Abstract
Whilst many multiparous women are obese (body mass index >30 kg/m2), obesity has been associated with impaired fecundity; however, the mechanism which links obesity to reduced fertility remains to be fully elucidated. Obese women, particularly those with central obesity, are less likely to conceive per cycle. Obese women suffer perturbations to the hypothalamic–pituitary–ovarian axis, menstrual cycle disturbance and are up to three times more likely to suffer oligo-/anovulation. A fine hormonal balance regulates follicular development and oocyte maturation, and it has been observed that obesity can alter the hormonal milieu. Leptin, a hormone produced by adipocytes, is elevated in obese women, and raised leptin has been associated with impaired fecundity. Obesity impairs ovulation but has also been observed to detrimentally affect endometrial development and implantation. The expression of polycystic ovary syndrome (PCOS) is regulated, in part, by weight, and so obese women with PCOS often have a more severe phenotype and experience more subfertility. Obesity also impairs the response of women to assisted conception treatments. Weight loss through lifestyle modification or bariatric surgery has been demonstrated to restore menstrual cyclicity and ovulation and improve the likelihood of conception. In this article, we will discuss the effect of obesity upon key reproductive mechanisms and its relation to fertility treatments.
The adverse effects of obesity on conception and implantation
Obesity is an increasingly prevalent health burden upon modern society. Most obese women are not infertile; however, obesity and its negative impact upon fecundity and fertility are well documented. Obese women are three times more likely to suffer infertility than women with a normal body mass index (BMI; Rich-Edwards et al. 1994). Obese women experience impaired fecundity both in natural and assisted conception cycles (Zaadstra et al. 1993, Crosignani et al. 1994). The mechanism through which its effect is exerted is more controversial. Obesity is characterised by excess lipid storage. Definitions of obesity can vary, but the most widely accepted definition adheres to the WHO BMI (kg/m2) criteria. A person is obese if his/her BMI is ≥30 kg/m2. There are degrees of obesity: class 1 (30.0–34.9 kg/m2), class 2 (35.0–39.9 kg/m2) and class 3 (≥40 kg/m2). Alternative, although less commonly used, parameters for the assessment of obesity include waist circumference and waist:hip ratio (WHR). A waist circumference >80 cm in women is an accepted indicator of visceral fat accumulation (Tamer Erel & Senturk 2009).
Population studies demonstrate an increasing prevalence of overweight and obese women, and maternal obesity detected an increase from 9.9 to 16.0% from 1990 to 2005 (Lewis 2007, Heslehurst et al. 2007). It has been proposed that obesity impairs fertility through an effect upon the control of ovulation, oocyte development, embryo development, endometrial development, implantation and pregnancy loss. This article aims to summarise the current understanding of how obesity might affect these processes in the context of natural and assisted conception.
Obesity and impaired reproductive potential
The negative effect of obesity upon fertility was described by Hippocrates, who wrote in his Essay on the Scythians ‘People of such constitution cannot be prolific …fatness and flabbiness are to blame. The womb is unable to receive the semen and they menstruate infrequently and little’ (Lloyd et al. 1978). Putative causes for conception delay in obese women can conceptually be categorised as pathophysiological, psychosocial and sociobiological. The bulk of this article will pertain to the pathophysiological aspects. However, the psychosocial and sociobiological aspects will touched upon at the end of this section.
Several population-based studies have shown subfecundity in overweight and obese women. The Nurses' Health Study compared 2527 married nulliparous women with anovulatory subfertility of 1 year with 46 718 married multiparous women with no history of subfertility. Multivariate analysis determined the relative risk of infertility for each BMI category, and the relative risks were reported as follows: 1.2 (BMI <16 kg/m2), 1.1 (BMI 16–17.9 kg/m2), 1.0 (BMI 18–19.9 kg/m2), 1.0 (referent BMI 20–21.9 kg/m2), 1.1 (BMI 22–23.9 kg/m2), 1.3 (BMI 24–25.9 kg/m2), 1.7 (BMI 26–27.9 kg/m2), 2.4 (BMI 28–29.9 kg/m2), 2.7 (BMI 30–31.9 kg/m2) and 2.7 (BMI ≥32 kg/m2). Therefore, above 23.9, the relative risk of subfertility was statistically significantly elevated (Rich-Edwards et al. 1994). Similarly, Grodstein et al. (1994) demonstrated a higher prevalence of anovulatory subfertility among the obese women. They compared 597 anovulatory women with 1695 primiparous controls; the relative risk of anovulatory subfertility in the obese women (defined in this study as BMI >27 kg/m2) was 3.1 (95% confidence interval (CI) 2.2–4.4) when compared to those with a normal BMI (20–24.9 kg/m2; Grodstein et al. 1994). A similar effect has been demonstrated in an observational study of 2112 consecutive pregnant women to investigate lifestyle factors that might impair fecundity, and a BMI >25 kg/m2 was significantly correlated with a prolongation of time to pregnancy (Hassan & Killick 2004).
Body fat distribution also has important reproductive ramifications, and central obesity as defined by an increased waist circumference or by an elevated WHR has been observed to have a negative impact on fecundity. A Dutch study monitored the effect of obesity upon fecundity in a donor insemination programme; 500 women were prospectively monitored. They observed that a 0.1 unit increase in WHR led to a 30% decrease in probability of conception per cycle (hazard ratio 0.706; 95% CI 0.562–0.887; Zaadstra et al. 1993).
Obesity can exert effects upon the hypothalamic–pituitary–ovarian (HPO) axis and as such disturb menstrual cyclicity and ovulation. A large questionnaire study of 26 638 women demonstrated that menstrual cycle irregularity and anovulation were correlated with being overweight or obese. Indeed, the grossly obese women had a rate of menstrual disturbance 3.1 times that of women with normal weight (Hartz et al. 1979). The effect of obesity (childhood and adult) on menstrual cyclicity was demonstrated in a longitudinal study of 5799 British women born in 1958. Obesity in childhood (age 7 years) and in early adulthood (age 23 years) was predictive of increased chance of current menstrual cycle disturbance (odds ratio (OR) 1.59 and 1.75 respectively). Likewise, when young obese women (age 23 years) were compared to women with normal weight, they were less likely to conceive, OR=0.69 (Lake et al. 1997). Whilst several studies have proposed disturbance to the HPO axis as a key pathophysiological factor in subfecundity in the obese women, impaired fertility has been demonstrated in obese women with normal menstrual cyclicity. A retrospective analysis of US data collected as part of the Collaborative Perinatal Project demonstrated a reduced fecundity for overweight (BMI 25.0–29.9 kg/m2; OR=0.92, 95% CI 0.84–1.01) and obese (BMI ≥30 kg/m2) women (OR=0.82, 95% CI 0.72–0.95). Fecundity remained reduced in overweight and obese women when only women with normal menstrual cycles were considered (Gesink Law et al. 2007).
Weight loss programmes have been observed to restore normal menstrual cyclicity, and an Australian group demonstrated the important role of weight loss in the management of obese anovulatory infertile women (Clark et al. 1995). Obese women who had not responded to clomiphene citrate were enrolled into a 6-month programme of weight loss by exercise and dietary change; the average weight loss was 6.3 kg. Resumption of ovulation was observed in 12 of the 13 women, and remarkably, 11 of these conceived (5 natural conceptions and 6 who were now responsive to ovulation induction with clomiphene citrate). In a follow-up study by the same group, data for 67 of 87 women who were enrolled in a weight loss programme were analysed. As previously, an encouraging proportion demonstrated resumption of natural ovulation (60 of 67) and 52 pregnancies (45 live births; Clark et al. 1998). In the same study, the cost effectiveness of a provider-led weight-loss programme was demonstrated, and it was calculated that the cost per baby before the programme was A$275 000, whereas following the programme, the cost per baby was estimated to be A$4600. This reduction was in part due to the reduction in reliance on assisted conception techniques and increased efficacy should they be required. Hollmann et al. (1996) demonstrated a significant increase in eumenorrhoeic women, after a cohort of obese women followed a weight-reducing diet. More recently, a study of 143 obese women with polycystic ovary syndrome (PCOS) has demonstrated that weight loss through lifestyle changes alone significantly improved menstrual frequency (Tang et al. 2006).
