Use of cyproterone acetate/ethinylestradiol in polycystic ovary syndrome: rationale and practical aspects

Abstract

Introduction: Polycystic ovary syndrome (PCOS) is a common, heterogeneous disorder characterised by hyperandrogenic skin symptoms, irregular menstruation and subfertility, increased risk of endometrial malignancy, and increased risk of preventable diseases associated with metabolic syndrome. Cyproterone acetate (CPA) 2 mg, combined with ethinylestradiol (EE) 35 μg, is indicated for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhea) and/or hirsutism, in women of reproductive age.

Objectives: To review the present knowledge about PCOS and summarize the role of CPA/EE in the care of patients suffering from this condition for the practitioner.

Methods: Experts with clinical interest and experience in treating symptoms of androgen excess performed a non-systematic review to provide updated information regarding the use of CPA/EE in patients with PCOS.

Results: Polycystic ovary-related hyperandrogenic skin symptoms are effectively treated by CPA/EE, reducing not only the symptoms but also their negative impact on quality of life and mental health. Proven additional benefits for these patients include the treatment of menstrual irregularities and reduction in endometrial cancer risk. Possible benefits include preservation of fertility. Treatment increases the risk for venous thromboembolic complications. The nature of other metabolic and cardiovascular long-term effects i.e., whether positive or negative, are still to be investigated.

Conclusions: Cyproterone acetate/ethinylestradiol provides effective treatment for PCO-related hyperandrogenic skin symptoms. This efficacy and additional benefits related to menstrual irregularities and endometrial cancer risk, have to be weighed against the risk of venous thromboembolic complications based on an individual benefit/risk evaluation.

Chinese abstract

引言：多囊卵巢综合征（PCOS）是一种常见的异质性疾病, 表现为多毛、痤疮等雄激素过多的皮肤症状、月经不调、不孕不育, 增加子宫内膜癌及与代谢综合征相关的的发生风险。2mg醋酸环丙孕酮（CPA）结合35μg炔雌醇（EE）用于治疗育龄妇女雄激素敏感性（伴或不伴皮脂溢）和/或多毛症有关的中重度痤疮。目的：回顾性分析PCOS现有的知识, 总结CPA/EE在改善PCOS患者中的作用。方法：对临床上治疗雄激素过多症有着丰富经验和兴趣的专家进行一项非系统性评估, 以提供有关PCOS患者CPA/EE使用的最新信息。结果：CPA/EE可以有效的治疗多囊卵巢相关的高雄激素性皮肤症状, 改善症状的同时也降低了对患者身心的负面影响。经验证明CPA/EE还可以治疗月经不规则及减少子宫内膜癌的风险。潜在的益处包括生殖力保护。但CPA/EE治疗会增加静脉血栓栓塞并发症的风险。其他代谢和心血管的远期效应（无论是利还是弊）仍有待确定。结论：炔雌醇/醋酸环丙孕酮为PCOS相关的雄激素过多的皮肤症状提供了有效的方法。对月经不规律和子宫内膜癌风险相关的功效和额外的益处必须根据个人利益/风险评估来衡量静脉血栓栓塞并发症的发生风险。

Keywords:

• Polycystic ovary syndrome
• hyperandrogenism
• cyproterone acetate
• ethinylestradiol
• venous thromboembolism

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age globally [1]. It affects 6–21% of women when assessed using the Rotterdam criteria [2]. Clinical presentation can vary widely but, in general, PCOS is characterised by irregular menses, hyperandrogenism (with either clinical symptoms or assessed by laboratory data) and polycystic ovary morphology, after excluding other endocrine causes such as hyperprolactinemia [3]. The ongoing confusion and debate around which criteria to use when diagnosing PCOS led to extension of the Rotterdam criteria to phenotypic definitions, which not only help with clinical research and practice but also aid the identification of women with PCOS who are at long-term metabolic risk (see Figure 1) [2,4].

Figure 1. Classification of polycystic ovarian syndrome phenotypes [2].

