Almost 50% of the women with polycystic ovary syndrome (PCOS) are obese. Obesity in PCOS affects reproduction via various mechanisms. Hyperandrogenism, increased luteinizing hormone (LH) and insulin resistance play a pivotal role. Several substances produced by the adipose tissue including leptin, adiponectin, resistin and visfatin may play a role in the pathophysiology of PCOS. Infertility in PCOS is related to anovulation. For induction of ovulation, clomiphene citrate and human gonadotrophins are first- and second-line treatments, respectively. Other treatment modalities include the use of insulin sensitizers, such as metformin as well as aromatase inhibitors and laparoscopic ovarian drilling, while in vitro fertilization is the last resort. Obesity can adversely affect infertility treatment in PCOS. Diet and lifestyle changes are recommended for the obese women before they attempt conception. The use of anti-obesity drugs and bariatric surgery in PCOS require further evaluation.
Highlights
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Obesity is one of the main characteristics of the polycystic ovary syndrome.
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Several substances secreted by the adipose tissue may participate in the pathophysiology of the syndrome.
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Obesity adversely affects the outcome of infertility treatment in anovulatory women with PCOS.
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Diet and lifestyle changes are recommended in obese women with PCOS.
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The use of anti-obesity drugs and bariatric surgery require further evaluation.
Introduction
The polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Based on the Rotterdam consensus workshop the prevalence of PCOS comes up to 15% .
Women with PCOS are overweight (35–80%; body mass index (BMI) above 25 kg/m ) or obese (20–69%; BMI above 30 kg/m ) and the rate is affected by various parameters including ethnicity . Obesity in women with PCOS not only involves the peripheral tissue but also a significant increase occurs in the intra-abdominal fat, which is independent of obesity .
Impact of obesity on reproduction
Women with PCOS, particularly those with regular menstruation, are not necessarily infertile. However, women with menstrual irregularities may have difficulties to conceive. The main cause of infertility in PCOS is the anovulation. Obesity seems to be an additional factor that contributes to the reduced fecundity . There are several mechanisms via which obese women with PCOS may have fertility problems.
Hyperandrogenism
Ovarian hyperandrogenism is a cardinal feature of PCOS. Intrinsic amplified steroidogenetic capacity of theca cells results in increased ovarian androgen secretion. Endocrine mechanisms may contribute to hyperandrogenism and these include pituitary luteinizing hormone (LH) hypersecretion, relative follicle-stimulating hormone (FSH) insufficiency, high levels of insulin and anti-Müllerian hormone (AMH) inhibiting aromatase activity. Ovarian hyperandrogenism in PCOS may arrest folliculogenesis through inhibition of granulosa cell proliferation and maturation, oestrogen and progesterone secretion, aromatase action and increase of 5a-reductase activity .
Obesity amplifies hyperandrogenism in PCOS resulting in increased total testosterone, free androgen index and decreased sex hormone-binding globulin (SHBG) . Obese women with PCOS exhibit a higher degree of insulin resistance and compensatory hyperinsulinaemia which contributes to androgen excess . It is obvious that obesity may deteriorate hyperandrogenism in women with PCOS, which is involved in anovulatory infertility.
Hypersecretion of LH
In women with PCOS, LH levels are frequently elevated due to anovulation and lack of progesterone and hyperandrogenaemia, which attenuates the progesterone negative feedback effect . However, obese PCOS women demonstrate a blunted LH secretion, through mechanisms acting at the pituitary and not the hypothalamic level . These mechanisms may involve insulin and leptin . According to the ceiling hypothesis, high LH levels in circulation may cause premature luteinization and anovulation . It seems than in lean but not obese women with PCOS, elevated LH is a significant mechanism of anovulation.
Hyperinsulinaemia
Obese women with PCOS demonstrate higher insulin resistance and hyperinsulinaemia than lean women with PCOS. Elevated insulin levels may cause premature maturation of granulosa cells, because they respond prematurely to LH (small follicles of 4 mm), which is in contrast to the normal response that occurs when follicles reach the 10-mm diameter . Furthermore, high insulin levels amplify LH-stimulated androgen secretion from the theca cells . A recent meta-analysis showed that obese/overweight PCOS women had lower insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels as compared to normal-weight PCOS women . This is another link between hyperinsulinaemia and hyperandrogenaemia, as it is known that insulin stimulates ovarian androgen synthesis through also its interaction with the IGF system and IGF-I potentiates LH-stimulated ovarian androgen synthesis, while this action may be negatively modulated by the IGFBP-1 . The role of hyperinsulinaemia is significant in deteriorating fertility in obese women with PCOS because when such women lose weight and subsequently become ovulatory they also have a reduction in insulin resistance and central adiposity .
