Management of Male Infertility
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Management of Male Infertility

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Management of Male Infertility Management of Male Infertility Presentation Transcript

  • XVIII Annual Ob-Gyn Conference, KUWAIT 2013 Management of Male Infertility What the GYN need to know Sandro C. Esteves, MD, PhD Director, ANDROFERT Campinas, Brazil
  • Contents DIAGNOSIS MEDICAL TREATMENT SURGICAL TREATMENT ASSISTED REPRODUCTION Esteves, 2 ANDROFERT, Referral Center for Male Reproduction
  • Management of Male Infertility Available at: http://www.androfert.com.br/review Esteves, 3 ANDROFERT, Referral Center for Male Reproduction
  • Semen Analysis Central Laboratory Investigation Esteves, 4 Functional Status of Reproductive Tract Seminal Fluid and Sperm ANDROFERT, Referral Center for Male Reproduction
  • WHO 2010: Recent fathers TTP≤12 mo. Volume (mL) Sperm count (x106/mL) Total count (x106) % Motile (total) % Motile (progressive) % Normal (strict criteria) % Alive 5% 1.5 15.0 39.0 40 32 4 58 Percentiles 50%* 95% 3.7 6.8 73.0 213.0 255.0 802.0 61 78 55 72 15 44 79 91 Cooper et al. Hum Reprod Update 2010 Esteves, 5 ANDROFERT, Referral Center for Male Reproduction
  • Esteves, 6 ANDROFERT, Referral Center for Male Reproduction
  • Sperm DNA Integrity Background Normal sperm chromatin essential for paternal genetic transmission Increased Sperm DNA Fragmentation Unexplained infertility Recurrent pregnancy loss Poor outcomes in IUI and IVF Principle Quantification of sperm DNA strand breaks Specimen Semen, spermatozoa Techniques Nuclear dyes (Acridine orange, SCSA) Direct assessment (TUNEL, COMET) Nuclear matrix assays (SCD) Esteves & Agarwal Int Braz J Urol 2011 Esteves, 7 ANDROFERT, Referral Center for Male Reproduction
  • Quick and Easy Test Sperm Chromatin Integrity Test (SCD) Intact DNA: Sperm with “Halo” Represents dispersed chromatin without breaks Absent/small “Halo”: Damaged DNA Represents DNA strand breaks Semen/Spermatozoa Quantitative Test: Normal: <20% sperm with fragmented DNA Feijo & Esteves Fertil Steril 2013 Esteves, 8 ANDROFERT, Referral Center for Male Reproduction
  • IUI Outcome in Men with High Sperm DNA Damage Live Birth Rates with Intrauterine Insemination 19% OR = 0.07 [95% CI: 0.01-0.48] 1.5% Normal Esteves, 9 Bungum et al. Hum Reprod 2007 Elevated ANDROFERT, Referral Center for Male Reproduction
  • IVF Outcome in Men with High Sperm DNA Damage Pregnancy by Method in Cases of Elevated Sperm DNA Fragmentation 42% Increased miscarriage in couples undergoing IVF/ICSI with high sperm DNA damage 26% IVF Meta-analysis of 16 studies and 2,969 couples ICSI Risk ratio (RR) = 2.16 95% CI: 1.54-3.03; p<0.00001 Robinson et al. Hum Reprod 2012 Bungum et al. Hum Reprod 2007 Esteves, 10 ANDROFERT, Referral Center for Male Reproduction
  • Sperm DNA Damage is Associated to Elevated Oxidative Stress DNA damage DNA Damage Evaluation of Evaluation of DNA damage DNA Damage Esteves & Agarwal Int Braz J Urol 2011 Esteves, 11 ANDROFERT, Referral Center for Male Reproduction
  • Oral Antioxidants for the Male 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 Showell MG et al. Cochrane Database Syst Rev 2011 Esteves, 12 ANDROFERT, Referral Center for Male Reproduction
