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Noncontraceptive use of oral combined hormonal contraceptives in polycystic ovary syndrome—risks versus benefits

  • Anuja Dokras
    Correspondence
    Reprint requests: Anuja Dokras, M.D., Ph.D., Department of Obstetrics and Gynecology, University of Pennsylvania, 3701 Market Street, Philadelphia, Pennsylvania 19104.
    Affiliations
    Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania
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      The use of steroid sex hormones for noncontraceptive benefits has been endorsed by several medical societies. In women with polycystic ovary syndrome (PCOS), hormonal contraceptives are first-line therapy for concurrent treatment of menstrual irregularity, acne, and hirsutism. The association of PCOS with obesity, diabetes, and dyslipidemia frequently brings up the debate regarding risks versus benefits of hormonal contraceptives in this population. In women with PCOS, the lack of large-scale studies evaluating the risks with varying doses of ethinyl estradiol, types of progestins, and presence of confounding factors such as obesity, smoking, and other cardiometabolic comorbidities is a significant limitation in these deliberations. Although it is important to assess the absolute risk for major morbidities including cardiovascular events, currently, there are a paucity of long-term data for these outcomes in PCOS. Most of the current studies do not suggest an increase in risk of prediabetes/diabetes, clinically significant dyslipidemia, inflammatory changes, or depressive/anxiety symptoms with oral contraceptive pill use. Screening of women with PCOS for cardiometabolic and psychiatric comorbidities is routinely recommended. This information should be used by health care providers to individualize the choice of hormonal contraceptive treatment, adequately counsel patients regarding risks and benefits, and formulate an appropriate follow-up plan.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/12729-23039
      The noncontraceptive health benefits of steroid sex hormones are well recognized in the general population (
      ESHRE Capri Workshop Group
      Noncontraceptive health benefits of combined oral contraception.
      ). Hormonal contraceptives regulate menses, improve dysmenorrhea and menorrhagia, treat premenstrual syndrome, prevent menstrual migraines, and treat pelvic pain related to endometriosis. These agents also decrease the risk of endometrial, ovarian, and colon cancer. One of the clear noncontraceptive benefits in women with polycystic ovary syndrome (PCOS) is improvement in common presenting symptoms such as menstrual irregularity and menorrhagia associated with anovulatory bleeding. Together with effective treatment of clinical signs of hyperandrogenism such as acne and hirsutism, combined hormonal contraceptives are the first line of treatment in this population. PCOS, however, is associated with several comorbidities such as obesity, diabetes, metabolic syndrome, and mood and anxiety disorders. Potential risks of combined hormonal contraceptive use such as weight gain, mood changes, and adverse effects on cardiometabolic risk factors may have a greater impact in women with PCOS. There are a number of options for prescribing hormonal contraceptives including different routes of administration, cyclic versus continuous use, different types of progestin, and progestin-only options. This review will focus on the noncontraceptive benefits of oral contraceptive pills (OCP) and discuss risks likely related to use in adult women with PCOS.

      Impact on acne and hirsutism

      Recent guidelines and best practice recommendations from several medical societies (
      • Zegro R.S.
      • Arslanian S.A.
      • Ehrmann D.A.
      • Hoeger K.M.
      • Murad M.H.
      • Pasquali R.
      • et al.
      the Endocrine Society
      Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.
      ,
      • Goodman N.F.
      • Cobin R.H.
      • Futterweit W.
      • Glueck J.S.
      • Legro R.S.
      • Carmina E.
      American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review guide to the best practices in the evaluation and treatment of polycystic ovary syndrome. Part 1.
      ,
      • Fauser B.C.
      • Tarlatzis B.C.
      • Rebar R.W.
      • Legro R.S.
      • Balen A.H.
      • Lobo R.
      • et al.
      Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.
      ) endorse the use of hormonal contraceptives (oral, patch, and vaginal ring) as first-line management for concurrent treatment of menstrual abnormalities and clinical signs of hyperandrogenism in women with PCOS. These medications improve acne and hirsutism by suppressing pituitary gonadotropin secretion and increasing sex hormone binding globulin levels (
      • Archer J.S.
      • Chang R.J.
      Hirsutism and acne in polycystic ovary syndrome.
      ), thereby decreasing bioavailable serum androgens. It has been suggested that there may be benefits from the use of third-generation hormonal contraceptives containing desogestrel, gestodene, and norgestimate, as they are less androgenic, or hormonal contraceptives containing antiandrogenic progestins such as dienogest, drosperinone, and cyproterone acetate, due to their antagonizing effects on the androgen receptor or inhibition of 5α-reductase activity (
      • Vrbíková J.
      • Cibula D.
      Combined oral contraceptives in the treatment of polycystic ovary syndrome.
      ,
      • Yildiz B.O.
      Approach to the patient: contraception in women with polycystic ovary syndrome.
      ). Although most studies demonstrating the efficacy of hormonal contraceptives in the treatment of acne and hirsutism do not include women with PCOS (
      ESHRE Capri Workshop Group
      Noncontraceptive health benefits of combined oral contraception.
      ,
      • Arowojolu A.O.
      • Gallo M.F.
      • Lopez L.M.
      • Grimes D.A.
      • Garner S.E.
      Combined oral contraceptive pills for treatment of acne.
      ), a few randomized controlled trials suggest improvement in hirsutism scores with the use of OCP monotherapy specifically in women with PCOS (
      • Martin K.A.
      • Chang R.J.
      • Ehrmann D.A.
      • Ibanez L.
      • Lobo R.A.
      • Rosenfield R.L.
      • et al.
      Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline.
      ). A recent systematic review has examined randomized controlled trials (RCT) comparing OCP with different doses of ethinyl estradiol and different types of progestins that have included Ferriman-Gallwey (FG) scores and androgen levels as endpoints (
      • Mendoza N.
      • Simoncini T.
      • Genazzani A.D.
      Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies.
      ). In the largest study in this review (n = 171), the most significant improvements in FG score were seen in the group using OCP containing cyproterone acetate compared with drosperinone (
      • Bhattacharya S.M.
      • Jha A.
      Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome.
      ). One small RCT examined the use of vaginal ring versus OCP in women with PCOS for 6 months and reported significant improvements in FG scores in both groups (
      • Battaglia C.
      • Mancini F.
      • Fabbri R.
      • Persico N.
      • Busacchi P.
      • Facchinetti F.
      • et al.
      Polycystic ovary syndrome and cardiovascular risk in young patients treated with drospirenone–ethinyl estradiol or contraceptive vaginal ring. A prospective, randomized, pilot study.
      ). Although most OCPs included in these trials contained third-generation progestins and antiandrogenic progestins, overall all groups showed improvements in FG scores and a decrease in serum androgen levels. In the general population, there is some evidence to suggest that extended-cycle OCP offers greater androgen suppression and prevents rebound ovarian function as seen during the pill-free interval of cyclic OCP therapy (
      • Legro R.S.
      • Pauli J.G.
      • Kunselman A.R.
      • Meadows J.W.
      • Kesner J.S.
      • Zaino R.J.
      • et al.
      Effects of continuous versus cyclical oral contraception: a randomized controlled trial.
      ). This could potentially be advantageous in women with PCOS; however, the effects of different cycle lengths of OCP administration on acne and hirsutism have not been examined in this population. In overweight/obese women with PCOS, lower doses of ethinyl estradiol (20 μg) have also been reported to effectively decrease androgens. Overall, these studies support the use of a low-dose OCP containing progestins with lower androgenic potential for the treatment of acne and hirsutism in women with PCOS.

