Obesity and Male Infertility

Sandro C. Esteves, MD, PhD

Director, ANDROFERT

Campinas, Brazil

Obesity and Male Infertility

Reproductive Andrology S urgery Workshop IIReproductive Medicine Unit - J ahra Hospital - Kuwait 2014

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?

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ANDROLOGY AND HUMAN REPRODUCTION C LINIC - REFERRAL C ENTER FOR MALE REPRODUCTIONS ESTEVES, 22014 December

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Obesity in Men at Reproductive Age

Esteves, 5 ANDROFERT, Referral Center for Male Reproduction

Is obese men at risk of infertility?

Obese men is about twice as likely to be

infertile as normal men



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Low Sperm Count in Obese Men

Meta-analysis of 21 studies (13,077 men)

Risk of Low Sperm Count:

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



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Marker Outcome Study

Oxidative stress

and DNA

integrity

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

Fariello et al.

BJU Int 2012

Oxidative stressDirect relationship between levels of

superoxide anion in seminal plasma and BMI

Tunc et al.

Andrologia 2011

DNA integrityDecreased sperm DNA integrity (Comet and

SCSA)

Kort et al. 2006;

Chavarro et al.

Fertil Steril 2011

ApoptosisIncreased % of sperm with

phosphatidylserine externalization

La Vignera et al.

J Androl 2012

ProteomicsDiabetes and obesity-associated proteomic

changes

Kriegel et al.

RBM online

2009

Obesity and Sperm Molecular Composition



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What are the changes in the semen

of obese men?

Decreased sperm count

Decreased sperm function and

proteomic profile



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Leptin, adiponectin and resistin• Involved in glucose metabolism, sexual maturation

and reproduction

• Excess leptin decreases Leydig cell function ( ITT) and has a direct negative effect on sperm

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



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Aromatase Polymorphism Modulate Relationship

between Weight and Estradiol Levels in Obese Men

Aromatase product of CYP19 gene

Most common polymorphism is tetranucleotide repeat (TTTAn)

Higher TTTAn (X-X) repeat associated with increased E2 levels



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What are the mechanisms?

There are 3 main mechanisms involved:

Oxidative Stress

Hormonal imbalance and hypogonadism

Accumulation of endocrine disruptors



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Does Weight Loss Improve

Semen Quality?

Håkonsen LB et al. Reprod Health. 2011

• 43 men BMI >33 kg/m2

• Healthy diet and daily exercise for 14 weeks

• Semen parameters (WHO) and sperm DNA fragmentation (SCSA)

• Hormone profile (FSH, LH, TT, SHBG)

• Confounders control (smoking, diseases, etc.)

0

232 193

71 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



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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



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Raman & Schlegel. J Urol. 2002

5.92.9

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)

Pre-treatment Post-treatment

Aromatase Inhibitors for

Obesity-related Male Infertility



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

Male Hypogonadism

Hypogonadic infertile males

Obesity and absence of aromatase hyperactivity

Recombinant hCG; 250 mcg/week; 12 weeks



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Bariatric Surgery

Reis et al, Reprod Sci 2012:

20 men; 2-year follow-up

No sperm quality changes; TT increased

Di Frega et al, HR 2005:

Six fertile men BMI > 40 kg/m2 (mean age 38)

Persistent azoospermia after surgery (~16 mo.)Normal hormone levels; Biopsy: Maturation arrest

Sermondade et al, RBM online 2012:

Three men BMI > 40 kg/m2 (mean age 38)

Worsening of semen parameters ~2 mo. Postop.ICSI with success in 2 cases



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Assisted Reproductive Techniques

Keltz et al, JARG 2010:

209 couples; retrospective

Likelihood of pregnancy in IVFdecreased if male partner was overweight (OR=0.21; 95% CI 0.07-1.49)

No effect in ICSI cycles

Bakos et al, Fertil Steril 2011:

305 couples; retrospective

Inverse relationship between blastocyst development/ pregnancy 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



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Treatment Outcome Study

Diet,

Exercise

Improvement in sperm count and morphology after 14-week weight loss program

Haloksen et al. 2011

Medication

Increased sperm count in obese men with aromatase hyperactivity treated with AI

Ramasany & Schlegel

2002

What we can do about it?

Bariatric

Surgery

2/3 studies showing worsening of semen parameters after bariatric surgery

Di Frega et al. 2005;

Sermondade et al.

2010; Reis et al. 2012

ARTDecreased PR and increased

miscarriage

Bakos et al. 2011; Keltz

et al. 2010



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Take-home Messages

Role of interventions to restore fertility is yet to be fully characterized

Androgen aromatization often increased, altering HPG axis. Other mechanisms involve physical, genetic and adipocyte-secreted factors

Low sperm count, increased sperm DNA damageand oxidative stress

Obesity is a risk factor for male infertility



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Health & Medicine

Obesity and Male Infertility