Women with PCOS are at risk of impaired quality of life, as well as psychological and behavioural disorders including depression, bipolar disorder, anxiety and eating disorders [5–8]. Beyond the burden of psychological impairment, there are also long-term metabolic and reproductive health risks (see Figure 2) including an increased risk of clinical elements of the metabolic syndrome, such as, obesity and diabetes, and infertility in women with PCOS [2,9]. The reproductive and metabolic changes associated with PCOS may also increase the risk of developing endometrial cancer [9,10].

Figure 2. Long-term consequences of PCOS.

Figure 3. Commonly presenting symptoms of PCOS [5,9].

The economic burden of PCOS and its associated short- and long-term sequelae are difficult to estimate accurately due to historic challenges in defining PCOS and the possible underestimation of the number of women affected. However, it is clear that both the high proportion of women affected and its associated long-term morbidity represent a significant financial burden to the women affected and the healthcare systems within which they receive care.

This review, developed on behalf of the global AWARE group, aims to improve recognition of PCOS and update clinical knowledge and understanding of how it presents. It also aims to highlight how the variable presentation impacts on treatment pathways within the different healthcare settings. Finally, the review sets out to evaluate the role of cyproterone acetate (CPA) 2 mg/ethinylestradiol (EE) 35 mcg in the management of PCO-related symptoms and to assess its use with respect to additional benefits and risks for the patients suffering from this common endocrine disorder. Thus, this review aims to providing evidence based information for safe prescribing.

Pathophysiology of PCOS

The pathophysiology of PCOS is complex and not fully understood [5,11,12]. Women with PCOS experience an increase in frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses which, in turn, results in an increase in the luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio. The dominance of LH over FSH increases ovarian androgen production and decreases follicular maturation. This leads to an increase in the level of biologically active testosterone and contributes to the clinical consequences of hyperandrogenemia in PCOS [13].

Abnormalities in both androgen metabolism and the control of androgen production, when accompanied by anovulation, increase the likelihood of metabolic dysfunction [2]. The majority of women with PCOS have insulin resistance and/or are obese [2,14]. Their elevated insulin levels increase GnRH pulse frequency and either contribute to or cause the abnormalities seen in the hypothalamic–pituitary–ovarian axis that lead to PCOS [13]. Normal patterns of gonadotropin secretion are essential for reproduction and any imbalance may contribute to decreased fertility and pregnancy problems [15]. The pathological imbalance of LH and FSH present in women with PCOS explains the rationale for pretreatment with combined hormonal treatment to increase fertility and improve pregnancy outcomes, however, more studies are needed regarding this important topic.

Family history of PCOS and a personal history of type 1, type 2 or gestational diabetes have been associated with an increased risk of developing PCOS [16–19]. The complexity of the metabolic and endocrinological relationship in PCOS is illustrated by the fact that type 2 and gestational diabetes are regarded not as only risk markers for development of PCOS but also consequences of the syndrome.

Long-term consequences of PCOS

Studies show a link between hyperandrogenic PCOS and disturbances in metabolic parameters which could lead to an increased risk of cardiovascular disease (CVD) [2,9,14]. Obesity, impaired glucose tolerance, type 2 diabetes and sleep apnoea are all more prevalent in women with PCOS when compared with the general population [20]. Although conventional cardiovascular risk calculators such as the Framingham Index have not been validated within this patient population, there is evidence to show a higher reported incidence of hypertension, impaired lipid and glucose metabolism, and an increased risk of developing gestational diabetes and type 2 diabetes [2,9,14]. This disturbance of metabolic parameters and diabetes can lead to higher risk of myocardial infarction and stroke [21,22]. As a consequence, UK Guidelines suggest that women presenting with PCOS who are overweight (BMI ≥25 kg/m²) and not overweight but with additional risk factors (such as aged >40 years, personal history of gestational diabetes or family history of type 2 diabetes) should have a 2-h post 75 g oral glucose tolerance test [14].

Polycystic ovary syndrome is associated with poorer pregnancy outcomes, for example, an increase in risk of pre-term delivery and pre-eclampsia [23–25]. Decreased quality of life, including an increased risk of depression and anxiety, are also important risks in untreated PCOS patients [5–8].