      Impact on risk of endometrial cancer

      Women with PCOS have several risk factors that predispose them to an increased risk of endometrial cancer, namely, obesity, diabetes, nulliparity, and infertility (
      • Navaratnarajah R.
      • Pillay O.C.
      • Hardiman P.
      Polycystic ovary syndrome and endometrial cancer.
      ). Although there are few studies with cohorts large enough to adequately assess the risk of endometrial cancer in women with PCOS (
      • Shen C.C.
      • Yang A.C.
      • Hung J.H.
      • Hu L.Y.
      • Tsai S.J.
      A nationwide population-based retrospective cohort study of the risk of uterine, ovarian and breast cancer in women with polycystic ovary syndrome.
      ), several systematic reviews and meta-analyses suggest a 2- to 3-fold increased risk (
      • Chittenden B.G.
      • Fullerton G.
      • Maheshwari A.
      • Bhattacharya S.
      Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review.
      ,
      • Haoula Z.
      • Salman M.
      • Atiomo W.
      Evaluating the association between endometrial cancer and polycystic ovary syndrome.
      ), including in the reproductive-age group (
      • Barry J.A.
      • Azizia M.M.
      • Hardiman P.J.
      Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis.
      ). These data translate into a 9% lifetime risk of developing endometrial cancer in the case of PCOS compared with a 3% lifetime risk in the general population (
      • Dumesic D.A.
      • Lobo R.A.
      Cancer risk and PCOS.
      ). The Endocrine Society clinical practice guidelines recommend increased awareness of endometrial cancer risk in women with PCOS, particularly in those with abnormal uterine bleeding, prolonged amenorrhea, diabetes, and/or obesity (
      • Zegro R.S.
      • Arslanian S.A.
      • Ehrmann D.A.
      • Hoeger K.M.
      • Murad M.H.
      • Pasquali R.
      • et al.
      the Endocrine Society
      Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.
      ). Although there are limited data specifically examining the effects of OCP on reducing the risk of endometrial cancer in PCOS, several studies in the general population suggest a 50%–70% risk reduction with prolonged OCP use (
      • Schlesselman J.J.
      Risk of endometrial cancer in relation to use of combined oral contraceptives. A practitioner’s guide to meta-analysis.
      ,
      • Vessey M.
      • Painter R.
      Oral contraceptive use and cancer. Findings in a large cohort study, 1968–2004.
      ,
      • Hannaford P.C.
      • Selvaraj S.
      • Elliott A.M.
      • Angus V.
      • Iversen L.
      • Lee A.J.
      Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner’s oral contraception study.
      ). This benefit has also been described in women using the levonorgestrel intrauterine device (
      • Soini T.
      • Hurskainen R.
      • Grenman S.
      • Maenpaa J.
      • Paavonen J.
      • Pukkala E.
      Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland.
      ).

