Scientificity and feasibility study of non-invasive central arterial pressure...
Obesity and Male Infertility
1. SandroC. Esteves, MD, PhD
Director, ANDROFERT
Campinas, Brazil
Obesity and Male Infertility
Reproductive Andrology Surgery Workshop II
Reproductive Medicine Unit -JahraHospital -Kuwait 2014
2. Contents
Is obese men at risk of infertility?
What are the changes in their semen?
Whatare the mechanisms?
What we can do about it?
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3. ANDROFERT
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Obesity in Men at Reproductive Age
5. Is obese men at risk of infertility?
Obese men is about twice as likely to be infertile as normal men
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7. 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;
Sermondadeet al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum ReprodUpdate. 2013
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8. Marker
Outcome
Study
Oxidativestress and DNA integrity
2-fold decrease in sperm mitochondrial activity (OS marker) and DNA integrity (Comet)
Farielloet al. BJU Int2012
Oxidative stress
Direct relationship between levels ofsuperoxide anion inseminal plasmaand BMI
Tuncet al. Andrologia2011
DNA integrity
Decreased sperm DNA integrity (Cometand SCSA)
Kortet al. 2006; Chavarroet al. FertilSteril2011
Apoptosis
Increased % of sperm with phosphatidylserineexternalization
La Vigneraet al. J Androl2012
Proteomics
Diabetes and obesity-associated proteomic changes
Kriegelet al. RBM online 2009
Obesity and Sperm Molecular Composition
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9. What are the changes in the semen of obese men?
Decreased sperm count
Decreased sperm function and proteomic profile
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12. Leptin, adiponectinand resistin
•Involved in glucose metabolism, sexual maturation and reproduction
•Excess leptindecreases Leydig cell function (ITT) and has a direct negative effect on sperm
Winters et al.J Androl2006; Jopeet al. IntJ Androl2003; Hofnyet al. FertilSteril2009; Bialaset al. Am J ReprodImmunol2009; Fraczek& KurpiszJ Androl2007; Lampiao& du PlessisReprodBiomed Online 2008
Adipocytes Secrete Adipose-derived Hormonesand Adipokines
IL-6, IL-10, TNF-α
•Increase NO production and Oxidative Stress
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13. Aromatase Polymorphism Modulate Relationship between Weight and Estradiol Levels in Obese Men
Aromatase product of CYP19 gene
Most common polymorphism is tetranucleotiderepeat (TTTAn)
Higher TTTAn(X-X) repeat associated with increased E2 levels
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14. What are the mechanisms?
There are 3main mechanisms involved:
Oxidative Stress
Hormonal imbalance and hypogonadism
Accumulation of endocrine disruptors
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16. Does Weight Loss Improve Semen Quality?
HåkonsenLB et al. ReprodHealth. 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
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
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17. Total Testosterone (ng/dL) and Estradiol (pg/mL) Levels
T/E2Ratio
Normal > 10
Zumoffet al. Metabolism 2003;Raman & Schlegel J Urol2002
T/E2<10
Aromatase Hyperactivity
Does Medication Improve Semen Quality?
Anastrozole1 mg q1d 60 days
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19. 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)
Pre-treatment
Post-treatment
Aromatase Inhibitors for
Obesity-related Male Infertility
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20. SC self-injection w/pre-filled syringe, qw
Male Hypogonadism
Hypogonadicinfertile males
Obesity and absence of aromatase hyperactivity
Recombinant hCG; 250 mcg/week; 12 weeks
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21. Bariatric Surgery
Reis et al, ReprodSci2012:
20 men; 2-year follow-up
No sperm quality changes; TT increased
Di Fregaet 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
Sermondadeet 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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22. Assisted Reproductive Techniques
Keltzet al, JARG 2010:
209 couples; retrospective
Likelihood of pregnancy in IVF
decreased if male partner was overweight (OR=0.21; 95% CI 0.07-1.49)
No effect in ICSI cycles
Bakoset al, FertilSteril2011:
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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23. Treatment
Outcome
Study
Diet, Exercise
Improvement in sperm count and morphology after 14-week weight loss program
Haloksenet al.2011
Medication
Increased sperm countin 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 parametersafter bariatric surgery
Di Fregaet al.2005; Sermondadeet al. 2010; Reis et al. 2012
ART
Decreased PR and increased miscarriage
Bakoset al. 2011; Keltzet al. 2010
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24. 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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Editor's Notes
Men with increased BMI were significantly more likely to be infertile than normal weight men, according to a research conducted at the National Institute of Environmental Health Sciences [Sallmen M, Sandler DP, Hoppin JA, Blair A, Baird DD. Reduced fertility among overweight and obese men. Epidemiology 2006; 17: 520–3.5].