Obese women are more likely to experience pregnancy loss once pregnant, and elevated miscarriage rates are seen following natural conception, ovulation induction and assisted conception. A retrospective analysis of women with PCOS undergoing ovulation induction demonstrated an increased frequency of miscarriage among obese women (BMI >28 kg/m2) when compared to normative controls (60 vs 27%, P<0.05; Hamilton-Fairley et al. 1992). A retrospective analysis of 5019 IVF/ICSI cycles in 2660 women in a Norwegian clinic observed a linear association between higher BMI and early pregnancy loss (<6 weeks) and miscarriage (6–12 weeks). The OR for early pregnancy loss was 1.69 (95% CI 1.13–2.51, P=0.003) in obese women (BMI >30 kg/m2) compared with women with normal weight (Fedorcsak et al. 2004). A recent meta-analysis demonstrated an increased risk of miscarriage among obese women (BMI >30 kg/m2) undergoing assisted conception (IVF/ICSI; OR=1.53, 95% CI 1.27–1.84; Maheshwari et al. 2007). A further meta-analysis also found that patients with a BMI >25 kg/m2 were found to have a significantly elevated odds of miscarriage regardless of the mode of conception (OR=1.67, 95% CI 1.25–2.25; Metwally et al. 2008).
Obese women may have reduced fecundity due to psychosocial and sociobiological factors. Prolonged time to conception could in part be secondary to a comparative reduction in sexual frequency. It has been demonstrated that obese people do not have sexual intercourse as frequently as thinner people, even if they have a co-habiting partner (Brody 2004). It was suggested that the decreased sex drive in the obese women may be derived from decreased dopamine activity and increased serotonin levels in the brain secondary to overeating. Additionally, chronic fat or sugar consumption could have psychopharmacological effects, relabelling sexual desire as a cue to eat (Brody 2004). Obese women are more likely to experience sexual dysfunction (Trischitta 2003). If obese women experience subfecundity due to pathophysiological factors, such sociobiological factors that contribute to a decline in coital frequency only serve to prolong the time to conception in this group of women.
Obesity: its effect upon the embryo, uterus and ovaries
The effect that obesity exerts upon fecundity can be categorised as hormonal, ovulatory/ovarian and endometrial. These will be discussed in turn below.
Obesity and its effect on regulatory hormones
A complex hormonal milieu works in balance to control the menstrual cycle, ovulation and development of the endometrium. Obesity has been demonstrated to perturb this balance via several direct and indirect mechanisms. Adipose tissue has been shown to disturb sex hormone secretion and bioavailability. Indirectly, obesity exerts its effect via leptin, insulin and the adipokines. Each will be considered below.
Sex steroids
Adipose tissue is an important site of steroid production and metabolism, conversion of androgens to oestrogens (aromatase activity), oestradiol (OE2) to oestrone and dihydroepiandrosterone to androstenediol (17β-hydroxysteroid dehydrogenase activity; Norman & Clark 1998). Additionally, adipose tissue is implicated in the control of the bioavailability through effects upon transport proteins and the sequestration of lipid-soluble steroid hormones in adipose tissue (Pasquali & Gambineri 2006), leading to an inflated steroid pool in obese women when compared with normal-weight controls (Gambineri et al. 2002) and altered delivery of androgens and oestrogens to their target organs. Serum concentration of sex hormone-binding globulin (SHBG) is lower in obese women. Serum SHBG concentration is increased by oestrogens, iodothyronines and GH; and decreased by insulin and androgens (von Schoultz & Carlstrom 1989). The net balance of regulatory disturbance in obesity leads to a reduction in the level of SHBG. Distribution of body fat has a significant impact upon serum SHBG concentration, with central obesity inducing a more profound reduction in serum concentrations. Serum SHBG is inversely proportional to WHR. Indeed, age- and weight-matched controls with peripheral obesity have comparatively higher serum SHBG concentrations than their centripetally obese counterparts (Pasquali & Casimirri 1993, Pasquali & Gambineri 2006). Elevated circulating levels of insulin are found in central obesity leading to a reduction in hepatic synthesis of SHBG (Norman & Clark 1998). A reduction in SHBG leads to elevated circulating free sex steroids such as testosterone, dihydrotestosterone and androstenediol, which leads to an increase in metabolic clearance of these hormones. There is, however, a compensatory increase in androgen synthesis, which creates a condition of relative functional hyperandrogenism. This is especially pronounced in those with central obesity. Indeed, it has been demonstrated that a reduction in visceral obesity is associated with a concomitant elevation in SHBG concentration and reduction in androgenicity (Leenen et al. 1994). This relative hyperandrogenaemia seen in obese women may have a pathophysiological effect upon ovarian function and contribute towards menstrual disturbance and oligo-anovulation.
LH
Hypersecretion of LH and an increased LH:FSH ratio have been demonstrated to be unfavourable for folliculogenesis; both conditions can be observed in obese infertile patients (Yen et al. 1970, Balen 1993, Butzow et al. 2000). Weight loss has been demonstrated to lead to a reduction in LH levels in patients with PCOS but does not alter the pulsatility of LH secretion (Guzick et al. 1994, Huber-Buchholz et al. 1999, Butzow et al. 2000). However, in lean women with PCOS, elevated LH is a major pathophysiological feature that leads to hyperandrogenaemia. In contrast, in obese women with PCOS, it is elevated insulin resistance that is the main driver of hyperandrogenism and its consequent effect upon follicular development and ovulation (Balen 2008, Balen et al. 2009).
Insulin
The ovary is a target organ for insulin; it acts via the insulin receptor and via the insulin-like growth factor 1 (IGF1) receptor. These receptors have been detected in granulosa, theca and ovarian stromal tissue in humans. Insulin stimulates ovarian steroidogenesis in theca and granulosa cells, and enhances the stimulatory effect of LH through LH receptor upregulation (Poretsky et al. 1999). Insulin also acts at the level of the pituitary, where it may enhance the sensitivity of the gonadotroph cells to the action of GNRH, further enhancing the stimulation of ovarian steroidogenesis (Poretsky et al. 1999). Further to this, insulin modulates the bioavailability of the sex steroids via inhibition of hepatic SHBG synthesis, and also inhibits hepatic and ovarian synthesis of IGF binding protein 1 (IGFBP1; Pasquali & Gambineri 2006). Obesity, especially central obesity, induces a state of hyperinsulinaemia and insulin resistance. Obesity-mediated insulin resistance has been related to free fatty acids, leptin and tumour necrosis factor-α (TNF) via modulation of receptor-mediated signalling (Matthaei et al. 2000).
In response to systemic insulin resistance, there is a compensatory increase in insulin secretion. The altered insulin metabolism (insulin resistance and hyperinsulinaemia) leads to reduced SHBG, hyperandrogenaemia and perturbation to the functionality of the IGF system, thereby increasing the likelihood of menstrual and ovulatory disturbance in obese women. Indeed, as proof of concept, weight loss of 5% or more in obese subjects has been demonstrated to favourably change insulin (decrease), IGF (decrease), SHBG (increase) and menstrual cyclicity in women with PCOS (Kiddy et al. 1989, 1992, Pettigrew & Hamilton-Fairley 1997, Butzow et al. 2000). Similarly, it has been demonstrated in obese women who lose weight and subsequently become ovulatory that weight loss is associated with a reduction in insulin resistance and central adiposity (Clark et al. 1995).
