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,
From the * Division of Reproductive Endocrinology
& Infertility, Department of Obstetrics & Gynecology; the
Department of Surgery (Urology); and the
Department of Physiology, University of Utah
School of Medicine, Salt Lake City, Utah.
| Correspondence to: Douglas T. Carrell, Associate Professor of Surgery (Urology), Physiology and OB-GYN, Director of IVF and Andrology Laboratories, University of Utah School of Medicine, 675 Arapeen Dr, Suite 205, Salt Lake City, Utah 84108 (e-mail: douglas.carrell{at}hsc.utah.edu). |
| Received for publication April 4, 2006; accepted for publication June 1, 2006. |
Male factors alone constitute 25%–30% of all cases of infertility, and they contribute to another 30% in combination with female factors. Known etiologies of male infertility include cryptorchidism, testicular torsion or trauma, varicocele, seminal tract infections, anti-sperm antibodies, hypogonadotropic hypogonadism, gonadal dysgenesis, and obstruction of the reproductive channels (Oehninger, 2000). Obesity was recently proposed for addition to this list (Jensen et al, 2004). Thus, obesity is a chronic disease resulting in compromised physical and psychological well-being, and it may contribute to reduced fecundity as well.
It is known that the incidence of obesity is reaching epidemic levels in the western world. For example, in the United States, the incidence of obesity increased from 12% to 17.9% between 1991 and 1998. In the same period, the incidence of male obesity increased from 11.7% to 17.9% (Mokdad et al, 1999). Recently, the prevalence of male obesity in the US was reported to be 30.6% (Hedley et al, 2004).
It is possible that the increasing prevalence of overweight and obesity accounts for a portion of the trend, albeit a widely debated one, of decreasing sperm counts over recent decades. Although complicated by varying sample sizes and methodologies for the assembled data, it has been estimated that sperm counts have been decreasing by as much as 1.5% each year in the United States, a finding similar to those for other Western countries and not present in other regions where obesity is less prevalent (Swan et al, 2000). These findings suggest a possible link between life style changes, obesity, semen quality, and possibly male fertility (Jensen et al, 2004).
Obesity and Pubertal Sexual Maturation
Obesity in adolescent girls is associated with increased height and earlier
pubertal development (Dunger et al,
2005). There is some evidence that development of sexual
characteristics takes place earlier as well
(Adair and Gordon-Larsen,
2001). In males, the relationship of body weight with sexual
development seems to be reversed. Wang et al studied a sample of 1501 boys and
1520 girls aged 8 to 14 years. They found that the prevalence of obesity was
lower in early-maturing boys and higher in early-maturing girls, compared with
the group who had average or late sexual maturity
(Wang, 2002). This finding was
challenged later by Laron, who found no significant difference in the
indicators of sexual maturation between obese and nonobese adolescents in both
genders; however, the number of patients in this study was small
(Laron, 2004).
On the other hand, pubertal development was shown to negatively influence the secretion of adiponectin by adipose tissue. Adiponectin has mainly antidiabetic and antiatherogenic effects. In a multiple regression model adiponectin levels in males were shown to be negatively correlated to the stage of pubertal development (r2 = .206, P < .001), body mass index (BMI) (r2 = .034, P = .021), and testosterone levels (r2 = .039). This analysis demonstrated that the decrease in adiponectin levels throughout pubertal development stages is more pronounced in obese males than controls (Bottner et al, 2004).
Hormonal Profile in Adult Obese Males
Obese males usually express a characteristic hormonal profile described as
"hyperestrogenic hypogonadotropic hypogonadism." In fact, both
total and free blood testosterone levels are shown to be decreased in obese
men. Total body fat, intra-abdominal fat, and subcutaneous fat have all been
associated with low levels of total and free testosterone
(Strain et al, 1982;
Haffner et al, 1993;
Tsai et al, 2004). It appears
that central obesity, in particular, is associated with a decrease in
circulating androgen levels. The decrease in androgen levels is proportional
to the degree of obesity (Giagulli et al,
1994). In obese males, adrenal androgens are diminished as well
(Tchernof et al,
1995).
|
The origin of hypoandrogenism in obese males is multifactorial (Table). It
is primarily attributable to an increase in circulating estrogens that appear
to result in relative hypogonadotropism, although the diminished levels of sex
hormone-binding globulin (SHBG) in obese individuals will by itself result in
reduced total testosterone levels, even in the face of unchanged production.