Odds-ratio of being infertile if obese is: >2.0 according to Sallmen; 1.5 [Hum Reprod 2007; 22:2488-93]
How does obesity affect male fertility?
Response: By decreasing sperm quality. Altered semen parameters ascribed to obesity include decreased sperm concentration, abnormal morphology, compromised chromatin integrity and abnormal motility.
• Jensen TK, Andersson AM, Jorgensen N, Andersen AG, Carlsen E, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 danish men. Fertil Steril 2004; 82: 863–70.
o A lower sperm concentration was observed in not only obese and overweight males but also in males who were signifi cantly underweight. This could serve as an indication that there may be an ideal range of BMI for normal spermatogenesis.
• Decreased sperm counts with increased BMI [Hum Reprod 2005; 20: 208-215]
• Martini AC, Tissera A, Estofan D, Molina RI, Mangeaud A, et al. Overweight and seminal quality: a study of 794 patients. Fertil Steril 2010; Jan 5, [Epub ahead of print].
o There was a negative association between BMI and motility, rapid motility, and a positive association between BMI and seminal fructose levels. No associations were found among BMI and sperm concentration or seminal testosterone levels.
• Hammoud AO, Wilde N, Gibson M, Parks A, Carrell DT, et al. Male obesity and alteration in sperm parameters. Fertil Steril 2008; 90: 2222–5.
o Among their 526 patients, the prevalence of a low progressively motile sperm count and furthermore low sperm concentration was greater with increasing BMI.
What are the pathophysiological mechanisms?
Physical conditions
Genital heat stress is a significant source of increased scrotal skin temperature, and even moderate and physiological elevation in scrotal skin temperature is associated with a substantially reduced sperm concentration
• Hjollund NH, Bonde JP, Jensen TK, Olsen J. Diurnal scrotal skin temperature and semen quality. The danish first pregnancy planner study team. Int J Androl 2000; 23: 309–18.
Hormonal mechanisms and adipokines (cytokines secreted by adipose-tissue)
• White adipose tissue, found in high levels in obese men, exhibits elevated aromatase activity and secretes adipose-derived hormones as well as adipokines. This estrogen excess is explained by overactivity of the aromatase cytochrome P450 enzyme, which is expressed at high levels in white adipose tissue and is responsible for a key step in the biosynthesis of estrogens. High levels of estrogens in obese males result from the increased conversion of androgens into estrogens, owing to the high bioavailability of these aromatase enzymes.
o Elevated estrogen and low testosterone: secondary hypogonadism
o Rising levels of Estrogens cause an inhibitory effect on the secretion of GnRH, FSH and LH: influence testosterone secretion (Deregulation of the normal ypothalamic–pituitary-–gonadal (HPG) axis)
Roth MY, Amory JK, Page ST. Treatment of male infertility secondary to morbid obesity. Nat Clin Pract Endocrinol Metab 2008; 4: 415–9.
• White adipose tissue is a major secretory and endocrine organ that secretes ~30 biologically active peptides and proteins that can be grouped as either adipose-derived hormones (for example, leptin, adiponectin and resistin) or adipokines (immunomodulating agents).
o Elevated levels of leptin (Leptin receptors are not only present in testicular tissue but also on the plasma membrane of sperm, suggesting that leptin may directly affect sperm through the endocrine system, independent of changes in the HPG axis
• Jope T, Lammert A, Kratzsch J, Paasch U, Glander HJ. Leptin and leptin receptor in human seminal plasma and in human spermatozoa. Int J Androl 2003; 26: 335–41
Leptin involved in glucose metabolism, as well as in normal sexual maturation and reproduction.