Leptin
Leptin is a 16 kDa messenger protein secreted by adipocytes, a product of the LEP (OB) gene. Its secretion is pulsatile, ∼32 pulses per 24 h (Licinio et al. 1997), secretion increasing with food intake and decreasing during starvation. Leptin is a key signalling protein, relaying the magnitude of the peripheral energy stores to the brain (hypothalamus), and it has metabolic and reproductive functions (Norman & Clark 1998, Messinis & Milingos 1999, Pasquali & Gambineri 2006). In the periphery, leptin has a role in fat metabolism and an effect upon glucose metabolism through an antagonistic relationship with insulin and reduced pancreatic secretion. Centrally, leptin signals body energy stores. Acting upon the hypothalamus, leptin induces a reduction in appetite and increase in energy expenditure (Messinis & Milingos 1999). Leptin has a regulatory role in reproductive function; it has stimulatory effects on the HPO axis at normal serum concentrations but can have inhibitory effects upon folliculogenesis and its control when levels are elevated, such as that seen during obesity (Tamer Erel & Senturk 2009). See Table 1 for a summary of the observed actions of leptin upon the reproductive system in obesity.
Putative reproductive effects of leptin in obesity.
| Putative effects of leptin in obesity |
|---|
| Dysregulation of GNRH secretiona |
| Altered ovarian steroidogenesisb |
| Dysregulation of folliculogenesisc |
| Dysregulation of perifollicular blood flowd |
Leptin exerts an effect upon the HPO axis at central and gonadal levels. Some investigators have found serum leptin concentrations to vary subtly during the menstrual cycle, with a subtle rise during the follicular phase and peaking coincident with the LH surge and then luteal phase (Brannian & Hansen 2002). Leptin receptors have been demonstrated in the hypothalamus and pituitary, and leptin has been implicated in the control of gonadotrophin secretion (Moschos et al. 2002, Pasquali & Gambineri 2006). Indeed, the obese Ob/Ob mice, which are genetically leptin deficient, display infertility and hypogonadism. Administration of recombinant leptin restores the hormonal disturbance and fertility (Chehab 1996). In humans, leptin plays an important regulatory role on the HPO axis and pubertal development; young women with congenital leptin deficiency or leptin receptor mutations do not undergo puberty, and administration of leptin can induce pubertal development (Clement et al. 1998, Farooqi et al. 1999).
Leptin also has activity at an ovarian level, and the leptin receptor and leptin receptor mRNA expression have also been demonstrated in rodent and human theca cells, granulosa cells, oocytes, endometrial cells and pre-implantation embryos (Cioffi et al. 1997, Karlsson et al. 1997, Zamorano et al. 1997, Agarwal et al. 1999, Cervero et al. 2005). In vitro, leptin has been observed to affect ovarian steroidogenesis. Leptin exerts a dose-dependent inhibition of OE2 synthesis in response to stimulation by FSH and IGF1 in cultured granulosa cells, and this may suggest a paracrine role for leptin (Zachow & Magoffin 1997, Brannian & Hansen 2002). Leptin has also been shown to suppress IGF augmentation of LH-stimulated androstenedione synthesis in theca cells (Agarwal et al. 1999). Additionally in rats, leptin at high concentration has been observed to interfere with normal follicular development, the development of a dominant follicle, oocyte maturation and as such ovulation (Duggal et al. 2000).
Leptin may also affect folliculogenesis by regulation of perifollicular blood flow, and leptin receptors have been demonstrated on human endothelial cells. In vitro studies have shown that leptin has a stimulatory effect upon endothelial cell proliferation and angiogenesis (Brannian & Hansen 2002). Leptin has a synergistic angiogenic action with fibroblast growth factor-2 and vascular endothelial growth factor. In mice, leptin has been observed to promote vascular permeability (Cao et al. 2001). Elevated leptin concentrations have been shown to progressively promote reactive oxygen species formation and oxidative damage in human endothelial cells (Bouloumie et al. 1999). High follicular fluid leptin concentrations have been correlated with a reduction in intrafollicular oxygen concentration in women undergoing IVF (Barroso et al. 1999). Localised action of leptin on the perifollicular vasculature could therefore interfere with delivery of oxygen and regulatory substances to the follicle and as such impair oocyte maturation (Van Blerkom et al. 1997, Brannian & Hansen 2002). Mouse follicles cultured in vitro exposed to high concentrations of leptin increase follicular steroidogenesis but reduce oocyte maturation to metaphase II (Swain et al. 2004). In a study of follicular fluid leptin concentration and assisted reproductive technology (ART) outcome, it was observed that follicular fluid leptin concentration was significantly lower in women who conceived within three cycles of IVF or gamete intrafallopian transfer (GIFT) when compared with age- and weight-matched controls (Mantzoros et al. 1997). Leptin may also exert an effect on endometrial development, and leptin receptor mRNA has been detected by RT-PCR in human endometrial tissue (Alfer et al. 2000). Leptin and its receptor have been observed in secretory endometrium, in which they may have a role in regulation of embryo implantation and endometrial receptivity (Castellucci et al. 2000, Gonzalez et al. 2000, Kawamura et al. 2003). As such, perturbations to the leptin system as seen in obesity may disturb endometrial receptivity and implantation leading to impaired fecundity.
Women with PCOS have been observed to have elevated serum leptin concentrations in comparison to weight-matched controls (Brzechffa et al. 1996, Vicennati et al. 1998, El Orabi et al. 1999, Messinis & Milingos 1999, Brannian & Hansen 2002). However, several contradictory studies did not demonstrate any significant differences in the serum leptin levels in women with PCOS when compared with age- and weight-matched controls, but the number of subjects in some of these studies was low, as such limiting the interpretation of the conclusions made (Chapman et al. 1997, Laughlin et al. 1997, Mantzoros et al. 1997, Micic et al. 1997, Rouru et al. 1997, Gennarelli et al. 1998). Women with PCOS may exhibit altered leptin sensitivity of the hypothalamic neuropeptide Y (NPY) neurons to leptin inhibition, and higher plasma NPY levels have been observed in women with PCOS compared to non-PCOS controls; this may perturb GNRH secretion (Baranowska et al. 1999, Messinis & Milingos 1999, Brannian & Hansen 2002). Women with a normal menstrual cycle have been observed to exhibit co-pulsatility of leptin and LH secretion, and impaired pulse synchronicity has been reported in women with PCOS (Sir-Petermann et al. 1999, Brannian & Hansen 2002). It has been suggested that the perturbation of leptin levels and sensitivity seen in PCOS may be linked to insulin resistance, although some controversy surrounds this. Indeed, it has been demonstrated that treatment of women with PCOS with insulin-sensitising agents induces a reduction in serum leptin levels (Krassas et al. 1998, Morin-Papunen et al. 1998, Pasquali et al. 2000, Kowalska et al. 2001). However, contradictory reports exist which do not demonstrate changes in leptin concentration following administration of insulin sensitisers (Mantzoros et al. 1997). Nevertheless, despite the controversy, it is tempting to speculate that if women with PCOS have tendency towards perturbations in the leptin system, then obese women with PCOS would be particularly prone to its detrimental effect upon the HPO axis leading oligo-anovulation.
Weight loss following a low-calorie diet leads to a reduction in circulating leptin and leptin mRNA expression in obese women with and without PCOS (Maffei et al. 1995, Messinis & Milingos 1999, Stamets et al. 2004, Gosman et al. 2006). In one study, a 10% reduction in body weight was found to lead to 53% reduction in serum leptin concentration (Considine et al. 1996). Bariatric surgery results in dramatically reduced serum leptin concentration, and the reduction in leptin has even been demonstrated to precede the weight loss (Faraj et al. 2003, Rubino et al. 2004). One might speculate that weight loss would improve reproductive potential in part by reducing circulating leptin concentration and the detrimental effect upon the HPO axis it exerts at higher concentrations.
Other adipokines
Adipocytes synthesise and release chemical messenger peptides that participate in metabolic regulation, including the action of insulin. It has been reported that some of these substances may affect reproductive function. Some of the peptides are uniquely expressed by adipose tissue, whilst others are more widely synthesised with adipose tissue contributing to the circulating pool (Gosman et al. 2006). Changes to body mass will alter the levels of such peptides. It is possible that this may have an impact upon reproduction; however, the direct effect of these adipokines upon reproductive function during obesity is difficult to prove definitively. They may also act indirectly by perturbing other regulatory systems. The relative importance of individual adipokines in reproduction is not clear, and their proposed actions are emerging with more work required to fully elucidate their role in obesity-related subfertility. Many of the reported effects have been demonstrated in rodent models, and the effects in humans require further evaluation. Individual adipokines and their reported effects in obesity are discussed below and summarised in Table 2.
