo mutations)

---

6. RECREATIONAL, IATROGENIC & ENVIRONMENTAL TOXINS

Drugs That Impair Male Fertility (Table 36-2)

---

7. GENETICS OF MALE INFERTILITY (Table 36-6)

• Chromosomal abnormalities found in ~7% of infertile, 5% of oligospermic, and 10-15% of azoospermic men
• Klinefelter syndrome (47,XXY) = two-thirds of infertility-associated chromosomal abnormalities
• Y microdeletions in 10-20% of idiopathic azoospermia or severe oligospermia (<5 M/mL)
• Key gene families: RBM (RNA-binding motif) and DAZ (deleted in azoospermia)
• Microdeletions in Yq11.23: AZFa, AZFb (most severe - DAZ gene), AZFc (mildest)
• Y microdeletions are transmitted to male offspring

---

8. AZOOSPERMIA: CLASSIFICATION & TREATMENT

A. Pretesticular Azoospermia

• Rare; caused by gonadotropin deficiency (hypogonadotropic hypogonadism - HH)
• Low LH, FSH, and testosterone
• Workup: prolactin levels, pituitary MRI
• Treatment: pulsatile GnRH, hCG, exogenous gonadotropins
• Best predictors of response: postpubertal onset, testicular volume >8 mL
• Iatrogenic (exogenous testosterone): stop testosterone; treat with clomiphene citrate, hCG, ± FSH
  • Median recovery: sperm concentration 6.5 M/mL at 4.5 months after cessation
  • Full recovery more likely if testosterone used <1 year

B. Testicular Azoospermia (Non-obstructive)

• Caused by gonadal failure = hypergonadotropic hypogonadism (elevated LH/FSH, low testosterone)
• Causes: genetic (Klinefelter, Y microdeletions), radiation, chemotherapy, torsion, varicocele, mumps orchitis, cryptorchidism
• Testicular atrophy often present
• Biopsy generally NOT recommended with confirmed hypergonadotropic hypogonadism
• With normal hormonal testing: diagnostic biopsy may be indicated
• If sperm found: ICSI with surgically retrieved sperm
• If no sperm and acquired cause (e.g., varicocele): correction may restore sperm to ejaculate

C. Posttesticular (Obstructive) Azoospermia

• Present in up to 40% of azoospermic men
• Associated with normal gonadotropin and testosterone levels
• Causes: CBAVD, acquired ductal obstruction, retrograde ejaculation
• CBAVD:
  • At least two-thirds have CFTR gene mutations
  • Usually associated with seminal vesicle agenesis (low semen volume, pH, and fructose)
  • Normal spermatogenesis expected - diagnostic biopsy generally not needed
  • Female partner CFTR carrier testing is mandatory
  • 10-25% incidence of renal agenesis - renal imaging required
• Retrograde ejaculation: associated with diabetes, bladder/prostate surgery; sperm isolated from neutralized urine for IUI or ART
• Treatment: vasectomy reversal (vasovasostomy or vasoepididymostomy)
  • Patency rates approaching 100%, pregnancy rates ~80%
  • Pregnancy typically within 24 months

---

9. VARICOCELE

• Abnormal dilation of veins within the spermatic cord
• Present in 13.5% of men who recently fathered a pregnancy and 31% of men with idiopathic oligozoospermia
• Pathophysiologic effects include elevated scrotal temperature, impaired testicular blood flow, and reflux of renal/adrenal metabolites
• A clinically palpable varicocele in an infertile male with abnormal semen parameters warrants treatment
• Surgical repair (varicocelectomy): improves semen parameters and pregnancy rates
• Generally not recommended for subclinical (non-palpable) varicoceles

