MANAGEMENT OF MALE INFERTILTIY By Dr Patrick I. Okonta DELSU/DELSUTH

PRE TEST 1. Male factor infertility is the sole contributor in 20% of all cases of infertility 2. The cause of male infertility can be diagnosed in about 65% of cases 3. Only one abnormal result of semen analysis is sufficient to make a diagnosis of male infertility 4. Sperm cells can still be obtained in semen samples with a diagnosis of complete azoospermia 5. Clomiphane citrate has been found to be effective in the treatment of male infertility.

LEARNING OBJECTIVES To understand the various causes and pathophysiology of male infertility To evaluate the evidence base for medical treatment of male infertility To discuss the role of surgery in the management of male infertility To appreciate the role of assisted conception in the management of male infertility

OUTLINE Introduction Physiology of spermatogenesis Aetiology and pathophysiology of male infertiltiy Medical management of male infertility Surgical management of male infertility Assisted conception in management of male infertility Take home points/ Conclusion

INTRODUCTION About 15% of couples are unable to achieve conception after one year of unprotected regular sexual intercourse Male factor is the sole contributor in 20% of cases of infertility. It is also a part contributor in another 30-40% of infertility. About 7% of all males are confronted with fertility problems It is important to rule out male factor early in the investigation of infertility in a couple

SPERMATOGENESIS

SPERMATOGENESIS

SPERMATOGENESIS It takes approx 72 days for sperm to fully develop About 50 days is in the semineferous tubules About 20 days in the epididymis undergoing further maturation Events that occurred within the previous 2 months can affect semen quality. Leydig cells produce about 5-10mg of testosterone daily Leydig cells have receptors for prolactin

AETIOLOGY Only in about 25% - 35% of cases can the cause for male infertility be found In 65% - 75% the cause is unknown- idiopathic

AETIOLOGY 1. Endocrine Hypogonadotrophic hypogonadism (<1%) Congenital : kallmann syndrome, Prader-Willi syndrome Acquired : Pituitary tumours, Craniopharyngioma, Prolonged anabolic steroid abuse Hyperprolactineamia (<1%) Associated with sexual dysfunction (ED, ↓ libido) Drugs Antidopamine agents –tricyclic antidepressants, Opiates, Cocaine Pituitary adenoma Hypothyroidism Idiopathic

Aetiology 2. Truama Immunological - Antisperm antibodies 4. Genetic Testicular torsion Transection of the vas deferens Complications of hernia repair Vasectomy Immunological - Antisperm antibodies ASA found in 3- 10% of semen samples of infertile men Pathophysiology Immobilsation of sperm Stimulation of complement mediated cell lysis Phagocytosis by macrophages Interference with sperm capacitation or acrsome reaction Defective sperm-oocyte interaction 4. Genetic Kliinefelta’s syndrome (XYY) Y chromosome microdeletion

Aetiology 5. Infections 6. Congenital urogenital abnormalities Childhood Mumps orchitis, Urethritis, Prostatitis, Orchitis, Epididymitis Pathophysiology Poor sperm motility Low sperm concentration Decrease ejaculate volume Increase oxidative stress DNA damage Poor capacity to fuse with oocyte 6. Congenital urogenital abnormalities Congenital absence of vas deferens Cryptochidism Anorchia (absence of the testes) 7. Erectile dysfunction (< 1%) 8. Ejaculatory dysfunction (0.3 – 2%)

Aetiology Varicoceole 10. Exogenous factors 11. Systemic disease Associated with decreased testicular volume Affects sertoli cells → decreased spermatogenesis Affects leydig cells → decreased testosterone production Pathophysiology ↑ temperature ↑ oxidative stress ↑ elaboration of proteins related to germ cell apoptosis 10. Exogenous factors Drugs e.g cytotoxic drugs Irradiation Heat Chemicals 11. Systemic disease Liver cirrhosis Renal failure

Clinical Evaluation History To identify risk factors or behavioural pattern STI Previous surgery Sexual history/ coital pattern Alcohol and drug use Exposure to toxicants Occupational history Systemic disease Previous fertility

Clinical Evaluation Physical Examination Secondary sex characteristics: hair distribution and escutcheon, voice. Gynaecomastia Genitalia Penis ; ext meatus to rule out hypospadias Testicular volume Vas deferens Palpate for varicoceole

Semen Analysis 2 or 3 samples to obtain baseline Preferable atleast 2 months apart Best collected in a room near the lab Duration of abstinence 2-7 days Sample obtained by masturbation Must not miss any portion of the semen during collection Kept at ambient temp of 20oC – 37oC

Lower reference values (5th centile) of semen of fertile men (WHO, 2010)

Further investigations Pellet sample after centrifugation for patients with azoospermia Hormonal assay LH, FSH, Testosterone, Prolactin, Semen, Urine m/c/s Scrotal and testicula USS with colour doppler Genetic/chromosomal studies

Medical Treatment for male infertility Hypogonadotrophic hypogonadism One of the few specific and effective tx for male infetility HCG 3000 -6000IU/week x 6 months, then FSH 75 -150IU 3 times/week Sperm is produced within 6-9 months of therapy IVF/ICSI may be considered if no pregnancy after 12 months or sperm density remains low <5 x 106