Observed alterations and reproductive-endocrine effects of the adipokines in obesity.
| Adipokine | Change in obesity | Proposed effects upon reproductive-endocrine targets |
|---|---|---|
| Adiponectina | Reduce | Increased insulin resistance |
| Interference with folliculogenesis | ||
| Modulation of sex steroid secretion | ||
| Proportionally lower levels in obese PCOS women | ||
| Interleukin-6b | Increase | Increased insulin resistance |
| Impaired LH secretion | ||
| Impaired response to LH | ||
| Impaired oestrogen secretion | ||
| Plasminogen activator inhibitor type-1c | Increase | Increased PAI1 directly correlate with development of metabolic syndrome |
| Increased miscarriage risk | ||
| Tumour necrosis factor-αd | Increase | Reduced insulin sensitivity |
| Inhibition of gonadotrophin secretion | ||
| Impaired steroidogenesis | ||
| Induces corpus luteum regression | ||
| Impaired endometrial development | ||
| Effects upon other adipokines | ||
| Increased leptin | ||
| Increased PAI1 | ||
| Reduced adiponectin |
Adiponectin is a protein secreted by the adipocytes, but serum levels drop in obesity and in insulin resistance (Gosman et al. 2006). Levels increase following weight loss and bariatric surgery (Yang et al. 2001, Gosman et al. 2006). Adiponectin has been implicated in the regulation of insulin sensitivity, serum concentrations being inversely related to insulin resistance (The ESHRE Capri Workshop Group 2006). It has been speculated that in obese states where circulating levels are lower, there would be a reduction in insulin sensitivity and this could lead to an effect upon the control of ovulation. Adiponectin has been detected within the ovary, in follicular fluid, the oocyte, the corpus luteum, theca cells, and it is weakly expressed in granulosa cells (Pierre et al. 2009). The direct effect of adiponectin in human ovarian function remains unclear; in animal models, adiponectin has been observed to influence follicular remodelling and folliculogenesis and to modulate sex steroid secretion via activation of its own receptor (adiponectin R1 and R2) and via modulation of the insulin/IGF system (Ledoux et al. 2006, Chabrolle et al. 2007, 2009, Campos et al. 2008, Pierre et al. 2009). Women with PCOS appear to have lower levels of adiponectin than non-PCO controls, and obese anovulatory women with PCOS have lower levels still, although this is not a consistent finding in the literature (Carmina et al. 2005, 2009, Toulis et al. 2009). It has been proposed that hypoadiponectinaemia in patients with PCOS or women with central obesity may contribute to worsening insulin resistance and its negative effect upon normal folliculogenesis (Escobar-Morreale et al. 2006).
Interleukin-6 (IL6) is an inflammatory mediator; approximately one-third of circulating levels are derived from adipocytes. Serum concentration increases in obesity and falls with weight loss (including bariatric surgery). Increased IL6 has been associated with a reduction in insulin sensitivity; reports suggest that IL6 has a detrimental effect upon fertility (Gosman et al. 2006). Some investigators have found that in rats, IL6 may act centrally to inhibit LH secretion (Rivier & Vale 1990); other investigators have not replicated such an effect (Watanobe & Hayakawa 2003). Suppressive activity of IL6 in the ovaries of rats and humans has been demonstrated. IL6 has been observed to prevent LH-triggered ovulation, inhibited LH-/FSH-induced oestrogen synthesis and suppress aromatase activity within granulosa cells (Deura et al. 2005, Gosman et al. 2006). Women with PCOS have been observed to have elevated serum and follicular IL6 when compared with non-PCOS controls whilst undergoing IVF (Amato et al. 2003). IL6, in the high levels seen in obese women, may impair fertility through interference with the HPO axis and impairment of endometrial development due to altered oestrogen secretion.
Plasminogen activator inhibitor (PAI) type-1 primarily regulates fibrinolytic activity in the blood. Circulating PAI1 is largely produced by white and visceral fat. PAI1 increases in obesity and has been correlated with development of the metabolic syndrome (Gosman et al. 2006). PAI1 has been associated with miscarriage in women with PCOS (Glueck et al. 1999, 2003). Plasma PAI1 has been observed to reduce after a low-calorie diet and after bariatric surgery. It is possible that PAI1 in high levels such as those seen on obese women impairs fertility through an adverse effect upon implantation and maintenance of the pregnancy (Gosman et al. 2006).
TNF is synthesised by adipocytes and other cells in the tissue matrix (Gosman et al. 2006). Circulating levels of TNF correlate with BMI and also increase in hyperinsulinaemic states (Bruun et al. 2002, 2003). TNF from adipocytes largely exerts local paracrine effects, but circulating TNF has been observed to affect insulin sensitivity (Gosman et al. 2006). TNF has been observed to affect several areas of the reproductive axis: inhibition of gonadotrophin secretion, ovulation, steroidogenesis, corpus luteum regression and endometrial development (Rivier & Vale 1990, Terranova & Rice 1997, Wood & Strauss 2002, Watanobe & Hayakawa 2003, Gosman et al. 2006). Disturbance of TNF in obesity may impair control of fertility at multiple levels.
Obesity and the oocyte
Several groups have observed that being overweight or obese can have a detrimental effect upon oocyte quality and/or maturity; these studies varied, however, in terms of definition of oocyte quality and obesity (Wittemer et al. 2000, Carrell et al. 2001, Dokras et al. 2006, Esinler et al. 2008). In a study done to assess the impact of isolated obesity upon ICSI outcome, it was observed that obese women (BMI >30 kg/m2) required higher total doses of gonadotrophin stimulation, despite significantly fewer oocyte–cumulus complexes and metaphase II oocytes being retrieved, suggesting that obesity may independently be a risk factor for impaired oocyte maturation (Esinler et al. 2008). In a retrospective analysis of IVF outcome in 1293 women, it was observed that the obese women despite developing the same number of follicles as normal-weight controls had significantly fewer oocytes retrieved and significantly fewer metaphase II oocytes (Dokras et al. 2006). Similarly, in a retrospective analysis of IVF outcome in relation to BMI, it was observed that overweight women (BMI >25 kg/m2) had relatively fewer metaphase II oocytes collected (Wittemer et al. 2000). Likewise, a further prospective analysis of outcome of IVF demonstrated a reduction in oocyte number and a reduction in the number of mature (metaphase II) oocytes retrieved in the obese women (BMI >30 kg/m2) – these reductions, however, were not statistically significant. In this study, it was observed that intrafollicular human chorionic gonadotrophin (hCG) concentration was significantly lower in obese women. It was suggested that a reduction in delivery of hCG to the follicles may be related to the impaired oocyte maturation (metaphase II) seen in obese women (Carrell et al. 2001). However, a recent large retrospective analysis of 6500 IVF cycles has failed to demonstrate a weight-related reduction in the number and maturity of oocytes retrieved. This study did, however, observe reduced implantation, pregnancy and live birth in the obese women. This study was significantly larger than the other cited publications; however, the background demographics were similar. A significant proportion of the women in Bellver et al. (2010) followed the short GNRH antagonist protocol, whereas all of those in the other cited studies followed the long GNRH agonist protocol. Whether this had any effect upon the findings in terms of oocyte quality is unclear.
