Male Infertility Phill Mcchesney BHB Mbchb FRANZCOG Mrmed CREI Introduction

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 • Meta-analysis suggests mean increase of 12M/ml and 11% increase in motility, variable morphology • Microsurgical inguinal/subinguinal ligation → lower recurrence (1-2%) • Radiological embolisation → higher recurrence (15%) Varicocoele

• Who to Treat? • ASRM consensus 2014 • Adolescents and young men with evidence of reduced ipsilateral testicular size • Male partner of infertile couple with evidence of abnormal semen parameters and minimal/no identified female factor, including consideration of age and ovarian reserve • Consider in NOA • 10-50% will have return of sperm to ejaculate, if NOA due to hypospermatogenesis or late maturation arrest • Higher rates of sperm retrieval (50-60% vs 30-40%) OR 2.51 Kirby et al 2016

• More recent evidence suggests a benefit before IVF/ICSI • OR LBR = 1.7 (1.02-2.72) Meta-analysis Kirby et al 2016 DNA Fragmentation • Associations • Age, Heat, Smoking, SSRIs, Varicocoele, Long ejaculatory interval

• Possible effects • Infertility, Miscarriage, ??genetic mutations

• How to test • SCSA • TUNEL

• Treatment • Lifestyle • Antioxidants e.g. Menevit • Frequent ejaculation • Varicocoelectomy • Testicular sperm vs ejaculated sperm Congenital Bilateral Absence of Vas Deferens (CBAVD) • 1% of infertile males • 6% of obstructive azoospermia

• Two genetic aetiologies • Mutations in CFTR gene • Abnormality with mesonephric duct differentiation • These patients have renal anomalies

• Features • Azoospermia • typically with low volume, low pH - due absent seminal vesicle secretions • Normal FSH (due normal spermatogenesis) • Normal sized testes, with full caput epididymis • Absent vas deferens on clinical examination

• MUST CHECK FEMALE CF CARRIER STATUS (+ siblings) Klinefelter Syndrome (10% of NOA) • 47 XXY (10% Mosaic) • 1 in 500 men, 70% never diagnosed • Most common cause of androgen deficiency • Classic features • Azoospermia with androgen deficiceny • 4ml testes • Taller than average, Arm span exceeds height • Feminine fat distribution, gynaecomastia, poor musculature, reduced body hair • Osteoporosis • Learning and behavioural difficulties • speech and reading, delayed motor development, reduced attention span, behavioural problems (esp in adolescence) • Endocrine issues(hypothryoidism, diabetes) • Tumours (leukaemia, lymphoma, teratoma, breast ca, mediastinal germ cell • Autoimmune (SLE, Coeliac) • Cardiovasular (venous ulcers, VTE) Medical Conditions

• Diabetes • Steriodogenic defect in Leydig cells →  T • Increased oxidative stress •  Sperm concentration and motility and increased abnormal morphology • Neuropathy → atonia of seminal vesicles, bladder, urethra • Erectile dysfunction

• Hyperthyroidism • Poor motility → improves upon treatment • Thyrotoxicosis →  spermatogenesis • Premature ejaculation

• Hypothyroidism • Delayed ejaculation • Inflammatory Bowel Disease • Crohns • Hypospermatogenesis • ? Related to fever, chronic illness, inflammatory mediators and/or nutritional status

• Ulcerative Colitis • Salazopyrine → impaired spermatogenesis and infertility • SA improves on switching to 5-ASA

• Both associated with anti-sperm antibodies • As are other diarrhoeal diseases

• Coeliac Disease • Delayed puberty • Subfertility • Impaired sperm conc, morphology and motility associated with ELEVATED testosterone, SHBG and Gonadotropins • Reversible on dietary improvement of gluten enteropathy • Rheumatoid Arthritis • Prolonged depression of testosterone during flares • Sexual dysfunction • No evidence on fertility

• Disease modifying drugs have potential significant impact on fertility

• Psoriasis • Impaired spermatogenesis • Correlates with extent and severity of disease (rather than with MTX or steroid use)

• Chronic Liver or Renal Disease • Hypothalamic hypogonadism • Alcoholic liver disease also associated with direct testicular damage Summary

• Arrange a semen analysis

• Always examine if abnormal • This will often give the answer

• FSH and T most useful bloods

• Don’t miss a testicular cancer

• Always consider drugs – prescribed and others