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Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age that is associated with significant adverse short- and long-term health consequences. Multiple metabolic aberrations, such as insulin resistance (IR) and hyperinsulinaemia, high incidence of impaired glucose tolerance, visceral obesity, inflammation and endothelial dysfunction, hypertension and dyslipidemia are associated with the syndrome. Assessing the metabolic aberrations and their long term health impact in women with PCOS is challenging and becomes more important as therapeutic interventions currently available for the management of PCOS are not fully able to deal with all these consequences. Current therapeutic management of PCOS has incorporated new treatments resulting from the better understanding of the pathophysiology of the syndrome. The aim of this review is to summarize the effect of old, new and emerging therapies used in the management of PCOS, on the metabolic aberrations of PCOS

Indroduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders in women of reproductive age, with an estimated incidence of 6-7 % according to the NIH criteria [Diamanti-Kandarakis et al. 1999]. Despite being prevalent it is still poorly understood, probably due to its heterogeneity, and is associated with significant adverse short- and long-term health consequences.

PCOS is defined by hyperandrogenism (clinical or biochemical), chronic anovulation, and/or polycystic ovaries [Diamanti-Kandarakis, 2008; Dunaif, 1997], with the exclusion of the adrenal, ovary and pituitary disorders. It is also characterized by multiple metabolic aberrations (Table 1), such as insulin resistance (IR) and hyperinsulinaemia [Dunaif, 1997; Dunaif et al. 1989], high incidence of impaired glucose tolerance [Ehrmann et al. 1999], visceral obesity, inflammation and endothelial dysfunction, hypertension and dyslipidemia resulting in an increased risk for diabetes and clinical or subclinical cardiovascular disease [González et al. 2009; Legro et al. 2001; Raja-Khan et al. 2011; Teede et al. 2010]. Compromised quality of life, anxiety and depression are also observed in PCOS [Barnard et al. 2007; Deeks et al. 2010; Jedel et al. 2010; Teede et al. 2010].

Table 1.

The metabolic aberrations of PCOS

Obesity

Insulin resistance, hyperinsulinaemia

IFG, IGT, type 2 Diabetes Mellitus

Dyslipediemia

Cardiometabolic: increased markers of CVD

CVD, cardiovascular disease

The etiology of PCOS remains unclear, but it is believed to result from complex interactions between genetic, environmental and behavioral factors. Hyperandrogenaemia, ovarian dysfunction and metabolic abnormalities - the main determinants of PCOS – all appear to be involved in a synergistic way in the pathophysiology of PCOS. However, the order of events remains unclear and is not known whether hyperandrogenism results from the hyperinsulinemia of IR or vice versa [Schuring et al. 2008]. However, increasing evidence supports a central role of insulin resistance and its compensatory hyperinsulinaemia in the pathogenesis of the syndrome [Baillargeon et al. 2003; De Leo et al. 2003; Nestler, 1997]. Insulin resistance and hyperinsulinaemia may insult ovarian function contributing to excessive androgen production [Nestler et al. 1998] and disruption of the ovulatory process [Phy et al. 2004] as well as to metabolic aberrations with short- and long-term sequalae.

The clinical impact of the metabolic aberrations in PCOS

It is well established that women diagnosed with PCOS, even in their twenties, demonstrate a cluster of metabolic and cardiovascular disturbances. Obesity is prevalent in women with PCOS [Gambineri et al. 2002] with more than 50% of women with PCOS being overweight or obese [Azziz et al. 2004]. Additionally women with PCOS tend to have an increased waist:hip ratio, indicative of increased rate of central (visceral) obesity in these women. Compared with peripheral fat, central fat is insulin resistant and recycles fatty acids more rapidly through lipolysis [Bergman et al. 2001; Björntorp, 1992; Steven et al. 2002]. Obesity is related to increased insulin resistance (IR), glucose intolerance and dyslipedemia in women with PCOS [Yildirim et al. 2003]. Insulin resistance is present in 60-80% of women with PCOS, with a higher prevalence observed in those who are obese [Carmina and Lobo, 2004; DeUgarte et al. 2005]. Obesity seems to be the major, but not the only factor in the development of insulin resistance. Studies indicated that post-receptor binding defects in insulin signaling are also responsible for IR in PCOS [Dunaif et al. 1989]. IR with resulting hyperinsulinemia also occurs frequently among lean as well as obese women with PCOS [Ehrmann et al. 1999; Ehrmann et al. 2005; Legro et al. 1999] and substantially increases the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) in women with PCOS. Up to 35-40% of women with PCOS have IGT and 10% develop T2DM during the third or fourth decade [Ehrmann et al. 1999; Legro et al. 1999; Solomon et al. 2002]. Whereas IGT and T2DM are common among women with PCOS, a significant percentage of mainly obese adolescents with PCOS are also at increased risk for IGT and T2DM [Palmert et al. 2002].

Dyslipidemia is also a common aberration in PCOS [Legro et al. 2001] and includes high levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) and decreased high-density lipoprotein cholesterol (HDL-C) levels [Legro et al. 2001]. Lipid abnormalities are present in 65-81% of PCOS and much higher levels are observed in those with higher insulin resistance [Legro et al. 2001]. Genetic, ethnic factors hyperandrogenaemia and obesity are also related with dyslipidemia in women with PCOS [Diamanti-Kandarakis et al. 2007; Economou et al. 2011].