A surrogate marker of oocyte quality in the context of IVF is fertilisation rate. In a prospective evaluation of the effect of obesity in IVF/ICSI in 162 patients, it was observed that obese women had a 45% lower fertilisation rate when compared with normal-weight controls (van Swieten et al. 2005). A prospective cohort study of 50 overweight (BMI >26 kg/m2) and 50 normal controls (BMI 18–25 kg/m2) observed that fertilisation rate was significantly reduced in overweight women (46.2 vs 61.3%, P<0.05; Salha et al. 2001). A more recent report has observed a more modest but statistically significant reduction in fertilisation rate in overweight women (BMI >24 kg/m2) compared with normal women (BMI <24 kg/m2), 51.7 vs 58.9% (Matalliotakis et al. 2008). However, other reports have not observed a weight-related reduction in fertilisation rate (Wittemer et al. 2000, Fedorcsak et al. 2004, Dokras et al. 2006, Esinler et al. 2008, Bellver et al. 2010). The heterogeneity of the studies above may be a reflection of differences in study design and variation in the definition of obesity. It highlights the necessity for prospective trials using the same regimes and definition of obesity.
Some authors suggest that the increased rates of miscarriage and very early pregnancy loss seen in obese women can be attributed to a reduction in oocyte quality (Fedorcsak et al. 2004, Lashen et al. 2004, Robker 2008). Impaired oocyte developmental competence may impair the developmental potential of the embryo, which may lead to an impaired implantation rate and subsequent abnormal implantation/trophoblastic invasion (Robker 2008). This has been observed in obese mice. Oocytes from obese mice and controls were fertilised and cultured in vitro. Oocytes from the obese mice displayed slower embryo development maintained through to the blastocyst stage. Additionally, there were perturbations to the distribution of blastomeres (Minge et al. 2008). This study also observed the effect of insulin-sensitising agents upon oocyte development. Rosiglitazone, a peroxisome proliferator-activated receptor-γ (PPARG) agonist, was observed to improve oocyte development potential in the obese mice (Minge et al. 2008), suggesting that insulin resistance and PPARG regulation may be involved in the pathogenic effect of obesity upon oocyte development.
Obesity and the endometrium
Several studies have attempted to define the effect of obesity on the endometrium. However, contradictory findings have been reported, and importantly studies varied in design (Cano et al. 2001, Bellver et al. 2003, 2007, Wattanakumtornkul et al. 2003, Styne-Gross et al. 2005). It has been proposed that the oocyte donation model provides the best human model for discriminating between the effects of obesity upon the oocyte/embryo and the endometrium and uterine receptivity (Bellver et al. 2007). The validity of this model has been questioned by some authors, who have suggested that crucial differences may exist between non-obese and obese women who require oocyte donation and those who do not, thereby creating a bias in the results using this model (Howards & Cooney 2008). A retrospective study of 2656 oocyte donation cycles with good quality embryos observed the effect of obesity in the recipient. Recipients were divided into groups: BMI <20, BMI 20–24.9, BMI 25–29.9 and BMI >30 kg/m2. Linear regression analysis demonstrated a negative trend in pregnancy rates with increasing BMI, with statistically significantly lower ongoing pregnancy rates in the overweight (38.9%) and obese (36.1%) women compared to normal controls (45.2%). However, implantation rates were similar in all groups suggesting an increased pregnancy loss rate in the obese women (Bellver et al. 2007). This large study addressed the methodological issues criticised in a previous study by the same group with the same findings by increasing sample size and including only one recipient cycle per patient (Bellver et al. 2003). A case–control study of 139 women undergoing 180 cycles of IVF (using own gametes) observed that women with a BMI >25 kg/m2 had reduced implantation and pregnancy rates with elevated rates of miscarriage (Loveland et al. 2001). In contrast, a smaller and underpowered study of 97 oocyte recipients investigated the effect of obesity upon pregnancy and implantation. The area under the receiver operating characteristic (ROC) curve was 0.51 (95% CI 0.41–0.62), suggesting no relationship between BMI and implantation rate. Likewise, there were no significant differences observed in pregnancy rates between the BMI strata (Wattanakumtornkul et al. 2003). Styne-Gross et al. (2005) investigated 536 first cycle donor oocyte recipients undergoing embryo replacement. No significant differences were observed in implantation or pregnancy rate; again ROC curve analysis observed no correlation between BMI and pregnancy.
The histopathological and molecular effect of obesity upon the endometrium remains to be fully elucidated. Leukaemia inhibitory factor (LIF) has been implicated in the regulation of implantation (Senturk & Arici 1998). In an analysis of women with unexplained recurrent pregnancy loss, a subgroup had endometrial glandular LIF examined. A significant negative correlation between glandular LIF and BMI was observed. However, no differences in endometrial morphology or steroid receptor concentration were observed in obese women (Metwally et al. 2007b). It has also been suggested that the state of relative hyperoestrogenaemia seen in the obese women may have a detrimental effect upon endometrial receptivity (Tamer Erel & Senturk 2009). Visceral obesity has been observed to alter insulin resistance, inflammatory mediators, coagulation and fibrinolysis. Obesity is associated with insulin resistance and hyperinsulinaemia, and elevated insulin levels have been associated with a reduction in glycodelin and a reduction in IGFBP1. Low levels of glycodelin have been associated with recurrent pregnancy loss. IGFBP1 has been observed to facilitate adhesion at the maternal–foetal interface. Therefore, perturbation of such molecules may contribute to reduced fertility at an endometrial level (Carrington et al. 2005, Levens & Skarulis 2008). Obese women have been observed to have elevated levels of acute phase proteins and pro-inflammatory cytokines (including IL6, PAI1 and TNF); these inflammatory markers are thought to exert a negative effect upon implantation and early embryonic development (Gosman et al. 2006, Esinler et al. 2008, Levens & Skarulis 2008). Therefore, one could speculate that the higher levels seen in the obese women might impart a negative influence upon implantation and subsequent pregnancy. Reduced expression of the glucose transporter 4 (SLC2A4, GLUT4) has been associated with the development of insulin resistance in muscle and adipose tissue in obese women and particularly those with PCOS (Rosenbaum et al. 1993, Mioni et al. 2004, Mozzanega et al. 2004). Reduced endometrial expression of SLC2A4 and SLC2A4 mRNA has been demonstrated in obese women with PCOS compared with lean PCOS and lean controls (Mioni et al. 2004). This may reflect insulin resistance at an endometrial level in obese PCOS women. Since insulin has also been implicated in the regulation of endometrial development, metabolism and receptivity, one could envisage that the development of endometrial insulin resistance would affect fertility (Hackl 1973, Straus 1984, Strowitzki et al. 1993).
The effect of obesity upon implantation rate has been inconsistently reported. Some authors have identified a reduction in implantation rates among the obese women (Loveland et al. 2001, Nichols et al. 2003, Bellver et al. 2010), whereas others have not demonstrated a weight-related reduction (Fedorcsak et al. 2004, Dechaud et al. 2006, Dokras et al. 2006). An unfavourable intrauterine milieu and impaired endometrial receptivity are plausible loci for the effect of obesity upon subfecundity; however, the evidence is inconsistent and obese women tend to suffer non-recurrent spontaneous pregnancy loss (Lashen et al. 2004, Bellver et al. 2006). This suggests that whilst the endometrium may play a part, oocyte quality is likely to be the more influential factor.
