Medical Management of Male Factor Infertility

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Medical Management of Male Factor Infertility

  1. 1. Sandro C. Esteves, MD., PhD. Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Medical Management of Male Infertility Reproductive Andrology Surgery Workshop 2014 Al Jahra Hospital, KUWAIT ISO 9001:2008
  2. 2. Available at: h"p://www.androfert.com.br/review   ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 APRIL ANDROFERT Medical Management of Male Infertility
  3. 3. Lecture  Outline   Overview Empiric Tx of idiopathic oligozoospermia Specific Tx for subclinical MAGI Hormonal Tx for hypo-hypo Aromatase inhibitors in obese-related male infertility Antioxidants for oxidative-stress alleviation ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 APRIL ANDROFERT
  4. 4. Empirical medical Tx of idiopathic oligozoospermia Guidelines on Male Infertility. European Association of Urology 2012   In  general,   NOT   EFFECTIVE   Androgens hCG/HMG/FSH Aromatase inhibitors Anti-estrogens Bromocriptine Alpha-blockers Systemic corticosteroids ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 APRIL ANDROFERT
  5. 5. Injectable testosteroned   GnRH FSH/LH Azoospermia Marked fall in ITT levels Between the seminiferous tubules, Leydig cells produce testosterone ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 APRIL ANDROFERT
  6. 6. Who benefit from medical Tx? Estradiol levels FSH & LH levels Total Testosterone levels <300 ng/dL (10.4 nmol/L) Normal/ Elevated T/E ratio <10 <1.2 mUI/ mL Hypogonadism category T/E ratio >10 (nl) Hypo- hypo Aromatase hyperactivity Pure Treatment ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 APRIL ANDROFERT
  7. 7. Deficient virilization; Hypotrophic testes Azoospermia Low FSH and LH (<1.2 mIU/L) Low total testosterone (<300 ng/dL) Hypogonadotropic hypogonadism Specific medical therapy • Congenital: Kallman syndrome Prader-Willi • Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 APRIL ANDROFERT
  8. 8. Classic treatment for male hypogonadism and infertility Urinary hCG 1,000-2,000 UI IM injections; twice or t.i.w; minimum 12 weeks Rec-hCG: SC self- injection w/pre-filled syringe, qw Fraietta & Esteves Clinics 2013 Adult onset hypo- hypo Specific medical therapy ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 APRIL ANDROFERT
  9. 9. Rec-hCG for male hypo-hypo Baseline Posttreatment Esteves & Papanikolaou Fertil Steril 2011 Series of men with adult-onset HH; Recombinant hCG (Ovitrelle 250 mcg) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 APRIL ANDROFERT
  10. 10. Who benefit from medical Tx? Total Testosterone levels <300ng/dL (10.4 nmol/L) FSH & LH levels Normal/ Elevated <1.2 mUI/ mL Estradiol levels T/E ratio <10 T/E ratio >10 (nl) Hypogonadism category Hypo- hypo Aromatase hyperactivity Pure Treatment ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 APRIL ANDROFERT
  11. 11. Estradiol levels in obese men is modulated by aromatase polymorphism Aromatase is a product of the CYP19 gene Most common polymorphism is tetranucleotide repeat (TTTAn) Higher TTTAn (X-X) repeat associated with increased E2 levels ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 APRIL ANDROFERT
  12. 12. Oligozoospermia in obese men Risk of Oligozoospermia: Overweight*: OR=1.28 (95% CI: 1.06-1.55) (95% CI: 1.59-2.62) *BMI greater than or equal to 25; **BMI greater than or equal to 30; Sermondade et al. Hum Reprod Update. 2013 Meta-analysis of 21 studies; 13,077 men ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 APRIL ANDROFERT
  13. 13. Obesity in men at reproductive age ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 APRIL ANDROFERT
  14. 14. Total Testosterone (ng/dL) and Estradiol (pg/mL) Levels T/E2 Ratio Normal > 10 Zumoff et al. Metabolism 2003; Raman & Schlegel J Urol 2002 T/E2 <10 Aromatase Hyperactivity Aromatase inhibitors in obese- related oligozoospermia Anastrozole 1 mg q1d 60 days ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 APRIL ANDROFERT
  15. 15. Raman & Schlegel. J Urol. 2002 5.9 2.9 5.5 15.6 3.5 15.6 0 5 10 15 20 T/E ratio Ejaculate volume (mL) Sperm Count (million/mL) Anastrazole (1mg q1d for 3-6 months) in Oligozoospermia Pre-treatment Post-treatment Aromatase Inhibitors for Obesity-related Male Infertility ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 APRIL ANDROFERT