      Impact on depressive and anxiety symptoms

      Women with PCOS have a higher prevalence of depressive and anxiety symptoms compared with controls. In a meta-analysis, reproductive-age women with PCOS had an increased risk of both depressive symptoms (odds ratio [OR], 4.04; 95% confidence interval [CI], 2.96–5.5) (
      • Dokras A.
      • Clifton S.
      • Futterweit W.
      • Wild R.
      Increased risk for abnormal depression scores in women with polycystic ovary syndrome: a systematic review and meta-analysis.
      ) and anxiety symptoms (OR, 6.88; 95% CI, 2.5–18.9) (
      • Dokras A.
      • Clifton S.
      • Futterweit W.
      • Wild R.
      Increased prevalence of anxiety symptoms in women with polycystic ovary syndrome: systematic review and meta-analysis.
      ). A recent systematic review including studies in the general population suggests that hormonal contraception does not appear to adversely affect mood in women with a history of depressive disorders (
      • Pagano H.P.
      • Zapata L.B.
      • Berry-Bibee E.N.
      • Nanda K.
      • Curtis K.M.
      Safety of hormonal contraception and intrauterine devices among women with depressive and bipolar disorders: a systematic review.
      ). In fact, three studies in this review showed that in women who met a threshold for depression on a screening instrument, depression scores improved after 3–11 months of OCP use. Very few studies have examined the impact of OCP use on depressive and anxiety symptoms in women with PCOS. One study found no effect of 6-month OCP use in lean women with PCOS on depressive and anxiety symptoms assessed by the Becks Depression Inventory, Hospital Anxiety and Depression Scale, and General Health Questionnaire screens (
      • Cinar N.
      • Harmanci A.
      • Demir B.
      • Yildiz B.O.
      Effect of an oral contraceptive on emotional distress, anxiety and depression of women with polycystic ovary syndrome: a prospective study.
      ). On the contrary, Thomson et al. reported an improvement in depressive symptoms assessed by CES-D scores after 10 weeks OCP use in overweight/obese subjects with PCOS (
      • Thomson R.L.
      • Buckley J.D.
      • Lim S.S.
      • Noakes M.
      • Clifton P.M.
      • Norman R.J.
      • et al.
      Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome.
      ). In the recently published OWL-PCOS study, overweight/obese women with PCOS were randomized to low-dose OCP use, lifestyle intervention for weight loss, or both for 4 months before fertility treatment with clomiphene (
      • Legro R.S.
      • Dodson W.C.
      • Kris-Etherton P.M.
      • Kunselman A.R.
      • Stetter C.M.
      • Williams N.I.
      • et al.
      Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome.
      ). In a secondary analysis of this study, OCP use was shown to decrease the prevalence of depressive symptoms from 13.3% to 4.4% (OR, 0.30; 95% CI, 0.09, 0.99; P<.05) and anxiety symptoms from 6.7% to 2.2% (OR, 0.32; 95% CI, 0.06, 1.64; P=.17) (
      • Dokras A.
      • Sarwer D.B.
      • Allison K.C.
      • Milman L.
      • Kris-Etherton P.M.
      • Kunselman A.R.
      • et al.
      Weight loss and lowering androgens predict improvements in health-related quality of life in women with PCOS.
      ). In the same study, intensive lifestyle interventions also resulted in improvements in prevalence of depressive symptoms from 22.7% to 15.9% (OR, 0.64; 95% CI, 0.34, 1.22; P=.17) and anxiety symptoms from 15.9% to 4.7% (OR, 0.30; 95% CI, 0.10, 0.85; P=.02). Although these studies are limited by small numbers, overall they indicate a beneficial or no adverse effect of short-term OCP therapy on depressive and anxiety symptoms. An improvement in quality-of-life parameters as assessed by PCOS Quality of Life Questionnaire, a validated questionnaire, in adolescents (
      • Harris-Glocker M.
      • Davidson K.
      • Kochman L.
      • Guzick D.
      • Hoeger K.
      Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin.
      ) and adults further supports the use of OCP in this population (
      • Cinar N.
      • Harmanci A.
      • Demir B.
      • Yildiz B.O.
      Effect of an oral contraceptive on emotional distress, anxiety and depression of women with polycystic ovary syndrome: a prospective study.
      ,
      • Thomson R.L.
      • Buckley J.D.
      • Lim S.S.
      • Noakes M.
      • Clifton P.M.
      • Norman R.J.
      • et al.
      Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome.
      ,
      • Legro R.S.
      • Dodson W.C.
      • Kris-Etherton P.M.
      • Kunselman A.R.
      • Stetter C.M.
      • Williams N.I.
      • et al.
      Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome.
      ).

      Impact on metabolic parameters and cardiovascular disease risk factors

      OCP may adversely affect some traditional cardiovascular disease (CVD) risk factors, thereby raising concerns for their use especially in obese women with PCOS. In the general population, some studies describe OCP use as being associated with glucose intolerance (
      • Rimm E.B.
      • Manson J.E.
      • Stampfer M.J.
      • Colditz G.A.
      • Willett W.C.
      • Rosner B.
      • et al.
      Oral contraception use and the risk of type 2 diabetes in a large prospective study of women.
      ,
      • Watanabe R.M.
      • Azen C.G.
      • Roy S.
      • Perlman J.A.
      • Bergman R.N.
      Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors.
      ), hypertension in both past and current users (
      • Chasen-Taber L.
      • Willett W.C.
      • Stampfer M.J.
      • Hunter D.J.
      • Colditz G.A.
      • Spiegelman D.
      • et al.
      A prospective study of oral contraceptives and NIDDM among U.S. women.
      ), and dyslipidemia, especially hypertriglyceridemia (
      • Ball M.J.
      • Ashwell E.
      • Jackson M.
      • Gillmer M.D.
      Comparison of two triphasic contraceptives with different progestogens: effects on metabolism and coagulation proteins.
      ,
      • Van Rooijen M.
      • Schoultz B.V.
      • Silveira A.
      • Hamsten A.
      • Bremme K.
      Different effects of oral contraceptives containing levonorgestrel or desogestrel on plasma lipoproteins and coagulation factor VII.
      ) and elevated C-reactive protein (CRP) levels (
      • Van Rooijen M.
      • Hansson L.O.
      • Frostegård J.
      • Silveira A.
      • Hamsten A.
      • Bremme K.
      Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response.
      ,
      • Krintus M.
      • Sypniewska G.
      • Kuligowska-Prusinska M.
      Effect of second and third generation oral contraceptives on C-reactive protein, lipids and apolipoproteins in young, non-obese, non-smoking apparently healthy women.
      ). It has been suggested that the use of OCP in women with PCOS may have a greater impact on CVD risk given the high prevalence of obesity, diabetes, impaired glucose tolerance, and dyslipidemia in this population (
      • Dokras A.
      Cardiovascular disease risk in women with PCOS.
      ,
      • Lim S.S.
      • Norman R.J.
      • Davies M.J.
      • Moran L.J.
      The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis.
      ). On the contrary, it has been suggested that lowering serum androgens with OCP treatment may have a metabolic benefit, as androgens have been shown to adversely affect insulin sensitivity, adipocyte function, fat distribution, and lipolysis in adipocytes (
      • Corbould A.
      Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?.
      ). Recent World Health Organization (WHO) (