In fact, weight correlates negatively with blood testosterone levels and
testosterone/estradiol ratio (Fejes et al,
2006). Both estrone and estradiol are increased in obese males
compared to controls (Schneider et al,
1979). The aromatization of C19 androgens like testosterone and
androstenedione is a key step in estrogen biosynthesis and is catalyzed by the
aromatase enzyme, a product of the CYP19 gene. It is believed that
the increase in estrogens in obese males is due to increased conversion of
adrenal and testicular androgens owing to the increase in available aromatase
enzyme in the fatty tissue (de Boer et al,
2005). Estrogen production by adipose tissue is dependent on the
availability of androgenic precursors in the circulation
(Simpson et al, 1999).
Estrogens are biologically active at much lower concentrations and production
rates than androgens (testosterone production in adult males is several mg per
day, whereas estradiol production in women averages 100 µg per day); thus
small increases in aromatization of androgens can result in changes in
estrogen levels that are substantial in relation to the range of normal
circulating levels. Increased circulating estrogen levels resulting from
increased peripheral conversion among the obese may therefore inappropriately
enhance negative feedback on gonadotropin secretion. Estradiol has significant
biologic activity in the hypothalamus and the pituitary. Estrogen receptors
(ER
and ERß) are present in several hypothalamic nuclei and in
pituitary gonadotropes, indicating that estrogen modulates the activity of
hypothalamus-pituitary axis. Estrogen acts on the hypothalamus to affect
gonadotropin-releasing hormone (GnRH) pulses and at the pituitary level to
regulate gonadotropin (follicle-stimulating hormone [FSH] and luteinizing
hormone [LH]) secretion (Akingbemi,
2005). In severe obesity, pituitary gonadotropin secretion appears
suppressed with normal or decreased levels of LH in the presence of decreased
levels of testosterone (Giagulli et al,
1994). Because aromatization also occurs in the hypothalamus
itself, precise dissection of the contribution of increases in circulating
estradiol associated with obesity to overall negative steroidal feedback on
pituitary gonadotropin secretion is problematic.
The hypothesis that elevated estrogen plays an important role in the androgen abnormalities in obesity is strongly supported by observations of the effect of the aromatase inhibitor letrozole on obese men. Among 10 severely obese men with markedly low testosterone levels and clinical symptoms of hypogonadism, letrozole administration for 6 weeks increased testosterone levels more than 3-fold from a mean baseline of 7.5 ± 1 nmol/l (mean ± SE) while diminishing circulating estradiol from 120 ± 20 to 70 ± 9 pmol/l (mean ± SE). Changes in levels in both steroids were highly statistically significant (P < .001), and were not accompanied by changes in SHBG. A 3-fold statistically significant increase in both LH and FSH occurred during treatment as well (de Boer et al, 2005). Unfortunately, this study did not include data on measures of semen quality. Raman and Schlegel reported a tripling of the testosterone-estradiol ratio among 16 overweight infertile men treated with the aromatase inhibitor anastrozole but did not report changes in semen parameters for this subgroup of a study cohort that included men with other known causes for male infertility, including varicocele and Klinfelter syndrome (Raman and Schlegel, 2002). The results of this suggest also that aromatase inhibition increases in testosterone levels and decreases in estradiol in nonobese males, such that the "correction" of hypoandrogenism in obese males during aromatase inhibition is an extension of a general effect of such medications. To the extent that lower circulating testosterone levels reflect decreased testicular testosterone production, lower intratesticular testosterone levels would be expected as well.