  16. 16. Who benefit from medical Tx? Estradiol levels FSH & LH levels Total Testosterone levels <300ng/ dL Normal/ Elevated T/E ratio <10 <1.2 mUI/ mL Hypogonadism category T/E ratio >10 (nl) Hypo- hypo Aromatase hyperactivity Pure Treatment ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 APRIL ANDROFERT
  17. 17. Pure hypogonadism ART Candidates Severe oligozoospermia Non-obstructive azoospermia Options Anti-estrogens u-hCG/rec-hCG ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 APRIL ANDROFERT
  18. 18. Ramasamy et al., J Urol. 2009 Ø  68 men with non-mosaic KS Ø  Non-obstructive azoospermia and hypogonadism Ø  ART candidates Ø  Medication to boost testosterone production: Aromatase inhibitor, hCG, anti-estrogens (2-3 months) Ø  Micro-TESE as SR method Ø  Positive response: increase in TT >100 ng/dL from baseline levels 72 55 Sperm Retrieval Rate (%) Positive response P  =  0.03   Medication before sperm retrieval in Klinefelter syndrome men (47,XXY) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 APRIL ANDROFERT
  19. 19. 51   51   Sperm retrieval rate (%) Positive response (n=252) No response (n=55) Ø  Case series (n=307): unselected group of men with testicular failure and low testosterone levels (300 nd/dL) Ø  Micro-TESE Ø  Medication to boost testosterone production: Aromatase inhibitor, hCG, anti-estrogens (min. 2-3 months) Ø  Positive response: posttreatment TT >250 ng/dL Medication prior to SR in unselected men with NOA Ramasamy et al., J Urol. 2011 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 APRIL ANDROFERT
  20. 20. 800   Before Clomiphene After 90d; 25mg/d Da Ros CT, Averbeck MA Int Braz J Urol 2012 Anti-estrogens in Hypogonadism 1000   1200   1400   600   400   200   0   ng/dL Upper Limit Lower Limit Lower Sperm Counts ITT levels fall Normal Testosterone Levels Negative central feedback ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 APRIL ANDROFERT
  21. 21. Medical Tx - Key Messages (1) Empirical medication for idiopathic oligozoospermia not recommended Infertile males with hypogonadism (TT<300) candidates for Tx hCG is the treatment of choice for adult-onset hypogonadotropic hyponadism ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 APRIL ANDROFERT
  22. 22. Medical Tx - Key Messages (2) Aromatase inhibitors helpful for overweight/obese men with aromatase hyperactivity (T/E<10) and oligozoospermia hCG/anti-estrogens helpful to boost testosterone production (sperm production?) in selected ART candidates Minimum Tx duration 8 weeks; monitor TT levels regularly to dose titration ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 APRIL ANDROFERT
  23. 23. Lecture  Outline   Overview Empiric Tx of idiopathic oligozoospermia Specific Tx for subclinical MAGI Hormonal Tx for hypo-hypo Aromatase inhibitors in obese-related male infertility Antioxidants for oxidative-stress alleviation ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 APRIL ANDROFERT
  24. 24. Subclinical Male Genital Tract Infection ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2014 APRIL ANDROFERT Urethritis, prostatitis AnN-­‐bacterial   properNes  (Zinc)  
  25. 25. Yanushpolsky et al 1996, Saleh & Agarwal 2002, Aziz et al 2004 Leukocytospermia >1.0 x 106 leukocytes per mL of semen marker of reproductive tract inflammation MacrophageNeutrophils Subclinical Male Genital Tract Infection (MAGI) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 APRIL ANDROFERT 25%   34%   39%   Normal Abnormal Abnl & Leukocytospermia % DNA Damage (SCSA)
  26. 26. Seminal Leukocytes Endtz Test Simple diagnostic method Peroxidase-negative Peroxidase-positive Granulocytes (Neutrophils) substrate + H2O2 + semen Esteves et al. CLINICS 2011; 66:1-10. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 APRIL ANDROFERT
  27. 27. •  Yanushpolsky et al, 1995; Erel et al., 1997 •  Branigan et al., 1995 Antibiotics •  Lackner et al., 2006 •  Gambera et al., 2007 Cicloxigenase-2 Inhibitors •  Oliva & Mutigner, 2006 Antihistamines •  Tremellen et al., 2007 •  Piombini et al., 2008 Antioxidants Treatment of Subclinical Male Genital Tract Infection and Associated Inflammatory Changes   ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 APRIL ANDROFERT
