Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis

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1 Human Reproduction Vol.22, No.2 pp , 2007 Advance Access publication November 10, doi: /humrep/del407 OPINION Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis S.Nader 1,3 and E.Diamanti-Kandarakis 2 1 Departments of Internal Medicine (Endocrinology) and Obstetrics/Gynecology/Reproductive Sciences, University of Texas Medical School, Houston, TX, USA and 2 1st Department of Medicine, Endocrine Section, University of Athens, Athens, Greece 3 To whom correspondence should be addressed at: 6431 Fannin Street, Suite 3604, Houston, TX 77030, USA. shahla.nader-eftekhari@uth.tmc.edu In the chronic treatment of polycystic ovary syndrome (PCOS), oral contraceptive pills (OCPs) are commonly used to induce regular menses, protect the endometrium and ameliorate androgenic symptoms. However, the long-term safety of OCP use in PCOS has not been established, and the literature reveals conflicting data concerning the metabolic effects of OCPs in this patient population, with outcomes ranging from improvement of glucose tolerance to the development of frank diabetes. This article presents new perspectives and a unifying hypothesis concerning the effects of OCPs on carbohydrate metabolism in PCOS and attempts to explain the divergent findings in published reports. Key words: carbohydrate metabolism/insulin resistance/polycystic ovary syndrome/oral contraceptive pills Introduction Chronic treatment of a disease requires critical appraisal of potential long-term risks, as well as benefits, of such treatment. Although the management of polycystic ovary syndrome (PCOS) with oral contraceptive pills (OCPs) has a long and established history of use (Ehrmann, 2005), conflicting data have emerged regarding potentially beneficial or adverse metabolic effects of this therapy in this patient population. This article provides new perspectives on this topic, and a unifying hypothesis is presented to explain the divergent reports found in the literature. PCOS PCOS is the most common endocrine disorder in reproductive age women, affecting 6% of this population (Diamanti- Kandarakis et al., 1999). The clinical issues in PCOS relate to menstrual irregularities and symptoms of androgen excess, mainly acne, hirsutism and alopoecia, as well as cystic ovaries. The 2003 Rotterdam consensus conference definition encompasses two of the three above features (Revised 2003 consensus, 2004). Although not part of the definition, it is widely acknowledged that obesity and insulin resistance are extremely common accompaniments of this syndrome (De Ugarte et al., 2005). OCPs OCPs are estrogen- and progestin-containing preparations. Their mechanism of action (Speroff and Fritz, 2005) is summarized in Table I. The estrogen component is almost always ethinyl estradiol (EE) in doses ranging from 15 to 50 μg. The progestin component is of variable potency and androgenicity. The composition of commonly used OCPs is summarized in Table II. Newer OCPs contain less androgenic progestins such as norgestimate, desogestrel and drospirenone. Relative androgenicities of these progestins are summarized in Table III (Phillips et al., 1990; Van der Vange et al., 1990; Carr, 1998). Certain OCPs, according to their progestin content, may also have antagonizing effects on the androgen receptor (Schindler et al., 2003) or may inhibit 5α reductase activity (Hammond et al., 2001). OCPs containing cyproterone acetate, an anti-androgen, are available in Europe but not in the USA. OCPs are commonly used in the management of patients with PCOS. They induce predictable cyclic menses, reduce luteinizing hormone secretion and thus lower ovarian androgen production; the estrogen component increases sex hormone-binding globulin, thus reducing free androgens (Ehrmann, 2005). The progestin component protects the endometrium from hyperplasia, and OCPs also provide contraception while allowing the use of other drugs, such as anti-androgens, in this patient population. Within 3 6 months of treatment, inflammatory acne counts are reduced by 30 60% with improvement in 50 90% of patients (James, 2005). OCPs are especially useful in patients with deep-seated nodules and helpful in patients relapsing on isotretinoin. Of the patients with androgen excess, 70 80% are hirsute; a decrease in free androgens reduces new hair growth and growth of terminal hair. However, it may take 6 9 months The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. 317 For Permissions, please journals.permissions@oxfordjournals.org