Insulin resistance, a predisposition of obesity, has also been reported to be associated with low testosterone levels. Age-adjusted fasting insulin and C-peptide were shown to be inversely correlated to total and free testosterone in men (Tsai et al, 2004). This association is confounded by the independent relation between SHBG and insulin resistance (Stellato et al, 2000). However, after adjusting for SHBG levels, low testosterone levels remain correlated with insulin resistance (Tsai et al, 2004). The direction of this association is not clear. In a recent review, men with type 2 diabetes had a mean decrease of testosterone levels of (–71.5 ng/dl, 95% CI: –116.4 to –26.8 ng/dl) compared to controls. Moreover, the analysis of prospective studies showed that the risk of developing type 2 diabetes was 42% (RR = 0.58, 95% CI: 0.39 to 0.87) lower in men with high testosterone levels (range, 449.6–605.2 ng/dl) than men with low testosterone levels (range 213.2–446.7 ng/dl) (Ding et al, 2006). Whether the association between glucose intolerance and low androgen levels is an independent relation remains a matter of debate, as any association between hyperinsulism and hypoandrogenism is confounded by the association of obesity with hyperinsulism and insulin resistance.
The third suggested cause of hypoandrogenism in obese males is sleep apnea. Patients with sleep apnea often have fragmented sleep course due to repetitive episodes of upper airway obstructions and hypoxia followed by arousal (Young et al, 2004). It has been demonstrated that patients with fragmented sleep have a blunted nocturnal rise of testosterone (Luboshitzky et al, 2001). Patients with obstructive sleep apnea have lower mean testosterone and LH values compared to both young and middle-aged controls. Morning testosterone levels were also found to be lower in patients with obstructive sleep apnea (Luboshitzky et al, 2005). Finally, in patients with obstructive sleep apnea, weight loss increases testosterone levels (Semple et al, 1984). These alterations in testosterone levels are likely to contribute to hypogonadism in a number of obese males. This observation is confounded by obesity, such that an independent effect on testosterone levels of sleep apnea separate from obesity requires further confirmation.
It is mandatory to mention leptin in the context of obesity and infertility. The role of leptin in reproduction was discovered in ob–/ob– mice. The lack of obesity (ob) gene encoding for leptin caused obesity and infertility in both male and female mice. Leptin administration in leptin deficient ob–/ob– mice restored fertility (Chehab et al, 1996). Obesity is associated with increased levels of circulating leptin, since white adipose tissue is the main site of leptin synthesis (Margetic et al, 2002). The effect of excess leptin on male reproduction is unknown. In hypogonadal men, testosterone substitution normalized elevated serum leptin levels (Jockenhovel et al, 1997). Leptin effects on reproduction are largely thought to be central, altering the hypothalamic pituitary axis (Margetic et al, 2002). Recent discovery of leptin in semen suggests a peripheral function as well (Aquila et al, 2005).
Obesity and Spermatogenesis
Body mass index is associated with alterations in sperm parameters in
several reports. In a recent study investigating factors associated with semen
quality among couples who visited an assisted reproduction clinic, the
prevalence of obesity among men with infertility (defined as at least 2
findings among density less than 10 million, total count less than 20 million,
motility less than 30%) was 3 times greater than among male partners of
couples with idiopathic or female factor infertility. Groups were small in
this study, and specific etiologies for lower sperm parameters among obese
subjects were not described. Among the 47 men in this study with normal semen
parameters at enrollment, but not among men with male infertility, sperm
density and total count showed a statistically significant negative
association with increasing BMI
(Magnusdottir et al, 2005).
