The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.
Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and/or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.
Definition of the polycystic ovary syndrome
The polycystic ovary syndrome (PCOS), one of the most common causes of ovulatory infertility, affects 1–5% of women. Over the years, after the first description by Stein and Leventhal in 1935,1 this syndrome has been defined in different ways. Finally, in 1990 the National Institutes of Health (NIH) established the new diagnostic criteria for this disorder, which are based on the presence of hyperandrogenism and chronic oligo-anovulation, with the exclusion of other causes of hyperandrogenism such as adult-onset congenital adrenal hyperplasia (CAH), hyperprolactinemia and androgen-secreting neoplasms.2 The observation of an increased prevalence of PCOS among family members as compared to the general population favored the hypothesis that, at the basis of this syndrome, a genetic component may exist whose inheritance is still a matter of controversy.3 However, the heterogeneous clinical characteristics of this syndrome indicate that a more complex interaction between genetic and environmental factors may cause this disorder.3
Several features of the ‘metabolic syndrome’, particularly insulin resistance and hyperinsulinemia, are inconsistently present in the majority of women with PCOS. This represents an important factor in the evaluation of PCOS throughout life, and implies that the PCOS by itself may not be a hyperandrogenic disorder exclusively related to young and fertile women, but may have some health implications later in life.4 Obesity is very common clinical feature in women affected by PCOS. In fact, approximately 50% of PCOS women are overweight or obese5 and the history of the weight gain frequently precedes the onset of oligomenorrhea and hyperandrogenism, suggesting a pathogenetic role of obesity in the subsequent development of the syndrome. Interestingly, some recent data have introduced the idea that in obese PCOS women the disorder may originate during intrauterine life, depending on the mother and also on birth weight.6 However, this fascinating hypothesis needs to be validated by further studies.
This review will try to highlight the pathophysiological mechanisms by which obesity may influence PCOS development and/or maintenance. In addition, we will summarize the modern concepts in the management of the obese PCOS.
Pathogenetic mechanisms by which obesity may promote or maintain PCOS
Together with the well-known actions at the level of classical target organs such as liver, adipose tissue and muscles, insulin plays a role in the regulation of other tissues/organs, particularly the ovary, besides the pituitary and the adrenal gland. At ovarian level, insulin acts by interacting with its own receptor and by the insulin growth factor (IGF) receptor type I, which have been detected in human models throughout all ovarian compartments, as granulosa, thecal and stromal tissues.7 It has also been definitively proved that insulin is able to stimulate ovarian steroidogenesis both in granulosa and thecal cells. In fact, insulin increases 17α-hydroxylase and 17–20 lyase (both components of the P450c17 enzyme system) activity8 and stimulates the expression of 3β-hydroxysteroid dehydrogenase in human luteinized granulosa cells.9 Conversely, the role of insulin on aromatase activity is rather discordant, in vitro studies having demonstrated either a stimulatory10 or a lack of effect.9 In addition, insulin appears to increase the sensitivity of pituitary gonadotropes to gonadotropin releasing hormone (GnRH) action7 and to potentiate the ovarian steroidogenic response to gonadotropins, by mechanisms probably related to an increase of the luteinizing hormone (LH) receptor number.7 Moreover, insulin is able to inhibit hepatic sex hormone binding globulin (SHBG) synthesis11 and both hepatic and ovarian IGF binding protein-1 (IGFBP-1) synthesis, which bind sex steroids and IGFs, respectively,12 to regulate ovarian growth and cyst formation7 and to modulate adrenal steroidogenesis. In vitro studies have shown that insulin may also increase 17α-hydroxylase and 17–20 lyase activity in the adrenals either directly13 or potentiating the responsivity of the enzyme to adrenocorticotropin hormone (ACTH) stimulation.14
The findings described above, together with the clinical evidence that a huge number of PCOS women show a condition of insulin resistance and hyperinsulinemia, suggested that insulin may play a pivotal role in the promotion or the maintenance of PCOS.7,15 The link between hyperinsulinemia and hyperandrogenism in PCOS women is summarized in Table 1. A molecular cause of insulin resistance has been identified as an excessive phosphorylation of serine residues of the insulin receptor. This molecular defect, which has been described in at least 50% of PCOS women,15 reduces the tyrosine kinase activity of the insulin receptor, thereby decreasing the signal transduction pathway. Alternatively, mechanisms such as mutations in insulin receptor gene or insulin receptor substrate-1 (IRS-1), an intracellular protein phosphorylated under the influence of the insulin-receptor tyrosine kinase,16,17 a cellular adenosine depletion,18 a deficiency in peroxisome proliferator-activated receptor-γ (PPAR-γ)19 or a defect at the post binding level, involving glucose transport,16 have also been proposed. In the presence of peripheral insulin resistance, pancreatic β cell insulin secretion increases in a compensatory fashion, leading to a hyperinsulinemic state.20 In addition, primary alterations of insulin secretion independent of the presence of insulin resistance,21 as well as defective insulin clearance in peripheral tissues, have been reported in PCOS.22 By these mechanisms the hyperinsulinemic state can be further increased. Interestingly, although in classical peripheral tissues insulin is able to down-regulate its receptors,23 their expression is conversely preserved in the ovary even in the presence of insulin resistance and hyperinsulinemia,7 probably by the interaction between insulin and other regulatory factors such as gonadotropins, sex steroids, IGFs and IGF binding proteins (IGFBPs).24 On the other hand, insulin may amplify its effect during the insulin resistance state by upregulating the IGF receptor type I.7
Some aspects of insulin action in obesity resemble those seen in PCOS. Many patients with obesity are insulin resistant and hyperinsulinemic, particularly when the abdominal phenotype is present. The mechanisms by which obesity may induce an insulin-resistance state have been extensively summarized elsewhere.25 Briefly, enlargement of adipose tissue mass, in particular of visceral fat depot, increases the availability of several metabolites (ie free fatty acids (FFA), lactate, etc), which are able to affect the secretion and the metabolism of insulin as well as its peripheral action.26 Insulin resistance in obesity can also be related to tumor necrosis factor-α (TNF-α) and to leptin, both products of adipose tissue. TNF-α mediates serine phosphorylation of IRS-1,27 which has been shown to interfere with the action of both insulin and IGF-I, by inhibiting insulin receptor and type I IGF receptor tyrosine kinases respectively, and by stimulating IGFBP production.7 TNF-α can also inhibit signaling through PPAR-γ.7 Leptin may contribute to the insulin resistance of obesity via mechanisms similar to TNF-α.7 The impact of obesity on insulin resistance and hyperinsulinemia in PCOS is reviewed in the paragraph on Metabolic abnormalities. To summarize, obesity seems to amplify the degree of insulin resistance and hyperinsulinemia in PCOS. In fact, although insulin resistance has been described to affect obese and also most normal-weight PCOS women, obese women, particularly those with the abdominal obesity phenotype, are usually more insulin resistant and more hyperinsulinemic than their normal-weight counterparts.5,18
These findings therefore indicate that obesity may substantially contribute to determine the insulin resistant state in PCOS. However, the possibility that a component of insulin resistance in PCOS women may be present regardless of the obese state cannot be excluded.