In women with PCOS, especially in the presence of obesity, increased markers of cardiovascular disease including C-reactive protein, endothelin 1, adiponectin, homocystein, von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1) [Diamanti-Kandarakis et al. 2006; Diamanti-Kandarakis et al. 2011; Diamanti-Kandarakis et al. 2004; Diamanti-Kandarakis et al. 2006] and oxidative stress markers have also been reported.[Diamanti-Kandarakis et al. 2008; Kodaman and Duleba, 2008a]

The insulin resistance and hyperinsulinaemia pathophysiologically implicated in the metabolic and reproductive abnormalities of PCOS [De Leo et al. 2003; Nestler, 1997] are the two major facets of the metabolic syndrome (MS) [Reaven, 1988]. MS is characterized by a cluster of metabolic disturbances, such as central obesity, impaired glucose tolerance, dyslipidemia and hypertension that are related to increased cardiovascular risk [Schneider et al. 2006]. PCOS is now considered as a female subtype of the metabolic syndrome and its potential health consequences are a lifelong issue. The prevalence of metabolic syndrome in women with PCOS varies widely, from 1.6-43% depending on the population studied [Apridonidze et al. 2005; Soares et al. 2008; Vrbíková, et al. 2005]. Factors inherent to each population including dietary and behavioral habits might be responsible for the observed differences. In women with PCOS the most prominent features of the metabolic syndrome in decreasing order are decreased HDL levels, obesity and hypertension [Apridonidze et al. 2005].

The presence of MS in the general population implies a twofold increase in the risk of developing cardiovascular disease (CVD) [McNeill et al. 2005]. The evidence for increased cardiovascular disease in women with PCOS is less clear though, despite the increase in the cardiovascular risk factors in these women. The evidence of cardiovascular events in premenopausal women with PCOS is limited and, despite the multitude of cardiovascular risk factors associated with PCOS, increased mortality due to cardiovascular disease has not been demonstrated [Pierpoint et al. 1998; Wild et al. 2000]. However recent studies in postmenopausal women with a history of PCOS have shown that these women have a decreased CVD-free interval of cardiovascular events. [Shaw et al. 2008] Longterm data are lacking, however, and the growing recognition of the metabolic aberrations that are present in women with PCOS along with aging has prompted considerations on the long-term sequelae of the syndrome.

The difficulties of assessment of metabolic aberrations in clinical practice

Polycystic ovary syndrome is a persisting challenge to the clinician as the phenotype of the syndrome can vary widely. Women with PCOS might present with severe menstrual irregularities, hyperadrogenism, IR and dyslipidemia, whereas others might have only mild metabolic and reproductive phenotypes that cannot be distinguished from normal women. Thus, assessing metabolic aberrations and their long-term health impact in these women can be a real challenge. Ethnicity, genetic background, personal and family history, degree of obesity must all be taken into account because they might aggravate or even trigger metabolic disturbances women with PCOS. The clinical assessment of metabolic aberrations in women with PCOS becomes more challenging and important as the therapeutic interventions currently available for the management of PCOS are not fully able to deal with all these consequences. Moreover, some of the therapeutic interventions, although beneficial for some of the aberrations, might exacerbate others. Clinicians treating women with PCOS have to remember that, because of the multifactorial spectrum of PCOS, a multifaceted therapeutic approach may be required.

The aim of the present review is to summarize the effect of old, new and emerging therapies (Table 2), currently available for the management of PCOS, on the metabolic aberrations that present in women with PCOS. Oral contracptives and antiadrogens are the oldest medications used in the treatment of PCOS. The increasing understanding of the role of insulin resistance in the pathogenesis of PCOS introduced newer tools in the treatment of PCOs, the insulin sensitizers. Gathering evidence indicates a role of new emerging therapies for the PCOS, such as statins and dietary products and nutrients and their effect on metabolic aberrations of PCOS will also be considered. Current literature on the effect of complementary and alternative medicine (CAM) in the metabolic aberrations of PCOS will also be considered, as recent studies suggest that its application might be beneficial in these women. Complementary and alternative medicine is frequently used in the general population and seems to be increased, with one in three Americans using it, but the prevalence of CAM used by women with PCOS is not yet known [Raja-Khan et al. 2011].

Table 2.

Therapeutic tools for the treatment of PCOS

A. The Old therapeutic tools

a. Oral contraceptives (OC)

b. Anti-androgens

B. The New therapeutic tools

a. Insulin sensitizers:

a1. Metformin

a2. Thiazolinediones

C. Emerging therapeutic tools

a. Statins

b. Acupuncture

c. Dietary products and nutrients.

c1. Vitamin D

c2. Herbal medicines

c3. Vitamin B12 and folate.

c4. AGEs low diet

AGES: advanced glycated end products

The old therapeutic tools

Oral contraceptives (OCs)

For many years the oral contraceptive pill (OC) has been the core therapy for PCOS. The combined oral contraceptives (COCs), are those more frequently used for this purpose. COCs contain an estrogen component (ethynyl-oestradiol) and a progestogen component that varies and binding to receptors of other steroid hormones [Soares et al. 2009]. OCs that comprise of only progesterone have also been used as a therapeutic option [Soares et al. 2009]. OC administration in women with PCOS, in most cases, normalizes menses and alleviates hirsuitism and acne and sometimes results in the regression of male-pattern alopecia [Glueck et al. 2002; Kahn and Gordon, 1999]. There is also evidence that the use of contraceptive pill reduces the risk of endometrial cancer [Wiegratz and Kuhl, 2004]. The effects of OC on the PCOS are multifactorial and complex and have been attributed to the observed reduction of LH secretion, inhibition of ovarian and adrenal androgen production and reduction of free testosterone due to increased production of sex hormone-binding globulin in the liver [Kahn and Gordon, 1999; Wiegratz and Kuhl, 2004].

