Obesity and Male Infertility

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Obesity and Male Infertility

  1. 1. Advances in OBGYN Conference, Oman 2013 Obesity and Male Infertility Sandro C. Esteves, MD, PhD Director, ANDROFERT Campinas, Brazil
  2. 2. Contents Is obese men at risk of infertility? What are the changes in their semen? What are the mechanisms? What we can do about it? Esteves, 2 ANDROFERT, Referral Center for Male Reproduction
  3. 3. Obesity and Male Infertility Available at: http://www.androfert.com.br/review Esteves, 3 ANDROFERT, Referral Center for Male Reproduction
  4. 4. Obesity in Men at Reproductive Age Esteves, 4 ANDROFERT, Referral Center for Male Reproduction
  5. 5. Esteves, 5 ANDROFERT, Referral Center for Male Reproduction
  6. 6. Is obese men at risk of infertility? Yes, an obese men is about twice as likely to be infertile as a normal men Esteves, 6 ANDROFERT, Referral Center for Male Reproduction
  7. 7. Jensen et al. Fertil Steril 2004; 82: 863; Hammoud et al. Fertil Steril 2008; 90: 2222; Kriegel et al. RBM Online 2009; 19: 660; Martini et al. Fertil Steril 2010; 94: 1739. Esteves, 7 ANDROFERT, Referral Center for Male Reproduction
  8. 8. Oligozoospermia in Obese Men Meta-analysis of 21 studies involving 13,077 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. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Reprod Update. 2013 Esteves, 8 ANDROFERT, Referral Center for Male Reproduction
  9. 9. Obesity and Sperm Molecular Composition Marker Outcome Study 2-fold decrease in sperm mitochondrial activity Oxidative stress (OS marker) and DNA integrity (Comet) in obese and DNA integrity men Fariello et al. BJU Int 2012 Tunc et al. Andrologia 2011 Oxidative stress Direct relationship between levels of superoxide anion in seminal plasma and BMI DNA integrity Decreased sperm DNA integrity (Comet and SCSA) Chavarro et al. in sperm of obese men Fertil Steril 2011 Apoptosis Increased percentage of sperm with phosphatidylserine externalization in obese men La Vignera et al. J Androl 2012 Proteomics Diabetes and obesity-associated proteomic changes in sperm of obese men Kriegel et al. RBM online 2009 Kort et al. 2006; Esteves, 9 ANDROFERT, Referral Center for Male Reproduction
  10. 10. What are the changes in the semen of obese men? Decreased sperm count (oligozoospermia) Decreased sperm function and proteomic profile Esteves, 10 ANDROFERT, Referral Center for Male Reproduction
  11. 11. Adipocytes Secrete Adipose-derived Hormones and Adipokines Leptin, adiponectin and resistin Involved in glucose metabolism, sexual maturation and reproduction; Excess leptin decreases Leydig cell function (ê ITT) and has a direct negative effect on sperm. IL-6, IL-10, TNF-α Increase NO production and Oxidative Stress Winters et al. J Androl 2006; Jope et al. Int J Androl 2003; Hofny et al. Fertil Steril 2009; Bialas et al. Am J Reprod Immunol 2009; Fraczek & Kurpisz J Androl 2007; Lampiao & du Plessis Reprod Biomed Online 2008 Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
  12. 12. Aromatase Polymorphism Modulate the Relationship between Weight and Estradiol Levels in Obese Men 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 Esteves, 14 ANDROFERT, Referral Center for Male Reproduction
  13. 13. What are the mechanisms? There are three main mechanisms involved: Oxidative Stress Hormonal imbalance and hypogonadism Accumulation of endocrine disruptors Esteves, 15 ANDROFERT, Referral Center for Male Reproduction
  14. 14. Esteves, 16 ANDROFERT, Referral Center for Male Reproduction
  15. 15. Does Weight Loss Improve Semen Quality? 43 men with BMI >33 kg/m2 Healthy diet and daily exercise for 14 weeks Changes based on % weight loss Total sperm count (million) Sperm DNA fragmentation (%) TT (ng/dL) Conventional semen parameters (WHO) and sperm DNA fragmentation (SCSA) P=0.02 232 Hormone profile (FSH, LH, TT, SHBG) Controlled for confounders (smoking, diseases, etc.) 193 115 87 29 7 0 3.5%-12% 1 3 12.1%-17% >17% Håkonsen LB et al. Reprod Health. 2011 Esteves, 17 ANDROFERT, Referral Center for Male Reproduction