Oligo- or amenorrhea in PCOS may predispose women to endometrial hyperplasia and eventually carcinoma [10]. Combined oral contraceptives (COCs) have been shown to decrease the risk of endometrial cancer [26–28] and also decrease of the risk of ovarian [27,28] and colon cancer [28], therefore, the use of treatments such CPA/EE in women with PCOS would at least not represent a disadvantage in this respect and in women at greater risk, such as those with PCOS, it could be an advantage. However, securing this benefit would require long-term treatment of CPA/EE and, presently, this is not included as a licensed indication.

Common presenting symptoms of PCOS

Common presenting symptoms of PCOS include hirsutism, acne, menstrual cycle abnormalities, clinical elements of the metabolic syndrome and infertility (see Figure 3) [5]. Hirsutism is a marker of hyperandrogenism and affects up to 70% of women with PCOS [9,29]. Although less prevalent and a less specific marker of hyperandrogenism, acne can affect 15–30% of women with PCOS [30,31] and it may represent the most important presenting symptom from the patient perspective [32]. Menstrual disturbances include oligomenorrhea or amenorrhea followed by prolonged erratic menstrual bleeding, and can affect up to 70% of women with PCOS [33,34]. Infertility affects 40% of women with PCOS and is primarily caused by anovulation [34].

Primary clinical presentation of PCOS may also change according to a women’s life stage [9]. At a young age, women are more likely to seek resolution of menstrual disorders, such as cycle control, as well as problems with clinical manifestations of hyperandrogenism in the skin i.e., hirsutism and acne [35,36]. With increasing age, the focus switches to a need to address subfertility and potential pregnancy complications and quality of life issues, and manage risk of metabolic complications and endometrial cancer [5,9,37]. At the perimenopausal or menopausal life stage, metabolic consequences continue to be of concern.

The reproductive and metabolic implications of PCOS diagnosis and likelihood of serious cardiovascular morbidity in later life call for a multidisciplinary, life-course approach to management and prevention that begins at the time of diagnosis [35,36]. Using a phenotypic approach to defining PCOS is helpful in identifying those women at greatest risk of metabolic dysfunction [2,4], for example, those with the classic PCOS phenotype i.e., A or B, are at greatest risk (see Figure 1).

Diagnosis of PCOS

Defining PCOS continues to be the subject of debate and diagnosis may vary according to which diagnostic criteria are used. Typically, the syndrome has an adolescent onset and slow progression. Therefore, any medical history indicating symptomatic onset beyond adolescence with rapid progression would suggest that the cause is unlikely to be PCOS. The Rotterdam criteria specify that diagnosis of PCOS must be based on two out of three of the following: chronic anovulation, hyperandrogenism (clinical or biochemical) and polycystic ovaries, once other aetiologies have been excluded [2].

Laboratory investigations can help to differentiate between clinical entities and serve as a measure of severity of dysfunction. Measurement of free testosterone at any time point in the menstrual cycle can provide an indication of biochemical hyperandrogenism in PCOS but the low sensitivity of routine assays can impede clear verification [38]. Analysis of serum anti-Müllerian hormone (AMH) in women with PCOS and controls show elevated levels in the former group, particularly in those with polycystic ovary morphology [39]. Generally, laboratory confirmation of diagnosis is achieved by the exclusion of disorders that mimic PCOS such as thyroid disease (serum thyroid-stimulating hormone [TSH]), prolactin excess (serum prolactin) and congenital adrenal hyperplasia (serum 17-hydroxyprogesterone [17-OHP]) (see Figure 4) [37].

Figure 4. Investigations and tests for confirming a diagnosis of PCOS [1,9,37].

Objectives of the comprehensive care of patients suffering from PCOS

The risk of metabolic and cardiovascular disease and gynaecological cancers associated with PCOS highlight the importance of early diagnosis and appropriate multidisciplinary management, including lifestyle modification [1]. Medical treatment mostly comprises a combined approach aimed at (see Figure 5) [9]:

Figure 5. Principles of management of PCOS [9].

• Addressing dermatological symptoms such as hirsutism and/or acne.