However, less well-understood remains the effect of OCs on the metabolic profile in PCOS. Early studies in the general population have indicated that use of OCs, containing high ethynyl-oestradiol (EE) doses, can induce insulin resistance (IR) and hyperglycaemia and changes in the lipid profile [Kalkhoff, 1975; Phillips and Duffy, 1973]. However, follow-up studies demonstrated a limited effect on metabolic risk with no clinical significant repercussions when low doses of COCs were used [Gaspard et al. 2003; Lopez et al. 2007]. The strong association of PCOS with insulin resistance has raised concerns over the potential unfavorable effects of OCs on the metabolic aspects of the syndrome [Nader and Diamanti-Kandarakis, 2007]. The effect of OCs on the metabolic aberrations of the PCOs has been subject of several studies with conflicting results. Great heterogeneity of the studies, differences in factors such as type of OC that has been used, age, anthropometric and genetic differences between the populations studied, methods that have been used to determine the metabolic effects and duration of follow up might account for the discrepancies observed [Nader and Diamanti-Kandarakis, 2007; Vrbíková and Cibula, 2005].

OCs and carbohydrate metabolism

Regarding the effects of OCs on carbohydrate metabolism, the results range from overt diabetes [Nader et al. 1997], to improvement of carbohydrate metabolism [Cagnacci et al. 2003; Escobar-Morreale et al. 2000]. Studies on the effect of OC on insulin resistance also gave conflicting results with some showing no change [Cibula et al. 2005] and others an increased insulin resistance [Mastorakos et al. 2006]. Current data indicate that COCs containing low EE doses (<50 μg) are associated with a lower risk for type 2 diabetes, but there are no definitive data about additional advantages on carbohydrate metabolism when ultra low doses of COCs are used. Also the progestogen with the lowest impact on carbohydrate metabolism needs to be determined [Chasan-Taber et al. 1997; Diamanti-Kandarakis et al. 2003; Rimm et al. 1992].

A recent metanalysis examined the effect of OCs on carbohydrate metabolism in women with PCOS without diabetes and concluded that OCs have a minimal effect on carbohydrate metabolism with no clinical consequences and that was independent of the rout of administration. The studies included in this metanalysis had poor methodology, such as small numbers and excluded overweight women [Lopez et al. 2007]. In another metanalysis the effect of OCs and metformin in PCOS was examined. No significant difference between the two treatments was found with regards the fasting glucose levels or diabetes development but metformin was superior to OCs in reducing fasting insulin levels. Due to the limitations of the current studies, further and longer studies are needed to establish the effect of OCs on glucose metabolism.

OCs and lipids

The most common lipid alterations observed in women with PCOS are increased TG levels and decreased HDL cholesterol levels, with increases in total cholesterol and LDL cholesterol being more rare [Berneis et al. 2007]. Moreover, these changes appear to be independent from body weight [Mastorakos et al. 2006]. Available studies on the impact of the OCs administration on the lipid profile in women with PCOS suffer the same limitations mentioned earlier including heterogeneity of the studies, small numbers and bad methodological design and present with conflicting results. In general the available literature indicates that OCs may increase LDL-cholesterol and total cholesterol and increase HDL-cholesterol [Cibula, et al. 2005; Falsetti and Pasinetti, 1995; Guido et al. 2004; Harborne et al. 2003; Hoeger et al. 2008; Lemay et al. 2006; Luque-Ramírez et al. 2007; Mastorakos et al. 2002; Morin-Papunen et al. 2003; Ozdemir et al. 2008; Rautio et al. 2005; Villaseca, et al. 2004; Vrbíková et al. 2004], and significantly increase TG [Hoeger et al. 2008; Mastorakos et al. 2002; Nader and Diamanti-Kandarakis, 2007; Prelević et al. 1990; Vrbíková and Cibula, 2005] or may have no effect at all [Korytkowski et al. 1995; Pasquali et al. 1999]. In contrast, administration of the progestogen-only pill in PCOS women does not seem to interfere with lipid parameters [Ozdemir et al. 2008; Villaseca et al. 2004]. However, these changes in lipid profile in women with PCOS on OC have not been studied with regards their implication for cardiovascular risk.

Increased TG, often together with increased total cholesterol levels, appear to be the commonest adverse effect of OC treatment in women with PCOS as indicated in studies both in adults and adolescents obese and lean with PCOS [Cibula et al. 2005; Guido et al. 2004; Hoeger et al. 2008; Mastorakos et al. 2002; Ozdemir et al. 2008; Prelević et al. 1990; Rautio et al. 2005; Villaseca et al. 2004; Vrbíková and Cibula, 2005]. The potential effect of OC on TG levels is thought to be due to the effect of the oestrogen component in the liver and resulting in reduction of triglyceride clearance [Jones et al. 2002]. Thus OC with lower EE might increase TG less and transdermal application of OC does not affect lipid profile in women with PCOS [Vrbíková et al. 2004]. Additionally in women with PCOS different OCs are found to result in increased HDL cholesterol levels [Cibula et al. 2005; Falsetti and Pasinetti, 1995; Guido et al. 2004; Harborne et al. 2003; Hoeger et al. 2008; Lemay et al. 2006; Luque-Ramírez et al. 2007; Mastorakos et al. 2002; Morin-Papunen et al. 2003; Ozdemir et al. 2008; Rautio et al. 2005; Villaseca et al. 2004; Vrbíková et al. 2004], an effect that seems to be mediated by the effect of the estrogen component on apolipoprotein A-I gene expression in the liver cells [Lamon-Fava et al. 1999]. However, studies have shown no effect on lipid profile in women with PCOS on OC [Diamanti-Kandarakis, 2008; Pasquali et al. 1999].