      World Health Organization. Medical eligibility criteria for contraceptive use. http://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.

      ) and Centers for Disease Control (CDC) (

      US medical eligibility criteria for contraceptive use. 2016. http://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf.

      ) guidelines on medical eligibility of contraceptive use published in 2016 include presence of obesity, hypertension, diabetes, and known dyslipidemias as relative contraindications to the use of OCP (category 2), indicating that the advantages of using OCP would generally outweigh any theoretical or proven risks (Table 1). The Androgen Excess (AE) PCOS Society recommends routine cardiovascular risk assessment in women with PCOS (Table 2).
      Table 1Medical eligibility criteria for using of combined hormonal contraceptives in women with increased metabolic risk and comorbidities associated with PCOS.
      ConditionMedical eligibility criteria categoryClarifications
      Obesity BMI ≥ 302
      Adequately controlled hypertension where blood pressure can be evaluated3
      Known dyslipidemias without other known CVD risk factors2Women with known severe genetic lipid disorders are at a higher lifetime risk for CVD and may warrant further clinical consideration
      Multiple risk factors for arterial CVD (older age, diabetes, hypertension, smoking, known dyslipidemias)¾Use of OCP may substantially increase CVD risk in the presence of multiple major risk factors, any of which alone would substantially increase risk of CVD.
      Depressive disorders1No data on bipolar and postpartum depression available
      History of gestational diabetes1
      Nonvascular diabetes (insulin and non–insulin dependent)2
      Thyroid disorders1
      Age, menarche to <40 years1Age ≥ 40 years: the risk of CVD increases with age and may also increase with combined hormonal contraceptive (CHC) use. In the absence of other adverse clinical conditions, CHCs can be used until menopause.
      Note: Adapted from the U.S. Medical Eligibility Criteria for Contraceptive Use

      US medical eligibility criteria for contraceptive use. 2016. http://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf.

      . 1: a condition for which there is no restriction for the use of the contraceptive method. 2: a condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3: a condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4: a condition that represents an unacceptable health risk if the contraceptive method is used.
      Table 2AE-PCOS Society recommendations for cardiovascular risk assessment in women with PCOS.
      At riskAt high risk
      Women with PCOS with any following risk factorsWomen with PCOS
      Obesity (especially increased abdominal adiposity)Type 2 diabetes mellitus
      Cigarette smokingOvert vascular or renal disease
      Hypertension
      Dyslipidemia (increased LDL-C and/or non-HDL-C)
      Subclinical vascular disease
      Impaired glucose tolerance
      Family history of premature CVD (<55 years of age in male relative, <65 years of age in female relative)