• Management of menstrual irregularities, for example, treatment with hormones (progestin-only therapy) to induce withdrawal bleeds, minimise risk of endometrial hyperplasia.

• Managing adverse metabolic changes for example, lowering insulin levels and improving insulin sensitivity.

Treatment targets

Lifestyle

Lifestyle modification involving a healthy diet and exercise and achievement of optimal BMI is important for all women affected by PCOS [38]. Evidence from observational studies shows that moderate weight loss (5–10%) in women with PCOS can improve insulin resistance as well as androgenic and reproductive outcomes [40].

Hyperandrogenism

Pharmacological treatment of PCOS is aimed at reducing the level of circulating androgens and controlling their effect at tissue level1 in order to ameliorate symptoms such as hirsutism and acne and reduce the risk of long-term metabolic consequences [17].

Combinations of EE and progestogens, especially those containing antiandrogenic progestogens such as CPA, chlormadinone acetate (CMA), drosperinone (DRSP) and dienogest (DNG), have traditionally been the first choice for management of PCOS [41,42]. In cases where hirsutism is very severe or there are contraindications to hormonal treatment, other therapies such as finasteride may be required [37].

Almost all COCs and estrogen/progestogen combinations contain EE as the estrogenic fraction. The antiandrogenic effect of the progestogen/EE combinations is achieved via a number of different mechanisms [42]:

• Increase in hepatic SHBG production can be achieved with all oestrogens in a dose-dependent manner; however, effect is much stronger using EE compared with the use of E2 [43,44].

• Suppression of LH secretion and thereby ovarian androgen production can be achieved with all progestogens (including androgenic progestogens such as levonorgestrel [LNG]) if used in ovulatory inhibition dosage.

• Competition for the 5-alpha-reductase and androgen receptors by progestogens; effect is strongest when using CPA [45].

• Competition on the androgen-receptor at tissue level with antiandrogenic progestogens like CPA, CMA, DNG and DRSP can block the action of testosterone.

• Direct action on ovarian androgen production, especially when using CPA as the antiandrogenic progestogen [46].

A combination of EE with a progestogen that possesses antiandrogenic activity is regarded as the most appropriate choice for the treatment of PCOS [41]. However, the antiandrogenic potential of COCs varies according to the type and dose of progestogens included [11]. Older progestogens such as norethisterone (acetate) (NET, NETA) and LNG, combined with EE, have been successfully used for treatment of acne, despite their primarily ‘androgenic’ action [47]; however, there is extremely limited data available for women with hirsutism or PCOS.

There is limited data regarding the use of newer progestogens, especially those that include DNG (strongly antiandrogenic), DRSP (antiandrogenic) and nomegestrol acetate (NOMAC) (very weak antiandrogenic) in PCOS patients. A cochrane collaboration review compared a number of COCs in the treatment of acne but PCOS was excluded as an indication in the reviewed studies [48]. Of nine placebo-controlled trials with data for analysis, all showed that COCs containing LNG, NET, norgestimate, DRSP, DNG or CMA reduced inflammatory and non-inflammatory facial acne lesions, severity grades and self-assessed acne when compared to placebo. Data showing any difference in the effectiveness of the type or dose of progestogens in comparison studies were limited and lacked clarity due to conflicting results.

Clinical trials (mostly open-label comparator studies conducted between 1985 and 2012) show a high efficacy of CPA/EE in the treatment of hyperandrogenic skin symptoms in women with PCOS as discussed in the accompanying publication. The use of CPA/EE in hyperandrogenic skin symptoms – A review [49].

Benefits and risks of the use of CPA/EE in PCOS

Benefits

Cyproterone acetate/ethinylestradiol is a reliable contraceptive for women who suffer from signs of androgenisation or where acne or other similar conditions are adversely affected by other ovulation inhibitors and those on drugs with teratogenic risks [50]. Concomitant use of other hormonal contraception is not required and must be avoided. Other benefits, which are especially useful in PCOS patients, include those generally regarded as class effects of COCs, namely, cycle regulation, reduction in dysmenorrhea, suppression of ovarian cysts, and reduction in risk of endometrial cancer from unopposed oestrogen stimulation in amenorrheic and severely oligomenorrheic women (see Figure 6) [51].

