The British Journal of Diabetes & Vascular Disease

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Review: Male obesity and reproductive potential

A. Ghiyath Shayeb and Siladitya Bhattacharya British Journal of Diabetes & Vascular Disease 2009 9: 7 DOI: 10.1177/1474651408101281 The online version of this article can be found at: http://dvd.sagepub.com/content/9/1/7

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Male obesity and reproductive potential

A GhiyAth ShAyeb, SilAdityA bhAttAchAryA
Abstract

he prevalence of overweight and obesity is increasing worldwide. There is an established association between female obesity and infertility but a similar link is yet to be proven in men. Herein we review publications, identified via keyword electronic database searches (19802008), which considered the influence of adiposity on male reproductive potential. It would appear that obesity has a detrimental effect on semen quality and that there are several potential mechanisms underlying this phenomenon. Br J Diabetes Vasc Dis 2009;9: 712 Key words: male infertility, obesity, semen.

studies have highlighted a trend towards deterioration in semen quality.3,4 hypotheses put forward to explain this decline include increased use of pesticides,5 environmental pollutants,6,7 lifestyle factors,8 and increasing male obesity.9 in this paper, we aim to review the literature on the association between obesity and male fertility, and discuss possible management options for this increasingly common problem.

Search methods
We searched the electronic databases MEDLINE (1980 to October 2008), EMBASE (1980 to October 2008), CINAHL (1982 to October 2008), as well as the Cochrane Database of Systematic Reviews, using the keywords obesity, male fertility, male infertility, semen, sperm, erectile dysfunction weight loss, and metformin. After refining the search, we identified nine primary papers on the potential association between male bMi and semen quality/ fertility. Of these, five were case series, two case-control, and two cohort studies. the main outcomes were semen quality in six studies and time to pregnancy in three (one study presented both semen parameters and reproductive history). Semen quality is normally based on four main parameters: semen volume, sperm concentration, sperm motility, and normal sperm morphology. criteria for a normal semen analysis result (as described by a WhO guideline, published in 1999) are shown in table 1.10

the prevalence of overweight (bMi > 25) and obesity (bMi > 30) is on the increase, especially in industrialised countries. this phenomenon has been highlighted by the WhO in The SuRF report 2: Surveillance of Chronic Disease Risk Factors. in 2002, 58.8% of british women were overweight and this figure is projected to rise to 63.8% by 2010. the situation is similar in men, with the proportion who were overweight or obese accounting for 62.5% in 2002 and expected to reach 67.8% in 2010.1 rising obesity rates are likely to have a detrimental effect on general health through their association with a number of chronic diseases. these include hypertension, ischaemic heart disease, chronic vascular disease, insulin resistance and diabetes mellitus. Fertility seems to have been neglected in most studies of the consequences of obesity in men, although a strong association has been demonstrated between female obesity and reproductive problems. Although ovulatory dysfunction and PcOS have received the most attention in the literature, studies on overweight embryo recipients in oocyte donation programmes have shown a subtle negative association between increased bMi and peri-implantation endometrial quality.2 the potential effects of increased bMi in men on male fertility have not been subjected to the same degree of scrutiny as female obesity. Over the years, a number of population-based

Introduction

Association between obesity and male fertility

in a danish study on 520 men, Kort et al. demonstrated a significant negative relationship between high bMi and the total number of normal appearing motile spermatozoa. in addition, men with bMi > 25 had fewer chromatin-intact normal-motile sperm cells per ejaculate.11 A second paper from denmark examined the relationship between bMi and semen parameters in a cohort of 1,558 young army conscripts (mean age 19 years)12 and reported a significant association between sperm count and bMi. Overweight, as well as underweight, men had lower sperm concentrations and lower total sperm counts than men with normal bMi between 20 and 25. bMi was not associated with any of the following: semen volume, sperm motility and normal morphology. high bMi in men was associated with increased serum levels of oestradiol and decreased levels of testosterone, ShbG and inhibin b. Serum FSh was higher in slim men. A retrospective analysis of data from 390 men suggested that high bMi was associated with reduced sperm concentration and motility.13 A recent paper combined data on 2,139 men from five previous studies14 and found that serum testosterone

University of Aberdeen, Aberdeen Maternity hospital, Aberdeen, UK. Correspondence to: Professor Siladitya Bhattacharya University of Aberdeen, Aberdeen Maternity hospital, Foresterhill, Aberdeen Ab25 2Zd, UK. tel: +44 (0)1224 550590; Fax: +44 (0)1224 559948 e-mail: s.bhattacharya@abdn.ac.uk

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Abbreviations and acronyms bMi CINAHL dFi ed EMBASE FSh PcOS ShbG WhO body mass index Cumulative Index to Nursing and Allied Health Literature dNA Fragmentation index erectile dysfunction Excerpta Medica Database follicle stimulating hormone polycystic ovarian syndrome sex hormone binding globulin World health Organization

table 2 summarises these studies and shows the degree of variation within them in terms of the sample population, outcome parameters and results.

