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  1. 2. Medical Therapy in Male Infertility 9 th Royan Int. Congress G. Pourmand, MD Urology Research Center, Medical Sciences/University of Tehran Aug. 2008
  2. 3. Causes of Male Infertility <ul><li>PRETESTICULAR </li></ul><ul><ul><li>Hypothalamic Disease s </li></ul></ul><ul><ul><ul><li>Gonadotropin deficiency (Kallmann Syndrome) </li></ul></ul></ul><ul><ul><ul><li>Isolated LH deficiency (Fertile eunuch) </li></ul></ul></ul><ul><ul><ul><li>Isolated FSH deficiency </li></ul></ul></ul><ul><ul><ul><li>Congenital Hypogonadotropic Syndrome </li></ul></ul></ul><ul><ul><li>Pituitary Diseases </li></ul></ul><ul><ul><ul><li>Pituitary Insufficiency (tumors, infiltrative processes, operation, radiation, deposits) </li></ul></ul></ul><ul><ul><ul><li>Hyperprolactinemia </li></ul></ul></ul><ul><ul><ul><li>Exogenous or Endogenous hormones (Estrogen- Androgen excess, Glucocorticoid excess, hyper- and hypothyroidism) </li></ul></ul></ul><ul><ul><li>Growth hormone deficiency </li></ul></ul>
  3. 4. Causes of Male Infertility <ul><li>TESTICULAR </li></ul><ul><ul><li>Chromosomal Causes </li></ul></ul><ul><ul><ul><li>Klinefelter Syndrome </li></ul></ul></ul><ul><ul><ul><li>XX Sex Reversal </li></ul></ul></ul><ul><ul><ul><li>XYY Syndrome </li></ul></ul></ul><ul><ul><li>Noonas Syndrome (Male Turner Syndrome) </li></ul></ul><ul><ul><li>Myotonic dystrophy </li></ul></ul><ul><ul><li>Vanishing Testis Syndrome </li></ul></ul><ul><ul><li>Sertoli-cell-only Syndrome </li></ul></ul><ul><ul><ul><li>Germ cell aplasia </li></ul></ul></ul>
  4. 5. Causes of Male Infertility <ul><li>TESTICULAR (Cont.) </li></ul><ul><ul><li>Y Chromosome Microdeletions (DAZ) </li></ul></ul><ul><ul><li>Gonadotoxins </li></ul></ul><ul><ul><ul><li>Radiation, Drugs </li></ul></ul></ul><ul><ul><li>Systemic Disease </li></ul></ul><ul><ul><ul><li>Renal Failure, Liver Cirrhosis, Sickle Cell Disease </li></ul></ul></ul><ul><ul><li>Defective Androgen Activity </li></ul></ul><ul><ul><ul><li>5a-reductase deficiency, androgen receptor deficiency </li></ul></ul></ul><ul><ul><li>Testis Injury </li></ul></ul><ul><ul><ul><li>Orchitis, Torsion, Trauma </li></ul></ul></ul><ul><ul><li>Cryptorchidism </li></ul></ul><ul><ul><li>Varicocele </li></ul></ul><ul><ul><li>Idiopathic </li></ul></ul>
  5. 6. Causes of Male Infertility <ul><li>POST-TESTICULAR </li></ul><ul><ul><li>Reproductive Tract Obstruction </li></ul></ul><ul><ul><li>CONGENITAL BLOCKAGES </li></ul></ul><ul><ul><ul><li>Cystic fibrosis </li></ul></ul></ul><ul><ul><ul><li>Young syndrome </li></ul></ul></ul><ul><ul><ul><li>Idiopathic epidiymal obstruction </li></ul></ul></ul><ul><ul><ul><li>Adult polycystic kidney disease </li></ul></ul></ul><ul><ul><ul><li>Ejaculatory duct Obstruction </li></ul></ul></ul><ul><ul><li>ACQUIRED BLOCKAGES </li></ul></ul><ul><ul><ul><li>Vasectomy </li></ul></ul></ul><ul><ul><ul><li>Groin and hernia surgery </li></ul></ul></ul><ul><ul><ul><li>Bacterial infections </li></ul></ul></ul><ul><ul><li>FUNCTIONAL BLOCKAGES </li></ul></ul><ul><ul><ul><li>Sympathetic nerve injury </li></ul></ul></ul><ul><ul><li>Pharmacologic </li></ul></ul>