Adipokines
Adipokines secreted by adipose tissue may mediate the deteriorating effects of obesity upon the phenotypic characteristics of women with PCOS. The roles of some of them are presented below:
Leptin
Leptin is secreted almost exclusively by the adipocytes and may serve as a link between fat tissue and the brain . Leptin may also have a role in reproductive function, acting at many levels of the hypothalamic–pituitary–ovarian (HPO) axis. In obese individuals, circulating leptin levels are high due to leptin resistance. Most studies have not shown significant differences in serum leptin levels in women with PCOS when compared with age- and weight-matched controls . Furthermore, circulating leptin levels did not differ significantly between ovulatory and anovulatory PCOS women . Similarly, PCOS did not appear to have an independent effect on the adipose expression of leptin mRNA and plasma levels . Current data do not suggest that leptin is significantly involved in the mechanisms that obesity deteriorates the PCOS phenotype.
Adiponectin
Adiponectin, a 30-kDa protein, is the most abundant serum adipokine, secreted exclusively by the adipose tissue. Adiponectin, in contrast to other adipokines, is down-regulated in obesity. Two meta-analyses showed that women with PCOS compared to normal women had lower levels of adiponectin, independently of body mass index (BMI) . Also, in obese as compared to lean women with PCOS, lower adiponectin concentrations have been found . Because adiponectin has direct insulin-sensitizing effects, additional decrease of adiponectin levels in obese PCOS women could intensify systemic insulin resistance and hyperinsulinaemia.
In vitro data have shown that adiponectin may reduce insulin-induced progesterone and androstenedione production as well as IGF 1-induced LH receptor, CYP11A1, and CYP17A1 gene expression in bovine theca cells, indicating a possible role of adiponectin in the pathophysiology of PCOS through the regulation of steroidogenesis . However, data regarding the relationship of circulatory levels of adiponectin to androgens are contradictory. Androgen excess has been suggested to directly influence adipocyte function by decreasing adiponectin secretion . Although it is currently unclear which is the triggering factor, it seems that a vicious circle is functional consisting of androgen excess favouring hypoadiponectinaemia which in turn facilitates ovarian androgen secretion.
Resistin
Resistin is a member of the cysteine-rich secretory proteins called ‘‘resistin-like molecules’’ (RELM) or ‘‘found in inflammatory zone’’ (FIZZ) and is secreted by adipocytes. Resistin is associated with insulin resistance in mice . Most, but not all, studies showed that resistin levels in blood are similar between PCOS and normal women. Besides, there was no difference of plasma resistin levels between PCOS and control women with or without insulin resistance . It has been suggested that resistin may have a local paracrine action in the regulation of insulin resistance in obesity and PCOS . However, blood resistin levels were similar among obese and non-obese women with PCOS . It seems that resistin is not a major mediator of obesity effects on PCOS phenotype.
Visfatin
Visfatin is mainly secreted from visceral adipose tissue, and has been shown to stimulate glucose uptake in adipocytes and muscle cells and suppress glucose release from adipocytes . A meta-analysis showed that plasma visfatin is higher in overweight/obesity, type 2 diabetes mellitus, metabolic syndrome and cardiovascular disease . Most, but not all, studies have shown increased visfatin levels in circulation of PCOS as compared to normal women . Further studies are needed to elucidate whether visfatin is implicated in the effects of obesity on PCOS.
Retinol-binding protein 4
Retinol-binding protein 4 (RBP4) is an adipokine secreted primarily by the liver and, to a lesser extent, by adipose tissue. RBP4 may be involved in the pathogenesis of insulin resistance. This adipokine may also herald the onset of the metabolic syndrome and studies in mouse have suggested that RBP4 plays a causative role in insulin resistance . Higher circulatory RBP4 levels have been found in PCOS women compared with controls. Furthermore, compared to controls, a significant up-regulation of RBP4 mRNA and higher protein levels in subcutaneous and omental adipose tissue were found in PCOS women . A correlation between RBP4 levels in blood and BMI in PCOS patients is inconclusive as yet in various studies. Therefore, more studies are needed to clarify the role of this adipokine in the obesity-induced deterioration of the characteristics of PCOS.