2 S.Nader and E.Diamanti-Kandarakis Table I. Actions of combined oral contraceptives Estrogen component (ethinyl estradiol) Suppression of follicle-stimulating hormone Stabilization of endometrium Potentiation of progestin action Suppression of dominant follicle formation Increase in sex hormone-binding globulin Decrease in free androgen Progestin component (variable according to preparation) Suppression of luteinizing hormone Inhibition of luteinizing hormone surge Unreceptive endometrium Hostile cervical mucus Decrease in ovarian androgen secretion Possibly androgen-blocking effects for this effect to be evident (Azziz, 2003), and anthropometric differences may affect clinical efficacy (Cibula et al., 2001). There are no extensive trials for alopoecia, but OCPs and androgen blockers are usually given, and in limited studies cyproterone has had some effect (Vexiau et al., 2002). OCP users also have a lower incidence of ovarian cysts, and ovarian volume decreases with their use. However, it appears that higher dose of estrogen is needed for significant protection against ovarian cysts (Holt et al., 2003). Dysfunctional, anovulatory bleeding is avoided by using OCPs, and the cycles are less heavy. The progestin component protects the endometrium and may reduce the risk of endometrial cancer, which is increased in PCOS (Balen, 2001). Although there are no data specific to PCOS, OCPs reduce this risk in the general population. In summary, there are clear clinical benefits of OCP treatment in PCOS. However, what is less clear is their long-term safety. PCOS and OCP: metabolic and vascular effects of both Features of the metabolic syndrome are commonly observed in patients with PCOS, and it is broadly recognized that PCOS is associated with adverse metabolic outcomes (Diamanti- Kandarakis et al., 2003). Even without PCOS, possible adverse long-term effects of OCP are under scrutiny. A recent metaanalysis of the association of low-dose contraceptive pills with cardiovascular arterial disease found an increased risk of myocardial infarction/stroke with low-dose pills with an odds ratio of 2.01, including an increased risk of ischaemic stroke with third generation OCPs (Baillargeon et al., 2005). Although there are no published studies showing increased occurrence of cardiovascular disease in PCOS, a possible exacerbation of adverse long-term outcomes of PCOS by OCPs is a public health concern. OCPs and carbohydrate and lipid metabolism in general population A potential link between adverse cardiovascular outcome and OCP is the deterioration of glucose tolerance and carbohydrate metabolism. Three epidemiologic studies have looked at this. A prospective study of over nurses in the Nurses Health Study with 12 years of follow-up showed a 10% greater risk of type two diabetes in past users of OCPs albeit with high-dose estrogen (Rimm et al., 1992). However, a more recent study of nurses with 4 years of follow-up showed no significant increase in risk with low-dose pills (Chasen-Taber et al., 1997). The most recent study, the 3rd NHanes cross-sectional survey, showed that past and present users did not differ from never users in glucose, insulin, C-peptide and haemoglobin A1C concentrations (Troisi et al., 2000). One of the earliest prospective studies on the effect of oral contraceptives on carbohydrate metabolism in the general population was performed by Wynn and Doar (1969). In this study, 91 women had oral and intravenous glucose tolerance tests performed before and during OCP therapy (high-dose pills). Both oral and intravenous glucose tolerance area under the curve (AUC) deteriorated in 78 and 70% of the women, Table II. Low-dose [<50-μg ethinyl estradiol (EE)] combined oral contraceptives Estrogen (μg) Progestin (mg) Commercial names Monophasic EE 35 Norethindrone (1) Orthonovum1/35, Necon 1/35 Norethindone (0.4) Ovcon 35 Ethynodiol (1) Demulen 1/35 Norgestimate (0.25) Orthocyclen Cyproterone (2) Gynofen, Diane 35 EE 30 Norethindrone (1.5) Loestrin /30 Norgestrel (0.3) Lo-ovral Desogestrel (0.15) Desogen, Marvelon Levonorgestrel (0.15) Levlen, Nordette Gestodene (0.075) Gynera, Minulet Drosperinone (3) Yasmin EE 20 Norethindrone (1) Loestrin 21 1/20 Levonorgestrel (0.1) Alesse, Levlite Desogestrel (0.15) Mircette, Mercilon Gestodene (0.075) Meliane, Harmonette Drosperinone (3) Yaz EE 15 Gestodene (0.06) Melodia Biphasic EE 30/40 Desogestrel ( ) Gracial Triphasic EE 30/40/30 Levogestrel ( ) Trilevlen, Triphasil EE 35 Norgestimate ( ) Orthotricyclen EE 25 Norgestimate ( ) Orthotricyclen LO EE 30/40/30 Gestodene ( ) Trigynera, Tri-Minulet 318