• Hofny ER, Ali ME, Abdel-Hafez HZ, El-Dien Kamal E, Mohamed EE, et al. Semen parameters and hormonal profile in obese fertile and infertile males. Fertil Steril 2009. [Epub ahead of print].
o Adipokines (tumor necrosis factor α (TNFα), interleukin 6 (IL-6), plasminogen activator inhibitor-1 and tissue factor)
Result in inflammation: can have a toxic effect on spermatozoa through the release of excess reactive oxygen species (ROS)
• Bialas M, Fiszer D, Rozwadowska N, Kosicki W, Jedrzejczak P, et al. The role of IL-6, IL-10, TNF-alpha and its receptors TNFR1 and TNFR2 in the local regulatory system of normal and impaired human spermatogenesis. Am J Reprod Immunol 2009; 62: 51–9.
• Fraczek M, Kurpisz M. Infl ammatory mediators exert toxic effects of oxidative stress on human spermatozoa. J Androl 2007; 28: 325–33.
• Lampiao F, du Plessis SS. TNF-alpha and IL-6 affect human sperm function by elevating nitric oxide production. Reprod Biomed Online 2008; 17: 628–31.
o Inhibin B
Declined with increasing obesity in young adult men, and values were 26% lower in men who were obese compared with normal weight men.
Positively correlated with the number of Sertoli cells: Sertoli cells support germ cells (decrease in Sertoli cells number: decrease in sperm count)
Winters SJ, Wang C, Abdelrahaman E, Hadeed V, Dyky MA, et al. Inhibin-B levels in healthy young adult men and prepubertal boys: is obesity the cause for the contemporary decline in sperm count because of fewer sertoli cells? J Androl 2006; 27: 560–4.
Environmental toxins
Most environmental toxins are fat-soluble and therefore accumulate in fatty tissue.
• Disrupt the normal hormone profile, because they are proven endocrine disruptors in male fertility.
o Hammoud AO, Wilde N, Gibson M, Parks A, Carrell DT, et al. Male obesity and alteration in sperm parameters. Fertil Steril 2008; 90: 2222–5.
Hormonal mechanisms and adipokines (cytokines secreted by adipose-tissue)
• White adipose tissue, found in high levels in obese men, exhibits elevated aromatase activity and secretes adipose-derived hormones as well as adipokines. This estrogen excess is explained by overactivity of the aromatase cytochrome P450 enzyme, which is expressed at high levels in white adipose tissue and is responsible for a key step in the biosynthesis of estrogens. High levels of estrogens in obese males result from the increased conversion of androgens into estrogens, owing to the high bioavailability of these aromatase enzymes.
o Elevated estrogen and low testosterone: secondary hypogonadism
o Rising levels of Estrogens cause an inhibitory effect on the secretion of GnRH, FSH and LH: influence testosterone secretion (Deregulation of the normal ypothalamic–pituitary-–gonadal (HPG) axis)
Roth MY, Amory JK, Page ST. Treatment of male infertility secondary to morbid obesity. Nat Clin Pract Endocrinol Metab 2008; 4: 415–9.
• White adipose tissue is a major secretory and endocrine organ that secretes ~30 biologically active peptides and proteins that can be grouped as either adipose-derived hormones (for example, leptin, adiponectin and resistin) or adipokines (immunomodulating agents).
o Elevated levels of leptin (Leptin receptors are not only present in testicular tissue but also on the plasma membrane of sperm, suggesting that leptin may directly affect sperm through the endocrine system, independent of changes in the HPG axis
• Jope T, Lammert A, Kratzsch J, Paasch U, Glander HJ. Leptin and leptin receptor in human seminal plasma and in human spermatozoa. Int J Androl 2003; 26: 335–41
Leptin involved in glucose metabolism, as well as in normal sexual maturation and reproduction.
• Hofny ER, Ali ME, Abdel-Hafez HZ, El-Dien Kamal E, Mohamed EE, et al. Semen parameters and hormonal profile in obese fertile and infertile males. Fertil Steril 2009. [Epub ahead of print].
o Adipokines (tumor necrosis factor α (TNFα), interleukin 6 (IL-6), plasminogen activator inhibitor-1 and tissue factor)
Result in inflammation: can have a toxic effect on spermatozoa through the release of excess reactive oxygen species (ROS)
• Bialas M, Fiszer D, Rozwadowska N, Kosicki W, Jedrzejczak P, et al. The role of IL-6, IL-10, TNF-alpha and its receptors TNFR1 and TNFR2 in the local regulatory system of normal and impaired human spermatogenesis. Am J Reprod Immunol 2009; 62: 51–9.