Figure 6. Benefits of CPA/EE in the treatment PCOS [37,49,51,73–75].

Side effects

Cyproterone acetate/ethinylestradiol is generally well tolerated with a side effect profile similar to that seen with COCs [50]. Side effects include headaches, nausea, weight gain, breast tenderness, and loss of libido. An increase of triglycerides should be considered clinically relevant in patients with pre-existing dyslipidemia, whereas mostly there are no other negative metabolic effects [52]. When looking at possible negative effects on metabolic parameters, it is an established fact that the use of COCs containing androgenic progestogens can have negative effects in lipid metabolism [53–56] and glucose metabolism [57–64], effects that are particularly relevant to women with a predisposition to metabolic disorders such as those with PCOS. Thus, from a metabolic point of view, in patients with PCOS, the authors believe that CPA/EE would appear to be a better option than other combined hormonal treatments containing androgenic progestogens such as LNG, which have been shown to have negative effects on lipids, especially on glucose metabolism.

Risks of treatment

Combined hormonal treatments, including COCs and antiandrogenic progestogen/EE combinations, are associated with an elevated risk of venous thromboembolism (VTE) when compared to risk in non-users [9,65–67].

The extent to which risk of VTE is increased is dependent on the type of progestogen and the dose of EE [65]. Meta analyses report pooled relative risk (RRs) of VTE compared with LNG was 1.3–1.5 for gestodene, 1.8–1.9 for DSG, 1.6–1.7 for DRSP and 1.6–1.8 for CPA [65]. The risk of VTE is generally reported to be higher with CPA/EE than with COCs, despite evidence from meta-analyses to show this is not the case and, in France, led to the formulation being withdrawn from the market temporarily [65]. There are few studies that specifically address this question with use of CPA/EE alone in women with PCOS and results are conflicting. Seaman et al. [68] looked at the risk of VTE in women with acne, hirsutism or PCOS receiving CPA/EE and EE and reported an increased risk in the incidence rate of VTE in women (8.05 per 10,000 women-years in CPA/EE users compared with 3.7 per 10,000 women-years in women using conventional COCs, such as those containing LNG. However, the authors did conclude that disease severity was an important component of the elevated VTE risk associated with CPA/EE exposure. A critical review of two more recent studies (cohort and case-control studies) by Shapiro and Dinger concluded that the ‘best evidence continues to suggest that the increased risk of VTE in oral contraceptive (OC) users is a class effect, higher for starters and women who restart after over a month break, and independent of the progestogen-type’ [67].

Whilst combinations with other antiandrogenic progestogens may have similar beneficial effects regarding skin problems, only three other antiandrogenic progestogens are available. In terms of the VTE risk profile, DRSP/EE seems to be similar to the risk using CPA/EE (although the data are contentious) and, until now, data on the VTE risk of CMA/EE and DNG/EE are missing. It should also be considered that, in many Asian countries, particularly China, combinations with CMA and DNG are not available. Therefore, the only alternative could be EE combined with androgenic progestogens such as LNG. However, it has been shown that this combination has negative effects on lipids and especially on glucose metabolism, which is especially detrimental to women with PCOS as discussed above.

When searching for literature regarding VTE risk of PCOS patients, it was surprising that only two retrospective studies could be found to show that the risk of VTE is elevated in PCOS itself [69,70], possibly related to decreased fibrinolytic activity [71]. In a population-based cohort study of over 43,000 women (aged 18–46 years) matched with an equivalent control group, Bird et al. [70] reported an overall prevalence of VTE of 23.7 per 10,000, with a 1.5 fold increased relative risk (RR) of VTE in women with PCOS and a two-fold increased risk in those women with PCOS using OCs. Okoroh et al. [69] reported a two-fold increase in risk of VTE in women with PCOS (prevalence rate per 10,000 of 37.4 and 19.4 in women with and without PCOS, respectively) irrespective of their age and whether they were using OCs [69]. Although an increased risk of arterial disease for women with PCOS seems to be well established [14], more studies and especially prospective, well designed trials are needed to assess the importance of VTE risk in women with PCOS.