Obesity and the embryo
Since early embryonic development is largely driven by the oocyte, one might expect that if obesity affects oocyte development, then it would affect embryonic development also. Inconsistent findings have been reported with respect to the effect of obesity upon embryo quality (Carrell et al. 2001, Fedorcsak et al. 2004, Spandorfer et al. 2004, Dechaud et al. 2006, Metwally et al. 2007a). In a prospective study of 247 women undergoing IVF, it was observed that obese (BMI >30 kg/m2) women had significantly poorer quality embryos compared with women with BMI 20–30 kg/m2 (Carrell et al. 2001). However, other researchers were unable to demonstrate significant differences in quality of the transferred embryos between the BMI strata (Fedorcsak et al. 2004, Spandorfer et al. 2004, Dechaud et al. 2006). Whilst the quality of the transferred embryos may not be significantly different in obese women, some authors have reported a reduction in the overall quality of the embryos created in an IVF cycle (Metwally et al. 2007a, Esinler et al. 2008). In a study of the effect of isolated obesity upon ICSI outcome, embryo quality was similar in all BMI strata. However, significantly fewer overweight (15.0%) and obese (10.7%) women had cryopreservation of surplus embryos when compared to women with a normal BMI (22.7%; Esinler et al. 2008). A retrospective analysis of 426 IVF/ICSI cycles observed that in young women (<35 years), obesity lead to a significant reduction in mean embryo quality, significant reduction in cryopreservation and a significant reduction in embryo utilisation. Interestingly, in older patients (>35 years), the above parameters were similar across the BMI strata (Metwally et al. 2007a). In contrast, a retrospective analysis of 6500 IVF cycles failed to demonstrate a difference in embryo quality and embryo cryopreservation across the BMI strata despite observing poorer outcomes in the obese women (Bellver et al. 2010). The series described by Bellver et al. is significant due to its size, and approaches a sample size similar to the combined data used in a recent meta-analysis (Maheshwari et al. 2007). By and large, the findings are similar, but some of the findings are incongruous with the meta-analysis such as finding no difference in oocyte and embryo quality or fertilisation rate; it would therefore be important to repeat the meta-analysis including this study. It must be recognised, however, that owing to the significant heterogeneity of the single centre studies included, the reliability of meta-analysis becomes less robust. Clearly, large multi-centre prospective trials are required to resolve this matter (see also section ‘Obesity and assisted conception’).
A relative gonadotrophin resistance is seen in obese women, as such obese women require a higher total dose of gonadotrophin when undergoing ovarian stimulation. It has been suggested that the higher doses of gonadotrophin may lead to impaired oocyte quality and embryo quality, leading to impaired embryonic development and implantation potential (Tamer Erel & Senturk 2009).
Obesity and PCOS
Women with PCOS are commonly overweight or obese (38–66%), although this does not form part of the diagnostic criteria for the disorder (Balen et al. 1995, Azziz et al. 2004, Norman et al. 2007). Obesity does, however, have a profound effect upon the expression of the syndrome and the symptoms which a woman experiences; obese women with PCOS have a more severe phenotype. In a series of 1741 British women with PCOS, it was observed that 70% had menstrual cycle disturbance; obese women with PCOS had a higher prevalence (78%) of disturbed menstrual cyclicity (Balen et al. 1995). Similar results were demonstrated in a smaller case series of 263 women with PCOS; obese PCOS women had an 88% chance of menstrual cycle disturbance, whereas non-obese women had a 72% chance (Kiddy et al. 1992). The mechanisms by which obesity influences the pathophysiology and clinical expression of PCOS are complex and yet to be fully elucidated; however, the mechanisms are likely to be similar to those in obese non-PCOS women, and since women with PCOS have a background of insulin resistance and hyperandrogenism, the deleterious effects of obesity upon reproduction will tend to be exaggerated (see Table 3). Central obesity is particularly associated with reproductive disturbance in PCOS leading to chronic oligo-/anovulation; a proposed mechanism includes hyperandrogenism secondary to an insulin-mediated overstimulation of ovarian steroidogenesis and decreased serum SHBG concentration (Davies 2006, Pasquali & Gambineri 2006, Norman et al. 2007). Women with PCOS are prone to develop insulin resistance; fasting and glucose-stimulated insulin concentrations are significantly higher in women with PCOS compared to those without PCOS. Obese women with PCOS are more prone to developing insulin resistance and hyperinsulinaemia, and more frequently exhibit the clinical manifestations of insulin resistance, acanthosis nigricans (Gambineri et al. 2002, Pasquali & Gambineri 2006). In abdominal obesity, insulin resistance develops and a compensatory hyperinsulinaemia occurs; however, the ovary remains responsive to insulin. Elevated levels of insulin lead to increase steroidogenesis and excessive androgen production by the ovarian theca cells (Dunaif 1997). Elevated local ovarian androgen production leads to premature follicular atresia and consequently increases the likelihood of oligo-/anovulation (Dunaif 1997, Poretsky et al. 1999, Morin-Papunen et al. 2000, Pasquali & Gambineri 2006, Norman et al. 2007).
Effect of obesity upon polycystic ovary syndrome (PCOS).
| Effect of obesity upon PCOS |
|---|
| Increased androgen levelsa |
| Reduced sex hormone-binding globulin levelsb |
| Reduced menstrual cyclicityc |
| Increased prevalence of oligo/anovulationc |
| Increased insulin resistanced |
| Impaired response to gonadotrophin during superovulatione |
| Increased chance of cycle cancellation (OR 1.86, 95% CI 1.13–3.06) |
| Reduced ovulation rates (OR 0.44, 95% CI 0.31–0.61) |
| Reduced chance of treatment success following ARTf |
| Increased risk of miscarriage (OR 3.05, 95% CI 1.45–6.44)g |
Acyclic excessive production of oestrogens may exert a positive feedback regulation upon LH release and negative feedback upon FSH release, leading to a rise in ovarian androgen production (Gambineri et al. 2002, Pasquali & Gambineri 2006). It has also been suggested that an increased tone in the opioid system seen in obese women with PCOS may, in part, favour the development of hyperinsulinaemia as β-endorphin has been observed to stimulate insulin secretion (Pasquali & Gambineri 2006). Obesity, particularly abdominal obesity, in PCOS favours a state of hyperandrogenaemia due to significantly lower SHBG and higher circulating androgen levels. Obese women with PCOS more frequently exhibit the clinical manifestations of hyperandrogenism and menstrual cycle disturbance (Holte et al. 1994, Gambineri et al. 2002). Thus, elevated androgen levels in obese women with PCOS favour a state of oligo-/anovulation and subfertility.
Obesity in women with PCOS reduces the likelihood of natural conception and also reduces the likelihood of conception following fertility treatment (Hamilton-Fairley et al. 1992, Clark et al. 1995, 1998, White et al. 1996, Wang et al. 2000). Elevated BMI in women with PCOS is associated with an increased risk of miscarriage (Hamilton-Fairley et al. 1992). A recent analysis of morbidly obese (BMI >40 kg/m2) women with PCOS undergoing IVF at an American clinic has found a significant impairment in clinical pregnancy rate in this group. These women had lower peak OE2 concentrations, fewer oocytes collected and impaired fertilisation rates, suggesting impaired follicular response and oocyte development in the morbidly obese women (Jungheim et al. 2009).
Menstrual cyclicity and the endocrine profile improve following weight reduction, proof of concept that obesity worsens the PCOS phenotype (Franks et al. 1991, Pasquali et al. 1997, Huber-Buchholz et al. 1999, Moran & Norman 2004, Tang et al. 2006, Norman et al. 2007). Even modest weight loss of 5–10% in obese women with PCOS has been observed to lead to improvements in hormonal profiles, menstrual cyclicity and fertility (Kiddy et al. 1992, Crosignani et al. 2003).
Obesity and assisted conception
A survey of studies reporting the effect of obesity upon ART outcome reveals inconsistent findings, although study design and definition of obesity are variable. However, the majority of the studies suggest that obesity has a deleterious effect upon ART. Obesity has been reported to affect ovarian stimulation in women undergoing treatment. Reported effects include prolonged ovarian stimulation, increased dose requirement of gonadotrophin, increased incidence of follicular asynchrony and increased cancellation rates (Mulders et al. 2003, van Swieten et al. 2005, Balen et al. 2006, Bellver et al. 2006, Maheshwari et al. 2007, Esinler et al. 2008). In a cohort study of women with PCOS undergoing ovulation induction with either clomiphene or gonadotrophins, it was observed that elevated BMI negatively affected ovulation rates. In this study, obese patients had significantly lower ovulation rates at 6 months of treatment: 79% in women with BMI of 18–24 kg/m2, compared with 15.3% with BMI 30–34 kg/m2 and 12% if BMI >35 kg/m2 (Al-Azemi et al. 2004). Some authors, however, have been unable to demonstrate any difference in ovarian response to stimulation in obese women (Lashen et al. 1999, Dechaud et al. 2006, Martinuzzi et al. 2008).