• Fraczek M, Kurpisz M. Infl ammatory mediators exert toxic effects of oxidative stress on human spermatozoa. J Androl 2007; 28: 325–33.
• Lampiao F, du Plessis SS. TNF-alpha and IL-6 affect human sperm function by elevating nitric oxide production. Reprod Biomed Online 2008; 17: 628–31.
o Inhibin B
Declined with increasing obesity in young adult men, and values were 26% lower in men who were obese compared with normal weight men.
Positively correlated with the number of Sertoli cells: Sertoli cells support germ cells (decrease in Sertoli cells number: decrease in sperm count)
Winters SJ, Wang C, Abdelrahaman E, Hadeed V, Dyky MA, et al. Inhibin-B levels in healthy young adult men and prepubertal boys: is obesity the cause for the contemporary decline in sperm count because of fewer sertoli cells? J Androl 2006; 27: 560–4.
Environmental toxins
Most environmental toxins are fat-soluble and therefore accumulate in fatty tissue.
• Disrupt the normal hormone profile, because they are proven endocrine disruptors in male fertility.
o Hammoud AO, Wilde N, Gibson M, Parks A, Carrell DT, et al. Male obesity and alteration in sperm parameters. Fertil Steril 2008; 90: 2222–5.
CYP19 is located in chromosome 15.
Genetics:
Hammoud et al. recently discovered that an aromatase polymorphism modulates the relationship between weight and estradiol levels in obese men. This could explain why only certain obese men experience this rise in estradiol and subsequent fertility problems, whereas others experience no fertility issues.
Hammoud A, Carrell DT, Meikle AW, Xin Y, Hunt SC, et al. An aromatase polymorphism modulates the relationship between weight and estradiol levels in obese men. Fertil Steril 2009.[Epub ahead of print].
Ramasamy and cols. (2009) have recently shown that men with Klinefelter syndrome with either normal or low baseline testosterone but who respond to medical therapy had a better chance of sperm retrieval. In their study, a total of 68 men with non-mosaic KS underwent 91 microdissection TESE attempts. Men with serum testosterone levels less than 300 ng/dL received medical therapy (aromatase inhibitors, clomiphene or human chorionic gonadotropin) prior to micro-TESE. Men who had a serum testosterone increase of >100 ng/dL from baseline had a 72% successful sperm retrieval rate (SRR) compared to men who had an increase <100 ng/dL (SSR=58%; p= 0.3). Increasing male age was associated with a trend toward lower SRR (p=0.05). The various types of preoperative hormonal therapies did not have different SRR, but men with normal baseline testosterone levels had the best SRR (86%) (see Table below).
Potential predictive factors for successful mTESE in patients with KS (Ramasany et al., 2009)
Total (n=91) Success (n=62) Failed (n=29) P-value
Age (yr) 33 32 35 0.05
Average Testicular Volume(mL) 3.5 3.9 2.7 n.s
Testosterone-Pretreatment(ng/dL) 172.3 178.6 148.5 n.s
Testosterone-Prior to Surgery(ng/dL) 299.6 328.0 212.0 0.002
T/E(Pretreatment) 6.3 7.1 4.9 0.03
T/E(Prior to Surgery) 12.5 13.6 10.0 0.04
LH(Pretreatment)(IU/L) 16.3 16.2 16.9 n.s
FSH(Pretreatment)(IU/L) 34.4 33.6 38 n.s
Overweight status of male partner was independently associated with decreased likelihood of clinical pregnancy after in vitro fertilization but not after intracytoplasmic sperm injection. A detrimental impact of higher male body mass was observed after adjusting for sperm concentration, suggesting that intracytoplasmic sperm injection may overcome some obesity related impairment of sperm-egg interaction
Obese men show increased plasma estradiol and low testosterone levels (GR-B).
Although FSH release is primarily under the control of inhibin, circulating estradiol has a substantial effect on FSH levels in men. Aromatase inhibition results in a three-fold increase in levels of FSH in eugonadal men and may potentially stimulate sperm production. AI may stimulate sperm production (GR-C); effects upon fertility are still to be determined.