Growth hormone (GH)-IGFs
IGF-I and IGF-II are well known effectors of ovarian functions. They exert their action through activation of two types of receptors as type I and II, which are present in granulosa, theca and stroma cells of the human ovary.28 The ovarian effects of both IGF-I and IGF-II in humans are summarized in Table 2. Briefly, they are able to stimulate ovarian progesterone (P) and oestradiol (E2) secretion and to increase the aromatase activity7 and androgen production in granulosa–luteal and thecal human cells, respectively.29 Activation of both type I and type II IGF receptors has also been associated with a reduction of IGFBP peripheral levels, as a result of an inhibition of IGFBP-1 and IGFBP-2 production and of an increased activity of IGFBP protease. A reduction of IGFBP level may increase the bioavailability of IGFs, inducing as a net effect a more potent stimulus of IGF-I and IGF-II at the level of target tissues. The IGF/IGFBP system is regulated by insulin. In particular, insulin amplifies the effects of itself and of IGFs as well by increasing the number of type I IGF receptors. Insulin is also able to inhibit IGFBP-1 production, leading to a further increase in bioavailable IGFs. Thus, hyperinsulinemia may lead to a self-perpetuating cycle of events resulting in the exaggeration of the effects of both insulin and IGFs at ovarian level. No differences in serum IGF-I and IGF-II levels between PCOS and non-affected control women have been described, regardless of body weight, but obese PCOS women have lower serum IGFBP-1 levels than their normal-weight counterparts.7 This probably represents an insulin-related effect, as a negative correlation between insulin levels and serum IGFBP-1 concentration has been described.7 However, serum IGF bioavailability is higher in normal-weight than obese PCOS women.30 This is probably due to differences in GH levels between non-obese and obese PCOS women. In fact, the occurrence of an increase in GH pulse amplitude, mainly attributed to an increased pituitary stimulation by the hypothalamic growth hormone releasing hormone (GHRH) has been demonstrated in normal-weight PCOS women.31 Conversely, a reduction of GH pulse amplitude and of 24 h mean GH levels, probably caused by a decreased GH response to GHRH stimulation, has been observed in obese PCOS patients.31 Similar findings have been found in obese non-PCOS women, therefore suggesting that the development of hyposomatotropinism in obese PCOS women may be an obesity-dependent event.32 In addition, in obese subjects an increased GH metabolic clearance rate has been described.33 Although mechanisms have not been fully elucidated, there is evidence that elevated FFA levels and increased insulin levels may play a pivotal role in determining reduced GH levels in obesity. Therefore, it is realistic to speculate that similar mechanisms may play a role in obese PCOS women.
In summary, IGFs may be involved in the pathogenesis of the hyperandrogenism in the PCOS. In normal-weight PCOS women IGF bioavailability seems to be increased by various mechanisms such as insulin-induced hepatic and ovary IGFBP-1 suppression and GH-induced hepatic IGF stimulation.30 On the contrary, in obese PCOS, IGF-1 bioavailability seems to be reduced in comparison to their normal-weight PCOS counterpart, although relatively higher than in non-affected women because of the combination of low GH and high insulin levels. Therefore, the IGF/IGFBP system in obese PCOS women seems to be differently expressed with respect to their normal-weight counterpart, suggesting a different pathogenetic impact of this system in obese and non-obese PCOS women. In particular, it could be suggested that insulin resistance and hyperinsulinemia may play a central role in obese PCOS patients, whereas abnormalities of the IGF-IGFBP system may be important in normal-weight PCOS women.