Among a sample of 1558 Danish military recruits, several semen parameters were
correlated with body mass index, with less favorable values reflecting
spermatogenesis observed in individuals with either above or below the BMI
range of 20–25 kg/m2
(Jensen et al, 2004). After
correction for multiple factors, including exposures, illnesses, and
abstinence period prior to sample collection, sperm concentration and total
count per ejaculate among men with BMI. 25 kg/m2 were reduced by
26.1% and 23.9%, respectively, when compared to the reference group with BMI
between 20 and 25 kg/m2. The frequency of sperm density less than
20 million/ml was 29% among the overweight men compared to 21.7% in the normal
weight reference group. Reductions in these measures were similar among the
subjects with BMI less than 20 kg/m2, such that total sperm count
and sperm concentration exhibited an inverted U-shaped distribution relative
to BMI. The endocrine findings in the heavy and thin men trended in opposite
directions relative to the reference BMI group in several instances, such that
total testosterone, FSH, inhibin B, and SHBG were lower and estradiol higher
in the overweight group relative to the reference group, while the reverse of
these observations obtained for the leaner men. Thus, putative endocrine
mechanisms underlying the apparent reduction in spermatogenesis, if any, among
the lean and overweight subgroups can be inferred to be quite different. In a
study of normozoospermic partners in an infertile population, sperm
concentration was reduced among men with BMI greater than 30 compared to
leaner members of the study group
(Koloszar et al, 2005). Kort
et al described the relation between sperm parameters and BMI in a generally
overweight selection of subjects. An index of semen quality appeared to
exhibit a decline with increasing BMI, as did the number of normal sperm per
ejaculate. In his study, the total number of normal spermatozoa correlated
negatively with body mass index in 520 semen analyses. The total number of
normal motile spermatozoa differed statistically according to weight group
(BMI < 25 kg/m2 = 18.6 x 106; BMI 
25
kg/m2 and < 30 kg/m2 = 3.6 x 106;
and BMI 30 = 0.7 x 106, P < .05, ANOVA)
(Kort et al, 2005). The
relationship between BMI and sperm parameters was not preserved when obesity
was expressed as waist/hip ratio. An absence of correlation with semen
parameters with waist/hip ratio has been reported elsewhere
(Fejes et al, 2005). A recent
report showed that bariatric surgery may result in male infertility. Six
severely obese men with at least 1 previous child were found to be azoospermic
after Roux-en-Y gastric bypass operation (di Frega et al, 2004).
To the extent that obesity is causal of diminished sperm count and sperm density, such findings may relate to endocrine abnormalities of obese males. Where lower total and free levels of testosterone are found, it can be inferred (though it has not been shown) that these levels reflect decreased testicular testosterone production, and therefore lower intratesticular testosterone levels would be expected as well. Intratesticular testosterone levels (normally 100-fold greater than circulating concentrations) are correlated with spermatogenesis (Coviello et al, 2004; Coviello et al, 2005; Jarow and Zirkin, 2005; Matthiesson et al, 2005). It is not known whether the modest reductions in testosterone levels associated with obesity are accompanied by a reduction in intratesticular testosterone concentrations sufficient to explain the reductions in sperm count that have been observed in obese subjects. Although the observations of Raman and Schlegel that effecting an increase in low testosterone-estradiol ratios with aromatase inhibition is accompanied by improvement in semen parameters during aromatase inhibition hints that this may be so, it is clear that this issue requires further investigation (Raman and Schlegel, 2002). Moreover, it is important to note evidence that diminished intratesticular testosterone concentrations alone, absent concomitant suppression of FSH, may be insufficient for effective suppression of spermatogenesis (Narula et al, 2002).
The consensus observation that obesity and overweight are associated with a reduction in semen quality must be qualified by the observation that the studies cited here demonstrate only trends, and many overweight and obese subjects have consistently been shown to exhibit normal semen quality. Moreover, it is important to consider the possibility that nutritional or lifestyle factors associated with overweight and obesity, rather than a direct effect of obesity per se, account for these frequently observed associations. In addition, it is notable that decreased sperm quality (morphology) has not been found in men with higher BMIs (Jensen et al, 2004; Magnusdottir et al, 2005). However, there is consistent enthusiasm in the literature, with considerable circumstantial support, for the hypothesis that alterations of sperm parameters associated with obesity can be attributed to inappropriate suppression of the hypothalamic-pituitary-gonadal axis by elevated estrogens derived from peripheral aromatization, and resulting decreased testosterone production reflected in low levels of circulating testosterone and intratesticular testosterone (Table).