  • Empirical Medical Treatment for Idiopathic Male Infertility Androgens hCG/HMG FSH Anti-estrogens Bromocriptine Alpha-blockers Systemic corticosteroids In general, NOT EFFECTIVE Guidelines on Male Infertility. European Association of Urology 2012 Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
  • Anti-estrogens for the Male 1400 ng/dL ITT levels ral ent fall ative c ck eg N feedba 1200 1000 Upper Limit 800 600 Normal Testosterone Levels 400 200 0 Esteves, 14 Lower Sperm Counts Lower Limit Before Clomiphene After 90d; 25mg/d Da Ros CT, Averbeck MA Int Braz J Urol 2012 ANDROFERT, Referral Center for Male Reproduction
  • Injectable Testosterone is Detrimental GnRH Azoospermia FSH/LH Marked fall in ITT levels Between the seminiferous tubules, Leydig cells produce testosterone Esteves, 15 ANDROFERT, Referral Center for Male Reproduction
  • Male Hypogonadotropic Hypogonadism Specific Medical Therapy Deficient virilization Hypotrophic testes Azoospermia Low FSH, LH and testosterone •  Congenital: Kallman syndrome Prader-Willi •  Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy Esteves, 16 ANDROFERT, Referral Center for Male Reproduction
  • Male Hypogonadotropic Hypogonadism Specific Medical Therapy Series of men with adult-onset HH Recombinant hCG; 250 mcg per week; 12 weeks SC self-injection w/pre-filled syringe, qw Esteves & Papanikolaou Fertil Steril 2011 Fraietta et al, Clinics 2013 Esteves, 17 ANDROFERT, Referral Center for Male Reproduction
  • Contents DIAGNOSIS MEDICAL TREATMENT SURGICAL TREATMENT ASSISTED REPRODUCTION Esteves, 18 ANDROFERT, Referral Center for Male Reproduction
  • Varicocele 35% subfertile men Lower Sperm Count and Quality Lower Sperm Function Elevated Oxidative Stress Levels Elevated Sperm DNA Damage Miyaoka & Esteves. Adv Urol 2012 Agarwal, Esteves, Hamada. Nature Urol Rev 2013 Esteves, 19 ANDROFERT, Referral Center for Male Reproduction
  • Varicocele Treatment for Infertility Indications (all criteria met): Infertile couples; Normal female or treatable female infertility; Abnormal semen analysis and/or sperm function test. ASRM Practice Committee, Fertil Steril 2008 Esteves, 20 ANDROFERT, Referral Center for Male Reproduction
  • Varicocele Surgery and Spontaneous Pregnancy Marmar et al., Fertil Steril 2008 Esteves, 21 ANDROFERT, Referral Center for Male Reproduction
  • Varicocele Treatment Technique   Recurrence   Postop Hydrocele   Retroperitoneal (Palomo)   7-35%   6-10%   Laparoscopy   2-7%   0-9%   Embolization   2-24%   NR   Inguinal (Ivanissevich)   0-37%   7%   Microsurgical Subinguinal   0-1%   0-1.6%   Miyaoka & Esteves. Adv Urol 2012 Esteves, 22 ANDROFERT, Referral Center for Male Reproduction
  • Fer&lity  Restora&on     Spontaneous   Pregnancy     Fer&lity   Improvement     ICSI   Outcomes   Fer&lity   Improvement     Sperm  Retrieval  in   Azoospermia   Esteves, 23 ANDROFERT, Referral Center for Male Reproduction
  • Male Factor and ART Varicocele Repair Sperm Retrieval Esteves, 24 ANDROFERT, Referral Center for Male Reproduction
  • Clinical Outcome of Intracytoplasmic Sperm Injection in Infertile Men With Treated and Untreated Clinical Varicocele SC Esteves, FV Oliveira, RP Bertolla ANDROFERT and Division of Urology, São Paulo Federal University, BRAZIL The Journal of Urology; Vol. 184: 1442-6, 2010 Varicocele Treated prior to ICSI (N=80) ICSI with Untreated Varicocele (N=162) Esteves, 25 ANDROFERT, Referral Center for Male Reproduction