Possible mechanisms for the effect of obesity on semen parameters and male fertility
there are several theories to explain the reasons behind the relationship between obesity and poor semen quality, and resulting poor male fertility. While studies have reported an association between obesity and poor reproductive performance, data to support causality are still lacking. by the same token, there is a dearth of interventional studies showing an improvement of fertility or semen quality after weight loss in obese men. the following mechanisms have been suggested in order to explain the link between male obesity and infertility:

Table 1.

World health Organization criteria for normal semen analysis10 Parameters 2 ml 20 106 per ml > 50% with forward progression > 40 106 sperm > 15% normal

Sperm chromatin integrity theory

Criteria Semen volume Sperm concentration Motility total sperm count Morphology

and inhibin b serum levels were 2532% lower in obese men, but failed to confirm a statistically significant relationship between bMi and semen parameters. in a further study involving only oligozoospermic men, Fejes reported a decreased testosterone:oestradiol ratio in overweight compared with slim men, with a further severe reduction in sperm concentration in the overweight group.15 All the above studies have explored the potential link between bMi and semen parameters. With regards to male fertility per se (as opposed to semen quality) Sallmen et al. reported that male overweight and obesity was associated with increased time to pregnancy and infertility (as defined by lack of conception despite 12 months of unprotected intercourse).16 A similar survey by Nguyen et al., based within the Norwegian Mother and child cohort study, has reported a similar association between male overweight/obesity and time to pregnancy/infertility after adjustments for coital frequency, womans bMi, age and smoking of both partners.17 A study based on the danish birth cohort showed that obesity in women, as well as men, was linked to increased time to pregnancy.18 in a fourth study on 87 men, men with children had a lower mean bMi than men without (28 kg/m2 vs. 31.6 kg/m2).19 the same study showed that male bMi was negatively correlated with serum testosterone, FSh, and inhibin b levels, but positively correlated with oestradiol levels. there was no correlation between bMi and semen parameters in this cohort.

this theory proposes that overweight and obese men have a higher proportion of spermatozoa with fragmented dNA. the integrity of sperm dNA is vital for paternal genetic contribution to a normal offspring.20 in a prospective study of 165 presumably fertile couples attempting to achieve a pregnancy, dNA chromatin integrity, defined as the susceptibility to dNA denaturation in situ and measured by Sperm chromatin Structure Assay, proved to be the best predictor of the couples inability to become pregnant. A semen sample with a dFi less than 30% was associated with fertility.21 Kort, in a separate study, reported a significantly higher dFi in overweight and obese men.11

Oxidative stress theory

Oxidative stress is caused by an excess of reactive oxidative species (molecules harbouring an unpaired electron) in a physiological environment. A few studies have noted that obesity and the metabolic syndrome commonly associated with it are linked to increased oxidative stress with lipid peroxidation.22,23 Several studies have revealed that, in addition to dNA oxidative injury, oxidative stress results in sperm membrane lipid peroxidation and impairs sperm motility as well as spermoocyte interaction.24,25

Hormonal imbalance theory

A number of studies have reported on altered sex hormone levels in overweight and obese men. in general, testosterone, ShbG and inhibin b levels all decrease with obesity, whereas oestradiol levels tend to increase.12,19 As a consequence, the testosterone:oestradiol ratio falls in overweight/obese men.15,26 in spite of the drop in ShbG levels, Zumoff et al. reported a negative correlation between free testosterone and high bMi.26 Most researchers in this field have reported decreased levels of total testosterone, free testosterone, and ShbG,27,28 but normal or low levels of FSh and luteinising hormone in the serum of obese men.12,19 however, not all agree with this concept. Jarow et al. showed an increase in both free testosterone and oestrogen