A Cochrane review [Costello et al. 2007], analyzed the results of four randomized controlled trials comparing OCs with metformin and found no significant difference between the two treatments in terms of clinical (development of T2DM, cardiovascular disease) and surrogate (insulin, glucose, total cholesterol) metabolic outcomes. However, a significant increase in TG in the OC group compared with metformin was shown. Moreover, a systematic review [Jing et al. 2008] of nine studies comparing EE/CPA with metformin, again showed no significant difference in the prevalence of T2DM, IGT or impaired fasting glucose but TG were significantly different between groups. Finally a recent metaanalysis of observational studies [Halperin et al. 2011] on the metabolic effects of OC use in women with PCOS has also shown that short-term use of OC was not associated with clinically significant metabolic changes in these women. The underlying studies used in this metanalysis though were heterogeneous, with a short follow-up period, and the observational nature of the data is somewhat of a limitation. Lack of robust data indicates the need for further studies in order to clarify the effect of OC use on lipid profile in women with PCOS. [Diamanti-Kandarakis et al. 2009]

OC and effect on other CV risks

Only few studies have addressed the effect of the use of COC in PCOS on thromboembolism. In a study the use of COC (35μg EE/2 mg cyproterone acetate) in women with PCOS detected an odds ratio for venous thromboembolism of 2.2 (95% CI: 1.35–3.58) and 7.44 (95% CI: 3.67–15.08) compared with users of other COCs and to non-users respectively.[Seaman et al. 2003] Generally due to lack of data on the effect of OC on the homeostasis of women with PCOS, extrapolation of data of healthy women on OCs is applied.

There are no studies to address the effect of COC on normotensive women with PCOS. COC can induce systolic hypertension and is thus contraindicated in hypertensive women with PCOS and should be discontinued if systolic hypertension develops [Goldenberg et al. 2003].

The results of weight gain in women with PCOS on COC remain conflicting, with one study indicating and increase in body weight [Vrbikova et al. 2006] and another showing no change on body weight or to waist:hip ratio. [Nestler, 2008]

To summarize, OC may have a negative effect on the metabolic aberrations of women with PCOS and the long-term benefits are unclear, especially in those with IGT, T2DM and dyslipidemia. Decision for their administration in women with PCOS should be based on the patient’s phenotype and history and should always be combined with lifestyle modifications in order to neutralize some of their adverse effects. Although there are some data suggesting the OCs with low dose of EE (< 50μg) are associated with lower metabolic risk, it is not yet proven if very low doses of EE (<20-15 μg) have additional advantages on the metabolic profile.

Anti-androgens

In women with PCOS, it has been speculated that hyperadrogenaemia may be one of the initiating factors of metabolic aberrations. Androgens exert this effect via the androgen receptor, which is expressed in the visceral fat [De Pergola et al. 2005] and up-regulation of lipolysis in visceral adipose tissue may reflect an androgen-induced metabolic defect of PCOS. Furthermore, androgens, by their direct action on the insulin signaling pathway, seem to contribute to peripheral insulin resistance in PCOS. [Diamanti-Kandarakis, 2008].

Anti-androgens, such as cyproterone acetate, spironolactone or flutamide have been used in women with PCOS mainly for the treatment of hirsuitism. They are usually administered in combination with OC because of the hyper-additive synergism of these medications, the risk of feminization in male fetuses and for minimization of irregular menses. Anti-androgens act by competitive inhibition of androgen-binding receptors or by decreasing androgen production [Falsetti et al. 2000]. In PCOS, the observed beneficial effects on some of metabolic aberrations with antiandrogen treatment may be attributed to the blockade of androgen receptor and reduction of androgen excess.

Cyproterone acetate has been the most often used as an effective antiandrogen [Archer and Chang, 2004; Diamanti-Kandarakis et al. 2003] with progesterone-like properties [Pelusi and Pasquali, 2003]. It can induce ovulation when it is used in combination with clomiphene citrate but may also have unfavorable consequences for women with PCOS as it can increase body weight and insulin resistance. [Diamanti-Kandarakis et al. 2006; Kidson, 1998].

Spirolactone is an aldosterone antagonist and a competitive inhibitor of the androgen receptor, which results in inhibition of androgen production and can also inhibit 5a-reductase activity. Data on metabolic effects of spironolactone in women with PCOs are limited and conflicting. In lean PCOS women, spironolactone administration resulted in increased HDL cholesterol levels and when it was used in combination with OC an increase in TG levels was also observed. [Karakurt et al. 2008; Zulian et al. 2005].

Flutamide, a nonsteroidal selective androgen receptor inhibitor without progestogenic activity, reduces the conversion of tostesterone to its more active metabolite, dihydrotestosterone, in target tissues [Diamanti-Kandarakis et al. 1998]. Its administration in women with PCOS results in significant amelioration of the clinical and biochemical androgenic manifestations but with minimal or no effect on insulin sensitivity and on insulin-stimulated glucose utilisation rate [Diamanti-Kandarakis et al. 1995, Moghetti et al. 2000]. However, flutamide treatment in women with PCOS significantly decreased total cholesterol, LDL cholesterol and TG and these changes in the lipid profile were independent of the changes in body weight in these women [Diamanti-Kandarakis, et al. 1998; Ibáñez et al. 2000]. When metformin was added to the treatment of flutamide and OC, a further metabolic benefit was observed with further reduction of LDL cholesterol levels and an increase in HDL cholesterol levels, but it did not prevent the OC-induced TG elevation [ Ibáñez et al.2004]. Moreover, in obese women with PCOS, flutamide treatment had an added benefit on lipid profile when it was added to their hypocaloric diet [Christakou and Diamanti-Kandarakis, 2008; Gambineri et al. 2006]

The new therapeutic tools

Insulin sensitizers

The strong pathophysiological connection of insulin resistance with PCOS aberrations supports the therapeutic use of insulin sensitizers in the management of PCOS. The extensive literature has shown that reduction in insulin levels pharmacologically ameliorates the sequelae of hyperinsulinemia and hyperandrogenemia. Insulin sensitizers, mainly metformin and thiazolinediones, can effectively manage the established metabolic derangements in PCOS, but whether they can prevent them is not yet established.