  6. 7. Causes of Male Infertility <ul><li>POSTTESTICULAR (Cont.) </li></ul><ul><ul><li>Disorders of Sperm Function or Motility </li></ul></ul><ul><ul><ul><li>Immotile Cilia Syndromes </li></ul></ul></ul><ul><ul><ul><li>Maturation defects </li></ul></ul></ul><ul><ul><ul><li>Immunologic infertility </li></ul></ul></ul><ul><ul><ul><li>Infection </li></ul></ul></ul><ul><ul><li>Disorders of Coitus </li></ul></ul><ul><ul><ul><li>Impotence </li></ul></ul></ul><ul><ul><ul><li>Hypospadias </li></ul></ul></ul><ul><ul><ul><li>Timing & Frequency </li></ul></ul></ul>
  7. 8. Reproductive Hazards in the Workplace TYPE OF EXPOSURE OBSERVED EFFECTS Decreased Sperm Count Abnormal Morphology Altered Sperm Trasnfer Altered Hormones/Sexual Performance Lead + + + + Dibromchloropropane + Carbaryl(Sevin ® ) + Ethlyene bromide + + + Plastic production (Sterene and acetone) + Ethylene glycol monoethyl ether + Welding + + Mercury vapor + Heat + + Military radar + Radiation (Chernobyl) + + + + Carbon disulfide + (From Carbone D, Thomas AJ: Medical therapy – Specific. AUA Postgraudate Course, 92 nd Annual Meeting of the AUA, New Orleans, LA, April 1997) (AUA, 1999)
  8. 9. Drug-induced Infertility SUPPRESSION OF HPG AXIS DIRECT GONADOTOXICITY IMPAIRED FERTILIZATION Anabolic steroids Ketoconazole Calcium channel blockers Cimetidine Sulfasaralazine Colchicine DES Valproic acid Nitrofurantoin Cyclosporine Sprironolactone Minocycline Phenothiazine Allopurinol
  9. 10. Chronic Conditions Associated with Male Infertility Diagnosis Percent of Infertility Mechanism Spinal cord injury Uremia Chronic liver disease Sickle cell anemia Myotonic dystrophy Cystic fibrosis 95 >50 >50 >50 80 90 Elevated scrotal temperature Hypogonadism Hypogonadism Hypogonadism Testicular atrophy Absence of vasa
  10. 11. Treatment of Male Infertility <ul><ul><li>Medical Therapy </li></ul></ul>2. Surgical Therapy Varicocelectomy Vasovasostomy Vasoepididymostomy TUR of ejaculatory duct obstruction 3. Assisted Reproduction Therapy (ART) Sperm processing, IUI, IVF 4. Artificial Insemination of Donor (AID)
  11. 12. Algorithm for the workup of isolated abnormalities in semen parameters Predominance of Single Abnormal Parameters Motility/ Forward progression TRUS Antibody test Endocrine evaluation Positive Semen processing Negative High(>1ml) Low(<1ml) Viscosity: hyperviscous Morphology: rare transient Density: Oligospermia <20×10 6 ml/cc volume Endocrine evaluation Varicocele Sperm washing Sperm washing: AIH Infection ART Steroids retry AIH, ART Varicocelecotomy Appropriate treatment Collection error Abnormality of sex glands AIH Mechanical None of above ED obstruction Retrograde ejaculation Urine centrifugaton Specific therapy TURED Specific or empirical medical therapy Specific or empirical medical therapy Empirical medical therapy Specific therapy
  12. 13. Evaluation of Oligospermic Men Normal serum testosterone, LH, FSH Oligospermic Azoospermic Varicocele No varicocele Idiopathic oligospermia Varicocelectomy Moderate & Severe oligospermia Mild oligospermia ICSI-IVF AID adoption Intrauterine insemination (after “swim-up” or Percoll) failed * ; Empirical therapy * * * *