SHBG is a glycoprotein produced in the liver acting as a carrier for different sexual steroid hormones. SHBG displays a higher binding affinity for testosterone (T) and dihydrotestosterone (DHT) and a lower affinity for E2.34 The concentrations of SHBG are stimulated by a number of factors such as cortisol, estrogens, iodothyronines and GH, and decreased by androgens, insulin, prolactin and IGF-I.35 Dietary factors may also affect SHBG concentrations, since both short-term and long-term high lipid intake have been shown to decrease SHBG serum levels.5 Mechanisms by which high lipid intake decreases SHBG concentrations are still unknown, even if a role of the increasing insulin levels after such diets has been proposed to explain this clinical finding. Decreased basal SHBG concentrations are detected in PCOS women, with a more pronounced SHBG reduction found in obese PCOS, and in particular in obese women presenting the abdominal phenotype.5 Due to its inhibiting effect on SHBG synthesis in the liver, insulin plays a dominant role in reducing SHBG levels in insulin-resistant PCOS patients, particularly in those with abdominal obesity.11 A number of physiopathological36 and epidemiological studies37 showed a significant negative correlation between SHBG and insulin blood levels in different physiological and pathological conditions. Lower SHBG levels in obese PCOS women may, in turn, be responsible for increased bioavailability of sex hormones at the level of target tissues. Theoretically, this may, in turn, be partly responsible for the development of the abdominal obesity phenotype. In fact, exposure to androgens has been found to increase visceral fat in either obese and normal-weight post-menopausal women.38
In summary, obesity, particularly the abdominal phenotype, may directly worsen hyperandrogenism in women with PCOS by reducing SHBG serum levels, therefore increasing the delivery of free androgens at the level of peripheral tissues. This can be explained by the degree of prevailing hyperinsulinemia and, possibly, by other factors, including dietary lipids.
A key step in androgen formation is the regulation of P450c17 enzyme which is located in the ovarian theca-interstitial cells and in the adrenal gland.38 Expression and activation of P450c17 gene in ovary and/or adrenal cortex is regulated by a number of hormones or growth factors including LH, ACTH, insulin and IGFs.38 Hyperactivity of the P450c17 enzyme represents the main mechanism leading to ovarian hyperandrogenism occurring in the great majority of PCOS patients.38 Whether hyperactivity of the P450c17 enzyme system is a primary event or secondary to peripheral or central factors is still unclear. The role of neuroendocrine factors, particularly LH, will be discussed below, whereas that of peripheral factors, including insulin and the IGF/IGFBP system, has been described above. Briefly, increased insulin and free IGF bioavailability in PCOS women can produce hyperandrogenism directly by stimulating ovarian androgen production. As discussed elsewhere, insulin also decreases levels of SHBG, with elevation of free androgens, and amplifies the ovary LH effect. In addition, insulin and IGFs may affect follicle maturation and atresia. In fact, both insulin and IGFs seem to be involved in the interruption of the normal follicle maturation favouring the formation of atretic follicles.7 The granulosa cell maturation arrest and the resulting deficient aromatase activity of atretic follicles may, in turn, be directly responsible for the increased ovarian androgen secretion. Other factors, such as the follicle stimulating hormone (FSH)-inducible inhibin–follistatin–activin system, produced by the granulosa cell and acting on the theca cell, may be implied in the dysregulation of ovarian steroidogenesis in PCOS women. Indeed, some in vitro studies have demonstrated that inhibin stimulates ovarian androgen production.39 As reported above, a phosphorylation of serine residues of the insulin receptor15 may be a factor leading to insulin insensitivity and, therefore, compensatory hyperinsulinemia in PCOS women. Interestingly, the same disorder seems to be responsible for the increased activity of the human P450c17 system as well.40 Therefore, the serine phosphorylation of both the P450c17 enzymatic system and the insulin receptor may represent a single primary genetic disorder which may contribute to explain the association between hyperandrogenism and insulin resistance in PCOS women.15
Hyperandrogenism of adrenal origin often coexists with that of ovarian origin in many PCOS women. Provided classical forms of CAH are excluded, mechanisms by which an increase in androgen synthesis occurs in the adrenal gland are still unknown, although central and peripheral factors have been variously proposed to explain it. Central factors may involve a pituitary hyper-responsiveness to corticotropin releasing hormone (CRH).41 Among peripheral factors, insulin seems to exert an important role, by its ability to increase the activity of 17α-hydroxylase and 17–20 lyase in the adrenals both directly13 and through a facilitation of ACTH stimulation.14 Interleukin-6 (IL-6) has also been proposed to modulate intra-adrenal steroidogenesis, by the ability of this cytokine to increase DHEA secretion.38 An interesting hypothesis was produced by Rodin and collegues,42 who reported that the activity of 11β-hydroxysteroid dehydrogenase enzyme, which interconverts cortisol to its inactive compound cortisone, may be increased in PCOS women. The enhanced oxidation of cortisol in PCOS may result in compensatory overstimulation of the hypothalamic–pituitary–adrenal (HPA) axis that could, in turn, increase the adrenal androgen formation. Similarly to these findings in PCOS subjects, an altered cortisol metabolism has also been detected in obese patients.43
Obesity seems to amplify the degree of hyperandrogenism in PCOS. Previous studies have shown that obese PCOS women have total44 and free T45 levels higher with respect to non-obese PCOS. Abdominal obesity may also further worsen the hyperandrogenic state in PCOS women.46,47 This is not an unexpected finding, since the increase of body weight and fat tissue in women is associated with several abnormalities of sex steroid balance. Such changes involve androgens and SHBG, their main carrier protein. Obese women have increased androgen production associated with an enhanced metabolic clearance rate, although the balance of these alterations allows the maintenance of normal circulating androgen levels.5,48 However, the percentage of free androgen fraction tends to be higher in obesity, particularly in the abdominal phenotype, due to the reduction of SHBG concentration.49 Abdominal obesity could therefore be defined as a condition of a relative ‘functional hyperandrogenism’.