Follicular recruitment during ovarian stimulation requires the serum FSH concentration to exceed a therapeutic threshold; this threshold varies between patients, but has been observed to be higher in women with elevated BMI. Higher doses of gonadotrophin required in obese women may be related to altered pharmacodynamics, altered OE2 metabolism and decreased SHBG concentrations (Tamer Erel & Senturk 2009). The absorption, metabolism and clearance of gonadotrophins injected s.c. have been observed to differ in obese women with PCOS (Fridstrom et al. 1997). A study of pharmacokinetics in healthy volunteers observed that there was no advantage in i.m. or s.c. injection in obese women (Steinkampf et al. 2003). Factors other than absorption and clearance of gonadotrophins may be responsible for increased dose requirement in obese women; obesity has been associated with a relative gonadotrophin resistance (Fedorcsak et al. 2001). Insulin resistance seen in obese women has been associated with a relative gonadotrophin resistance (Homburg et al. 1996, Fulghesu et al. 1997, Dale et al. 1998). A meta-analysis of patient predictors for the outcome of gonadotrophin ovulation induction confirmed a positive correlation between obesity and the amount of gonadotrophin required, and a weighted mean difference (WMD) of 771 IU is more required in obese women (95% CI 700–842). Ovulation rate was observed to be impaired in the obese women (OR 0.44, 95% CI 0.31–0.61; Mulders et al. 2003). As discussed above, leptin concentrations are elevated in obese women, and it has been suggested that high intrafollicular leptin concentrations are associated with relative gonadotrophin resistance during ovarian stimulation in IVF, through a postulated inhibitory effect upon FSH-stimulated steroid synthesis by granulosa cells (Zachow & Magoffin 1997, Agarwal et al. 1999, Tamer Erel & Senturk 2009). The elevated doses of gonadotrophin used to compensate for the relative gonadotrophin resistance induced by obesity may be deleterious, potentially leading to impairment of embryonic developmental potential and implantation (Fedorcsak et al. 2001). There is also a postulated detrimental effect upon uterine receptivity. In mice, superovulation induces abnormal embryonic development, decreased invasional capacity of blastocysts in vitro and impaired implantation rates (Ertzeid & Storeng 1992, Ertzeid et al. 1993).
Obese women undergoing IVF/ICSI have lower live birth rates. It is thought that this is the cumulative effect of lower implantation and pregnancy rates, higher miscarriage rates and increased obstetric complications (Bellver et al. 2006). Whilst some authors have reported lower pregnancy and live birth rates in obese women undergoing assisted conception treatments (Wang et al. 2000, Carrell et al. 2001, Loveland et al. 2001, Nichols et al. 2003, Fedorcsak et al. 2004, Bellver et al. 2010), others have been unable to demonstrate reduction in success rates in obese women (Lashen et al. 1999, Wittemer et al. 2000, Dechaud et al. 2006, Martinuzzi et al. 2008, Matalliotakis et al. 2008). A retrospective analysis of outcomes in 3586 patients undergoing IVF/ICSI/GIFT observed that the cumulative chance of achieving at least one pregnancy was significantly reduced in the obese women when compared to normal controls (BMI 20–24.9 kg/m2), obese group (BMI 30–34.9 kg/m2, OR 0.73, 95% CI 0.57–0.96) and very obese group (BMI >35 kg/m2, OR 0.50, 95% CI 0.32–0.77; Wang et al. 2000). In a retrospective analysis of 5019 IVF/ICSI cycles in 2660 women, it was observed that obesity (BMI >30 kg/m2) was associated with a significant reduction in live birth rates (OR 0.75, 95% CI 0.57–0.98) and a significantly elevated chance of miscarriage (OR 1.68, 95% CI 1.13–2.51; Fedorcsak et al. 2004).
A retrospective study of 417 women undergoing their first IVF cycle observed the effect of BMI upon IVF. A high prevalence of PCOS was seen in the obese category; therefore, the authors performed subset analyses comparing the BMI strata in the PCOS and non-PCOS groups. Whilst no significant differences were observed in the non-PCOS obese groups, it was observed that obesity in women with PCOS lead to a significant reduction in implantation and ongoing pregnancy rates (Martinuzzi et al. 2008). Additionally, an interesting finding was that obese women were significantly more likely to encounter difficulty in observing the air bubble during ultrasound-guided embryo transfer and were more likely to have blood on or in the catheter after embryo transfer, factors which have been associated with poorer success rates after embryo transfer (Martinuzzi et al. 2008). A retrospective study at a US centre observed the outcomes of IVF/ICSI in lean (BMI 18.5–24.9 kg/m2) and obese (BMI >30 kg/m2) women with and without PCOS. It was observed that lean women had more favourable cycle characteristics, but there were no significant differences in terms of implantation, clinical pregnancy, miscarriage or live birth rates (McCormick et al. 2008).
The distribution of body fat is also important, central/abdominal obesity having a larger impact upon fertility. A study of 220 women undergoing IVF observed that a WHR >0.8 was associated with a significant reduction in pregnancy rate (OR 0.42, 95% CI 0.2–0.9). In this same study, BMI was not, however, found to correlate with IVF outcome (Wass et al. 1997). Changes in weight have been observed to influence treatment success; a unit increase of BMI has been shown to reduce the odds of a pregnancy following IVF by 0.84 and conversely weight loss improving the odds of achieving a pregnancy by a factor of 1.19 for each unit reduction in BMI (Ferlitsch et al. 2004). In a recent systematic review and meta-analysis, the effect of elevated BMI on IVF outcome was investigated. Pooled analysis demonstrated that patients with BMI >25 kg/m2 had a lower chance of pregnancy after IVF (OR 0.71, 95% CI 0.62–0.81). Patients with an elevated BMI required significantly more gonadotrophin for ovarian stimulation, for BMI >25 kg/m2, WMD 210.08 (95% CI 149.12–271.0), and for BMI >30 kg/m2, WMD 361.94 (95% CI 156.47–567.40). Elevated BMI was observed to increase the risk of miscarriage, BMI >25 kg/m2 (OR 1.33, 95% CI 1.06–1.68) and BMI >30 kg/m2 (OR 1.53, 95% CI 1.27–1.84). However, the authors stated that there was insufficient evidence to determine the effect on live birth rates, and called for more rigorous prospective work to determine the true effect of BMI (Maheshwari et al. 2007). A summary of the reported effects of obesity upon ART is given in Table 4.
Effects of obesity upon assisted reproductive technology (ART).
| Effects of obesity upon ART |
|---|
| Impaired USS image quality due to adipose tissuea |
| Increased duration of stimulation |
| Increased total gonadotrophin dose required (WMD 361.94, 95% CI: 156.47, 567.40; BMI <30 vs >30)b |
| Increased follicular asynchronyc |
| Increased cycle cancellation (OR 1.35, 95% CI: 0.99, 1.84; BMI >30 vs <30)d |
| Poor response to superovulatione |
| Reduced follicular hCG concentration on day of ovum pickup (inverse correlation with BMI (r=−0.353, P<0.001))f |
| Relative reduction in number of cumulus–oocyte complex recovered at ovum pickupg |
| Relative reduction in metaphase II oocytes recovered at ovum pickuph |
| Reduced number of surplus good quality embryos available for cryopreservationi |
| Reduced pregnancy rates (OR 1.47, 95% CI: 1.20, 1.80; BMI <30 vs >30)j |
| Increased miscarriage rates (OR=1.53, 95% CI: 1.27, 1.84; BMI >30 vs <30)k |
OR, odds ratio; WMD, weighted mean difference.
Homburg et al. (1996), Fulghesu et al. (1997), Dale et al. (1998), Fedorcsak et al. (2001), Mulders et al. (2003) and Maheshwari et al. (2007).
Mulders et al. (2003), van Swieten et al. (2005), Balen et al. (2006), Bellver et al. (2006), Maheshwari et al. (2007) and Esinler et al. (2008).
