Sandro C. Esteves, MD, PhD Director, ANDROFERT

Campinas, Brazil

Obesity and Male Infertility

Advances in OBGYN Conference, Oman 2013

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

Available at:

http://www.androfert.com.br/review

Obesity and Male Infertility

Esteves, 3 ANDROFERT, Referral Center for Male Reproduction

Obesity in Men at Reproductive Age

Esteves, 4 ANDROFERT, Referral Center for Male Reproduction

Esteves, 5 ANDROFERT, Referral Center for Male Reproduction

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

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

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

Marker Outcome Study Oxidative stress and DNA integrity

2-fold decrease in sperm mitochondrial activity (OS marker) and DNA integrity (Comet) in obese men

Fariello et al. BJU Int 2012

Oxidative stress Direct relationship between levels of superoxide anion in seminal plasma and BMI

Tunc et al. Andrologia 2011

DNA integrity Decreased sperm DNA integrity (Comet and SCSA) in sperm of obese men

Kort et al. 2006; Chavarro et al. 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

Obesity and Sperm Molecular Composition

Esteves, 9 ANDROFERT, Referral Center for Male Reproduction

What are the changes in the semen of obese men?

Esteves, 10 ANDROFERT, Referral Center for Male Reproduction

Decreased sperm count (oligozoospermia)

Decreased sperm function and proteomic profile

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.

Esteves, 13 ANDROFERT, Referral Center for Male Reproduction

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

Adipocytes Secrete Adipose-derived Hormones and Adipokines

IL-6, IL-10, TNF-α Increase NO production and Oxidative Stress

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

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

Esteves, 16 ANDROFERT, Referral Center for Male Reproduction

Does Weight Loss Improve Semen Quality?

Håkonsen LB et al. Reprod Health. 2011

43 men with BMI >33 kg/m2

Healthy diet and daily exercise for 14 weeks

Conventional semen parameters (WHO) and sperm DNA fragmentation (SCSA)

Hormone profile (FSH, LH, TT, SHBG)

Controlled for confounders (smoking, diseases, etc.)

0

232 193

7 1 3 29

87 115

3.5%-12% 12.1%-17% >17%

Changes based on % weight loss Total sperm count (million) Sperm DNA fragmentation (%) TT (ng/dL)

P=0.02

Esteves, 17 ANDROFERT, Referral Center for Male Reproduction

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

Does Medication Improve Semen Quality?

Anastrozole 1 mg q1d 60 days

Esteves, 18 ANDROFERT, Referral Center for Male Reproduction

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

Esteves, 19 ANDROFERT, Referral Center for Male Reproduction

Ramasamy et al., J Urol. 2009; 182: 1108-13.

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.

72 55

Sperm Retrieval Rate (%)

Positive response

P = 0.03

Aromatase Inhibitors for Obesity-related Male Infertility

Esteves, 20 ANDROFERT, Referral Center for Male Reproduction

SC self-injection w/pre-filled syringe, qw

Male Hypogonadism

Hypogonadal infertile males

Obesity and absence of aromatase hyperactivity Recombinant hCG; 250 mcg per week; 12 weeks

Esteves, 21 ANDROFERT, Referral Center for Male Reproduction

di Frega et al. Hum Reprod 2005; Sermonande et al. RBO online 2012; Reis et al. Reprod Sci 2012

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

Esteves, 22 ANDROFERT, Referral Center for Male Reproduction

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

53.2

35.9 36.1

Clinical pregnancy (%)

Outcome of ART by BMI (Kg/m2)

18.1-24.9 25.0-29.9 ≥30

Keltz et al. J Assist Reprod Genet. 2010; Bakos et al Fertil Steril 2010

Esteves, 23 ANDROFERT, Referral Center for Male Reproduction

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

What we can do about it?

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 Decreased PR and increased pregnancy loss Bakos et al. Fertil Steril 2011; Keltz et al. JARG 2010

Esteves, 24 ANDROFERT, Referral Center for Male Reproduction

Take-home Messages

The role of interventions to restore fertility of obese men is yet to be fully characterized.

Peripheral androgen aromatization is often increased in obese men thus altering HPG axis. Other mechanisms involve physical, genetic and adipocyte-secreted factors.

Obese men have lower sperm count, as well as increased sperm DNA damage and oxidative stress.

Obesity is a risk factor for male infertility.

Esteves, 25 ANDROFERT, Referral Center for Male Reproduction