      Impact on glucose tolerance

      In the general population, OCP use has not been associated with an increased risk of developing type 2 diabetes (
      • Chasen-Taber L.
      • Willett W.C.
      • Stampfer M.J.
      • Hunter D.J.
      • Colditz G.A.
      • Spiegelman D.
      • et al.
      A prospective study of oral contraceptives and NIDDM among U.S. women.
      ). Furthermore, use of OCP in women with insulin- or non-insulin-dependent diabetes has limited effect of daily insulin requirements or long-term control of diabetes. A recent Cochrane review examined the effects of hormonal contraceptives on glucose tolerance and concluded that there were no significant effects on carbohydrate metabolism in women without diabetes (
      • Lopez L.M.
      • Grimes D.A.
      • Schulz K.F.
      Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus.
      ). However, none of the studies included a placebo group, a variety of different OCP formulations were used, and most studies had body mass index (BMI) cutoffs, thereby possibly limiting the generalizability of these data to the PCOS population. Young women with PCOS have a twofold increased risk of diabetes independent of the high prevalence of obesity (
      • Moran L.J.
      • Misso M.L.
      • Wild R.A.
      • Norman R.J.
      Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis.
      ). Therefore, it is important to examine the effects of OCP on glucose tolerance specifically in these subjects. In a meta-analysis including women with PCOS treated with OCP for 3–12 months (
      • Halperin I.J.
      • Kumar S.S.
      • Stroup D.F.
      • Laredo S.E.
      The association between the combined oral contraceptive pill and insulin resistance, dysglycemia and dyslipidemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of observational studies.
      ), there was no significant change in fasting glucose levels (29 studies), insulin levels (33 studies), insulin resistance (HOMA-IR, 11 studies), or glucose disposal rate (5 studies) with OCP use. These studies did not include clinical endpoints such as 2-hour oral glucose tolerance test (OGTT) or HbA1c levels, most OCP used contained cyproterone acetate, and in the majority of the studies the mean BMI was <30, limiting the generalizability of the findings to the U.S. population. In the OWL-PCOS study, overweight/obese women had higher glucose area under the curve during the 2-hour OGTT, and the insulin-derived index worsened after 16 weeks of OCP use (
      • Legro R.S.
      • Dodson W.C.
      • Kris-Etherton P.M.
      • Kunselman A.R.
      • Stetter C.M.
      • Williams N.I.
      • et al.
      Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome.
      ). Very few studies have examined glucose metabolism as an endpoint after randomizing women with PCOS to different types of OCP (
      • Mendoza N.
      • Simoncini T.
      • Genazzani A.D.
      Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies.
      ). In one RCT, women with PCOS receiving a drosperinone-containing OCP had a significant decrease in fasting glucose and insulin levels after 6 months, while those using a desogestrel-containing OCP had a significant increase in both these parameters (
      • Kriplani A.
      • Periyasamy A.J.
      • Agarwal N.
      • Kulshrestha V.
      • Kumar A.
      • Ammini A.C.
      Effect of oral contraceptive containing ethinyl estradiol combined with drospirenone vs. desogestrel on clinical and biochemical parameters in patients with polycystic ovary syndrome.
      ). No subject developed diabetes in this study. One RCT comparing the use of the contraceptive vaginal ring versus OCP containing drosperinone showed improvement in the glucose area under curve after 2-hour OGTT after 6 months of vaginal ring use (
      • Battaglia C.
      • Mancini F.
      • Fabbri R.
      • Persico N.
      • Busacchi P.
      • Facchinetti F.
      • et al.
      Polycystic ovary syndrome and cardiovascular risk in young patients treated with drospirenone–ethinyl estradiol or contraceptive vaginal ring. A prospective, randomized, pilot study.
      ). Overall the current studies suggest no significant change in carbohydrate metabolism with short-term use of OCP in women with PCOS; however, most studies included small numbers of primarily lean/overweight subjects with limited duration of follow-up and few included clinical endpoints such as impaired glucose tolerance or diabetes. Women with PCOS using OCP should therefore be screened for changes in glucose metabolism at regular intervals, especially if they are overweight/obese or have a family history of diabetes.

      Impact on dyslipidemia

      Recently updated WHO and CDC guidelines specifically addressed OCP use in women with known dyslipidemias in the absence of other CVD risk factors (

      World Health Organization. Medical eligibility criteria for contraceptive use. http://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.

      ,

      US medical eligibility criteria for contraceptive use. 2016. http://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf.

      ). These revised recommendations state that the risk of using OCP in these conditions is category 2 and that routine screening for dyslipidemias before initiating therapy is not warranted (Table 2). The absolute CVD risk is very low in women in the reproductive-age group; subsequently, the risk of myocardial infarction or stroke associated with OCP use remains very low (

      World Health Organization. Medical eligibility criteria for contraceptive use. http://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.

      ,

      US medical eligibility criteria for contraceptive use. 2016. http://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6503.pdf.

      ). There does not appear to be a clear association between dyslipidemias and venous thromboembolic (VTE) events; however, women with known genetic hyperlipidemic disorders may be at a higher lifetime risk of CVD and pancreatitis. The characteristic dyslipidemic profile associated with insulin resistance is high serum triglycerides (TG) and low high-density lipoprotein (HDL-C) levels, which is also the most common metabolic abnormality detected in young women with PCOS (
      • Dokras A.
      • Bochner M.
      • Hollinrake E.
      • Markham S.
      • Vanvoorhis B.
      • Jagasia D.H.
      Screening women with polycystic ovary syndrome for metabolic syndrome.
      ). A large meta-analysis including 30 studies showed that TG levels were 26 mg/dL higher (95% CI, 17–3), HDL-C levels 6 mg/dL lower (95% CI, 4–9), and low-density lipoprotein (LDL)-C levels 12 mg/dL higher (95% CI, 10–16) in women with PCOS compared with in controls (
      • Wild R.A.
      • Rizzo M.
      • Clifton S.
      • Carmina E.
      Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis.
      ). Mean TG levels were greater than 150 mg/dL in only three of the 30 studies, while mean HDL-C levels were lower than 50 mg/dL in 20 of the 30 cohorts. A meta-analysis examining the effects of treatment of women with PCOS with OCP demonstrated paradoxical changes in serum lipids, namely, significant increase in HDL-C levels (P<.004, 29 studies), with persistence of this effect on removing poor and fair quality studies (P<.01). On the other hand, there was a significant increase in TG levels (P=.004, 25 studies). However, on removal of poor and fair quality studies, the association was not significant (
      • Halperin I.J.
      • Kumar S.S.
      • Stroup D.F.
      • Laredo S.E.
      The association between the combined oral contraceptive pill and insulin resistance, dysglycemia and dyslipidemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of observational studies.
      ). When analyzing studies longer than 6 months, there was increased association between OCP use and increased serum TG levels. However, there was no association with change in serum LDL-C levels. The estrogenic component of OCP is associated with an increase in serum HDL-C and apolipoprotein A-I, a major protein constituent of HDL-C, and decrease in hepatic lipase activity (
      • Walsh B.W.
      • Schiff I.
      • Rosner B.
      • Greenberg L.
      • Ravnikar V.
      • Sacks F.M.
      Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins.
      ). On the other hand, very low density lipoprotein levels increase because of enhanced production of apolipoprotein B and TG. As low HDL-C levels are associated with increased CVD risk, it can be proposed that an increase in HDL-C levels with use of OCP may in fact have a beneficial effect. However, use of drugs such as the cholesterol ester transfer protein inhibitor torcetrapib and niacin, to increase serum HDL-C levels, have both failed to reduce cardiovascular events in large clinical trials (
      • Barter P.J.
      • Caulfield M.
      • Eriksson M.
      • Grundy S.M.
      • Kastelein J.J.
      • Komajda M.
      • et al.
      Effects of torcetrapib in patients at high risk for coronary events.
      ,
      • Khera A.V.
      • Patel P.J.
      • Reilly M.P.
      • Rader D.J.
      The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality.
      ). There are no studies examining change in HDL-C levels with incidence of arterial thrombotic events in women with PCOS; however, a slight increase in the risk of myocardial infarction in women using hormonal contraceptives has been reported (
      • Lidegaard Ø.
      • Løkkegaard E.
      • Jensen A.
      • Skovlund C.W.
      • Keiding N.
      Thrombotic stroke and myocardial infarction with hormonal contraception.
      ). It is currently unclear how an increase in serum HDL-C levels possibly accompanied by an increase in TG levels will impact long-term CVD risk in the PCOS population. Although the WHO and CDC guidelines do not recommended screening for dyslipidemias before initiating OCP therapy, the AE-PCOS Society and Endocrine Society guidelines recommend screening all women with PCOS routinely for dyslipidemia (
      • Wild R.A.
      • Carmina E.
      • Diamanti-Kandarakis E.
      • Dokras A.
      • Escobar-Morreale H.F.
      • Futterweit W.
      • et al.
      Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society.
      ). Use of low-dose OCP in women with PCOS and isolated dyslipidemia with periodic follow-up is an acceptable option given the low absolute risk of arterial thrombotic events.