Medical Treatment for male infertility 2. Hyperprolactineamia Dopamine agonist Bromocryptine 0.625mg – 1.25 mg dly, then increase to upto 2.5mg -10mg Cabergoline Initial dose 0.25mg – 0.5mg weekly, then 0.25-3mg weekly Cabergoline better than bromodryptine

Medical Treatment for male infertility 3. Genital infection Treat according to antibiotics sensitivity pattern Empirical tx Single dose of fluoroquinolone followed by a 2 week tx with doxycycline 3rd generation quinolones (levofloxacin, sparfloxacin) Tx results in increase quality but no evidence of increase probability of conception

Medical Treatment for male infertility 4. Ejaculatory dysfunction Treatnment depends on the cause Spinal cord injury (86% of cases) Tx = Electrical stimulation Non spinal cord causes α – agonist Eg pseudoephedrine 60mg PO daily, Imipramine 25mg PO bd, ephedrine 50mg PO qid Chlorpheniramine , phenylpropanalamine

Medical Treatment for male infertility 5. Erectile dysfunction Definition Consistent inability to attain or maintain a penile erection of sufficient quality to permit satisfactory sexual intercourse (NIH 1993) Treatment Treat or remove indentified course Psychological counselling Phosphodiesterase type 5 inhibitors eg Sildenafil (Viagra), Tadalafil (Cialis) . This is better than hormone tx for ED Penile injection with Alprostadil (caverject impulse), papaverine Penile pumps Penile implants.

Empirical Medical Treatment for Idiopathic Male Infertility 1. Gonadotrophin injection Tx should be atleast for 9 months Systematic review of evidence Compared with placebo tx showed a significantly higher pregnancy rate per couple within 3 months of completing tx 13.4% Vs 4.4% (Attia et al 2007)

Empirical Medical Treatment for Idiopathic Male Infertility 2. Dopamine agonist (Bromocryptine) Meta analysis of evidence Compared with placebo : Bromocryptine Placebo Pregnacy rate 5% 7% Conclusion Bromocryptine offers no benefit for ideopathic male infertility Vanderekhure et al 2001

Empirical Medical Treatment for Idiopathic Male Infertility 3. Anti-oestrogens (clomiphane, tamoxifen) Metanalysis Anti-oestrogen Placebo Pregnanct rate 15.4% 12.5% Conclusion No significant difference to recommend antioestrogens for increasing fertility of males with idiopathic oligo-asthenospermia Vanderekhure et al 2007

Empirical Medical Treatment for Idiopathic Male Infertility 4. Aromatase inhibitors Eg Testolactone, Anastrozole) These prevent breakdown of testosterone to oestrogen → reduction in negative feedback of E2 Conclusion No effect on semen parameters

Empirical Medical Treatment for Idiopathic Male Infertility 5. Androgens Based on the belief that testosterone could have either A direct effect on spermatogenesis, or An indirect effect via rebound increase in gonadotrophins after initial suppression after cessation of tx Systematic review of evidence base No direct benefit on sperm parameters and pregnancy rate

Empirical Medical Treatment for Idiopathic Male Infertility 6. Anti-oxidants Vit C,E, Zinc, Selenium Based on the fact that high levels of reactive oxygen species decrease fertility through Sperm DNA damage; Decrease sperm motility; Defective sperm membrane integrity; Defective oocyte-sperm fusion Systematic review of evidence Anti-oxidants could improve sperm motility, but less impact on sperm conc. & morphology Conclusion: Oral anti-oxidants might improve pregnancy rate in couples with male infertility -Ross et al 2011

Surgical management of Male Infertility Varicocoelectomy Benefits to fertility somewhat controversial Cochrane review of 2009 concluded that varicocoele repair for otherwise unexplained infertility could not be recommended However other reports suggests an improvement in semen parameters Agarwal et al 2007, Borman et al 2008 Conclusion There seems to be a benefit of surgical tx of varicocoele on the rate of spontaneous pregnancy

Assisted conception in male infertility 1. Intra uterine insemination Indication Mild to moderate oligospermia Note Sperm has to be prepared Atleast 3 cycles, therafter abandon the procedure Often done with ovulation induction Success actually better with unexplained infertility and sperms with good motility

Assisted conception in male infertility 2. Intrcytoplasmic sperm injection ICSI Has revolutionalised outcome for male infertility Only a single sperm is needed for fertilisation Indication Severe oligospermia Mild to moderate oligospermia after failed IUI Azospermia

Take home points/Conclusion Male infertility contributes equally to infertility in couples. Male factor infertility should be excluded early in the investigation of the infertile couple. Medical treatment is only effective in a minority of cases. Empirical medical therapy has a limited role in the treatment of idiopathic male infertility. Varicocoelectomy can improve semen parameters in patients with severe varicocoele Assisted reproduction has a significant role in helping couples with male factor infertility achieve a pregnancy

POST TEST 1. Male factor infertility is the sole contributor in 20% of all cases of infertility 2. The cause of male infertility can be diagnosed in about 65% of cases 3. Only one abnormal result of semen analysis is sufficient to make a diagnosis of male infertility 4. Sperm cells can still be obtained in semen samples with a diagnosis of complete azoospermia 5. Clomiphane citrate has been found to be effective in the treatment of male infertility.

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