Fertility Associates - Leaders in Fertility Male Infertility Phill McChesney BHB MBChB FRANZCOG MRMed CREI Introduction • Male reproductive dysfunction is sole or contributory cause of 50% of infertile couples • Some health issues are more prevalent in infertile men and must be sought • E.g. androgen or gonadotropin deficiency, testicular cancer • >50% = primary spermatogenic failure (5% of all men) • 25% = obstruction • <25% = erectile/ejaculatory/sexual dysfunction, hypogonadotropin hypogonadmism, antisperm antibodies Terminology • Oligospermia = <15M/ml • Azoospermia = no sperm in ejaculate • Obstructive • Non obstructive • Aspermia = complete ejaculatulatory failure • Cryptozoospermia = occasional sperm in ejaculate • Teratozoospermia = poor morphology • Asthenozoospermia = poor motility Causes of male infertility • Hypothalamic – Pituitary Disorders • Primary Gonadal Disorders • Disorders of Sperm Transport Hypothalamic – Pituitary Disorders • Idiopathic isolated gonadotropin deficiency • Kallmann syndrome • Single gene mutations (e.g. GnRH/FSH/LH) • Hypothalamic/pituitary tumours (e.g. craniopharygioma, macroadenoma) • Hyperprolactinaemia • Drugs (androgens, estrogens, glucocorticoids, opiates) • Critical illness or injury • Chronic systemic illness or malnutrition • Infections (e.g. meningitis) • Obesity Primary Gonadal Disorders • Klinefelter syndrome • Y chromosome microdeletions • Single gene mutations (e.g. androgen/estrogen/FSH receptor) • Cryptorchidism • Varicocoele • Infection (viral orchitis, leprosy, TB) • Drugs (e.g. alkylating agents, ETOH, antiandrogens, cimetidine, nitrofurantoin) • Radiation • Environmental gonadotoxins (e.g. heat, smoking, metals, organic solvents, pesticides) • Chronic illness (renal insufficiency, cirrhosis, cancer, Sickle cell disease, amyloidosis, vasculitis, coeliac) Disorders of sperm transport • Epididymal obstruction or dysfunction • Congenital bilateral absence of vas deferens (CBAVD) • Infections causing obstruction of vas (gonorrhoea, chlamydia, TB) • Vasectomy • Kartagener syndrome (primary ciliary dyskinesia + situs inversus) • Young syndrome (obstructive azoo + bronchiectasis + sinusitis) • Ejaculatory dysfunction (spinal cord disease, autonomic dysfunction) History • Systemic disease • Diabetes, thyroid dysfunction, renal insufficiency, lung/sinus disease • Systemic disease or high fever in preceding 3 months (time from germ cell to mature spermatid) • Sexual history • Puberty, STI, erectile or ejaculatory dysfunction • Previous paternities • Surgery • Inguinal, scrotal, urethral, retroperitoneal, prostate, bladder neck • Unilateral cryptorchidism → 30% low sperm count • Bilateral cryptorchidism → 50% low sperm count • Toxins • Environmental (Alcohol, cigarettes, marijuana, caffeine, heat, etc) • Medicines (Anabolic steroids, chemo/radiation, cimetidine, sulphur drugs, nitrofurantoin, SSRIs, Ca Channel blockers) Examination • General • Body habitus, limb length, gynaecomastia, virilisation • Surgical scars in inguinal region • Genital • Penis • urethral strictures, hypospadias • Testes • Normal = >4cm longitudinal axis and > 16ml • Seminiferous tubules occupy 80% of testicular volume • A factory problem is usually associated with a small factory • Epididymis • Fullness, induration, tenderness = possible obstruction • Vas • ? Present. ?discontinuity • Varicocoele Investigation • Semen Analysis • Concentration, Motility, Morphology • +/- Antibodies • +/- DNA Fragmentation • Post ejaculatory urine • In men with low volume azoospermic samples unless another cause of azoospermia identified • Typically <1ml ejaculate and acidic Investigations… • Hormone studies • FSH (normal 2-8) • Testosterone (normal 9-30) • LH • Prolactin • FSH reflects number of Sertoli and germ cells • Sertoli Cell Only associated with significantly elevated FSH • Normal spermatogenesis in solitary testis may have marginally elevated FSH • NOA associated with diffuse maturation arrest and normal volume testes typically has normal FSH Hormones and Azoospermia • Normal FSH + Normal T • Need to consider retrograde ejaculation, failure of emission, obstruction (but can be maturation arrest) • FSH + T = hypergonadotrophic hypogonadism = primary testicular failure • FSH + T = hypothalamic or pituitary dysfunction • Need to measure LH and PRL • Normal PRL + FSH + LH + T = hypogonadotropic hypogonadism • Need to consider MRI and further hormonal testing Investigations… • Genetic Tests • Karyotype • For Men with Sperm Count < 10 M/ml • Y Microdeletion • For Men with Sperm Count < 5M/ml • AZFa and AZFb – highly unlikely to have sperm found • AZFc – sperm commonly found in ejaculate or TESE (13% of NOA, 6% of severe oligo) • In Men with NOA, 15-27% will have a definable genetic abnormality • CFTR mutation • For men with CBAVD • Should also have renal USS due 10-15% renal anomalies Investigations… • Scrotal USS • Excludes testicular cancer • Confirmation of varicocoele • Transrectal USS • If ejaculatory duct obstruction is suspected • Low volume (<1ml) acidic ejaculate with normal hormone profile Treatment Options • Treat correctable causes • Optimise lifestyle • Remove detrimental medications • Gonadotropins for hypogonadotropic hypogonadism • Surgery • Vasectomy reversal • Varicocoele Repair • Ejaculatory duct obstruction • ART • IUI for mild oligospermia or ejaculatory/intercourse issues • ICSI cornerstone of modern treatment • Donor Sperm Surgical Sperm Retrieval for Azoospermia • 4 Commonly used methods • PESA = Percutaneous Epididymal Sperm Aspiration • TESA = Testicular Sperm Aspiration • TESE = Testicular Sperm Extraction • mTESE = microdissection Testicular Sperm Extraction • PESA • Used only for obstructive azoospermia e.g. post vasectomy • Should not be used if considering vasectomy reversal in future • Insulin syringe used to aspirate sperm directly from epididymus • TESA • Note recommended for NOA • 18g butterfly with 10ml syringe for suction, tubules then teased out • TESE • Essentially an open biospy of testis • mTESE • Open biospy with operating microscope (15-25x magnification) under general anaesthesia • Seminiferous tubules that appear prominent and full compared to surrounding tubules are harvested • Success • Obstructive Azoospermia • Almost certainly retrieve sperm using TESE • PESA is least successful → 40-95% depending on aetiology • Nonobstructive Azoospermia • Correlates highly with the underlying histopathologic diagnosis • Hypospermatogenesis 80-95% • Maturation arrest 44-62%% • Sertoli Cell Only 16 - 48% Male Age • As men age • sperm motility and morphology decline • DNA fragmentation increases • Paternal age >40 leads to increased rates of miscarriage, independent of maturnal age • Increased risk of autism, schizophrenia and achondroplasia Lifestyle • Alcohol • > 20 standard drinks per week reduces numbers of pregnancies • Caffeine • Possible dose-response effect • Reduce intake to 100-200mg/day • Equivalent to < 2 cups of coffee • Smoking • Reduces sperm production, motility, morphology • Increases DNA Damage • Child born to a father who smokes has 4x risk of childhood cancer • Reduces success of IVF and ICSI • NB: Maternal smoking reduces sperm count 25% in offspring Lifestyle… • Marijuana • Decreases sperm density, motility and morphology • Inhibits capacitation and acrosome reaction • Modulates apoptosis of Sertoli cells and decreases Leydig T production • Environmental pollutants • Phthalates – used in large variety of products (plasticizers, viscosity control) • Reduces semen quality • Pesticides • 40% reduction in semen quality • Organic Solvents • Low motile sperm counts in men with moderate to high exposure • Lead • Sperm count and viability inversely correlated with serum Pb level • Accumulates in testes and can replace Zn in protamine causing conformational change Obesity • Reduces Testosterone • Associated with decreased sexual function and cardiovascular risk • Obstructive Sleep Apnoea (OSA) reduces Testosterone • 50% of OSA have ED. 50% of ED have OSA • Most papers suggest reduction in sperm concentration and increase in DNA damage • Half papers suggest negative effect on motility • Just under half suggest negative effect on morphology • Conflicting results on IVF pregnancies • ? More effect on natural conception • Risk of metabolic disease in offspring Medications Hypogonadotropic hypogonadism • Congenital • Idiopathic hypogonadotropic hypogonadism (IHH) • Kallmann Syndome = original description = mutation in KAL1 gene = sex linked • Isolated GnRH deficiency with Anosmia • Several other genes now described with different inheritance • Acquired • Tumour, infection, infiltrative diseases, pituitary infarction, drug use, etc • Gonadotropin Therapy with hCG +/- FSH • Process may take 6-24 months • Spontaneous conceptions usually occur once sperm density increases to ~5M/ml • NB: No evidence gonoadotropins benefit in cases of normogonadotropic or hypergonadotropic men Varicocoele • Pathological dilatation of pampiniform venous plexus of spermatic cord • ~15% of post pubertal men • ~40% of infertile men • Mechanism of action unclear • Higher testicular temperature • Higher levels of DNA fragmentation related to ROS • Reflux of renal/adrenal metabolites • Classification • Subclinical = USS only • Grade 1 = palpable only on Valsalva • Grade 2 = easily palpable • Grade 3 = present on visual inspection of scrotum • Only clinically palpable varicocoeles have been clearly associated with infertility • Varicocoele Repair • Time to improvement in semen parameters is 3-6 months •