The role of estrogen in male reproductive health was highlighted with the growing public concerns that exposures to environmental chemicals with estrogenic activity may impact human reproductive health (Oliva et al, 2001). Obese men have been shown to exhibit higher levels of circulating estradiol and/or elevated estradiol/testosterone ratios in multiple studies (Schneider et al, 1979; Jensen, 2004; Fejes, 2006). Estrogens may affect spermatogenesis directly within the testis as well as by alterations in gonadotropin secretion by the pituitary. Excess estrogen has a direct deleterious effect on spermatogenesis in animal models (Goyal et al, 2003). However, elevated circulating estradiol owing to increased peripheral aromatization in obesity may not importantly affect intratesticular estrogen concentrations. It is true, also, that elevated circulating estrogen levels, as seen among obese men, have not specifically been linked to infertility. If there is an obesity-estrogen link, it may lie in the observation that obesity increases the accumulation and levels of estrogenic and endocrine disrupting environmental toxins that can affect fertility (Magnusdottir et al, 2005). The evidence cited thus far leads to the conclusion that obesity negatively influences sperm production (concentrations and total count), though further studies will be required to settle whether this effect is convincingly a cause for infertility attributable to obesity by itself.
To the extent that reduced total sperm counts and sperm concentration result from obesity, it is certainly true also that fertility does correlate with total count and sperm density. It has been shown that altered spermatogenesis and abnormal sperm parameters are correlated to subfertiltiy and infertility of a couple. Slama et al demonstrated that the ratio of conception for subjects <20 x 106/ml sperm compared to those >20 x 106/ml was 0.68 (95% CI: 0.52–0.91). This study also demonstrated that factors in addition to sperm density, such as morphology, may be important to fertility, and in this regard evidence that obesity adversely affects sperm morphology is lacking (Slama et al, 2002). In couples trying to conceive for the first time, the probability of succeeding increases with sperm count up to 40 million/mL (Bonde et al 1998). Most of the previously discussed alterations in the physiology of obese males can affect their reproductive potential and lead to subfertility or infertility.
Obesity and Erectile Dysfunction
The association between obesity and erectile dysfunction can frequently be
shown to comprise another mechanism by which obesity may contribute to
infertility. Erectile dysfunction is defined as the persistent or recurrent
inability to achieve or maintain an erection sufficient for satisfactory
sexual intercourse. In men reporting symptoms of erectile dysfunction, 79% of
the subjects are found to be overweight or obese
(Feldman et al, 2000). The
relation between obesity and erectile dysfunction can be explained in part by
the elevated levels of several proinflammatory cytokines in obese individuals.
These markers of inflammation are positively associated with endothelial
dysfunction that is linked directly to male erectile dysfunction through the
nitric oxide pathway (Sullivan et al,
1999). It is not clear if the association is due to an independent
effect or due to cardiovascular risk factors that are commonly associated with
obesity (Chung et al, 1999). In
fact, well-recognized risk factors for cardiovascular diseases, such as
smoking, diabetes, hypertension, and dyslipidemia, have strong epidemiological
links with erectile dysfunction (Feldman
et al, 2000). Hypoandrogenism contributes to the sexual
dysfunction found in obese males (Seftel,
2005). Whether obesity is coupled with erectile dysfunction
independently or through cardiovascular risk factors or hypoandrogenism, it is
evident that obese men have a higher incidence of erectile dysfunction that
affects their sexual life and fertility. In a randomized study, obese men who
received detailed advice about how to achieve a loss of 10% or more in their
total body weight by reducing caloric intake and increasing their level of
physical activity had a higher rate of weight loss and improvement in erectile
dysfunction than controls (Esposito et al,
2004).
It is known that erectile dysfunction is associated with infertility. In a recent study where participants answered the Sexual Health Inventory for Men questionnaire, 27% of infertile men reported an abnormal score (erectile dysfunction) compared to 11% of the control fertile group (O'Brien et al, 2005). In a survey of health professionals, obesity was associated with a 1.3 relative risk for erectile dysfunction (Bacon et al, 2003).