  13. 14. Evaluation of Azoospermic Men Normal serum testosterone, LH, FSH Oligospermic Azoospermic Post ejaculation urine specimen Assess ejaculatory process by Hx and P/E Sperm absent Evidence for retrograde ejaculation Sperm present Semem fructose Re-exam Vas No evidence for retrograde ejaculation Retrograde ejaculation Neurologic exam negative positive Congenital absence of seminal vesicle Exploration, vasogram and/or Testicular biopsy Obstruction of ductal system absent present Obstruction of ED Testicular failure TRUS
  14. 15. Johnsen score 10 Full spermatogenesis 9 Many late spermatids, sloughing 8 Few late spermatids 7 No late spermatids, many early spermatids 6 Few early spermatids, arrest of spermatogenesis at the spermatid stage 5 No spermatids, many spermatocytes 4 No spermatids, few spermatocytes, Arrest of spermatogenesis 3 Spermatogonia only 2 No germ cells, Sertoli cells only 1 No seminiferous epithelial cells
  15. 16. Johnsen score <ul><ul><li>113 Patients with male infertility </li></ul></ul>Mean Score Normal testes Moderate hypospermatogenesis Acquired hypopituitarism Severe hypospermatogenesis Sertoli cell-only syndrome Klinefelter’s syndrome 9.38 7.80 6.09 5.32 2.0 1.25 (Johnsen,1970)
  16. 17. Medical Therapy <ul><ul><li>According to causes </li></ul></ul><ul><ul><li>Specific Medical Therapy </li></ul></ul><ul><ul><li>Non-specific (Empirical Medical Therapy ) </li></ul></ul><ul><li>II. According to drugs </li></ul><ul><ul><li>Hormonal therapy </li></ul></ul><ul><ul><li>Non-hormonal therapy </li></ul></ul>
  17. 18. Criteria for Post-therapeutic Success <ul><ul><li>Duration : 3~6 months, at least one full spermatogenic cycle </li></ul></ul><ul><ul><li>Parameter : Semen analysis & hormonal assay </li></ul></ul>Volume >2.0ml pH >7.2 Sperm concentration >20×10 6 /ml Total sperm count >40×10 6 /ejaculate Motility >50% (grade a+b) or >25% (grade a) Morphology >15% by strict criteria Viability >75% WBC <1×10 6 /ml WHO criteria of normal semen, 1999
  18. 19. Specific Medical Therapy <ul><ul><li>Adaptation symptoms </li></ul></ul><ul><ul><ul><ul><li>Endocrine Disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pyospermia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Immunologic Infertility with Antisperm Ab </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Retrograde Ejaculation </li></ul></ul></ul></ul><ul><ul><li>Success rate: Above 70~80%, relatively high therapeutic success rate </li></ul></ul>
  19. 20. Endocrine disorders : Causes <ul><ul><li>Hypogonadotropic hypogonadism </li></ul></ul><ul><ul><li>Hyperprolactinemia </li></ul></ul><ul><ul><li>Congenital adrenal hyperplasia </li></ul></ul><ul><ul><li>Anabolic steroid abuse </li></ul></ul><ul><ul><li>Thyroid dysfunction </li></ul></ul><ul><ul><li>Hypergonadotropic hypogonadism & Testicular dysfunction </li></ul></ul><ul><ul><li>Androgen receptor, short CAG repeat sequence </li></ul></ul><ul><ul><li>Hyperestrogenemia </li></ul></ul>
