ReviewMedical management of metabolic dysfunction in PCOS
Highlights
► Metformin may improve metabolic profile in women with hyperinsulinemia. ► Thiazolidinediones improve insulin sensitivity but carry significant risks. ► Statins improve several metabolic abnormalities but likely not insulin resistance. ► Benefits of use of orlistat, acarbose, naltrexone and orlistat are not proven. ► Long-term benefits of use of any medical treatment in PCOS is not certain.
Introduction
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting between 6% and 8% of women in reproductive age [1]. It is associated not only with reproductive and cosmetic sequelae, but also with significantly increased risk of metabolic dysfunction including insulin resistance with consequent compensatory hyperinsulinemia, dyslipidemia, systemic inflammation, increased oxidative stress, and endothelial dysfunction (Fig. 1) [2], [3]. In the long-term, women with PCOS may develop type 2 diabetes mellitus, hypertension and atherosclerosis; ultimately, they are more likely to suffer from cardiovascular and cerebrovascular diseases [4], [5], [6].
First-line therapy for metabolic dysfunction typically consists of lifestyle modifications including a diet and exercise regimen. Unfortunately, long-term success of lifestyle modifications is often not achieved. Consequently, there is an urgent need to develop and validate appropriate pharmacologic interventions to improve metabolic function in women with PCOS. This brief review will present several currently available medical treatments of selected features of metabolic dysfunction and will discuss pros and cons of their use in PCOS.
Section snippets
Metformin
Metformin is a biguanide widely used in treatment of type 2 diabetes mellitus and, more recently, in treatment of other conditions including PCOS. The primary mechanism of action of metformin is believed to be related to reduction of hepatic gluconeogenesis [7], [8]. In addition, metformin improves glucose uptake by peripheral tissues, decreases fatty acid synthesis and increases fatty acid oxidation. Metformin may also improve insulin sensitivity of skeletal muscles and reduce appetite.
Thiazolidinediones
Thiazolidinediones encompass a family of related compounds acting as peroxisome-proliferator-activated receptor-γ (PPRAγ) agonists. Thiazolidinediones improve insulin sensitivity at the level of peripheral tissues including skeletal muscle and adipocytes. Beneficial effects of thiazolidinediones including rosiglitazone and pioglitazone on insulin sensitivity in women with PCOS have been documented in multiple studies including placebo-controlled trials [21], [23], [24], [25], [26].
Acarbose
Acarbose is a complex oligosaccharide inhibiting α-glucosidase in the brush border of the small intestine. It decreases digestion of polysaccharides and hence reduces glucose absorption in the gut and decreases postprandial insulin levels. To date few studies addressed the effects of acarbose on women with PCOS [32], [33], [34], [35], [36]. In only two studies acarbose reduced insulin level and/or parameters of insulin resistance [32], [35] while in other studies no improvement was noted [33],
Naltrexone
Naltrexone is a competitive nonselective antagonist of opioid receptors. Use of naltrexone in treatment of PCOS is based on the evidence that PCOS is characterized by increased activity of sympathetic nervous system, altered central opioid tone and elevated beta-endorphin release [37], [38], [39] There is also a growing body of evidence demonstrating that beta-endorphins exert profound effects on insulin release [37].
In several studies oral administration of naltrexone in women with PCOS
Orlistat
Orlistat is a gastric and pancreatic lipase inhibitor reducing absorption of dietary fats by inhibition of hydrolysis of triglycerides. It has been approved for management of obesity and has been recently tested in several trials evaluating women with PCOS [46], [47], [48], [49]. In three of these studies, orlistat improved parameters of insulin sensitivity and reduced insulin level with concomitant decrease of BMI [46], [47], [49]. However, in one of the studies, orlistat while reducing BMI,
Vitamin D
The primary role of vitamin D pertains to regulation of calcium homeostasis and bone metabolism. Vitamin D promotes intestinal absorption of dietary calcium. Vitamin D receptors are present in most tissues in the body and effects of vitamin D include inhibition of cell proliferation, induction of cell differentiation and immunomodulation. Low levels of vitamin D are associated with insulin resistance while administration of Vitamin D may improve insulin sensitivity; however, the mechanisms of
Statins
Statins are competitive inhibitors of the rate-limiting enzyme in the cholesterol biosynthetic pathway: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins improve the lipid profile, primarily by decreasing total cholesterol and LDL-cholesterol levels [57], [58]. Statins also exert many other potentially beneficial effects including improvement of nitric oxide-mediated endothelial function as well as anti-inflammatory and anti-proliferative actions [59], [60]. In the long-term,
Conclusions
At first glance, review of the literature may suggest the availability of a plethora of medical treatments to correct metabolic dysfunction associated with PCOS. However, upon closer inspection of the studies, the evidence for real long-term benefit of currently available treatments is, at best, very limited. Metformin appears to alleviate some aspects of metabolic dysfunction, but the improvement is modest while the side effects are very common and significant. Furthermore, response to
Acknowledgment
Supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant R01-HD050656.
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