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Table 2. Population studied Male partners of couples presenting with infertility Fragmentation index young military recruits parameters, testis size, serum reproductive hormones Male partners of couples presenting with infertility Population from five separate occupational or environmental semen studies First pregnancy planners, gardeners, farmers, ASclePiOS study (employees of 10 different companies), iNUeNdO study (partners to pregnant spouses) Oligozoospermic men with infertility 42 routine semen analysis parameters, serum reproductive hormones certified pesticide applicators in two states of USA and their spouses the Norwegian Mother and child cohort Study Fathers of children and male partners of couples seeking fertility treatment the danish National birth cohort 47,835 couples couples 26,303 pregnancies 87 5,526 infertility (> 12 months) with unprotected intercourse 12 months to achieve the pregnancy reproductive history, routine semen analysis parameters, serum reproductive hormones time to pregnancy Paternity () time to pregnancy () infertility in obese men () testosterone/oestradiol ratio () Sperm concentration() combined) reproductive hormones five studies parameters, serum 2,139 (in the routine semen analysis self reported erectile dysfunction 390 Sperm concentration and motility, 1,558 routine semen analysis parameters, Sperm dNA 520 routine semen analysis Number of participants Outcome measures Parameter affected in overweight men

Summary of studies investigating male body mass index and semen quality/fertility

Study and year

Country

Kort

USA

total normal motile sperm count () Sperm dNA Fragmentation index () Sperm concentration, total sperm count, testosterone, ShbG, and inhibin b () Free Androgen index, and oestradiol () Sperm concentration and motility () erectile dysfunction (=) testosterone and inhibin b () Oestrogen level () Semen parameters (=)

et al. 200611

Jensen

denmark

et al. 200412

THE bRITISH jOURNAL Of DIAbETES AND VASCULAR DISEASE

hammoud

USA

et al. 2008

Aggerholm

denmark

et al. 200714

Fejes

hungary

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et al. 200615

Sallmen

USA

et al. 2006

16

Nguyen

Norway

et al. 200717

Pauli

USA

et al. 2008

19

testosterone, FSh, and inhibin b () estrogen level () Semen analysis parameters (=) time to pregnancy ()

ramlau-hansen

denmark

2007

18

Key: () = increased; () = decreased; (=) = no association found; FSh = follicle stimulation hormone; ShbG = sex hormone binding globulin.

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in obese men, mainly as a consequence of low ShbG levels, although the free testosterone/free oestrogen ratio was decreased.29 Ashok et al. reported a negative correlation between bMi and total, as well as free, serum testosterone.30 even inappropriately normal levels of gonadotrophins in the presence of low free serum testosterone signifies a suppression of the hypothalamicpituitary axis.25 hofstra et al. demonstrated an increased incidence of isolated hypogonadotrophic hypogonadism in men referred for obesity treatment.31 elevated levels of oestrogens produced by aromatisation of androgens in peripheral adipose tissue in obese men provide a possible explanation for suppression of the hypothalamicpituitary axis.

Increased scrotal temperature theory

Suprapubic and thigh fat have been postulated to cause elevated scrotal temperature, thus decreasing sperm quality and fertility.32 Shafik et al in 1981 described two types of scrotal fat distribution, normal and infertile.33 they used the term scrotal lipomatosis to describe the abnormally distributed scrotal fat which was present in 38 of 44 infertile men (24 of these 38 were obese). the authors reported that scrotal lipectomy resulted in improvement in semen quality. As a result of this, el-Sibai et al. proposed that there is an increased local aromatisation of androgen to oestrogen in the proximity of these fat deposits which could suppress spermatogenesis.34 they also showed a significantly increased level of oestradiol in the pampiniform plexus of subfertile patients with scrotal lipomatosis, in comparison with a control group.

who are significantly obese with bMi > 35 kg/m2.48 in a randomised controlled trial, addition of metformin to lifestyle modification and reduced energy intake did not confer any further benefit in terms of weight loss or menstrual cyclicity. Weight loss was similar across both arms of this trial (with or without metformin). An increase of menstrual cyclicity was observed only in those who lost weight, regardless of whether or not they received metformin. More recently, a three arm randomised controlled trial compared metformin alone, clomifene citrate alone, or a combination of both drugs for the treatment of anovulatory infertility.49 the live birth rate was 22.5% in the clomiphene group, 7.2% in the metformin group (the difference was statistically significant), and 26.8% in the combination therapy group (significantly higher than the metformin group, but not the clomifene only group). the results of this large, well-conducted, trial do not support the use of metformin for induction of ovulation in obese women with PcOS. thiazolidinedione derivatives, while potentially more effective than metformin for improving insulin sensitivity, are inappropriate for use in those seeking fertility, and have the unwanted effect of actually increasing weight, although this is largely due to fluid retention.45