  16. 16. Does Medication Improve Semen Quality? Total Testosterone (ng/dL) and Estradiol (pg/mL) Levels T/E2 Ratio Normal > 10 T/E2 <10 Aromatase Hyperactivity Anastrozole 1 mg q1d 60 days Zumoff et al. Metabolism 2003; Raman & Schlegel J Urol 2002 Esteves, 18 ANDROFERT, Referral Center for Male Reproduction
  17. 17. Aromatase Inhibitors for Obesity-related Male Infertility Anastrazole (1mg q1d for 3-6 months) in Oligozoospermia 20 15.6 15 10 5.9 15.6 2.9 5 3.5 5.5 0 T/E ratio Ejaculate volume (mL) Pre-treatment Sperm Count (million/mL) Post-treatment Raman & Schlegel. J Urol. 2002 Esteves, 19 ANDROFERT, Referral Center for Male Reproduction
  18. 18. Aromatase Inhibitors for Obesity-related Male Infertility Case series: 68 men with Klinefelter Syndrome; Hypogonadism and azoospermia; Sperm retrieval by micro-TESE; Medication to boost testosterone production: Aromatase inhibitor, hCG, anti-estrogens (min. 2-3 months); Positive response: increase in TT >100 ng/dL from baseline levels. Esteves, 20 Positive response 72 55 P = 0.03 Sperm Retrieval Rate (%) Ramasamy et al., J Urol. 2009; 182: 1108-13. ANDROFERT, Referral Center for Male Reproduction
  19. 19. Male Hypogonadism Hypogonadal infertile males Obesity and absence of aromatase hyperactivity Recombinant hCG; 250 mcg per week; 12 weeks SC self-injection w/pre-filled syringe, qw Esteves, 21 ANDROFERT, Referral Center for Male Reproduction
  20. 20. Bariatric Surgery Reis et al (2012): 20 men; 2-year follow-up No changes in sperm quality; increase in TT levels Di Frega et al (2005): Six fertile men BMI > 40 kg/m2 (mean age 38) Resulted in persistent azoospermia ~16 mo. later Normal hormone levels; Biopsy: Maturation arrest Sermondade et al (2012): Three men BMI > 40 kg/m2 (mean age 38) Resulted in severe oligoasthenozoospermia ~2 mo. later ICSI with success in 2 cases di Frega et al. Hum Reprod 2005; Sermonande et al. RBO online 2012; Reis et al. Reprod Sci 2012 Esteves, 22 ANDROFERT, Referral Center for Male Reproduction
  21. 21. Assisted Reproductive Techniques Keltz et al (2010): 209 couples; retrospective Likelihood of pregnancy decreased in IVF if male partner was overweight (OR=0.21; 95% CI 0.07-1.49) No effect in ICSI cycles Bakos et al (2011): 305 couples; retrospective Inverse relationship between blastocyst development and pregnancy outcomes, and BMI Outcome of ART by BMI (Kg/m2) 18.1-24.9 25.0-29.9 ≥30 53.2 35.9 36.1 Clinical pregnancy (%) Keltz et al. J Assist Reprod Genet. 2010; Bakos et al Fertil Steril 2010 Esteves, 23 ANDROFERT, Referral Center for Male Reproduction
  22. 22. What we can do about it? Treatment Outcome Study Diet, Exercise Significant improvement in total sperm count and morphology in 42 obese men enrolled in a 14-week weight loss program Haloksen et al. Reprod Health 2011 Medication Increased sperm count and sperm retrieval rate in obese men with aromatase hyperactivity treated with AI; Increased sperm retrieval rates in KS patients treated with AI and/or hCG Ramasany & Schlegel J Urol 2002; Ramasany et al. J Urol 2009 Bariatric Surgery Case series showing worsening of semen parameters after bariatric surgery or no changes Di Frega et al. Hum Reprod 2005; Sermondade et al. RBM online 2010; Reis et al. 2012 ART Bakos et al. Fertil Steril Decreased PR and increased pregnancy loss 2011; Keltz et al. JARG 2010 Esteves, 24 ANDROFERT, Referral Center for Male Reproduction
  23. 23. Take-home Messages Obesity is a risk factor for male infertility. Obese men have lower sperm count, as well as increased sperm DNA damage and oxidative stress. Peripheral androgen aromatization is often increased in obese men thus altering HPG axis. Other mechanisms involve physical, genetic and adipocyte-secreted factors. The role of interventions to restore fertility of obese men is yet to be fully characterized. Esteves, 25 ANDROFERT, Referral Center for Male Reproduction

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