Impact of obesity on reproduction
Women with PCOS, particularly those with regular menstruation, are not necessarily infertile. However, women with menstrual irregularities may have difficulties to conceive. The main cause of infertility in PCOS is the anovulation. Obesity seems to be an additional factor that contributes to the reduced fecundity . There are several mechanisms via which obese women with PCOS may have fertility problems.
Hyperandrogenism
Ovarian hyperandrogenism is a cardinal feature of PCOS. Intrinsic amplified steroidogenetic capacity of theca cells results in increased ovarian androgen secretion. Endocrine mechanisms may contribute to hyperandrogenism and these include pituitary luteinizing hormone (LH) hypersecretion, relative follicle-stimulating hormone (FSH) insufficiency, high levels of insulin and anti-Müllerian hormone (AMH) inhibiting aromatase activity. Ovarian hyperandrogenism in PCOS may arrest folliculogenesis through inhibition of granulosa cell proliferation and maturation, oestrogen and progesterone secretion, aromatase action and increase of 5a-reductase activity .
Obesity amplifies hyperandrogenism in PCOS resulting in increased total testosterone, free androgen index and decreased sex hormone-binding globulin (SHBG) . Obese women with PCOS exhibit a higher degree of insulin resistance and compensatory hyperinsulinaemia which contributes to androgen excess . It is obvious that obesity may deteriorate hyperandrogenism in women with PCOS, which is involved in anovulatory infertility.
Hypersecretion of LH
In women with PCOS, LH levels are frequently elevated due to anovulation and lack of progesterone and hyperandrogenaemia, which attenuates the progesterone negative feedback effect . However, obese PCOS women demonstrate a blunted LH secretion, through mechanisms acting at the pituitary and not the hypothalamic level . These mechanisms may involve insulin and leptin . According to the ceiling hypothesis, high LH levels in circulation may cause premature luteinization and anovulation . It seems than in lean but not obese women with PCOS, elevated LH is a significant mechanism of anovulation.
Hyperinsulinaemia
Obese women with PCOS demonstrate higher insulin resistance and hyperinsulinaemia than lean women with PCOS. Elevated insulin levels may cause premature maturation of granulosa cells, because they respond prematurely to LH (small follicles of 4 mm), which is in contrast to the normal response that occurs when follicles reach the 10-mm diameter . Furthermore, high insulin levels amplify LH-stimulated androgen secretion from the theca cells . A recent meta-analysis showed that obese/overweight PCOS women had lower insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels as compared to normal-weight PCOS women . This is another link between hyperinsulinaemia and hyperandrogenaemia, as it is known that insulin stimulates ovarian androgen synthesis through also its interaction with the IGF system and IGF-I potentiates LH-stimulated ovarian androgen synthesis, while this action may be negatively modulated by the IGFBP-1 . The role of hyperinsulinaemia is significant in deteriorating fertility in obese women with PCOS because when such women lose weight and subsequently become ovulatory they also have a reduction in insulin resistance and central adiposity .
Adipokines
Adipokines secreted by adipose tissue may mediate the deteriorating effects of obesity upon the phenotypic characteristics of women with PCOS. The roles of some of them are presented below:
Leptin
Leptin is secreted almost exclusively by the adipocytes and may serve as a link between fat tissue and the brain . Leptin may also have a role in reproductive function, acting at many levels of the hypothalamic–pituitary–ovarian (HPO) axis. In obese individuals, circulating leptin levels are high due to leptin resistance. Most studies have not shown significant differences in serum leptin levels in women with PCOS when compared with age- and weight-matched controls . Furthermore, circulating leptin levels did not differ significantly between ovulatory and anovulatory PCOS women . Similarly, PCOS did not appear to have an independent effect on the adipose expression of leptin mRNA and plasma levels . Current data do not suggest that leptin is significantly involved in the mechanisms that obesity deteriorates the PCOS phenotype.
Adiponectin
Adiponectin, a 30-kDa protein, is the most abundant serum adipokine, secreted exclusively by the adipose tissue. Adiponectin, in contrast to other adipokines, is down-regulated in obesity. Two meta-analyses showed that women with PCOS compared to normal women had lower levels of adiponectin, independently of body mass index (BMI) . Also, in obese as compared to lean women with PCOS, lower adiponectin concentrations have been found . Because adiponectin has direct insulin-sensitizing effects, additional decrease of adiponectin levels in obese PCOS women could intensify systemic insulin resistance and hyperinsulinaemia.