  • Sperm Retrieval and Intracytoplasmic Sperm Injection in Men With Nonobstructive Azoospermia, and Treated and Untreated Varicocele K Inci, M Hascicek, O Kara et al. Department of Urology, Hacettepe University, Ankara, Turkey The Journal of Urology Vol. 182,1500-5, 2009 Microsurgical varicocele repair prior to sperm retrieval ICSI (N=66) Sperm Retrieval in the presence of varicocele (N=30) Successful Sperm Retrieval OR: 2.63 (95% CI: 1.05-6.60; P=0.03) 53% 30% Treated Varicocele Untreated Varicocele Esteves, 26 ANDROFERT, Referral Center for Male Reproduction
  • Sperm Retrieval in Azoospermia Normal sperm production Mechanical blockage Vasectomy, Post-infectious, Congenital Esteves, 27 Sperm production deficient or absent Cryptorchidism, Radiation, Chemotherapy, Trauma, Genetic, Orchitis, Varicocele, Gonadotoxins, Unexplained ANDROFERT, Referral Center for Male Reproduction
  • Obstructive Azoospermia Technique Acronym Percutaneous Epididymal Sperm Aspiration PESA Microsurgical Epididymal Sperm Aspiration MESA Testicular Sperm Aspiration TESA Esteves & Agarwal. Sperm Retrieval Techniques. Cambridge University Press, 2011 Esteves, 28 ANDROFERT, Referral Center for Male Reproduction
  • http://androfert.com.br/videos Esteves, 29 ANDROFERT, Referral Center for Male Reproduction
  • http://androfert.com.br/videos Esteves, 30 ANDROFERT, Referral Center for Male Reproduction
  • Obstructive Azoospermia PESA + rescue TESA OBSTRUCTIVE  AZOOSPERMIA PESA alone 97.3 % 100% 96.6% 96.3% 78.1 % CBAVD Successful Retrievals Esteves, 31 Vasectomy Post-­‐infection Esteves et al. J Urol 2013 ANDROFERT, Referral Center for Male Reproduction
  • Non-Obstructive Azoospermia Sperm production minimal or absent for sperm in ejaculate Technique Geographic location unpredictable TESE Testicular Sperm Aspiration Testicular Sperm Extraction Microsurgical Testicular Sperm Extraction Acronym Success TESA 15-50% TESE 20-60% Micro-TESE 40-67% Esteves & Agarwal. Sperm Retrieval Techniques. Cambridge University Press, 2011 Esteves, 32 ANDROFERT, Referral Center for Male Reproduction
  • Esteves SC, Int Braz J Urol 2013 http://androfert.com.br/videos
  • Sperm Retrieval and ICSI in Azoospermia Non-obstructive Obstructive 100 41.4 P<0.01 47 64 43.3 61 20 Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%) OR=0.033 95% CI: 0.007-0.164; p<0.001 34.2 Live Birth (%) OR=0.38 95% CI: 0.23-0.61; p<0.001 Esteves et al. Asian J Androl. In press Esteves, 34 ANDROFERT, Referral Center for Male Reproduction
  • TESA-ICSI and Sperm DNA Damage Sperm % TUNEL + % CPR Ejaculated (N=18) 23.6 6 Testicular (N=18) 4.8 44 <0.001 <0.05 P value Greco et al. Hum Reprod 2005 DNA damage in Testicular Spermatozoa (13.3%) is three-fold lower compared with Ejaculated Spermatozoa (39.7%)* *Absolute differences between two specimens ranging from -3.3% to -56.3%. Moskovtsev et al. Fertil Steril 2010 Esteves, 35 ANDROFERT, Referral Center for Male Reproduction
  • Take-home Messages Routine semen analysis not a good male fertility discriminator. Sperm DNA damage provides information of great prognostic value. Antioxidants helpful to decrease oxidative stress and DNA damage. Specific medical therapy only valid for hypogonadism Microsurgical varicocele repair increases chances of spontaneous and assisted conception Sperm retrieval is routinely used in ART. Reproductive potential of surgically-retrieved sperm depends on type of azoospermia Esteves, 36 ANDROFERT, Referral Center for Male Reproduction
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