---

10. TREATMENT OF MALE FACTOR INFERTILITY

Medical Treatment

• Reversible infectious or endocrine causes are generally responsive to treatment
• Exogenous testosterone is contraindicated in male subfertility treatment (negative pituitary feedback reduces intratesticular testosterone and spermatogenesis)
• FSH injections: may improve pregnancy rates; benefit for clomiphene citrate is less clear
• Zinc + folic acid: associated with improved sperm concentration and morphology
• Glutathione, carnitine, and vitamin E: do not appear to affect semen parameters
• Antioxidants may reduce sperm DNA fragmentation

Surgical Treatments

• Varicocele repair
• Vasectomy reversal (vasovasostomy, vasoepididymostomy)
• Surgical sperm retrieval for obstructive/non-obstructive azoospermia (PESA, TESA, microTESE)

Assisted Reproduction

Intrauterine Insemination (IUI)

• Best-studied insemination technique
• Semen processed (washing, density gradient centrifugation) to remove seminal factors and isolate pure sperm
• Combined with ovarian stimulation for optimal results
• Indicated for: male factor with >2M motile sperm, unexplained infertility, cervical factor, same-sex female couples
• Pentoxifylline (phosphodiesterase inhibitor) may enhance sperm motility during processing

Intracytoplasmic Sperm Injection (ICSI)

• Used in 93% of US ART cycles for male factor infertility
• Involves direct injection of a single live sperm into the oocyte cytoplasm
• Bypasses limitations of sperm motility and defects in capacitation, acrosome reaction, and zona pellucida binding
• Indications for ICSI:
  • Semen analysis: <2 million motile sperm, <5% motility
  • Surgically retrieved sperm
  • Teratozoospermia
  • Unexplained infertility
  • Previous IVF fertilization failure
  • Preimplantation genetic diagnosis (PGD)
• Fresh > frozen specimens; ejaculated > surgically retrieved sperm for success rates
• Risks of ICSI:
  • Oocyte degeneration: 5-19%
  • Slightly higher sex chromosome abnormalities and translocations vs. conventional IVF
  • Possible increased risk of imprinting disorders
  • One study noted higher autism incidence with ICSI vs. IVF

Donor Sperm

• Frozen specimens recommended (to allow quarantine for HIV seroconversion - 6 months)
• Screening: HIV, hepatitis B/C, syphilis, gonorrhea, chlamydia, cytomegalovirus
• Genetic history screening for Mendelian and polygenic conditions

---

11. POSTCOITAL TEST

• Cervical mucus examined microscopically shortly after periovulatory intercourse
• Positive: ≥1 progressively moving sperm per high-power field
• Negative: no sperm or only non-progressive/immobile sperm
• Limited utility; largely replaced by direct semen analysis

---

12. INFERTILITY EVALUATION ALGORITHM

1. History & physical examination of both partners
2. Semen analysis - two samples 4 weeks apart
3. If abnormal: hormonal assessment (LH, FSH, testosterone, prolactin)
4. Karyotype and Y-chromosome microdeletion testing for azoospermia or severe oligospermia
5. CFTR gene testing for CBAVD
6. Transrectal US for suspected ejaculatory duct obstruction
7. Renal imaging when unilateral/bilateral vasal absence diagnosed (10-25% renal agenesis)
8. Testicular biopsy: selected cases to differentiate obstructive vs. non-obstructive azoospermia

---

Recent Evidence (2024-2025)

• A 2025 systematic review and meta-analysis (PMID: 40431450) evaluated dietary supplements for male infertility and their effects on pregnancy, live birth, and sperm parameters.
• A 2024 systematic review and meta-analysis (PMID: 39537384) examined the association between male viral infections and infertility.
• A 2025 systematic review (PMID: 40238039) reviewed the impact of obesity on reproductive health, including male fertility.

---

Clinical pearl: Male factor is the sole or contributing cause in up to 50% of infertile couples. A structured approach beginning with semen analysis, followed by hormonal and genetic evaluation, allows most cases to be classified and directed toward appropriate treatment - ranging from lifestyle modification and medical therapy to surgical correction or ART with ICSI.