Hyperandrogenism per se may play a role in favouring insulin resistance and the simultaneous development of the abdominal obesity phenotype in PCOS women. In fact, androgens may induce the insulin-resistance state both through the activation of the lipolytic cascade, leading to an increased serum FFA release, and the modification of the muscle histological structure. The local stimulation of FFA efflux is mainly described to occur in the visceral fat depot, due to the high androgen receptor density present at this level.50 The direct effect of T at the level of muscle structure has been described in female rats51 where the administration of T induced a decrease in red, oxidative, insulin-sensitive, type I muscle fibers, an increase in white, glycolytic type II less insulin-sensitive fibers, a reduction of capillary density and an inhibition of glycogen synthase system. Such alterations have been subsequently confirmed in biopsies derived from women affected by hyperandrogenism and severe insulin resistance state.52 The close interaction between hyperandrogenism and development of insulin resistance state has been further confirmed by the results obtained in clinical trials in which administration of antiandrogen therapy such as flutamide and spironolactone led to a partial but significant improvement of the insulin-resistance state.53,54,55 Altogether, these data seem to definitively point to an important role of hyperandrogenism in the development of insulin resistance in PCOS women. Thus, a vicious circle between hyperandrogenism and hyperinsulinemia could be suggested to represent the specific biological basis for the development of the obese-PCOS phenotype in women.
In summary, obesity further increases the degree of hyperandrogenism in PCOS women. Consequently, obese PCOS women tend to be more hyperandrogenic than their normal-weight counterparts. Specific mechanisms of action of obesity include more severe hyperinsulinism, more reduced SHBG concentrations and, probably, alterations of the cortisol–cortisone metabolic pathways. The role of leptin in this context is still under debate. In fact, leptin appears to directly stimulate ovarian 17α-hydroxylase activity.56 However, whether leptin excess could play a role in the development of the hyperandrogenism in obese PCOS women remains to be elucidated by future studies.
In women with PCOS, high levels of estrone (E1) and of free E2 have been detected as a result, at least in part, of reduced concentrations of SHBG.34 The acyclic production of extraglandular estrogen may lead to a positive feedback on LH secretion and a negative feedback on FSH secretion, giving an increase of the circulating LH/FSH ratio.57 The elevated levels of LH substantially contribute to the development of hyperplasia of the ovarian stroma and thecal cells, further increasing androgen production and in turn providing more substrate for extraglandular aromatization and perpetuation of chronic anovulation. Obesity per se represents a condition of ‘functional hyperestrogenism’. In fact, the estrogen production rate positively correlates with body weight and the amount of body fat.5 Moreover, due to reduced SHBG synthesis and lower circulating SHBG concentrations, the free E2 fraction increases in obese women, thus enhancing exposure of target tissues to unbound estrogens.5 Estrogen metabolism is also altered in obese women, due to a decreased formation of inactive E2 metabolites, specifically 2-hydroxyestrogens, and to a higher production of E1 sulfate.5 As a final result, an increased balance of active to inactive estrogens is often detected in obese subjects. This may represent an additional mechanism amplifying the positive feedback on LH secretion, therefore favouring increased ovarian androgen synthesis, at least in selected obese PCOS women. However, as discussed below, this still represents a controversial issue.
An elevation of circulating LH concentration is inconsistently found in PCOS women and seems to occur as a result of a GnRH-mediated increase in the amplitude and frequency of pulsatile LH secretory pattern.58,59 On the other hand, an increased LH bioactivity is an almost invariable feature of PCOS, but the mechanism responsible for this alteration still remains unclear.60 It is a matter of debate whether the increase of gonadotrophins, when present, may be attributed to a primary abnormality of the hypothalamic–pituitary axis or may be secondary to alterations in peripheral signaling. As reported in the previous paragraph, the elevation of circulating LH concentration may be due to inappropriate estrogen feed-back to neuroendocrine centers.57 In particular, several data seem to indicate that hyperoestrogenemia not counteracted by P, as occurs during anovulation state, may favor the LH hyper-responsiveness to GnRH.59 In fact, both spontaneous ovulation or exogenous P administration are associated with a normalization of LH secretion in PCOS women.58 Whether this mechanism may be operative in obese women with PCOS remains, however, a matter for speculation. In fact, several studies61,62 found a negative correlation between LH and body weight in PCOS women, possibly depending on reduced LH pulse amplitude and reduced LH response to GnRH.62 Potential factors involved in the different LH pituitary secretion between normal-weight and obese PCOS women may be insulin and neurotrasmitters such as β-endorphin and catecholamines.59 In fact, a significant correlation between insulin and LH levels has been found in PCOS women. Moreover, increased opioid tone and reduced dopaminergic tone have also been described.59 Some authors have also proposed that fat-associated factors, such as leptin, acting at hypothalamic or pituitary level, may dampen LH secretion in the obese state.58
Clinical studies have repeatedly shown that obese PCOS women are characterized by significantly lower LH concentrations than their normal-weight counterparts61,62 and that, in very obese PCOS women, LH concentrations frequently resemble the normal range.62
Altogether, these data seem to indicate that increased LH secretion does not play a pivotal pathogenetic role in the majority of obese PCOS women. On the other hand, the impact of obesity in LH pulse amplitude and frequency is difficult to define, due to the lack of studies on LH pulsatility secretion in PCOS women according to different body weight and obesity phenotype.