      Impact on metabolic syndrome

      Due to limited data on longitudinal follow-up of PCOS cohorts, it is not clear whether changes in only one or two metabolic risk factors, especially at a young age, will have a significant impact on long-term risk of CVD. Metabolic syndrome assesses the composite risk of diabetes and CVD by evaluating early abnormalities in known CVD risk factors, namely, hypertension, diabetes, dyslipidemia, and obesity (
      • Wannamethee S.G.
      • Shaper A.G.
      • Lennon L.
      • Morris R.W.
      Metabolic syndrome vs Framingham risk score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus.
      ). Metabolic syndrome as defined by National Cholesterol Education Panel - Adult Treatment Panel III criteria is defined as the presence of at least three of the following five criteria (TG ≥ 150 mg/dL, HDL-C < 50 mg/dL, blood pressure ≥ 130/≥85 mmHg, waist circumference > 88 cm, and fasting glucose ≥100 mg/dL) (
      • Grundy S.M.
      • Cleeman J.I.
      • Daniels S.R.
      • Donato K.A.
      • Eckel R.H.
      • Franklin B.A.
      • et al.
      Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.
      ). The prevalence of metabolic syndrome in women with PCOS is significantly increased even at a young age 47 and is more pronounced in the hyperandrogenic phenotypes (
      • Panidis D.
      • Tziomalos K.
      • Misichronis G.
      • Papadakis E.
      • Betsas G.
      • Katsikis I.
      • et al.
      Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study.
      ). In a meta-analysis, including 2,256 women with PCOS and 4,130 controls, the OR for metabolic syndrome independent of obesity was 2.2 (95% CI, 1.36–3.56) (
      • Moran L.J.
      • Misso M.L.
      • Wild R.A.
      • Norman R.J.
      Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis.
      ). In the OWL-PCOS study, treatment of overweight/obese women with PCOS with low-dose OCP for 4 months resulted in increased TG levels (>150 mg/dL; P=.02) but no significant change in serum HDL-C levels and blood pressure (
      • Legro R.S.
      • Dodson W.C.
      • Kris-Etherton P.M.
      • Kunselman A.R.
      • Stetter C.M.
      • Williams N.I.
      • et al.
      Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome.
      ). The risk of metabolic syndrome, however, was significantly increased compared with baseline (OR, 2.47; 95% CI, 1.42, 4.27). More significantly, the group randomized to OCP use with lifestyle intervention consisting of caloric restriction with meal replacements, weight loss medication (either sibutramine, or orlistat), and increased physical activity to promote a 7% weight loss demonstrated no change in risk of metabolic syndrome (OR = 0.72; 95% CI, 0.44, 1.17), indicating that simultaneous incorporation of intensive lifestyle changes can mitigate the potential adverse impact of OCP. These findings need to be replicated in larger cohorts of both lean and obese women and using less androgenic OCP that may have potentially fewer metabolic effects. Currently, there are no recommendations for comprehensive metabolic screening of women prescribed OCP. However, the AE-PCOS society recommends checking blood pressure and BMI in all women with PCOS at each visit and obtaining a complete lipid panel and a 2-hour OGTT (especially in obese women) every 2 years. These recommendations should be followed particularly in overweight/obese women with PCOS using OCP to identify and treat early changes in metabolic risk and to assess the suitability of ongoing use of OCP.