Metformin

Metformin, a biguanide, is an insulin sensitizer that has been used widely in the treatment of T2DM. Its mechanism of action is complex and pleiotropic and is exerted on several tissues. Its principal action is in the liver with suppression of gluconeogenesis and hepatic glucose output, but it also enhances peripheral insulin action in the skeletal muscle and reduces glucose absorption from the digestive tract, with no significant direct effect on pancreatic insulin production [Baillargeon et al. 2003; Glueck et al. 2003]. The effect of metformin on insulin-stimulated glucose uptake in the adipose tissue remains disputable, with some data to support an effect on adipose tissue lipolysis [Diamanti-Kandarakis et al. 2010]. Metformin also ameliorates lipid profile via various mechanisms [Diamanti-Kandarakis et al. 1998; Palomba et al. 2009; Viollet et al. 2006], and directly inhibits thecal androgen production [Attia, et al. 2001]. In women with PCOS, treatment with metformin appears to improve cardiometabolic parameters by improving insulin sensitivity, lowering blood glucose and androgen levels and possibly by its effects on body weight. These effects of metformin are more potent when it is combined with lifestyle intervention (Figure 1).

Figure 1.

The potential effects of metformin on the metabolic aberrations of PCOS.

Increased body weight and central obesity are associated with increased cardiometabolic risk in women with PCOS [Diamanti-Kandarakis et al. 2010]. Obesity is common in women with PCOs and weight loss in these women is of major importance. Recent data suggest that metformin may normalize appetite in obese women with PCOS by restoring neuropeptide Y secretion, which is impaired in these women [Barber et al. 2008; Romualdi, De Marinis et al. 2008]. However, the effect of metformin on body weight reduction and fat distribution in women with PCOS remains controversial and further studies are necessary to clarify these matters. A Cohrane Library review of randomized clinical trials on the effect of metformin on PCOS features could not confirm any weight-reducing effect [Lord et al. 2003]. More recent studies suggested a dose-dependent effect of metformin on body weight reduction, with higher doses of the drug being more potent on this aspect. No placebo arm was included in these studies, however [Bruno et al. 2007; Harborne et al. 2005]. A trial has indicated that in obese women with PCOS metformin can reduce body weight, but in this study possible lifestyle modifications at the period of the study were not taken into account [Trolle et al. 2007].

Studies on the effect of metformin on central adiposity are also heterogeneous with regards to the methods used to measure central fat mass and are of short duration. A Cochrane review found no evidence for an effect of metformin on waist:hip ratio in women with PCOS [Lord et al. 2003]. When computed tomography was used for visceral fat measurements in a RCT, the use of metformin in obese women with PCOS had no effect on visceral fat reduction compared with placebo. However, the intervention with metformin was of short duration and the study lacked sensitivity to detect modest fat mass reductions [Lord et al. 2006]. Studies of longer duration where metformin was combined with lifestyle interventions have demonstrated a significant reduction in visceral fat mass [Gambineri et al. 2006; Gambineri et al. 2004; Pasquali et al. 2000; Tang et al. 2006] and this effect also seemed to be dose dependent [Bruno et al. 2007].

Randomized controlled trials on the effect of metformin on the natural history of hyperglycemia in women with PCOS are lacking. A metanalysis of 13 controlled trials in women with PCOS concluded that metformin is potent in the reduction of fasting insulin levels [Lord et al. 2003]. In euglycemic women with PCOS, studies with hyperinsulinaemic-euglycemic clamps demonstrated that metformin reduces insulin resistance, increases insulin-stimulated glucose disposal [Diamanti-Kandarakis et al. 1998] and thus may prevent the development of T2DM. In a small retrospective study, the use of metformin in women with PCOS for 43 months showed a much lower conversion rate from normal glucose tolerance to IGT than previous observed (1.4% versus 16-19%) and none of the women, even those with IGT at the base line, developed diabetes [Sharma et al. 2007]. Another observational study in a large cohort of women with PCOS on metformin and diet indicated that the progression to diabetes depends on the baseline insulin sensitivity and glucose levels [Glueck et al. 2008]. However further studies are necessary to elucidate the effect of metformin in the development of diabetes in women with PCOS.

Metformin has been shown to improve lipid abnormalities in PCOS. Overall the available data support a beneficial effect of metformin on lipid profile but not in normolipidemic patients without IR at baseline [Sahin et al. 2007]. This effect of metformin seems to be multifactorial but may mainly rely upon its effect on its main metabolic tissues [Palomba et al. 2009]. Metformin in the liver, via inhibition of acetyl-CoA carboxylase activity, decreases free fatty acid (FA) synthesis and increases mitochondrial FA oxidation and thus reduces plasma triglycerides [Cleasby et al. 2004; Zang et al. 2004]. Additionally, metformin suppresses the expression of the lipogenic gene in the liver. The effect of metformin on insulin resistance and body weight reduction also contributes to the improvement of lipid profile in these women [Diamanti-Kandarakis et al. 1998] as does its direct effect on inhibition of theca androgen production [Attia et al. 2001]. Androgen excess has been linked with atherogenic lipid profile in PCOS, particularly with reduced HDL cholesterol levels [Diamanti-Kandarakis et al. 2007].

A plethora of clinical trials has examined the effect of metformin on lipid profile in women with PCOS but their results are conflicting. Differences in the characteristics of populations studied and in their phenotypes, use of different metformin doses and inclusion of normolipidemic patients in the studies without apparent insulin resistance are some of the factors that may account for the different findings.