Management of obese men with infertility

Advice on weight loss and lifestyle is an obvious first step in the management of obese men, and one which is likely to reduce the risk of chronic diseases associated with high bMi. to date, there are no interventional studies which demonstrate a beneficial effect of weight loss on semen parameters or male fertility. however, a few studies have demonstrated that weight loss in obese men can improve deranged serum sex hormone levels. bastounis et al. have demonstrated a significant decrease in oestradiol and an increase in FSh, total testosterone, and ShbG in morbidly obese men who lost weight following vertical banded gastroplasty.50 in a randomised controlled trial, Kaukua et al. showed that a successful weight loss programme resulted in an increase in ShbG and testosterone, as well as a decrease in insulin, and leptin.51 the results were confirmed by Niskanen et al. who showed that the improvement in hormone levels was maintained, even after completion of the weight loss programme.52 these results were replicated in three further studies.53-55 thus, hypogonadotrophic hypogonadism, and concurrent hyperoestrogenaemia in obese men appears to be correctable by weight loss, regardless of how this is achieved. the choice of method used to achieve weight loss needs to be individualised. While dietary modification and exercise are the logical first steps, bariatric surgery may be an option in a selected group of morbidly obese men. the role of insulin sensitizers on weight loss and hormonal profile in men is still to be investigated, but the results from similar studies on fertility in females are not very encouraging. Nevertheless it should be remembered that insulin sensitising agents (metformin and thiazolidinedione/glitazones) are not anti-obesity agents. they

Sexual dysfunction theory

erectile dysfunction has been reported to be more common among men with high bMi.35-43 Published work has linked ed with obesity and metabolic syndrome and some studies have identified it as an early marker of cardiovascular disease in overweight individuals.44 thus, increased sexual difficulties experienced by the overweight male can contribute to their fertility problems.

Are there any lessons to learn from the management of female obesity-associated infertility?
the overwhelming majority of anovulatory women who attend infertility clinics have PcOS and at least 40% of them are obese. these women tend to be more insulin resistant than weight-matched controls.45 Women with PcOS have hyperandrogenism, morphological changes in the ovaries (polycystic appearance on ultrasound scan), elevated levels of circulating luteinizing hormone, and insulin. the use of insulin sensitising agents for the management of PcOS has evoked a great deal of interest. two systematic reviews46,47 revealed the paucity of the literature on this subject; the majority of published studies had very small sample sizes. Available evidence suggests that metformin ameliorates hyperandrogenism and abnormalities of gonadotropin secretion and can restore menstrual cyclicity in women with PcOS, but appears to be less effective in women

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Key messages
the incidence of obesity is rising Male obesity has been linked to deterioration in

semen quality
Obesity can potentially impair male fertility via

different mechanisms
Optimising body weight may improve male fertility

counter different aspects of insulin resistance and therefore have wide ranging physiological effects. there is evidence from a number of studies that weight loss, as part of a healthier lifestyle, can help to improve ed.56-59 in a randomised controlled trial comparing detailed weight loss advice with general information, erectile function in the intervention group improved significantly. changes in bMi and physical activity were independently associated with improvement in the erectile Function Score.56 thus, while there are no data to prove that weight loss reverses infertility, optimising bMi in obese men can normalise sex hormone levels and improve erectile dysfunction. it is also biologically plausible to suggest that, if obesity increases dNA fragmentation, oxidative stress, and scrotal hyperthermia, losing weight may reverse some, if not all, of these processes and eventually lead to improved fertility. this hypothesis remains to be proven in an adequately powered evaluative study.

Summary
As the incidence of obesity continues to rise, more clinicians will encounter cases of weight-related infertility in their day-to-day practice. there is convincing evidence to link obesity with infertility in women but not in men. Available data suggest that obesity in men may affect semen quality, and there is growing awareness of a number of potential mechanisms underlying this phenomenon. While optimising body weight is clearly beneficial in terms of enhancing general health, further research is necessary to evaluate its role in improving fertility.

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