  20. 22. Endocrine disorder 1. Hypogonadotropic hypogonadism ◈ Cause <ul><li>Congenital </li></ul><ul><ul><li>Prader-Willi syndrome </li></ul></ul><ul><ul><li>( Obesity, motor weakness and mental retardation and small eextremities) </li></ul></ul><ul><ul><li>Laurence-Moon-Bardet-Biedle syndrome </li></ul></ul><ul><ul><li>( Retinitis pigmentosa, polydactylism and memory loss) </li></ul></ul><ul><ul><li>Kallman’s syndrome </li></ul></ul><ul><ul><li>( Adolescence delay and absence of olfactory sense) </li></ul></ul><ul><li>Aquired </li></ul><ul><ul><li>Radiation treatment </li></ul></ul><ul><ul><li>Hypophysis adenoma </li></ul></ul>
  21. 23. Endocrine disorder 1. Hypogonadotropic hypogonadism GnRH <ul><ul><li>Nasal Spray </li></ul></ul><ul><ul><li>Buserelin </li></ul></ul>Gonadotrophin <ul><ul><li>hCG </li></ul></ul><ul><ul><li>r-FSH </li></ul></ul><ul><ul><li>hMG </li></ul></ul>◈ Treatment
  22. 24. Endocrine disorder 2. Hyperprolactinemia ◈ C ause Idiopathic Pitituary tumor Hypothyroidism Epilepsy Medication: phenothiazine, tricyclic antidepressant <ul><li>◈ Diagnosis  serum prolactin </li></ul><ul><ul><ul><ul><ul><li>CT, MR of sella </li></ul></ul></ul></ul></ul><ul><li>◈ Treatment : bromocriptine </li></ul>
  23. 25. Endocrine disorder 3. Congenital Adrenal Hyperplasia <ul><ul><li>◈ Cause </li></ul></ul><ul><ul><li>21-hydroxylase-> </li></ul></ul><ul><ul><li>Decreased cortisol Secretion -> </li></ul></ul><ul><ul><li>ACTH Increased level </li></ul></ul><ul><ul><li>◈ Diagnosis : Serum 17-hydroxyprogesterone </li></ul></ul><ul><ul><li>Urine pregnanetriol </li></ul></ul><ul><ul><li>◈ Treatment : fluorocortisone, 0.05~0.3mg/day </li></ul></ul>
  24. 26. Endocrine disorder 4. Anabolic steroid abuse Anabolic steroid abuse Hypogonadotropic Hypogonadism Anabolic steroid stop If not normalized · hCG 2,000 IU IM Spermatogenesis promotion hCG 3,000 IU IM · Tamoxifen 10mg 2×/day Normalized < 3month · recombinant FSH 75~150 IU H-P-G axis negative feedback mechanism
  25. 27. Endocrine disorder 5. Hypothyroidism ◈ Not recommended for screening test in asymptomatic pt. ◈ Treatment: Thyroid hormone pill (Levothyroxine sodium, T4) once a day, preferably in the morning. Initial dose: 25 mcg qd, p.o., Maintenance : 100~400 mcg/day
  26. 28. Endocrine disorder 6. Hypogonadism & testicular dysfunction Serum testosterone↓ & gonadotrophin normal or ↑ Testosterone (T), Estradiol (E2) measurment T(ng/dl) / E2(pg/dl) ratio > 10 T(ng/dl) / E2(pg/dl) ratio < 10 Measuring serum testosterone & estradiol (E2) after 1 mnth of treatment <ul><ul><li>Antiestrogen : </li></ul></ul><ul><ul><li>clomiphene citrate 25mg qd </li></ul></ul><ul><ul><li>tamoxifen 10mg bid </li></ul></ul><ul><ul><li>hCG 2,000 IU 3×/wk </li></ul></ul><ul><ul><ul><li>Aromatase inhibitor </li></ul></ul></ul>Recheck every 3 month
  27. 29. Endocrine disorder 7. Hyperestrogenemia Inhibition of conversion of androgen to estrogen ◈ Use Brand name Dose Testolactone Teslac ® (Bristol-Meyers Squibb) 50mg~100gm/day Anastrozole Arimidex ® (AstraZeneca) 1mg /day Letrozole Femara ® (Novartis) 2.5mg/day ◈ Treatment : Aromatase inhibitor ◈ Diagnosis: 1. Serum E2 > 50pg/dl 2. T (ng/dl) / E2 (pg/dl) ratio < 10