  28. 28. Subclinical Male Genital Tract Infection Azitromycin 1.0g single dose (couple)+ frequent ejaculation (every 2-3 days) + Antioxidants 42% leukocytospermia resolution (N=278; Androfert) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 APRIL ANDROFERT
  29. 29. OxidaNve  Stress   30%-80% of infertile men have elevated markers of OS Agarwal et al., Urology 2006 An  emerging   explanaNon  for   several  cases  of   male  inferNlity   Oral Antioxidants ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 APRIL ANDROFERT
  30. 30. Chemical species with unpaired electron capable to oxidize lipids, proteins and nucleic acids: Superoxide anion (•O-2) Hydroxyl radical (•OH) Hydrogen peroxide (H2O2) Peroxyl radical (ROO•) Hypochlorite ion (OCl-) Generated from aerobic metabolism of sperm and leukocytes’ mitochondria Lampiao et al., 2012 Reactive Oxygen Species (ROS) Sperm and Seminal Plasma Antioxidants: Enzymatic (SOD, catalase, GPX): inactivate ROS by conversion into other substances Non-enzymatic (ascorbic acid, alpha-tocopherol, carnitine, etc.): neutralize ROS ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 APRIL ANDROFERT
  31. 31. Rationale of Oral Antioxidants use OA classified according to their mechanism of action: Catalytic: enhances the already present antioxidant enzymes (Glutathione, N- acetyl-cysteine). Scavenging: Water soluble: react with oxidants in the cytosol (Vitamin C) Lipid soluble: protect cell membrane from lipid peroxidation (Vitamin E) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 APRIL ANDROFERT
  32. 32. Outcome No. studies Effect size (OR; 95% CI) Live birth 3 4.85 [1.92, 12.24] Pregnancy rate 15 4.18 [2.65, 6.59] DNA fragmentation 1 -13.80 [-17.50, -10.10] Miscarriage, sperm count, sperm motility 6-16 No effect Oral Antioxidants Showell MG et al. Cochrane Database Syst Rev 2011 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 APRIL ANDROFERT
  33. 33. Oral Antioxidants •  Short-term use appear to be safe •  Caution against indiscriminate use of high dosages for long periods Beneficial Kodama 1997 Dawson, 1992 Kessopoulou, 1995 Vezina, 1996 Vicari, 2001; 2002 Lenzi, 2003; 2004 Cavallini, 2004 Comhaire, 2005 Grecco 2005 Menezo 2007 Tremellen 2007 Piomboni 2008 Gil Villa 2009 No effect Giovenco, 1987 Moilanen, 1993 Iwanier, 1995 Rolf, 1999 Sigman, 2006 Detrimental long-term use and high doses; increased mortality in cancer population- based studies. Heinonen, 1994 Lonn, 2005 Bjelakovic, 2007 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 APRIL ANDROFERT
  34. 34. How to use Antioxidant Therapy
 Ascorbic acid (Vit. C) α- tocopherol (Vit. E) Glutathione N-acetyl-cysteine Carnitine, Coenzyme Q10 Lycopene. Picnogenol Pentoxifylline. Selenium Shao-Fu-Zhu-Yu-Tang Astaxanthin Lepidium meyenii α -linolenic acid and lignans Folic acid, Zinc Select antioxidant formulation and dosage Testing for Leukocytes in Semen Differentiate between sperm and leukocyte source of ROS Varicocele Genital Infection Smoking Medication Drug abuse Systemic diseases Pollution Radiation Focus on identifying and controlling source of increased ROS ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 APRIL ANDROFERT
  35. 35. Oral Antioxidants How I prescribe Vitamin C 500mg; Vitamin E 400 mg Folic acid 2 mg, Zinc 25 mg Selenium 26 mcg Minimum 2 months Old concept ~80 days New concept ~60 days From initiation of sperm production to ejaculation Misell LM et al. J Urol. 2006 Esteves & Agarwal. Novel concepts in male infertility. Int Braz J Urol 2011 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 APRIL ANDROFERT
  36. 36. Asymptomatic leukocytospermia is mainly caused by urethritis ROS production increase with an increase in leukocyte numbers Antibiotic therapy is suggested, but effect on fertility is still unclear (GR-B) Medical Tx - Key Messages (3) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 APRIL ANDROFERT
  37. 37. Oxidative stress impairs sperm function and is a risk factor for male infertility (GR-A) OA supplementation for subfertile males improve the chances of live birth for couples undergoing ART (GR-A) Well-designed studies are needed to determine the best candidates for OA therapy and which formulation and dosages yield better results Medical Tx - Key Messages (4) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 APRIL ANDROFERT
  38. 38. Thank you Obrigado ‫شكرا‬

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