1. Advances in OBGYN Conference, Oman 2013
Obesity and Male Infertility
Sandro C. Esteves, MD, PhD
Director, ANDROFERT
Campinas, Brazil

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. Obesity and Male Infertility
Available at:
http://www.androfert.com.br/review
Esteves, 3
ANDROFERT, Referral Center for Male Reproduction

4. Obesity in Men at Reproductive Age
Esteves, 4
ANDROFERT, Referral Center for Male Reproduction

5. Esteves, 5
ANDROFERT, Referral Center for Male Reproduction

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. 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. 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. 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. 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

13. 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

14. 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

15. 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

16. Esteves, 16
ANDROFERT, Referral Center for Male Reproduction

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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