3 PCOS and OCP: metabolic issues Table III. Androgenicity of combined oral contraceptive progestins Androgenicity according to sex hormone-binding globulin elevations from most to least androgenic Monophasic levonorgestrel Monophasic norethindrone, triphasic levonorgestrel Triphasic gestodene, biphasic desogestrel, monophasic desogestrel Monophasic cyproterone acetate Androgenicity according to relative binding affinities to androgen receptors in rat prostate from most to least androgenic Levonorgestrel Gestodene Desogestrel Norgestimate Androgenicity according to androgen-to-progestin receptor-binding ratio from most to least androgenic Levonorgestrel Gestodene Desogestrel Norgestimate Progestins with anti-androgenic effect Drospirenone (+) Cyproterone acetate (++) respectively, and 13% developed chemical diabetes during OCP therapy. Significant elevations of plasma insulin after both oral and intravenous glucose were also observed following therapy. In their discussion, the authors wrote 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 and further on in their paper, they commented that the answer may only become apparent in years time. In a comprehensive review entitled The influence of female sex steroids on glucose metabolism and insulin action, Godsland (1996) summarized the literature as showing that OCPs were generally associated with reduced glucose tolerance, hyperinsulinaemia and insulin resistance. It was felt that the estrogen component was primarily responsible, but the progestin component could modify these effects by changing insulin half-life and delaying estrogen metabolism. Progestins, especially the more androgenic progestins, could also directly induce insulin resistance. A broad survey of the literature has been consistent with the above review, showing mainly slight deterioration of oral glucose tolerance tests with the use of lower dose OCP. Intravenous glucose tolerance tests have also been consistent with estrogen-induced insulin resistance (Petersen et al., 1999). Two euglycaemic clamp studies have been performed. One showed no change in insulin sensitivity using a cyproterone OCP (Scheen et al., 1993), and the second showed reduced sensitivity using pills containing either desogestrel or gestodene (Perseghin et al., 2001). The effect of OCP on lipid metabolism in the general population has generally shown an increase in triglycerides, especially with less androgenic OCP (Van Rooijen et al., 2002). High-density lipoprotein (HDL) cholesterol may increase with low androgenic OCP or may occasionally decrease if the pill is of high androgenicity. Effects of OCPs on carbohydrate metabolism in PCOS Effects of OCPs on carbohydrate metabolism in PCOS have not been extensively or systematically studied. There have been variables of age, and anthropometric and genetic make-up of the population studied, and different laboratory methods have been used to assess these effects (Vrbikova and Cibula, 2005). In addition, different OCPs have been used with different dosage of estrogen, type of progestin and formulation of the pill. Some of the studies have included control subjects and many have not. The outcome of these studies has been extremely variable, with the results showing (i) improvement (Pasquali et al., 1999; Escobar-Morreale et al., 2000; Cagnacci et al., 2003), (ii) no change (Falsetti and Pasinetti, 1995; Armstrong et al., 2001; Cibula et al., 2002; Elter et al., 2002; Morin-Papunen et al., 2003; Sabuncu et al., 2003; Guido et al., 2004; Cibula et al., 2005), (iii) deterioration (Korytkowski et al., 1995; Morin-Papunen et al., 2000; Cagnacci et al., 2003; Palep-Singh et al., 2004; Vrbikova et al., 2004) or (iv) development of frank diabetes (Nader et al., 1997). Thus, the range of response has covered all possibilities. Effects of OCPs on carbohydrate metabolism in PCOS: a unifying hypothesis To explain the diverse effects of OCPs on carbohydrate metabolism in PCOS, we propose the following unifying hypothesis. Let us accept the following effects of OCPs: namely estrogens impair insulin action dose-dependently and