  28. 30. Endocrine disorder 8. Androgen receptor, short CAG repeat sequence <ul><ul><li>◈ Cause </li></ul></ul><ul><ul><li>Androgen receptor, Short CAG-repeat sequence </li></ul></ul><ul><ul><li>◈ Treatment </li></ul></ul><ul><ul><ul><li>High dose testosterone </li></ul></ul></ul><ul><ul><ul><li>Antiestrogen </li></ul></ul></ul>
  29. 31. Pyospermia, Leukocytospermia Urethritis (most common) Prostatitis Epididymitis Seminal vesiculitis Leukocyte ↑ ROS↑* Sperm motility ↓ & fertility ↓ Causative or Empirical Antibiotics Diagnosis: * Semen analysis * Endtz test * Pap smear * Giemsa stain * Peroxidase stain * IHC stain(monoclonal Ab) Diagnosis (WHO) : leukocyte in sperm >1×10 6 /ml * ROS ; Reactive Oxygen Species
  30. 32. Pyospermia Treatment Chlamydiae trachomatis : Doxycycline 100mg, bid 10days or Ciprofloxacin 400mg, bid 10days or Tetracycline 500mg, bid 10days Neisseria gonorrhea : Ceftriaxone 250mg, i.m. qd 후 Doxycycline 10mg, bid 10days Alternative treatment If, hypersensitive to cephalosporin Spectinomycin 2g, i.m. If, hypersensitive to tetracycline Erythromycin 500mg, qid 10days Unknown Cause Ciprofloxacin, trimethoprim-sulfamethoxazole, bid 2~12wk
  31. 33. Detection test for Antisperm Ab (WHO guidelines ; Normal<10%) SpermMAR test (WHO guidelines ; Normal<20%) Indirect Immunobead Test, IBT(×400)
  32. 34. Antisperm Antibody Infertility with antisperm antibody Corticosteroid or immunosuppression After 3month Antisperm antibody and semen analysis <ul><ul><ul><li>Sperm washing, IUI or ICSI </li></ul></ul></ul>Improvement * No improvement * Pregnancy Ratio : prednisolone 6~50% cyclosporine 33% * ; Combined empirical medical therapy
  33. 35. Antisperm Antibody Corticosteroid <ul><ul><li>prednisolone 60~90mg/day in 5~7day </li></ul></ul><ul><li> prednisolone 20mg p.o. week 1~3 or </li></ul><ul><li>10mg p.o. week 4 </li></ul><ul><ul><li>prednisolone 20~40mg/day </li></ul></ul>Immunosuppression <ul><ul><li>cyclosporine 5~10mg/day in 6 months </li></ul></ul>◈ Treatment
  34. 36. Retrograde Ejaculation Anatomic Y-V plasty Open prostatectomy Transurethral resection of prostate Transurethral incision of bladder neck Neurologic Retroperitoneal LN dissection DM Pharmacologic Pelvic surgery Spinal cord injury Idiopathic ◈ Cause
  35. 37. Retrograde Ejaculation <ul><ul><li>◈ Treatment </li></ul></ul><ul><ul><li>Medication </li></ul></ul>ephedrine 25~50mg qid × 2wk pseudoephedrine 60mg qid × 2wk phenylpropanolamine 75mg bid × 2wk imipramine 25mg tid × 2wk
  36. 38. Anejaculation <ul><ul><li>◈ Cause : </li></ul></ul><ul><ul><li>Psychological anejaculation (anorgasmic) </li></ul></ul><ul><ul><li>Physical (organic) anejaculation </li></ul></ul><ul><ul><ul><li>◈ Treatment </li></ul></ul></ul><ul><ul><ul><li>Treatment depends on the cause and includes psychosexual counseling, drugs such as ephedrine and imipramine, vibrator therapy and electroejaculation. </li></ul></ul></ul>