Roger Clemens

Polycystic Ovarian Syndrome (PCOS) is a heterogeneous condition that is considered to be the most prevalent endocrinopathy (a disease marked by dysfunction of an endocrine gland) in women of reproductive age (Dunaif, A., 1997; Futterweit, W., 1999; Mason, H. et al., 2008). The syndrome is characterized by chronic, hyperandrogenic anovulation (overproduction of male hormones that leads to absence of normal ovulation) and results in various complex pathologies, most of which can directly or indirectly lead to infertility.

The prevalence of PCOS is more than 6%, according to major epidemiological studies (Diamanti-Kandarakis, E. et al., 1999; Asuncion, M. et al., 2000; Azziz, R. et al., 2004). This review will focus on four key pathologies that accompany PCOS, namely dyslipedemia, insulin resistance, abdominal adiposity, and hypertension, and their involvement with endothelial dysfunction and consequent cardiovascular disease outcome.

Aside from the hyperandrogenic concerns, growing evidence supports the cardiovascular risk in patients with PCOS (Sukalich, S. and Guzick, D., 2003). This risk includes but is not restricted to a greater risk of myocardial infarction (Dahlgren, E. et al., 1992) and significant carotid artherosclerosis (Guzick, D.S. et al., 1996; Talbott, E.O. et al., 2000). In terms of the surrogate markers linked to cardiovascular risk, PCOS patients show a trend toward increased triglyceride levels and low high density lipoprotein cholesterol levels, a hallmark of atherogenic dyslipedemia (Bickerton, A.S. et al., 2005; Apridonidze, T. et al., 2005). Moreover, the hyperandrogenemia and hyperinsulinemia and resultant insulin resistance exacerbate the situation and promote atherosclerosis.

Several lines of evidence suggest that the metabolic and reproductive abnormalities that eventually materialize in PCOS are due to insulin resistance. Although the cause-effect relationship between hyperinsulinemia and hyperandrogenism is unresolved, they have nevertheless been linked extensively in the literature (Burghen, G.A. et al., 1980) and the subsequent insulin resistant state prevails in approximately 50–70% of women with PCOS (Dunaif, A., 1997).

A large number of studies have identified specific defects in classic target tissues involved in insulin activity that are connected to insulin resistance (Venkatesan, A.M. et al., 2001; Dunaif, A. et al., 1992; Ciaraldi, T.P. et al., 1992; Dunaif, A. et al., 1995; Dunaif, A. et al., 2001; Courbould, A. et al., 2005). These include adipose tissue, fibroblasts, and skeletal muscle. There have been aberrant signaling pathways at the molecular level that have been implicated in PCOS. Evidence from in vitro and in vivo studies suggests that there exists a correlation between hyperinsulinemia and endothelial dysfunction as signified by elevated levels of endothelin-1 (Wolpert, H.A. et al., 1993; Ferri, C. et al., 1995; Ottosson-Seeberger, A. et al., 1997; Hu, E.R. et al., 1993).

Since visceral adipose tissue functions as an active metabolic and endocrine organ (Kershaw, E.E. and Flier, J.S., 2004), its accumulation can lead to insulin resistance, dyslipedemia, hypertension, and prothrombotic and proinflammatory states that are all part of the etiologies of PCOS (Kershaw, E.E. and Flier, J.S., 2004; Ehrmann, D.A., 2005). Adipose tissue can modulate the secretion of adiponectin, leptin, tumor necrosis factor α (TNF-α), interleukin-6, and plasminogen activator inhibitor-1 (Escobar-Morreale, H.F. et al., 2005; Escobar-Morreale, H.F. et al., 2006). The stimulation of C-reactive protein by TNF-α is an upstream mediator of endothelial dysfunction (Diamanti-Kandarakis et al., 2006). Abdominal adiposity, as evidenced by an increased omentum, or blanket of internal abdominal fat, could therefore lead to an insulin resistant state, which in turn could play an important early role in mediating endothelial injury and subsequent atherosclerosis.

Although the incidence of hypertension is not common in young females with PCOS, obesity seems to be a key contributor. More than 50% of PCOS patients are overweight with characteristic truncal adiposity (the percentage of trunk-to-total skin folds ratio) (Gambineri, A. et al., 2002). The abdominal adiposity is independently correlated to aberrant steroidogenesis (Escobar-Morreale, H.F. et al., 2007), leading to activation of endocrine signaling via visceral fat. The increase in adiposity results in an increased secretion of angiotensinogen, causing increased levels of angiotensin II. Angiotensin II could then contribute to hypertension in these patients. The proinflammatory signal cascade eventually contributes to an increased incidence of cardiovascular disease.