Some studies have indicated that hyperinsulinaemic PCOS patients treated with metformin had a significant reduction in total cholesterol, LDL cholesterol and TG levels and an increase in HDL cholesterol levels [Banaszewska et al. 2006; Ibáñez et al. 2000; Santana et al. 2004]. Severely obese PCOS patients, however, showed no improvement either in insulin sensitivity or in lipid profile on metformin treatment [Tang et al. 2006] and other studies indicated an improvement of the HDL cholesterol only [Fleming et al. 2002; Moghetti et al. 2000]. Doses of metformin as low as 1.5 g/day in some trials improve lipid profile [Santana et al. 2004] but appear to be ineffective in others [Palomba et al. 2009]. A metanalysis on the effect of metformin on lipid profile in women with PCOS highlights the lack of substantial evidence on this subject. This metanalysis concluded that use of metformin in women with PCOS reduces LDL cholesterol levels but has no significant effect on total cholesterol, HDL cholesterol and TG levels [Lord et al. 2003]. To conclude, available evidence suggests a beneficial effect of metformin on lipid profile in women with PCOS. Some patients though do not appear to respond but it remains unclear what differentiates them from the responders.

Finally, metformin appears to improve several cardiovascular and atherogenic factors such as endothelium-dependent vasodilatation [Muniyappa et al. 2007], endothelin 1, adhesion molecules [Diamanti-Kandarakis et al. 2005], C-reactive protein [Morin-Papunen et al. 2003] and advance glycated end products (AGEs) [Diamanti-Kandarakis et al. 2007].

Metformin then appears to have multiple favorable results on the metabolic aberrations in women with PCOS. It should be used in these women as an adjuvant to lifestyle intervention as their effect on improving cardiometabolic parameters is additive.

Thiazolinediones

The insulin sensitizers thiazolinediones (TZDs), also known as glitazones, are synthetic ligands and their action is mediated by binding and activating the nuclear receptor peroxysome proliferator-activated receptor gamma (PPARγ) [Desvergne and Wahli, 1999; Sørensen et al. 1998]. They improve insulin sensitivity by regulating genes involved to adipose tissue metabolism. Activation of PPARγ by TZDs increases insulin sensitivity mainly in adipocytes and muscle cells [Girard, 2001] and also stimulates differentiation of adipose cells [Gurnell et al. 2003; Komar, 2005; Staels and Fruchart, 2005]. TZDs can also stimulate glucose transporter expression and other proteins in the insulin pathway [Picard and Auwerx, 2002]. All these modifications are associated with a decrease in plasma FFA and TG concentrations [Girard, 2001; Yamauchi et al. 2001].

Practically, pioglitazone is the only TZD that can be used today. Troglitazone, the first representative of this class of medications, was withdrawn from the worldwide market in 2000 because of its hepatotoxicity. Rosiglitazone was also suspended recently from the European market (September, 2010) due to its association to increased cardiovascular mortality [Nissen and Wolski, 2007] and the FDA in USA has decide that rosiglitazone could be obtained only under a very stringent restricted program.

Current literature is insufficient to support a clear metabolic benefit of the use of TZDs in women with PCOS. Pioglitazone monotherapy in obese women with PCOS showed a trend towards improvement of lipid profile [Romualdi et al. 2003], but no benefit was found in obese PCOS with diet-refractory insulin resistance when rosiglitazone was added [Lemay et al. 2006]. When pioglitazone was administered to thirteen women with a suboptimal response to metformin monotherapy an increase in HDL cholesterol levels was observed [Glueck et al. 2003].

In addition to lipids TZDs may improve other cardiovascular risk factors. In women with PCOS administration of TZDs improved endothelium-dependent vasodilatation [Jensterle et al. 2008; Naka et al. 2011; Paradisi et al. 2003], and decreased serum levels of C-reactive protein (CRP) [Tarkun et al. 2005] and PAI-1 [Ehrmann et al. 1997].

More and longer-term data are needed to establish the effect of TZDs on the metabolic aberrations of women with PCOS.

Emerging therapeutic tools

Statins

Statins are an emerging and promising new therapeutic option for women with PCOS. They act by a selective inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), the rate-limiting enzyme in the cholesterol biosynthesis pathway [Anon, 1994; Sacks et al. 1996]. Their benefit on reduction of cardiovascular morbidity and mortality in primary and secondary prevention trials is well proven [Downs et al. 1998; Anon, 1994; Sacks et al. 1996; Shepherd et al. 1995].

In women with PCOS statins appear to have diverse actions and in addition to lipid reduction, mainly LDL cholesterol levels, they target the underlying stimulation of thecal androgen production and steroidogenesis [Izquierdo et al. 2004], and the effects of insulin resistance and hyperinsulinaemia associated with the pathophysiology of PCOS [Kodaman and Duleba, 2008b]. They also express anti-oxidant, antiflammatory and antiprolifarative effects [Kodaman and Duleba, 2008a; Wassmann et al. 2002] and together with the lipid reduction these alterations can have a beneficial effect on the long-term cardiovascular morbidity and mortality associated with PCOS (Figure 2).

Figure 2

The effects of statins on the metabolic aberrations of PCOs.

