Shahla Nader, M.D., Department of Internal Medicine (Endocrinology) and Obstetrics, Gynecology & Reproductive Sciences, University of Texas Medical School – Houston, 6431 Fannin Suite 3.604, Houston, Texas 77030, E-mail: Shahla.Nader-Eftekhari[at]uth.tmc.edu

Introduction

Polycystic ovary syndrome is the most common endocrine disorder in young women, affecting approximately 6% of reproductive age women. Clinically, manifestations include menstrual irregularity, signs and symptoms of androgen excess, and cystic ovaries. While not part of the definition, it is widely acknowledged that obesity and insulin resistance are important components of the pathophysiology in many (but not all) of these patients and insulin-mediated ovarian androgen secretion has been demonstrated [1]. Oral contraceptive pills (OCP) have long played an important role in the treatment of this disorder. Oral contraceptives contain estrogen (usually ethinyl estradiol) and a progestin (variable, according to the pill); these suppress gonadotropins and hence the drive to ovarian androgen secretion. The estrogen component also increases sex hormone-binding globulin (thus lowering free androgens). In addition, the progestin component protects the endometrium from hyperplasia. Thus, OCP induce regular cycles and reduce androgenic manifestations such as acne, hirsutism, and alopecia.

Metabolic/Cardiovascular Effects of OCP in the General Population

The possibility that OCP may have adverse metabolic/cardiovascular effects was raised as long ago as 1969 when Wynn and Doar performed oral and intravenous glucose tolerance tests in 91 normal women before and during OCP therapy [2]. Both tests showed deterioration of glucose tolerance and increased insulin concentrations in the women studied and 13% developed clinical diabetes. In their discussion, the authors commented that “the most important question of all, namely whether the impairment of glucose tolerance and increased plasma insulin levels will accelerate the rate of development of clinical diabetes and also of atherosclerosis requires careful consideration.” These potential adverse effects did not receive much publicity, possibly because over the ensuing years the dose of ethinyl estradiol in OCP was reduced from 50 µg to as low as 20 µg in the USA and 15 µg in Europe, to decrease side effects and the risk of thromboembolic disease. The metabolic impact of current, commonly used OCP was discussed and highlighted in a comprehensive review by Godsland [3]. He showed that OCP were generally associated with reduced glucose tolerance, hyperinsulinemia, and insulin resistance. While it was felt that the estrogen component was primarily responsible, it was also shown that more androgenic progestins in OCP could further impair insulin action. In the general population, OCP increase triglycerides and may increase HDL cholesterol, especially OCP containing progestins of low androgenicity.

The relationship of OCP with myocardial infarction, stroke, and venous thromboembolic disease, in the general population, was reviewed by the Practice Committee of the American Society of Reproductive Medicine and the risks were considered to be low in young patients and non-smokers [4]. However, a more recent meta-analysis of the association of current use of low-dose OCP and cardiovascular arterial disease demonstrated increased risk (odds ratio 2.01) of cardiac and vascular arterial events, including a significant risk of vascular arterial complications even with less androgenic 3rd generation OCP [5].

Metabolic/Cardiovascular Effects of OCP in PCOS

The metabolic syndrome is a multidimensional risk status for both atherosclerotic cardiovascular disease and type 2 diabetes [6]. While there are no published studies demonstrating increased occurrence of cardiovascular disease in polycystic ovary syndrome (PCOS) patients, features of the metabolic syndrome and adverse markers of cardiovascular disease are often observed in such patients [7]. Thus the potential for OCP-induced exacerbation of adverse long-term outcomes is a real concern in this population of patients. The available literature on the effects of OCP on carbohydrate metabolism in PCOS patients is varied and conflicting. Variables in published studies have included age, and genetic and anthropometric make-up of the population studied. In addition, different laboratory methods were utilized to assess effects and a number of different OCP formulations were used to treat the patients. The outcome of these studies, as regards carbohydrate metabolism, has shown improvement, no change, deterioration, or the development of frank diabetes: that is, all possible outcomes have been demonstrated.

To explain these diverse effects, a unifying hypothesis has been proposed [8], namely that the composite effect of OCP on carbohydrate metabolism and insulin sensitivity in PCOS is determined by the interplay of the following factors:

1. Estrogen induced impairment of carbohydrate tolerance and insulin sensitivity.
2. Progestin induced impairment of insulin sensitivity, especially progestins with higher intrinsic androgenicity.
3. The endogenous insulin sensitivity of the individual, itself determined genetically, environmentally, and by other factors, such as puberty (which is an insulin resistant state)
4. Lowering of free androgens which may improve insulin action.

These factors and interactions may explain why insulin sensitivity may improve in a thin PCOS patient (the effect of lowering free androgens in an otherwise fairly insulin sensitive subject), while carbohydrate tolerance and insulin sensitivity may deteriorate in an obese PCOS patient, especially if she is insulin resistant genetically, or is in pubertal transition (OCP-mediated insulin resistance is not off-set by the improvement induced by the androgen-lowering effect of the pill). The greater the insulin resistance, the worse appears to be the effect of the pill. This was previously demonstrated by Doar and Wynn who showed an additive effect of obesity and OCP on the impairment of insulin sensitivity [9]. It was also demonstrated by Nader et al. who administered OCP to 16 extremely obese, insulin resistant subjects, two of whom developed diabetes [10]. Triglycerides and HDL increase in PCOS patients on OCP and pills of lesser androgenicity lead to higher triglyceride concentrations [8]. Finally, an abnormal adipocytokine profile deteriorated in PCOS patients, when given OCP [11].

Summary and Conclusions

While OCP provide cycle control and ameliorate androgenic symptoms in patients with PCOS and may improve carbohydrate metabolism in the thin androgenic patient, they pose a metabolic risk for the PCOS patient who is obese and insulin resistant. In such patients, concomitant use of agents that may modify these effects, such as metformin, is advisable. Informing health care providers and patients of such risks and identifying those at risk remain worthy challenges.

References

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