progestins may modify these effects. Progestins also vary in their androgenicity, and there is substantial evidence linking androgens themselves to insulin resistance. Androgens have also been shown to lead to the accumulation of visceral fat. Studies on transsexuals by Polderman et al. (1994) and Elbers et al. (1997) have shown these effects, respectively, as have more recent studies in adolescent girls (Coviello et al., 2006). Given the above, it is likely that the effects of OCPs on carbohydrate metabolism in PCOS will be determined by (i) the degree of androgenicity of the woman and the androgen-lowering effect of the pill, (ii) genetically determined endogenous insulin sensitivity, (iii) anthropometric differences that can affect insulin action and (iv) the natural history of PCOS or environmental influences. The latter includes puberty, which is associated with decreased insulin sensitivity (Moran et al., 1999). 319

4 S.Nader and E.Diamanti-Kandarakis A few prismatic studies illustrate these concepts. Dahlgren et al. (1998) studied overweight PCOS subjects who were given either a 50-μg EE preparation along with reverse sequential cyproterone 100 mg versus a GnRH analogue. Euglycaemic clamp studies were performed before and after treatment. For obvious reasons, there was a marked decrease in free androgens in both groups. However, whereas there was improvement in insulin sensitivity in the GnRH analoguetreated group (reduction of both androgens and estrogen), the estradiol cyproterone-treated group deteriorated (the effect of high-dose estrogen in subjects who were already insulin resistant). In another study, Cagnacci et al. (2003) compared a monophasic 35-μg EE/cyproterone pill versus a biphasic 40/30 EE/desogestrel pill. Intravenous and oral glucose tolerance tests were performed. Whereas there was improvement of insulin sensitivity with the cyproterone pill (lowering of androgens with a non-androgenic pill), there was deterioration with the desogestrel pill (a more androgenic pill and/or a different formulation with a higher initial dose of estrogen). The effect of different progestins of potentially different androgenicity was also illustrated by Ibanez and de Zegher (2004a). They studied post-adolescent PCOS subjects who were already taking flutamide and metformin along with a 20-μg EE-/gestodenecontaining OCP. After some months of the above treatment, the subjects were randomized to replacement of the gestodene OCP with a drospirenone OCP containing 30 μg of EE. Compared with those who remained on gestodene, the switch to drospirenone was accompanied by a reduction in total and abdominal fat and an increase in lean body mass (a less androgenic OCP reduced the abdominal fat and potentially improved the metabolic profile despite the higher dose of estrogen in the drospirenone pill). Quartiles of PCOS Take a point in time in a woman s life and assume a degree of insulin sensitivity/resistance that is determined genetically, environmentally (obesity) and by other factors such as her degree of androgenicity and pubertal status. Imagine women falling somewhere on an arbitrary scale of insulin sensitivity, at that point in time, ranging from the more sensitive to the most resistant. Four quartiles or groups of PCOS can theoretically emerge. These groups are assigned arbitrarily by the authors to match four categories of responses to OCP, as outlined below. Quartile 1 These individuals have near-normal genetic insulin sensitivity. They are thin, and their only adverse factor is their androgenicity. Treatment with OCP may lead to improvement in carbohydrate metabolism (lowering of androgens improved glucose tolerance). Quartile 2 These patients have near-normal or mildly impaired genetic insulin sensitivity. They may be of normal weight or mildly overweight. Their androgenicity is also an adverse factor. Treatment with OCP may show no change in carbohydrate metabolism (as the potential impairment of glucose tolerance by the OCP is offset by the androgen-lowering effect of the pill). Quartile 3 These individuals may have moderately impaired genetic insulin sensitivity. They may be moderately overweight. Other adverse factors could include their androgenicity, puberty or the use of an androgenic OCP. The outcome with OCP treatment may be deterioration in carbohydrate metabolism (impairment of glucose tolerance by the OCP may be greater than the benefit of the androgen-lowering