Clinical trials have investigated the metabolic effects of statins in women with PCOS. The effect of simvastatin in women with PCOS was examined recently in a randomized, prospective trial [Duleba et al. 2006] and was followed by a cross over study evaluating the effect of simvastatin and a COC on PCOS [Banaszewska et al. 2007]. As expected total and LDL cholesterol levels were decreased and TG were not affected in the statin arm of the studies, while there were small increases of these parameters in the COC group. In both groups there was a small but significant increase in HDL cholesterol levels. In addition statin treatment had a more pronounced decrease on markers of systemic inflammation and atherosclerosis, such as CRP and adhesion molecules compared with the COC group alone, with no additive effect on insulin sensitivity and fasting glucose levels. In a randomized double blind placebo of atorvastatin versus placebo in women with PCOS, atorvastatin improved lipid profile and reduced CRP and serum insulin levels [Sathyapalan et al. 2009]. PCOS is associated with hyperlipidemia and endothelial dysfunction with low-grade inflammation and thus the improvement of lipid profile with statins and the reduction of CRP and pro- inflammatory adhesion molecules is of particular importance in this group [Preiss and Sattar, 2007].

Studies with atorvastatin have also demonstrated a reduction in AGEs, in patients with non-alcoholic liver disease [Kimura et al. 2010]. AGEs are highly reactive molecules that may induce structural and vascular changes [Vlassara and Palace, 2002]. In women with PCOS an increased level of AGEs has been found [Diamanti-Kandarakis et al. 2008; Diamanti-Kandarakis et al. 2007] and thus statins may offer an added benefit in these women.

The use of statins in the medical treatment of women with PCOS appears to have pleotropic cardiometabolic benefits, but further studies of longer duration are needed to confirm the whole spectrum of their clinical implications in these group. Based on the available evidence and due to their potential teratogenicity, statins currently are not recommended to be used in women with PCOS and dyslipidemia who are planning pregnancy.

Acupuncture

Recently, a few studies have emerged on the use of acupuncture in women with PCOS. Acupuncture uses needles for manual or electrical sensory stimulation of somatic afferent nerves innervating the skin and muscles. Thus acupuncture may modulate somatic and autonomic activity and metabolic and endocrine functions. Its therapeutic effect depends on the needling ‘dose’, that is the intensity, the frequency, the type of stimulation and the intervals between stimulations [White et al. 2008] and psychological factors [Sherman et al. 2010]. Evidence suggests that electrical stimulation of needles, electro-acupuncture (EA), may offer some benefits in women with PCOS such as improvement hyperadrogenism and of menstrual frequency [Jedel et al. 2011]. Clinical evidence on the effect of acupuncture on the metabolic parameters of PCOS is lacking. Experimental evidence from animal studies though suggests a possible benefit of EA with repetitive muscle contraction on metabolic variables as it may activate a physiological processes similar to those resulting from physical exercise. In particular, in the periphery via activation of muscle fibers may modulate autonomic nervous system activity [Sato and Sato, 1992], increase blood flow [Jansen et al. 1989], improve peripheral insulin sensitivity in a dose-dependent manner [Mannerås et al. 2008] and in skeletal muscle increase glucose uptake [Holmäng et al. 2002] and GLUT-4 expression [Lin et al. 2009] (Figure 3). As these parameters are involved in the pathophysiology of the PCOS their improvement may have beneficial effects on the metabolic profile of PCOS. Moreover, acupuncture stimulates neuropeptide release in the central nervous system, such as β-endorphin secretion, and may result in blood pressure and sympathetic nerve activity reduction [Jonsdottir, 2000]. Decreased sympathetic nerve activity is thought to be related to the decreased circulating testosterone levels and improvement of menstrual irregularities in women with PCOS on low-grade EA and exercise [Jedel et al. 2011]. Additionally, in women with PCOS, low-frequency acupuncture can reduce high circulating β-endorphin levels in the peripheral blood resulting in reduction of hypeinsulinaemia and increasing insulin sensitivity [Chen and Yu, 1991; Stener-Victorin et al. 2000].

Figure 3.

The effect of low- frequency electrical acupuncture on the skeletal muscle

Thus, although clinical trials are lacking, experimental animal data indicate that acupuncture with electrical stimulation may be of benefit on the cardiometabolic aberrations of PCOS. Clinical randomized control studies though are needed to confirm this potential effect. These studies will be challenging as they are difficult to design for many reasons such as differences in stimulating techniques, variety of sham procedures and acupuncture points used, number and duration of treatments used [White et al. 2008]. Also one needs to overcome the particularly potent placebo effect in acupuncture studies [Linde et al. 2010] and thus double-blind studies are almost impossible to perform or design [Florakis et al. 2008].

Dietary products and nutrients

Recently attention has been paid to the emerging role of dietary products and nutrients, such as vitamins D, B12 and folate, and herbal supplements in the treatment of PCOS. Existing data, derived mainly from small and uncontrolled trials, indicate that various dietary supplements might be of some benefit in women with PCOS. However, the current literature should be enriched with better-designed controlled studies before any definite conclusions on the role of dietary supplements on PCOS can be drawn.

Vitamin D

Clinical studies have largely but not consistently indicate a role of vitamin D deficiency in the pathogenesis of insulin resistance and T2DM and MS [Chiu et al. 2004; Isaia, et al. 2001]. The gene encoding the vitamin D receptor regulates about 3% of the human genome and affects genes that are important for glucose and lipid metabolism and blood pressure regulation [Freundlich et al. 2008; Holick, 2007; Pittas et al. 2007]. In women with PCOS low levels of vitamin D are associated with obesity and insulin resistance, impaired β-cell function, IGT and metabolic syndrome, indicating a possible role of Vitamin D in the pathogenesis of PCOS [Hahn et al. 2006; Wehr et al. 2009]. Administration of vitamin D in women with PCOS improved insulin resistance and lipid profile, but the conducted studies were small and uncontrolled [Kotsa et al. 2009; Selimoglu et al. 2010]. Some evidence also indicates a possible effect of Vitamin D on ovulation [Rashidi et al. 2009]. Further studies are warranted to establish the role of Vitamin D in PCOS treatment.