PCOS women are characterized by increased levels of plasma immunoreactive β-endorphin.5 In humans β-endorphin administration increases insulin secretion from β cells.63 An inhibition of the opioid tone may induce a decreased hyperinsulinemia in PCOS women as a consequence of reduced insulin secretion and improved hepatic clearance.64 In addition, β-endorphin administration reduces LH release in normal women but not in PCOS women, suggesting a condition of β-endorphin resistance in the PCOS.5
Obesity by itself is characterized by an increased opioid system activity.5 Moreover, infusion of physiological doses of β-endorphin has been found to induce a significant increase in insulin concentration in obese but not in normal-weight subjects, suggesting β cell hypersensitivity to opioids in the obese state.65 In addition, both acute and chronic administration of opioid antagonists, such as naloxone and naltrexone, are able to suppress both basal and glucose-stimulated insulin blood concentrations in obese women, particularly in those with the abdominal phenotype,66 but not in normal-weight controls. An increased β-endorphin response to acute CRH administration has also been found in women with abdominal obesity.67 However, there are no studies investigating the net contribution of obesity to the opioid tone and its ability to regulate insulin in PCOS women.
As reported above, many PCOS women present with increased adrenal androgen concentrations. This suggests that in these patients a dysregulation of the HPA axis may exist. The aforementioned data produced by Rodin and colleagues42 suggest that in PCOS women an increased catabolism of cortisol may determine a compensatory hyperactivation of the HPA axis with the subsequent increased androgen formation by the adrenal gland. According to an increased response of adrenal androgens68 and of ACTH and cortisol41 to CRH administration the existence of a PCOS women subset has been proposed. Mechanisms for the exaggerated response of ACTH to hCRH in PCOS women remain unknown. However, according to the ability of somatostatin analog treatment to abrogate ACTH hyperesponsiveness after CRH challenge69 some authors proposed a role for somatostatin in determining this dysregulation. Obesity, particularly the abdominal phenotype, is also characterized by a hyperactivity of the HPA axis (reviewed in Pasquali and Vicennati67). Two distinct alterations have been proposed. The first, which appears to be central in origin, is characterized by altered ACTH pulsatile secretory dynamics, hyper-responsiveness of the HPA axis to different neuropeptides and acute stress events, dysregulation of the noradrenergic control of the CRH–ACTH system and, possibly, to distinct dietary factors. The other appears to be located in the periphery, namely the visceral adipose tissue, which is characterized by elevated cortisol traffic and increased cortisol clearance, due to the influence of several distinct factors, including alterations of the enzymes involved in cortisol metabolism. In addition, it is well known that P is able to interact with glucocorticoid receptors,50 therefore high P concentrations, such as those found during the luteal phase of the menstrual cycle, by competing with cortisol, may reduce the effects of this hormone and further activate the HPA axis. This assumption is confirmed by the finding that in obese women with irregular or absent ovulation, an impairment in the cortisol activity is frequently detected.50
In summary, in both PCOS and abdominal obese women several alterations of the HPA axis may be present. The high prevalence of abdominal obesity in PCOS seems to suggest a potential linkage between abdominal obesity and abnormalities of HPA axis in PCOS women. However, more detailed studies are needed to discriminate the single contribution of PCOS and obesity, respectively, in causing a disturbance of the HPA axis.
Diet is a well-known factor playing a role in the regulation of sex steroid metabolism. Several studies have demonstrated that high-lipid and low-fiber diet is related to an increase in androgen circulating levels.5 Moreover, as reported above, very high lipid intake has been found to decrease SHBG blood levels and increase free androgen index.5,70 In some reports PCOS women were found to have a higher intake of saturated lipids and a lower intake of fibers when compared to control groups.71 Low-fiber and high-lipid intake has been considered one of the nutritional factors which favour the onset and development of obesity in industrialized countries.72
Therefore, it can be speculated that a low-fiber–high-lipid diet may act negatively on sex steroid metabolism in selected groups of PCOS women, by increasing androgen availability and by favouring the development of obesity.
Clinical features of obese women with PCOS
Various studies evaluated the impact of obesity on the hyperandrogenic state in women with PCOS. They uniformly demonstrate that obese PCOS women are characterized by significantly lower SHBG plasma levels31,44,45 and worsened hyperandrogenism45 in comparison with their normal-weight counterparts. In addition, a negative correlation between body fat mass and circulating androgens has been reported in other studies.5,7 Moreover, it has been repeatedly described that a higher proportion of obese PCOS women complained of hirsutism and menstrual disturbances than normal-weight women did.45
Therefore, there is consistent evidence that the increase of body weight may favour a worsened hyperandrogenic state in women with PCOS.