      Impact on venous and arterial thromboembolism

      It is well recognized that the use of OCP in the general population increases the risk of venous thromboembolism (VTE), and this was confirmed in a recent Cochrane review of 26 studies (relative risk, 3.5; 95% CI, 2.9, 4.3) (
      • de Bastos M.
      • Stegeman B.H.
      • Rosendaal F.R.
      • Van Hylckama Vlieg A.
      • Helmerhorst F.M.
      • Stijnen T.
      • et al.
      Combined oral contraceptives: venous thrombosis.
      ). The effect size depended on the dose of ethinyl estradiol, and although the risk of VTE for OCP containing gestodene, desogestrel, cyproterone acetate, and drospirenone was similar, it was about 50%–80% higher than with a levonorgestrel-containing OCP. Although some studies do not indicate an increased risk of VTE with the use of different progestins, it has been proposed that the impact of the progestin may be related to its ability to counteract or modulate the effects of estrogen (recently reviewed in Fertility and Sterility) (
      • Sitruk-Ware R.
      Hormonal contraception and thrombosis.
      ). In a study examining a large claims database, a higher prevalence of VTE events was reported in women with PCOS (374.2 per 100,000 person-years) compared with women without PCOS (193.4 per 100,000 person-years). Interestingly, women using OCP in this cohort had a lower risk of VTE events (OR, 0.8; 95% CI, 0.73–0.97), and the authors attributed this finding to a lowering of androgens with use of OCP (
      • Okoroh E.M.
      • Hooper W.C.
      • Atrash H.K.
      • Yusuf H.R.
      • Boulet S.L.
      Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003–2008.
      ). A second study also examining a health plan claims database conversely reported a twofold increased risk of VTE in women with PCOS taking hormonal contraceptives and a 1.5-fold increased risk in women with PCOS not taking these medications (
      • Bird S.T.
      • Hartzema A.G.
      • Brophy J.M.
      • Etminan M.
      • Delaney J.A.
      Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis.
      ). Although these studies controlled for age, obesity, and metabolic comorbidities, they did not examine dose of ethinyl estradiol or type of progestin and have the usual limitations associated with querying an administrative claims database. There is also some evidence suggesting an increased but low absolute risk of myocardial infarction and stroke in women using OCP. A large Danish study reported small differences in myocardial infarction and stroke risk when using OCP containing 20 μg versus 30–40 μg ethinyl estradiol and minimal differences when comparing different progestins (
      • Lidegaard Ø.
      • Løkkegaard E.
      • Jensen A.
      • Skovlund C.W.
      • Keiding N.
      Thrombotic stroke and myocardial infarction with hormonal contraception.
      ). As expected, the risk of both venous and arterial thromboembolic events significantly increased with age. Overall these studies indicate that the risk of venous and arterial thrombosis is low in the young population, and continued use of low-dose OCP in the PCOS population needs regular assessment of associated risk factors.