Herbal medicines

Herbal medicines have also been considered for the treatment of PCOS. Studies conducted using Chinese herbal medicine (CHM) and green tea and spearmint tea. Traditionally there are a lot of different preparations of CHM, but there are safety concerns as many of these preparations fall out of any kind of control. Their efficacy is also not proven as the existing studies are small and uncontrolled with poor methodological quality and the use of different preparations in each study makes it difficult to draw any conclusions.

CHM has been used for the treatment of IGT, T2DM and PCOS but the evidence for benefit for all three conditions is weak. The exact pathophysiological mechanism for efficacy of CHM remains unknown and different mechanism might be implicated for the different preparations. In PCOS in rats some preparations seem to induce favorable alterations in glucose metabolism and insulin resistance [Yang et al. 2011; Zhao et al. 2011] and thus may have a favorable effect on hyperadrogenism [Dvorak and Vrzal, 2011; Zhao et al. 2011] . A review of CHM in PCOS [Zhang et al. 2010] highlighted all the above mentioned problems with these studies and also underlined that in certain occasions CHM has been given as adjuvant therapy to other medications such as clomiphene. Thus for CHM further studies are needed to establish safety and efficacy before they can be recommended for use in women with PCOS.

Tea, which is widely consumed, has been shown in animal and human studies to have some beneficial effects on glucose and lipid metabolism [Chantre and Lairon, 2002; Dulloo et al. 1999] on hormonal profile [Chan et al. 2006] and on body weight reduction and induction of ovulation [Sun and Yu, 2000]. Improvement of all these parameters could be of importance in women with PCOS. In a small RCT in PCOS women green tea resulted in a non-significant body weight reduction but no change was seen in glucose levels and lipid profile [Chan et al. 2006]. Further studies are needed to examine the effect of tea on the metabolic parameters of PCOS.

Vitamin B12 and folate

It has been demonstrated in patients with MS that Vitamin B12 administration improves insulin resistance. In PCOS patients, insulin resistance, obesity and elevated homocystein levels are associated with lower serum vitamin B12 concentrations [Kaya et al. 2009]. In another study supplementation of folate increased the effect of metformin on the vascular endothelium in women with PCOS, but the mechanism remains unknown [Palomba et al. 2010]. Thus these preliminary data suggest a possible role of the above supplements in women with PCOS but further studies are needed.

AGE-low diet

Women with PCOS are at increased atherogenic risk and endogenous AGEs seem to play a significant role [Chen et al. 2008; Dvorak and Vrzal, 2011; Eisenberg et al. 1993; Eyvazzadeh et al. 2009]. Serum and tissue AGE levels seem to depend on endogenous and exogenous sources [Goldberg et al. 2004]. Diet has been shown to be a significant source of AGE, and contemporary methods of cooking (precooked fast-food meals heated in high temperatures) dramatically increase AGE concentration. Studies in animal and humans with diabetes indicated that dietary AGE restriction results in significant reduction of circulating AGE levels and prevents progression of atherosclerosis [Hofmann et al. 2002; Uribarri et al. 2003; Vlassara et al. 2002]. Thus a high-AGE diet in women with PCOS could increase the atherosclerosis risk [Diamanti-Kandarakis, Katsikis et al. 2008]. However the pathogenetic role of dietary AGEs is not clear. Studies indicate that they may be implicated in direct and indirect insulin resistance mechanisms [Diamanti-Kandarakis et al. 2001; Paradisi et al. 2001]. Studies demonstrated that AGEs and their receptor RAGE are expressed in human ovarian tissue and a stronger localization of both was observed in the granulosa cell layer of PCOS ovaries. [Diamanti-Kandarakis et al. 2007] Data from studies in rats indicated that a high-AGE diet for prolonged periods is associated with increased deposition of AGEs in ovarian tissue, suggesting an impact of environmental factors on ovarian tissues. [Diamanti-Kandarakis et al. 2007] Thus reduction in dietary AGEs might be of benefit in women with PCOs. Low AGE diet [Uribarri et al. 2003] and administration of aminoguanide [He et al. 1999] effectively reduced serum AGE concentration in diabetes.[Diamanti-Kandarakis et al. 2007] In women with PCOS orlistat seem to be potent to reduce serum AGE concentration by decreasing their absorption [Diamanti-Kandarakis et al. 2006].

Conclusions

Polycystic ovary syndrome is characterized by multiple metabolic aberrations, which are of great importance due to their potential lifelong consequences. The therapeutic management of these metabolic aberrations has evolved to incorporate new treatments resulting from the better understanding of the pathophysiology of the syndrome. Although treatment should be individualized, it should not target only isolated symptoms. Unfortunately the medications currently available for the treatment of PCOS are not fully able to deal with all the metabolic consequences and might have negative effects on different parameters. Longer, randomized controlled trials, which will address the cardiovascular risk, are needed to establish the benefit and safety of the available treatments on the metabolic aberrations of the PCOS. Therapies that might be addressing the multifaceted disturbances of individual subgroups might emerge as the preferable treatment.

Footnotes

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The authors have no conflicts of interest.

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The effects of old,new and emerging medicines on metabolic aberrations in PCOS

Abstract

Indroduction

The clinical impact of the metabolic aberrations in PCOS

The difficulties of assessment of metabolic aberrations in clinical practice

The old therapeutic tools

Oral contraceptives (OCs)

OCs and carbohydrate metabolism

OCs and lipids

OC and effect on other CV risks

Anti-androgens

The new therapeutic tools

Insulin sensitizers

Metformin

Thiazolinediones

Emerging therapeutic tools

Statins

Acupuncture

Dietary products and nutrients

Vitamin D

Herbal medicines

Vitamin B12 and folate

AGE-low diet

Conclusions

Footnotes

References