In vitro data have shown that adiponectin may reduce insulin-induced progesterone and androstenedione production as well as IGF 1-induced LH receptor, CYP11A1, and CYP17A1 gene expression in bovine theca cells, indicating a possible role of adiponectin in the pathophysiology of PCOS through the regulation of steroidogenesis . However, data regarding the relationship of circulatory levels of adiponectin to androgens are contradictory. Androgen excess has been suggested to directly influence adipocyte function by decreasing adiponectin secretion . Although it is currently unclear which is the triggering factor, it seems that a vicious circle is functional consisting of androgen excess favouring hypoadiponectinaemia which in turn facilitates ovarian androgen secretion.
Resistin
Resistin is a member of the cysteine-rich secretory proteins called ‘‘resistin-like molecules’’ (RELM) or ‘‘found in inflammatory zone’’ (FIZZ) and is secreted by adipocytes. Resistin is associated with insulin resistance in mice . Most, but not all, studies showed that resistin levels in blood are similar between PCOS and normal women. Besides, there was no difference of plasma resistin levels between PCOS and control women with or without insulin resistance . It has been suggested that resistin may have a local paracrine action in the regulation of insulin resistance in obesity and PCOS . However, blood resistin levels were similar among obese and non-obese women with PCOS . It seems that resistin is not a major mediator of obesity effects on PCOS phenotype.
Visfatin
Visfatin is mainly secreted from visceral adipose tissue, and has been shown to stimulate glucose uptake in adipocytes and muscle cells and suppress glucose release from adipocytes . A meta-analysis showed that plasma visfatin is higher in overweight/obesity, type 2 diabetes mellitus, metabolic syndrome and cardiovascular disease . Most, but not all, studies have shown increased visfatin levels in circulation of PCOS as compared to normal women . Further studies are needed to elucidate whether visfatin is implicated in the effects of obesity on PCOS.
Retinol-binding protein 4
Retinol-binding protein 4 (RBP4) is an adipokine secreted primarily by the liver and, to a lesser extent, by adipose tissue. RBP4 may be involved in the pathogenesis of insulin resistance. This adipokine may also herald the onset of the metabolic syndrome and studies in mouse have suggested that RBP4 plays a causative role in insulin resistance . Higher circulatory RBP4 levels have been found in PCOS women compared with controls. Furthermore, compared to controls, a significant up-regulation of RBP4 mRNA and higher protein levels in subcutaneous and omental adipose tissue were found in PCOS women . A correlation between RBP4 levels in blood and BMI in PCOS patients is inconclusive as yet in various studies. Therefore, more studies are needed to clarify the role of this adipokine in the obesity-induced deterioration of the characteristics of PCOS.
Impact of obesity on infertility treatment
Ovulation induction is the treatment of choice for anovulatory infertility in women with PCOS . The first line of treatment is diet and lifestyle changes. This, however, is time consuming and on several occasions the women do not comply. Several pharmaceutical compounds are used for ovulation induction in PCOS. The extent to which excessive body fat can affect the treatment outcome during ovulation induction in PCOS has not been fully addressed.
Diet and lifestyle changes
Exercise combined with energy-restricted diet is the preferred method that can restore the disturbed reproductive function in obese women with PCOS. Although the mechanism is not fully understood, recent data have suggested that in overweight and obese women with PCOS dietary management and exercise, alone or in combination, improve reproductive function possibly via an insulin sensitivity-enhancing mechanism and may affect serum AMH levels .
Body weight reduction during the periconceptual period might have an impact on the conceptus. It is advisable, therefore, that an attempt to lose weight via various methods to be completed before the achievement of a pregnancy .
Clomiphene citrate
Clomiphene citrate is considered the first-line treatment for ovulation induction in anovulatory infertile women with PCOS . In properly selected PCOS patients, the cumulative pregnancy rate after six cycles of treatment exceeds 60% and after 10 cycles 90% .
Clomiphene resistance, that is, the inability of the ovaries to respond to this drug during 6 months treatment, has been associated with various hormonal and clinical characteristics of the women including BMI . It has been recently shown that structured exercise training combined with a hypocaloric diet for 6 weeks was adequate to increase the response to clomiphene and the ovulation rate in overweight and obese PCOS patients .