PCOS women are characterized by a high prevalence of several metabolic abnormalities which are strongly influenced by the presence of obesity. Adequate confirmation on the genuine role of obesity in determining hyperinsulinemia and insulin resistance in women with PCOS derives from studies comparing groups of normal-weight and obese PCOS women. Both fasting31,44,73,74 and glucose-stimulated31,75 insulin concentrations are in fact significantly higher in obese than in non-obese PCOS subgroups. Accordingly, studies examining insulin sensitivity by using different methods such as the euglycemic hyperinsulinemic clamp technique,44,75 the frequent sample intravenous glucose test (FSivGT)31,74 and the insulin test76 further demonstrated that obese PCOS women had significantly lower insulin sensitivity than their non-obese PCOS counterparts and, therefore, a more severe insulin-resistant state. The percentage of women affected by PCOS and obesity presenting glucose intolerance is rather high, ranging from 20 to 49%,15 therefore substantially above the prevalence rates reported in premenopausal women in population-based studies. On the contrary, glucose intolerance in normal-weight PCOS women is uncommon.15 Altogether, this may indicate that obesity per se plays an important role in altering the insulin–glucose system in PCOS. In addition, several recent studies identified some defects of insulin secretion in obese women with PCOS.31,74 Using the FSivGT, Dunaif and colleagues74 reported that obese PCOS women may present inadequate insulin secretion to compensate for the peripheral insulin resistance state, suggesting a relative β cell dysfunction with respect to that expected based on the degree of insulin resistance. However, regardless of alterations of insulin secretion, in a 10 y follow-up study we found that both fasting and glucose-stimulated insulin and C-peptide tended to further significantly increase in PCOS women, suggesting a worsened insulin resistant state with time.77 In the same study we also found that several women developed impaired glucose tolerance. Longitudinal data are therefore warranted to investigate which factor, namely progressive insulin resistance and/or subtle alterations of insulin secretion, may predict the well-documented susceptibility of obese PCOS women toward type 2 diabetes.4 Although PCOS per se may be associated with alterations of both lipid and lipoprotein metabolism, the presence of obesity usually leads to a more atherogenic lipoprotein pattern. A greater reduction of high-density lipoproteins (HDL)s44,73 together with a higher increase of both triglycerides44,67,73 and total cholesterol44 levels were in fact observed in obese with respect to the normal-weight PCOS women.
Menses abnormalities and fertility
PCOS is one of the most common causes of anovulation and endocrine infertility in women.78 Several studies have clearly demonstrated that menses abnormalities are more frequent in obese than normal-weight PCOS women.45,79 Moreover, there is evidence that a reduced incidence of pregnancy and blunted responsiveness to pharmacological treatments to induce ovulation may be more common in obese PCOS.78 In a prospective study carried out among 158 anovulatory women, the dose of clomiphene required to achieve ovulation was positively correlated with body weight.80 Both insulin resistance and hyperinsulinemia, which parallel the increase of body fat, may be responsible for the alteration of both spontaneous and induced ovulation observed in the obese PCOS women. Administration of insulin sensitizing agents, such as metformin81,82 and troglitazone83 was in fact associated with improved menstrual cyclicity in women with PCOS. Moreover, a recent double-blind placebo-controlled collaborative study, performed in a large cohort of PCOS women,84 demonstrated that short-term metformin treatment increased both spontaneous and particularly low dose (50 mg daily for 5 days) clomiphene-induced ovulation rate. It has also been found that, compared to normal-weight, obese PCOS women may have lower ovulatory response to pulsatile GnRH analog administration.85 Accordingly, the pregnancy rate after a low-dose human menopausal gonadotropin (hMG) or pure FSH administration may be significantly lower in obese than in normal-weight PCOS women.86 Finally, in recent studies on PCOS women conceiving after in vitro fertilization or intracytoplasmatic sperm injection, it was observed that those with obesity had higher gonadotrophin requirement during stimulation,87 fewer oocytes, a higher abortion rate and lower live-birth rate than their non-obese counterpart.88 In conclusion, a decreased efficiency of the different treatments for ovulation and fertility induction may be expected in obese PCOS women. The presence of hyperinsulinemia is probably the major factor responsible for this undesirable condition.
The impact of body fat distribution
It is well documented that women with PCOS have a high prevalence of abdominal body fat distribution, even if they are normal-weight.89 The impact of abdominal obesity on PCOS may be greater than expected, since this phenotype is associated with a more pronounced hyperandrogenism and insulin resistance than the peripheral one. We have repeatedly demonstrated that the androgen profile and insulin basal levels as well as the insulin response to a glucose load are significantly higher in the subgroup with abdominal body fat distribution than in the group with the peripheral type, regardless of BMI.46,47 This has been confirmed in studies using dual-energy X-ray absorptiometry (DEXA) to define different obesity phenotypes.90 Holte et al91 found a significant association between abdominal fat mass and insulin resistance evaluated by the euglycemic hyperinsulinemic clamp technique. They also found a highly significant correlation between FFA concentrations and insulin resistance, which supports the concept that an increase of FFA flux from the highly lypolytic abdominal fat to the liver and muscles may represent the most important link between abdominal obesity and the insulin resistance state.91 Moreover, this subgroup of PCOS women may have a more unfavorable lipid profile, namely higher triglyceride and very-low-density lipoprotein (VLDL) and lower HDL cholesterol concentrations.47 In addition, PCOS women with the abdominal phenotype present a higher prevalence of menses abnormalities and acanthosis nigricans (a cutaneous marker of insulin resistance) and a tendency towards worsened hirsutism.47 As discussed above, abdominal obesity is associated with profound alterations of both production and metabolic clearance rates of major androgens and reduced SHBG blood levels. In abdominally obese PCOS women androgens could, in turn, play a role in regulating tissue metabolism. In fact, at the level of visceral depots, T stimulates lipolysis and, therefore, increases FFA efflux.50 In addition, at the level of the muscle, T modifies the histological structure by increasing type II, less insulin-sensitive fibers. These androgen-dependent mechanisms may have a further important impact on the insulin resistance state.
In summary, in women with PCOS, abdominal obesity per se may play a key role in determining both altered androgen metabolism and insulin resistance in a vicious circle manner. This may be of importance in phenotyping PCOS and in the therapeutic strategy aimed at reducing both hyperinsulinism and hyperandrogenism.