Genetic Causes of Obesity and Male Infertility
Recognition of the possibility that infertility found in an obese subject
may relate to underlying undiagnosed genetic or developmental abnormalities
that adversely affect spermatogenesis independently of obesity is important
both to researchers and clinicians.
Genetic factors that contribute to obesity are often complex and rely on the interaction of several genes in association with environmental factors such as nutrition and activity levels (Boutin and Froguel, 2001). This multifactorial mechanism explains the majority of cases of common obesity. However, there are conditions where obesity and infertility can result from a defined chromosomal or genetic defect. These defined genetic causes are rare and invoke measures and mechanisms beyond the primary effects of obesity itself on male infertility. Detection of such aberrations allows couples to be informed about the potential to transmit genetic abnormalities to their offspring. Klinfelter syndrome is the most common chromosomal disease causing infertility in men. This syndrome results from a numerical aberration in sex chromosome. The typical karyotype is 47,XXY. The diagnosis is confirmed by a karyotype analysis of blood lymphocytes (Kamischke, 2003). The numerical chromosome aberrations in this syndrome are due to nondisjunction predominantly during meiotic divisions occurring in germ-cell development or less frequently in early embryonic mitotic cell divisions. Phenotypically, patients can be obese with feminine pattern of fat distribution and gynecomastia; however, obesity is not a consistent feature. They have tall stature, small testis, hypogonadism, and severe alteration in spermatogenesis resulting in severe oligozoospermia or azoospermia (Diemer and Desjardins, 1999). In adult patients, about 70% complain of decreased libido and impotence. It is not known if the defect in the testis arises from an intrinsic problem in germ cells or is due to lack of support from the Sertoli cells (Lanfranco, 2004).
Prader-Willi syndrome is characterized by diminished fetal activity,
hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism,
and morbid obesity. It is the most common syndromal cause of human obesity
(Farooqi, 2005). This is an
imprinting disease caused by the absence of the paternal segment 15q11.2-q12,
either through deletion (75%) or through loss of the entire paternal
chromosome with presence of 2 maternal homologues (22%). Prometaphase banding
examination can visualize deletions of chromosome 15 that account for
70%–80% of cases (Goldstone,
2004). Cryptorchidism is found in 80%–100% of patients with
this syndrome (Suzuki et al,
2002). Testicular biopsy shows undifferentiated Leydig cells and
arrested spermatogenesis at the late spermatid level
(Diemer and Desjardins,
1999).
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Other genetic entities resulting in male obesity and infertility are the Laurence-Moon and Bardet-Biedl syndromes. These are rare autosomal recessive disorders. The differentiation between these 2 syndromes is not unanimous. For many they constitute different expressions of a single entity "Laurence-Moon-(Bardet-)Biedl syndrome" (Yamada et al, 2000). They include common multiple defects, including mental retardation, retinal pigmentary dystrophy, hypogonadism, and morbid obesity (Mohsin et al, 2003). Polydactylia is found mainly in Laurence-Moon syndrome. Known genetic abnormalities include defects in the 4 loci BBS1 to BBS4. Infertility is frequent, but some patients have normal testicular function and spermatogenesis (Diemer and Desjardins, 1999).
Summary
The parallel change in obesity and sperm count suggests a potential link
between obesity and male fertility. Obesity is associated with altered
spermatogenesis and erectile dysfunction. The altered spermatogenesis is
mainly due to hypoandrogenism and the deleterious effect of increased levels
of estrogens. All these factors can affect the ability of a male to
participate in the conception of a child (Figure). This review is a call for
more focused studies to unveil the extent of the correlation between obesity
and decreased sperm count and to quantify the contribution of obesity to male
infertility. In the absence of clinical trials, treatment options for obese
infertile males are limited and should be targeted toward reversing the
hormonal profile and the erectile dysfunction.
Footnotes
DOI: 10.2164/jandrol.106.000125
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