Fertility after weight loss
Weight loss improves reproductive function in overweight and obese women (Clark et al. 1995, 1998, Hollmann et al. 1996, Crosignani et al. 2003, Tang et al. 2006). It is, therefore, of paramount importance that overweight and obese women attending subfertility clinics are given the necessary advice and support to achieve the necessary weight loss. The first line of approach should be through lifestyle modification with careful counselling on diet and exercise; dietary education and guidance should ideally be given by a trained dietician. Overweight and obese women should be advised to follow a restricted calorie diet and to concomitantly undertake a programme of exercise containing a sufficient quantity of aerobic activity. Good evidence exists to support the use of supervised weight loss or group programmes in terms of improved weight loss, ovulatory frequency, pregnancy rates and cost efficiency per pregnancy achieved, although the provision of such services will be limited by local resources (Guzick et al. 1994, Clark et al. 1995, 1998, Hollmann et al. 1996, Tang et al. 2006, Balen & Anderson 2007). An industry has been created out of extolling the virtues of various diets and dieting regimes; however, there is little evidence to suggest that one is particularly better than another in terms of improving reproductive potential. The most important feature for achieving weight loss is maintaining a negative energy balance. Calorie restriction, however this might be achieved, should be advised (Norman et al. 2004, Balen & Anderson 2007). One must be careful not to promote extreme rapid dieting and acute very low calorie diets, as these have been associated with poor compliance and poor ART outcomes (Tsagareli et al. 2006). When counselling overweight and obese women regarding weight loss, it is essential to emphasise the importance of making lifestyle modifications that are sustainable and healthy. In some women, it may be appropriate to resort to weight-reducing agents where initial attempts at weight loss through diet and exercise have failed (Padwal & Majumdar 2007). However, caution should be exercised when prescribing, and such women should be kept under careful surveillance. Orlistat, a lipase inhibitor that reduces gastrointestinal fat absorption, is largely regarded as safe to use in this context. Orlistat has been observed to improve weight loss, insulin resistance and hyperandrogenaemia in obese women with PCOS (Jayagopal et al. 2005, Panidis et al. 2008, Cho et al. 2009, Metwally et al. 2009). Any weight-reducing agent used should be stopped when pregnancy is confirmed.
Increasingly, bariatric surgery is used to treat morbid obesity in women of reproductive age who have been unable to achieve adequate weight loss through dietary modification and exercise. In the US, between 2003 and 2005, more than 50 000 women aged 18–45 underwent bariatric surgery annually (Maggard et al. 2008). Bariatric surgery involves either reducing the stomach capacity (e.g. gastric band) or reducing absorption through anatomical modification and reducing capacity (e.g. Roux-en-Y gastric bypass) or reducing absorption through anatomical modification (e.g. biliopancreatic diversion). Bariatric surgery is considered when BMI >40 kg/m2 or BMI >35 kg/m2, and serious concomitant medical problems are exacerbated by obesity (NIH Conference 1991, Merhi 2007, Guelinckx et al. 2009). Rapid weight loss follows the surgery; the majority of the weight loss occurs in the first year. Pregnancy is best avoided during this time (Maggard et al. 2008).
The reproductive aberrations induced by obesity improve after bariatric surgery. Bariatric surgery can lead to improvements in menstrual cyclicity (Teitelman et al. 2006). A questionnaire study of women undergoing bariatric surgery observed oligomenorrhoea in 40% of premenopausal women presenting for bariatric surgery. After weight stabilisation, 81% of the oligomenorrhoeic women had become eumenorrhoeic. Pre-operatively, 25% of women reported infertility, after surgery of these women, all who tried to conceive were successful (Deitel et al. 1988). It is likely that the reduction in adipose tissue reverses the negative hormonal/paracrine influence over the reproductive system, restoring the fertility potential in these women. Twelve morbidly obese women with PCOS underwent bariatric surgery and were followed up in a longitudinal study. Post-operative weight loss was associated with a marked improvement in clinical and biochemical hyperandrogenism. Likewise, weight loss was associated with restoration of menstrual cyclicity. In the majority of these women, the diagnosis of PCOS could not be sustained after the weight loss due to an amelioration of symptoms (Escobar-Morreale et al. 2005). An observational study of 24 morbidly obese women with PCOS undergoing Roux-en-Y gastric bypass demonstrated improved menstrual cyclicity in all women and reduced hirsutism in half. Five conceived naturally (Eid et al. 2005), highlighting the sensitivity of the condition to changes in body weight. Other case series have observed improved natural conception rates post-operatively (Bilenka et al. 1995, Marceau et al. 2004). Interestingly, bariatric surgery may not be so beneficial for male fertility, and a case series of six previously fertile men were observed to develop secondary subfertility and azoospermia (secondary to spermatogenic arrest) following profound weight loss after a Roux-en-Y gastric bypass (di Frega et al. 2005).
When considering fertility after bariatric surgery, the obstetric impact of the surgery is paramount. The risk of obstetric complications (including gestational diabetes, macrosomia and hypertensive disorders) is reduced following operative induced weight loss when compared to morbidly obese women. However, nutritional deficiencies can occur, particularly with the malabsorptive forms of bariatric surgery or with non-compliance with supplements. Deficiencies in iron, vitamin A, vitamin B12, vitamin K, folate and calcium can occur leading to maternal complications (e.g. anaemia) and foetal complications (e.g. congenital abnormalities, in utero growth retardation; Guelinckx et al. 2009). It is inadvisable to conceive during the period of rapid weight loss as this is most likely to result in nutritional and metabolic instabilities (Balen & Anderson 2007, Maggard et al. 2008). Women conceiving after bariatric surgery should receive careful counselling by a dietician to reduce the risk of nutritional deficiency. Indeed, some reports of poor pregnancy outcome have occurred in patients where nutritional advice and supplementation have not been adhered to (Guelinckx et al. 2009).
Conclusions
Obesity impairs reproductive outcome significantly. Notwithstanding its effect upon the likelihood of conceiving, it has important consequences upon the health and outcome of the ensuing pregnancy. The British Fertility Society has issued policy and practice guidelines advising clinicians to advise patients to aim for a normal BMI prior to commencing fertility treatment. Indeed, these guidelines recommend deferring any treatment until a woman's BMI <35 kg/m2, and recommending that BMI <30 kg/m2 is preferable (Balen & Anderson 2007). In summary, obesity has been observed to impair both natural and assisted conception. The exact pathophysiological mechanism through which obesity exerts its detrimental effect remains uncertain. However, animal and human data exist highlighting a negative effect at all levels of HPO axis (Fig. 1). It is likely that obesity exerts its effect upon conception and implantation through a cumulative impairment of several processes. Obesity affects ovulation, oocyte maturation, endometrial development, uterine receptivity, implantation and miscarriage. Weight loss through diet and exercise is the first-line therapy for all obese women seeking fertility treatment, and robust evidence exists to support this. Some improvement in reproductive function following weight loss surgery has been observed; however, conclusions drawn from the current literature must been interpreted with caution owing to the quality of the original data. As such, bariatric surgery cannot be recommended as a first-line fertility treatment for the obese women owing to operative morbidity and mortality and lack of clear supportive data. When considering fertility issues in obese women, one must consider the obstetric and neonatal consequences of a pregnancy. Since pregnancy is a more risky endeavour in the obese women, pre-conception counselling should always mandate the achievement of stable normal weight prior to natural or assisted conception. This will improve both fertility and feto-maternal health in the ensuing pregnancy.
Summary of the reported effects of obesity upon the hypothalamic–pituitary–ovarian axis and effect upon reproductive potential. The findings in the reported literature have varied; please see the main text for a fuller account of the reported effects and how consistently they have been observed. IL6, interleukin-6; IR, insulin resistance; PAI1, plasminogen activator inhibitor type-1; SHBG, sex hormone-binding globulin; TNF, tumour necrosis factor-α.
Citation: REPRODUCTION 140, 3; 10.1530/REP-09-0568
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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This paper is one of five papers that form part of a special Focus Issue section on Obesity. The Guest Editor for this section was J E Norman, Edinburgh, UK.