Treatment of women with obesity and PCOS
Effect of weight loss
There is long-standing clinical evidence concerning the efficacy of weight loss upon clinical and endocrinological features of obese women presenting PCOS. However, the effects of weight loss on the clinical course of women with obesity and PCOS have not been as deeply investigated as the pharmacological management of the syndrome. Weight loss improves menses abnormalities and, most importantly, both ovulation and fertility rate.7 The reduction of T, androstenedione (A) and dehydroepiandrosterone-sulphate (DHEAS) levels and the increase of SHBG concentrations appear to be responsible for the amelioration of the signs and symptoms reported after weight loss in obese PCOS women. Moreover, there are indications that weight loss may decrease LH pulse amplitude which, in turn, can be followed by reduced androgen production.91 The key factor responsible for these effects is the reduction of the insulin level which is obviously associated with an improvement of the insulin resistant state. A concomitant decrease in T and insulin concentrations (both basal and glucose-stimulated) has been described regardless of body weight variations.92 Diet-induced reduction of insulin levels has been demonstrated to decrease the P450c17α enzyme activity and consequently the ovarian androgen production.93 In addition, reduction of leptin associated with the weight loss may lead to a deactivation of the neuroendocrine control of ovarian steroid secretion.94 The best therapeutic strategy for favouring weight loss in obese PCOS women has not been investigated. However, conventional hypoenergetic diets have proved their efficacy both in reducing hyperandrogenism and improving fertility.95 There are no studies investigating the effects of different regimens. On the other hand, in one study a moderate weight loss of just over 5% was found96 to achieve the same effects described after more sustained weight loss.94 In addition, long-term trials investigating the effects of weight maintenance over several years are still needed. As discussed in the following paragraph, whether hypocaloric dieting combined with chronic treatment with insulin sensitizers may be more effective than diet alone is still under debate. However, based on our results,94 we can conclude that this combination may further improve the effects of diet on body weight loss, and on the reduction of visceral fat depots, and may produce a greater amelioration of insulin sensitivity and hyperandrogenism and menses abnormalities. To summarize, weight loss in women with obesity and PCOS not only reduces total and visceral fat, but also restores normal menstrual cycles and improves the fertility rate in a large proportion of affected women, by reducing androgen and insulin concentrations and improving insulin sensitivity. Notably, the effects of dietary-induced weight loss on androgens seem to be specific to obese hyperandrogenic women, since they have not been reported in non-PCOS obese women.97
As concluded above, diet itself may positively effect hormonal and metabolic parameters in PCOS obese women. However, insulin suppression obtained after diazoxide administration has been shown to reduce T and to increase SHBG concentrations in obese and PCOS hyperandrogenic women without affecting body weight.98 The same treatment has been described to be ineffective in normal-weight controls.99 Therefore, drug-induced reduction of insulin levels has been proposed as the primary goal to be achieved. We have commercially available insulin-sensitizers, such as metformin, a drug belonging to the class of biguanides100 and thiazolidinediones, which are selective ligands for PPARγ, a member of the nuclear receptor superfamily of ligand-activated transcription factors,101 and drugs under investigation, such as D-chiro-inositol, a component of the signal transduction system of insulin.24,102 The efficacy of these compounds in ameliorating hyperinsulinemia and insulin resistance and hyperandrogenism in women with PCOS is briefly summarized in the following paragraph.
Clinical studies with insulin lowering drugs
Velasquez et al first demonstrated that metformin administration in obese PCOS women was not only able to significantly improve insulin levels, but also to decrease LH and T concentrations, regardless of changes in body weight, with a significant improvement of menses abnormalities in most patients.82 The finding of the beneficial effect of long-term metformin treatment on fertility has been confirmed by many other studies, as recently reviewed by Oberfield.103 Short-term metformin administration (1500 mg/daily for 1 month) has been shown to reduce insulin levels and 17α-hydroxyprogesterone and LH response to leuprolide.8 Higher plasma insulin and lower serum A levels associated with less severe menstrual abnormalities before treatment seem to be predictive of a beneficial outcome of metformin treatment.104 An improvement of the ovulation rate in obese PCOS women has also been described after short-term use of metformin. As reported above, recent data indicate that administration of this drug may also remarkably increase clomiphene-induced ovulation in comparison to placebo.83,84 However, there are some studies105 finding no improvement of insulin resistance and hyperandrogenism during metformin administration on PCOS. The differences in results between studies might be related to the methods used to evaluate insulin resistance, to the criteria used for recruitment (entity of obesity and of insulin resistance), to the number of subjects included in the study and to the duration of treatment. Recently, we performed a 6 month double-blind controlled study to investigate the effect of a combined metformin administration (500 mg twice daily) and hypoenergetic diet on insulin, androgens and fat distribution in a group of abdominally obese women with and without PCOS.94 A greater reduction of body weight and abdominal fat, particularly the visceral depots, and a more consistent decrease of serum insulin, T, and leptin concentrations were observed after metformin administration in PCOS abdominally obese women when compared to placebo. In PCOS patients these changes were associated with a significant improvement of hirsutism and menses abnormalities. These findings led us to conclude that hyperinsulinemia and abdominal obesity may have complementary effects in the pathogenesis of PCOS.
There are few studies on the effects of thiazolidinediones in PCOS. Troglitazone (400 mg daily) has been shown to improve total body insulin sensitivity in obese PCOS women, resulting in lower circulating insulin levels. A substantial improvement of the PCOS-derived metabolic and hormonal alterations was observed after administration of this drug, as indicated by a decline of T and of triglycerides and plasminogen activator inhibitor type I, which are risk factors for the development of cardiovascular diseases.83,106 In addition, short-term troglitazone administration has been found to improve spontaneous ovulation in anovulatory PCOS women.7 There are no clinical studies using the new thiazolidinediones, rosiglitazone and pioglitazone in PCOS women.