      Impact on adipocyte distribution and function

      The prevalence of obesity is high in PCOS all over the world with evidence for central predisposition or an increase in visceral adiposity (
      • Carmina E.
      • Bucchieri S.
      • Esposito A.
      • Del Puente A.
      • Mansueto P.
      • Orio F.
      • et al.
      Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance.
      ,
      • Puder J.J.
      • Varga S.
      • Kraenzlin M.
      • De Geyter C.
      • Keller U.
      • Muller B.
      Central fat excess in polycystic ovary syndrome: relation to low-grade inflammation and insulin resistance.
      ). As mentioned above, androgens may predispose to central body fat distribution contributing to dyslipidemia and exacerbating insulin resistance (
      • Corbould A.
      Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?.
      ,
      • van de Woestijne A.P.
      • Monajemi H.
      • Kalkhoven E.
      • Visseren F.L.
      Adipose tissue dysfunction and hypertriglyceridemia: mechanisms and management.
      ). Although there is insufficient evidence to support a causal relationship between use of hormonal contraception and weight gain (
      • Gallo M.F.
      • Lopez L.M.
      • Grimes D.A.
      • Carayon F.
      • Schulz K.F.
      • Helmerhorst F.M.
      Combination contraceptives: effects on weight.
      ), very few studies have examined change in body fat distribution with OCP use in PCOS. OCP treatment in lean adolescents and adults is associated with an increase in total and abdominal fat mass (
      • Ibáñez L.
      • de Zegher F.
      Ethinyl estradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity.
      ,
      • Aydin K.
      • Cinar N.
      • Aksoy D.Y.
      • Bozdag G.
      • Yildiz B.O.
      Body composition in lean women with polycystic ovary syndrome: effect of ethinyl estradiol and drospirenone combination.
      ,
      • Ibáñez L.
      • Díaz M.
      • Sebastiani G.
      • Marcos M.V.
      • López-Bermejo A.
      • de Zegher F.
      Oral contraception vs insulin sensitization for 18 months in nonobese adolescents with androgen excess: posttreatment differences in C-reactive protein, intima-media thickness, visceral adiposity, insulin sensitivity, and menstrual regularity.
      ), despite significant decreases in serum androgens, suggesting other underlying mechanisms for potential increase in fat mass. In contrast, in overweight women, no change in body fat distribution was observed after 12 months OCP use (
      • Glintborg D.
      • Mumm H.
      • Altinok M.L.
      • Richelsen B.
      • Bruun J.M.
      • Andersen M.
      Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-month randomized treatment with metformin and/or oral contraceptives in polycystic ovary syndrome.
      ). In the OWL-PCOS study, treatment of overweight/obese women with OCP for 4 months resulted in a significant decrease in visceral fat distribution (mean change from baseline of 66.3 [95% CI, –127.1, –5.5]; P<.03) (
      • Legro R.S.
      • Dodson W.C.
      • Kris-Etherton P.M.
      • Kunselman A.R.
      • Stetter C.M.
      • Williams N.I.
      • et al.
      Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome.
      ). Visceral adiposity is associated with adipocyte dysfunction, characterized by inflammation and impaired adipokine secretion. A meta-analysis including women with PCOS showed that circulating CRP levels were 96% higher compared with controls (31 studies; 95% CI, 71%–122%; z = 7.32); however, there was no difference in serum IL-6 and TNFα levels (
      • Escobar-Morreale H.F.
      • Luque-Ramírez M.
      • González F.
      Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis.
      ). Few studies have examined the impact of OCP on serum adipokines in women with PCOS and show mixed results. Lean women treated with OCP exhibited an increase (
      • Díaz M.
      • Chacón M.R.
      • López-Bermejo A.
      • Maymó-Masip E.
      • Salvador C.
      • Vendrell J.
      • et al.
      Ethinyl estradiol–cyproterone acetate versus low-dose pioglitazone-flutamide-metformin for adolescent girls with androgen excess: divergent effects on CD163, TWEAK receptor, ANGPTL4, and LEPTIN expression in subcutaneous adipose tissue.
      ,
      • Christakou C.
      • Kollias A.
      • Piperi C.
      • Katsikis I.
      • Panidis D.
      • Diamanti-Kandarakis E.
      The benefit-to-risk ratio of common treatments in PCOS: effect of oral contraceptives versus metformin on atherogenic markers.
      ) or no change in CRP levels after 6 months (
      • Orio F.
      • Muscogiuri G.
      • Giallauria F.
      • Savastano S.
      • Bottiglieri P.
      • Tafuri D.
      • et al.
      Oral contraceptives versus physical exercise on cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: a randomized controlled trial.
      ). In a small study, the same investigators reported that treatment with OCP was associated with an increase in inflammatory gene expression in SC adipose tissue biopsies in adolescents (
      • Díaz M.
      • Chacón M.R.
      • López-Bermejo A.
      • Maymó-Masip E.
      • Salvador C.
      • Vendrell J.
      • et al.
      Ethinyl estradiol–cyproterone acetate versus low-dose pioglitazone-flutamide-metformin for adolescent girls with androgen excess: divergent effects on CD163, TWEAK receptor, ANGPTL4, and LEPTIN expression in subcutaneous adipose tissue.
      ). Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties and independently predicts diabetes (
      • Lara-Castro C.
      • Luo N.
      • Wallace P.
      • Klein R.L.
      • Garvey W.T.
      Adiponectin multimeric complexes and the metabolic syndrome trait cluster.
      ). Serum adiponectin levels have been shown in a meta-analysis including 16 studies to be significantly lower in women with PCOS compared with in controls (
      • Toulis K.A.
      • Goulis D.G.
      • Farmakiotis D.
      • Georgopoulos N.A.
      • Katsikis I.
      • Tarlatzis B.C.
      • et al.
      Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis.
      ). This observation was independent of obesity and serum T levels but was associated with insulin resistance. Androgen receptors are present in preadipocytes and adipocytes (
      • Dieudonne M.N.
      • Pecquery R.
      • Boumediene A.
      • Leneveu M.C.
      • Giudicelli Y.
      Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids.
      ), possibly influencing the distribution of visceral adiposity and changes in adiponectin secretion (
      • Virtue S.
      • Vidal-Puig A.
      Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective.
      ). The effects of OCP on adiponectin levels in women with PCOS are also unclear. Some studies report no change in adiponectin levels using a third-generation OCP for 6–12 months in overweight women (
      • Glintborg D.
      • Mumm H.
      • Altinok M.L.
      • Richelsen B.
      • Bruun J.M.
      • Andersen M.
      Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-month randomized treatment with metformin and/or oral contraceptives in polycystic ovary syndrome.
      ,
      • Moran L.J.
      • Meyer C.
      • Hutchison S.K.
      • Zoungas S.
      • Teede H.J.
      Novel inflammatory markers in overweight women with and without polycystic ovary syndrome and following pharmacological intervention.
      ), while others report an increase in serum adiponectin levels after 6 months of treatment in obese women associated with a decrease in androgens levels (
      • Escobar-Morreale H.F.
      • Luque-Ramírez M.
      • González F.
      Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis.
      ). Although it is important to consider the impact of OCP on adipose tissue distribution and function, all these studies included small numbers of subjects and showed mixed results.

      Conclusion

      Hormonal contraceptives are a first-line treatment for the management of common problems such as menstrual irregularity, hirsutism, and acne in women with PCOS. After establishing the diagnosis of PCOS, assessment of comorbidities such as diabetes, hypertension, obesity, dyslipidemia, depression, and anxiety is recommended. This information will better enable the clinician to individualize treatment and counsel the patient regarding the risks versus benefits of hormonal contraceptives. Although there are few comparative trials to assess the optimal combination hormonal contraceptive, lower doses of ethinyl estradiol combined with a less androgenic progestin can effectively manage common symptoms in PCOS. OCP can be prescribed in healthy obese women; however, physicians should provide information regarding weight loss strategies and resources available in the community. Women with one or more well-controlled CVD risk factors should have a comprehensive assessment and will likely require more frequent follow-up to monitor the long-term impact of OCP use. In a woman with multiple major risk factors, any of which alone would substantially increase the risk of CVD, use of OCP may increase her risk to an unacceptable level. However, the WHO guidelines caution against a simple addition of categories for each risk factor; for example, a combination of two risk factors assigned a category 2 may not necessarily warrant a higher category. The AE-PCOS Society guidelines for CVD risk stratification in women with PCOS can be used to offer personalized and comprehensive counseling when prescribing OCP and to recommend appropriate follow-up.

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