Weight reduction is of paramount importance and cornerstone of every therapeutic strategy in PCOS. Although obesity does not seem to be the primary insult in PCOS, many studies have demonstrated the beneficial impact of weight reduction on the manifestations of the syndrome and especially insulin sensitivity, risk for diabetes and adverse cardiovascular risk profile (199). The effect of weight reduction by a hypocaloric low-fat diet on the metabolic and endocrine variables was studied in obese women with PCOS
(200). The insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique, which is the gold standard in evaluating insulin resistance. After the diet intervention, insulin sensitivity improved and did not differ significantly from the body mass index matched normo-ovulatory control women.
In another study, the effect of dietary intervention on insulin sensitivity and lipids, fibrinolysis and coagulation was examined also in obese women with PCOS (201). Insulin sensitivity was assessed by the eyglycemic clamp technique before and after a very low-calorie, protein-rich diet for 4 weeks that was followed by a low-calorie, low-fat diet for 20 weeks. After the 24-week intervention, insulin sensitivity was significantly increased along with a significant reduction of total serum cholesterol and fasting triglyceride. Additionally, there was a significant reduction of fasting glucose and insulin. After the 20-week follow-up program, insulin sensitivity was still significantly increased and PAI-1 was significantly improved.
Weight reduction also decreases androgen levels and restores ovulation in women with PCOS (202). Most of the studies suggest a significant reduction in total testosterone and a significant increase in SHBG, positively affecting the free testosterone levels. This effect is probably as a result of the improvement in hyperinsulinemia that directly affects ovarian androgen production.
Thiazolidinediones (TZDs) are novel insulin-sensitizing agents that improve peripheral insulin resistance in adipose tissue and skeletal muscle and are currently widely used for the treatment of type 2 diabetes. Recent studies have shown that the TZD troglitazone, improves total body insulin action in PCOS resulting in lower circulating insulin levels without altering body weight and lowered circulating androgen, estrogen, and luteinizing hormone (LH) levels (203). In addition to improving insulin resistance, troglitazone reduced PAI-1 levels (204) and was also shown to improve ovulation in a dose-related fashion (205). More recently, troglitazone was shown to improve endothelial function in women with PCOS to near normal levels (206). The latter agent was withdrawn from the market after reports of hepatotoxicity.
Rosiglitazone which is currently Food and Drug Administration (FDA)-approved for the treatment of type 2 diabetes is another insulin sensitizer that was shown to enhance both spontaneous and clomiphene- induced ovulation in overweight and obese women with PCOS (207). Pioglitazone, also another FDA-approved insulin sensitizer, when added to metformin lowered insulin, glucose, insulin resistance, insulin secretion, and dehydroepiandrosterone sulfate, whereas it increased HDL-C and SHBG along with an improvement in menstrual regularity (208).
Metformin is an oral hypoglycemic agent that is extensively used for the treatment of type 2 diabetes mellitus. Its mechanism of action involves decreasing hepatic glucogenolysis that leads to a decrease in hepatic glucose output. To a lesser extent metformin increases peripheral glucose-mediated glucose uptake (209).
Metformin (1500 mg), when administered daily for 4-8 weeks in obese women with PCOS, resulted in a decrease in insulin and free testosterone levels (210). Metformin at the above dose improved insulin sensitivity, decreased serum LH and increased serum follicle-stimulating hormone and SHBG (211). Higher plasma insulin, lower serum androstenedione and less severe menstrual abnormalities are baseline predictors of clinical response to metformin (212). Metformin is also very useful in lean and normal weight women with PCOS (213). In this population, metformin treatment for 4-6 weeks resulted in a decrease in fasting and glucose-stimulated insulin levels, decreased free testosterone concentrations, and increased SHBG.
One of the greatest challenges is whether metformin should be used in all women with PCOS to prevent or delay the development of type 2 diabetes. In the recently reported Diabetes Prevention Program, metformin therapy in nondiabetic persons with elevated fasting and postload plasma glucose concentrations, reduced the incidence of type 2 diabetes by 31% (214). In nondiabetic women with PCOS, metfomin therapy throughout pregnancy was associated with a 10-fold decrease in the development of gestational diabetes (215).
Women with PCOS very often require medications to induce ovulation. Metformin is very beneficial in ovulation induction when administered in combination with medications such as clomiphene citrate and this improves pregnancy rates (216). Also, metformin, improved fertilization and pregnancy rates when administered to clomi-phene-citrate-resistant women with PCOS who were undergoing in vitro fertilization (217). Additionally, metformin administration during pregnancy reduced first-trimester pregnancy loss (218). Metformin's beneficial reproductive effects are clearly attributed to amelirioration of hyperinsulinemic insulin resistance.
It has been established that HRT is beneficial in reducing osteoporosis and alleviating climacteric symptoms. HRT has also been shown to have beneficial effects on risk factors for CVD. However, data from recent clinical trials indicate that HRT, in the form of continuous combined CEE with MPA, has no cardioprotective effects and is not recommended for primary or secondary prevention of CVD in postmenopausal women.
Data on HRT in postmenopausal women with diabetes are scarce but are of major importance, because these women are characterized by hyperandrogenicity, insulin resistance, and dyslipidemia and are at a higher risk for developing CHD. Evidence from the available data suggest that short-term unopposed oral estradiol has a beneficial effect on glucose homeostasis, lipid profile, and other components of the metabolic syndrome, which may be compatible with a reduced risk of CHD. The addition of a progestogen may attenuate some of these favourable effects. On the other hand, HRT consisting of continuous combined transdermal 17^-estradiol and oral norethisterone, reduces plasma triglycerides and cholesterol concentrations, factor VII activity and von Willebrand factor antigen levels without concomitant changes in adiposity and glycemic control. These effects, allied with favorable effects on CRP and potential beneficial effects on vascular reactivity, suggest that this regimen may hold particular advantage for women with diabetes. Comparative studies are urgently needed to test this hypothesis.
On the basis of the current knowledge, NAMS has established consensus on the following issues: (a) controlling cardiovascular risk factors through pharmacological and nonpharmacological means can significantly decrease the risk for developing cardiovascular events, (b) a broad-based recommendation for ERT/HRT cannot be made; rather the benefits and risks must be weighted in the context of each woman's risk factors, (c) when ERT/HRT is recommended, the greatest benefits may be obtained from use of transdermal estrogen preparations, low doses of oral estrogens, progesterones instead of progestin, and/or nonandrogenic preparations, although more research is needed in this area, and (d)
counseling can help maximize the patient's adherence to multiple medication regimens and increase her understanding of the potential benefits and risks of ERT/HRT (147).
Thus, a century after the first description of the "evil effects" of the female sex hormones, their actual role in CVD remains controversial. However, as Marie Curie said "Nothing in life is to be feared, it is only to be understood" and so to this end, research is this area needs to continue.
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