Among other insulin-sensitizing agents, the potential use of D-chiro-inositol in PCOS treatment is currently under investigation. Inositolglycans have been described as mediating insulin action on thecal steroidogenesis.24 Taking into consideration these in vitro findings, Nestler et al proposed D-chiro-inositol therapy for PCOS women, demonstrating in a placebo-controlled trial that this drug is able to decrease insulin secretion during the oral glucose tolerance test and to concomitantly increase plasma SHBG. These hormonal changes have been described as being accompanied by a significant restoration of spontaneous ovulation.107
In conclusion, the data from the literature strongly support the hypothesis that in women with obesity and PCOS, improvement of hyperinsulinemia can be associated with various clinical benefits, including reduced hyperandrogenism and related clinical features and improved menses cyclicity and ovulation. In addition, the use of insulin-sensitizers could be viewed as a potential strategy to control the metabolic syndrome and prevent the increased susceptibility to develop diabetes and cardiovascular diseases later in life. On the other hand, this is an unanswered question that needs to be verified by appropriate long-term interventional studies.
As previously reported, several studies have demonstrated that antiandrogens, as well as reducing androgen levels, may significantly improve insulin resistance and hyperinsulinemia in either obese and non-obese PCOS women. These effects have been observed regardless of the type of drug used, the results observed being substantially similar for spironolactone,55 flutamide,54,108 finasteride54,55 or GnRH agonists.108 On the other hand, there are no studies investigating the effect of pure antiandrogens on body compartments and fat distribution in these women. One study109 using a GnRH agonist has shown an increment in abdominal fat and total visceral adipose volume in a cohort of hyperandrogenic anovulatory women. However, these results cannot be translated to pure antiandrogens because a GnRH agonist induces a decrease in both estrogen and androgen secretion. In addition, no studies have investigated the combined effect of antiandrogens and hypoenergetic dieting with or without insulin sensitizers. Preliminary data from our group, obtained in a 6 month study on a group of obese PCOS women, seem to be consistent with a beneficial effect of this combination in selectively reducing visceral fat (unpublished data).
Over the years oral contraceptives have been widely used in women with PCOS. The actions of these compounds involve several mechanisms. The progestagen component decreases the frequency of GnRH pulses and LH secretion, thus reducing ovarian estrogen and androgen production, while estrogen induces P receptors in the hypothalamus and also increases SHBG concentration.110 Many studies have documented a reduction in T levels and the best results are described in subjects with hyperandrogenic states such as PCOS patients. Moreover, hirsutism may improve during long-term oral contraceptive treatment, but usually reverses with discontinuation of the therapy. The most clinically efficacious approach using oral contraceptives in PCOS women can be obtained combining estrogen with cyproterone acetate, which has both progestagen and anti-androgen activity and also induces hepatic metabolism and increases T clearance.111,112,113 In combination with estrogens, cyproterone acetate is almost as effective as GnRH agonist at suppressing serum LH and T, and the clinical efficacy of the two treatments are equivalent.114 In addition, by investigating the long-term effect of oral contraceptive therapy on metabolism and body composition in a group of PCOS women we found a significant reduction of waist circumference and of WHR, as well as of basal insulin levels and an improvement of glucose tolerance in some subjects.77 These favorable effects were not, however, observed in a group of non-treated women, who had worsened fasting and glucose-stimulated insulin levels. Although controversy still exists concerning the effect of oral contraceptive preparations on glucose metabolism and insulin secretion and action in non-PCOS women, the results of this study indicate a potential benefit of long-term estro-progestagen compounds in body composition and the glucose-insulin system at least in PCOS women.
In spite of the potential benefits of the use of orlistat or sibutramine, the drugs currently available for treating obesity, there are no trials investigating their effects in obese PCOS women.
Summary and conclusions
In this review we have analyzed the clinical characteristics and physiopathological aspects of obesity-associated PCOS. Obese women with PCOS seem to be characterized by a different hormonal environment from that of normal-weight affected women. The main differences are more severe hyperinsulinemia and insulin resistance and lower SHBG levels when compared with either normal-weight PCOS women or weight-matched controls. Moreover, the presence of obesity, particularly the abdominal phenotype, in PCOS women appears to increase the availability of active androgens and oestrogens and worsen hirsutism, menstrual cyclicity and fertility rate. On the other hand, obese PCOS women present lower GH-IGF system activity than their normal-weight counterparts. This is in agreement with the concept that there is a pathophysiological heterogenicity of the syndrome. In particular, it has been proposed that insulin resistance and hyperinsulinemia may play a central role in obese patients, whereas abnormalities of the GH-IGF system are important in non-obese PCOS women. Other additional factors, however, are involved in the complex system by which obesity may favour the development of the PCOS, as schematized in Figure 1. The primary role of hyperinsulinemia and insulin resistance as a pathogenetic factor is supported by the evidence that, by reducing insulin levels, both hyperandrogenism and related clinical features tend to ameliorate. However, whatever the mechanism, weight loss represents the first-line approach in the treatment of obese PCOS women, since it improves hyperandrogenism in most of them and, by itself, it may favour spontaneous ovulation and better fertility rate in approximately 25% of women. On the other hand, an individual susceptibility to develop PCOS is required, since simple obesity represents a condition where there is a normal peripheral androgen concentration and where menstrual disturbances and other clinical evidence of hyperandrogenism are much less common than in obese PCOS women.