There is little dispute in the medical and scientific community that a modest weight loss (≥5% body weight) can result in significant improvements in cardiovascular risk profile as well as insulin sensitivity. Not surprisingly, these benefits also extend to women with PCOS, resulting in improved reproductive function (Marsh, K. and Brand-Miller, J., 2005; Crosignani, P.G. et al., 2003; Norman, R.J. et al., 2004; Stamets, K. et al., 2004; Douglas, C.C. et al., 2006).

--- PAGE BREAK ---

Interestingly, it has been recently proposed that women with PCOS may have an increase in circulating ghrelin (Norman, R.J. et al., 2004). Ghrelin is a hormone that is secreted prior to a meal, resulting in a need to feed, accompanied by decrease in energy expenditure, increased gastric motility, and acid secretion. High ghrelin levels in PCOS patients could therefore result in a persistent abnormal energy balance state, which can be restored by a calorie deficit and weight loss through diet and/or exercise (Norman, R.J. et al., 2004). However, the vicious cycle of cravings mediated by insulin resistance makes it increasingly difficult for women who suffer from PCOS to lose weight. This factor combined with the psychological effects of increased BMI, hirsutism (excessive coarse and pigmented male-like body hair growth pattern in women), and acne, makes adherence to an exercise or diet program increasingly difficult.

From a dietary perspective, the optimal dietary composition for women with PCOS is unclear, in part due to the heterologous nature of the syndrome. In the past, low glycemic index (GI) diets have been recommended without any clinical evidence of efficacy. A recent study in the American Journal of Clinical Nutrition was the first to provide objective evidence to justify the use of low GI diets in the management of PCOS (Marsh, K.A. et al., 2010). The authors found a significant improvement in menstrual cyclicity and several biochemical measures of the disease (Marsh, K.A. et al., 2010).

Interestingly, the study also showed a significant interaction between the diet and metformin, a biguaninde that is frequently used to ameliorate the insulin resistance in women with PCOS. This finding is not surprising, in that low-carbohydrate diets and extreme calorie restriction have been touted increasingly in the media as an instant weight-loss solution. The idea then, for women with PCOS would be to reduce the circulating glucose through diet, thereby, in essence, creating a metformin-like effect without the drug. However, for women with PCOS, this issue is more complicated.

Recent studies from the University of California, San Francisco, have shown that an increase in cortisol as a result of calorie restriction may be particularly detrimental in PCOS patients (Tomiyama, A.J., et al., 2010). In addition, the loss of vitamins and micronutrients that typically accompany very low carbohydrate diets can wreak havoc on women with PCOS, who by default, have defects in how their bodies process and utilize micronutrients. Moreover, the benefits of vitamin supplementation and omega-3 fatty acids is well documented for PCOS (Cussons, A.J. et al., 2009; Zacche, M.M. et al., 2009; Wehr, E. et al., 2009; Mahmourdi, T. et al., 2009; Kotsa, K. et al., 2009). All in all, while weight loss is essential in improving the metabolic, hormonal, and cardiovascular profile in women with PCOS, a combination of diet, exercise, and medication management is probably the most effective route.

In summary, it appears that we now have increasing evidence that a diet rich in fruits and vegetables to supply micronutrients and consisting of lean protein may be the optimal diet for women with PCOS. Management of symptoms can be achieved through the concurrent use of drugs until the desired weight loss and accompanying ablation of symptoms is achieved.

by Daya Perkins, Ph.D.,
Contributing Editor
Global Pharmaceutical Sciences Fellow,
Allergan Inc., Irvine, Calif. 
[email protected]

by Larisa Yedigarova, M.D., Ph.D.,
Contributing Editor 
Assistant Professor of Clinical Obstetrics & Gynecology,
Division of Maternal-Fetal Medicine,
Keck School of Medicine,
University of Southern California, Los Angeles. 
[email protected]

by Roger Clemens, Dr.P.H.,
Contributing Editor 
Scientific Advisor,
ETHorn, La Mirada, Calif. 
[email protected]