effect of the pill). Quartile 4 These individuals have severely impaired genetic insulin sensitivity. They may be severely obese. Other adverse factors include their androgenicity, puberty or the use of an androgenic OCP. The outcome of OCP treatment may possibly be the development of frank diabetes. As was illustrated by Doar and Wynn (1970), there is an additive effect of obesity and OCP on the impairment of glucose intolerance or, stated differently, the greater the insulin resistance the worse the effect of the pill. In the study by Nader et al. (1997), 2 of 16 subjects developed frank diabetes following the use of low-dose OCP. Their mean weight was 96 kg with a body mass index (BMI) of 36, and the subjects were recruited only if they exhibited acanthosis nigricans, that is, they were severely insulin resistant. A few more prismatic studies will illustrate these concepts. Morin-Papunen and colleagues did two separate studies (2000 and 2003) on two different groups of PCOS patients. The same cyproterone-containing OCP was used in both groups. Whereas the obese women given the pill had increased glucose AUC during the oral glucose tolerance test, non-obese women given the same OCP had no change in glucose tolerance. The effect of natural history is well illustrated by Pasquali et al. (1999). In this study, 37 women with PCOS were re-evaluated 10 years after their initial assessment. OCPs were offered at the first visit, but 21 of the 37 subjects never took the pill. Oral glucose tolerance tests were performed initially and at last evaluation. In these 21 subjects, the results indicated an increased insulin AUC consistent with the deterioration in insulin sensitivity. They had an initial BMI of 32.7, which increased to 34.4 despite dietary advice at the onset; their deterioration is assumed to relate to the progressive increase in weight during the follow-up interval. The other 16 patients took OCPs for an average of 97 months. Their glucose tolerance AUC actually improved, and basal insulin levels declined significantly. However, these individuals had a much lower BMI to begin with: 28.8, which decreased to 27.9 on followup. Thus, lowering of androgens and weight loss allowed them to be quartile 1 PCOS. Also, Sabuncu et al. (2003) studied obese PCOS subjects and administered a cyproterone-containing OCP versus the same OCP plus the appetite-suppressant drug sibutramine. The patients were advised to lose weight and both groups did so, more with the sibutramine. Oral glucose tolerance tests were performed. The AUC for glucose remained 320

5 PCOS and OCP: metabolic issues unchanged in the OCP-alone group (perhaps because of weight loss). However, the patients who took the combination OCP and sibutramine had a decreased AUC for insulin and glucose compared with pretreatment values (significantly greater weight loss allowed a change in quartile compared with their counterparts above). Lipid metabolism and other effects of OCPs in PCOS HDL cholesterol generally increases following OCP treatment in PCOS as do triglycerides. Higher triglyceride concentrations are seen with less androgenic progestins (Mastorakos et al., 2002). Other effects of OCPs in PCOS have been extensively studied by Ibanez and de Zegher (2004b), who looked at abnormal adipocytokines in these patients. They showed that abnormal adipocytokines, hypertriglyceridaemia and body adiposity became worse in a group of adolescents and young women given a drospirenone pill, and this corrected towards the norm with the addition of flutamide and metformin. They also showed that, both individually and together, flutamide and metformin lead to beneficial effects on these adverse factors (Ibanez et al., 2004; Ibanez and de Zegher, 2005). Summary and conclusions OCPs provide cycle control and contraception, ameliorate androgenic symptoms and protect the endometrium. Estrogens impair carbohydrate tolerance, dose-dependently, as do androgens and progestins of greater androgenicity. The composite effect of OCPs on glucose tolerance and insulin sensitivity is determined by the interplay of the above actions with the insulin sensitivity of the individual, itself determined genetically, environmentally and by other factors, such as puberty. The environmental influence may vary over time. OCPs increase HDL and triglycerides, and this effect varies with the progestin. 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