Aromatase inhibitors
Letrozole is the main representative of this category that is used in clinical practice. Letrozole and clomiphene are equally effective in inducing ovulation in women with PCOS . However, due to possible teratogenic effects, letrozole is regarded as an ‘off-label’ medication for infertility treatment, an issue however that has been debated . Regarding the role of BMI, data are limited. A recent study has shown no difference in the outcome between women with a BMI <30 kg/m 2 and BMI ≥30 kg/m 2 .
Low-dose FSH
Low-dose protocols of human menopausal gonadotrophin (HMG) or FSH (step-up and step-down) are used as second-line treatment for ovulation induction in PCOS in case of clomiphene resistance or failure . With the step-up protocol, mono-ovulation takes place in about 70% of the cycles . High cumulative pregnancy and live birth rates have been reported following ovulation induction in anovulatory women with clomiphene and low-dose FSH .
The effectiveness of treatment with gonadotrophins in PCOS is affected by various parameters including BMI. In a retrospective analysis of data, women with BMI >28 kg/m 2 undergoing ovulation induction showed a lower ovulation rate and an increased miscarriage rate than normal controls, although the proportion of women who became pregnant was similar with that of women with normal BMI . It has been found that obese as compared to lean women require higher doses of gonadotrophins possibly due to the higher number of immature follicles and the higher insulin resistance and free androgen index . Nevertheless, in the step-up protocol a rather complicated prediction model has been proposed that precludes its use in daily practice. In this context, the predicted FSH dose was found to be higher than the observed response dose . Similarly, the individual effective dose of FSH was calculated in the step-down protocol based on various characteristics such as BMI, clomiphene resistance or failure, free IGF-I, and FSH . It is evident that, although BMI plays a critical role in the prediction of the outcome of treatment with ovulation induction in PCOS, a quantitative approach to the real effect has not been investigated.
Laparoscopic ovarian drilling
Laparoscopic ovarian drilling (LOD) is considered a second-line treatment in women with PCOS, which competes with FSH in case of clomiphene resistance. An extremely low multiple pregnancy rate has been shown with LOD.
Obesity seems to affect the effectiveness of LOD, as it has been shown in a retrospective study of 200 PCOS patients, pre-treated with clomiphene unsuccessfully . According to that study, in women with a BMI ≥35 kg/m 2 ovulation and pregnancy rates were significantly lower as compared to moderately overweight and normal-weight women. It was shown however, that BMI did not have any influence on the conception once ovulation was achieved.
Insulin sensitizers
Insulin resistance is one of the characteristics of obese women with PCOS. Insulin sensitizers are used in clinical practice to increase the sensitivity of these women to insulin. The most important representative of this category of drugs is metformin. Prospective randomized trials have demonstrated that metformin used as first-line treatment for ovulation induction in PCOS is inferior to clomiphene in terms of live birth rate . According to more recent data, metformin might be effective in combination with clomiphene in women with clomiphene resistance .
As insulin resistance is a characteristic of the obese women, not unexpectedly, treatment with metformin improved the metabolic and reproductive function . Nevertheless, it was shown recently that the possibility to achieve a pregnancy while on metformin was greater in women with a lower than with a higher BMI . In this context, metformin could be used as a first-line treatment in women with a BMI<32 kg/m 2 . However, a recent meta-analysis demonstrated that in such women metformin is not better than clomiphene as first-line treatment . It has been recommended, due to the non-significant improvement in outcomes, to use metformin only in cases with an impaired glucose tolerance .
In vitro fertilization
In vitro fertilization (IVF) is a third-line treatment for PCOS unless other infertility factors are present. Regarding the efficacy of treatment, it seems that there is no significant difference in fertilization, pregnancy and live birth rates as compared to controls, although a higher number of oocytes is usually recovered in PCOS . In IVF/intracytoplasmic sperm injection (ICSI) cycles, obesity and PCOS were found to independently decrease oocyte size . An increased miscarriage rate was found in a mixed population of obese women undergoing IVF/ICSI as compared to women with normal weight, while a tendency for a higher miscarriage rate was found in women with a BMI >25 kg/m 2 regardless of the mode of conception. Although obese women with PCOS require higher amounts of gonadotrophins for ovarian stimulation, the ideal protocol has not been identified. On the other hand, metformin administration at any stage of the IVF treatment did not improve pregnancy and live birth rates, except that the risk of the ovarian hyperstimulation syndrome (OHSS) was significantly reduced .
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