Contraindications to the use of combined hormonal treatments in PCOS

The long-term safety of combined hormonal treatment, particularly regarding risk of cardiovascular disease, means that World Health Organization (WHO) medical eligibility criteria guidelines for contraindications to COC should be observed in women with PCOS as for all women taking COCs/combination therapy [72] and an individualized treatment approach taken according to patient characteristics and symptoms [41,72]. Although COCs are generally not contraindicated in PCOS, some of the features associated with PCOS, such as obesity and insulin resistance, may represent a relative contraindication for their use [72]. Contraindications relating to the use of CPA/EE reflect those of COCs. However, CPA/EE should not be used solely for contraception; it should be reserved for those women requiring treatment for androgen-dependent conditions [50].

Identifying treatment priorities in PCOS

The management of PCOS should be tailored to each woman’s specific goals, reproductive interests, and particular symptomatic presentation [42]. As already discussed, the presenting primary complaint may vary depending on age or ethnic variation. Treatment may focus on initial resolution of the symptom generating the greatest level of distress, such as hirsutism or infertility, and require a multidisciplinary approach. When discussing long-term management of PCOS, women should be advised of the risks and benefits of treatment and the elements of lifestyle management that may assist in reducing the metabolic and cardiovascular consequences of the syndrome. Recognition of the symptoms of VTE and knowledge of how to respond are also important.

Conclusions

The primary indication of CPA/EE is treatment of the symptoms of hyperandrogenism, such as acne and hirsutism, which commonly present in women with PCOS. Improvement of biochemical hyperandrogenism with CPA/EE leads to a reduction in both short- and long-term risks of PCOS, namely, metabolic syndrome, onset of new diabetes and endometrial cancer. Short-term pre-treatment using CPA/EE may also increase the fertility and improve pregnancy outcomes, however, more research is needed. In addition, CPA/EE also works as a contraceptive and provides the typical non-contraceptive benefits offered by a COC, such as reduction in irregular bleeding and dysmenorrhea and risk reduction of ovarian, colon and endometrial cancer. For women with PCOS, the benefit of greatest importance is the reduction of endometrial cancer risk as this is proven to be increased in women with the syndrome; whereas changes in the risk of ovarian cancer remain subject to debate.

Use of combined hormonal treatments are associated with an elevated risk of VTE when compared to non-users. In some, but not in all studies, a higher risk of VTE has been observed with CPA/EE when compared to combined hormonal treatments containing LNG. However, observational data have found there to be a very low VTE risk amongst women in China, despite the high prevalence of PCOS. Although there is some evidence to show that PCOS itself may increase the VTE risk, more data is needed to prove if this relationship, up to now seen only in two retrospective observational studies, is causal. Presently, it seems that possible risks in the arterial system, such as metabolic syndrome and diabetes, are more important considerations for women with PCOS.

When evaluating patient suitability for treatment of PCOS symptoms with CPA/EE, healthcare providers should consider identical individual factors associated with prescribing COCs, including acquired or genetic risk factors such as obesity, smoking, advancing age, hereditary thrombophilia and immobility before prescribing. All management of PCOS must include lifestyle changes aimed at reducing obesity and metabolic deterioration.

Acknowledgements

Three of the authors (A. Kubba, A. Aguilar, and A.O. Mueck) are members of the AWARE group, an independent panel of physicians with expert interest in androgen excess in women. Other members include Johannes Bitzer, Thomas Römer, Agnaldo Lopes da Silva Filho and Deng ChengYan.

Formation of the AWARE group and the group?s meetings were supported by Bayer AG. Members received honoraria for attendance at meetings but no honoraria was paid for contributions to this manuscript. Professor Ruan did not attend any meetings and no honorarium was paid for her contribution to the manuscript. This publication and its content are solely the responsibility of the authors. Medical writing assistance was provided by Clark Health Communications under the direction of the authors and paid for by Bayer AG.

Disclosure statement

Angela Aguilar has participated and given lectures in symposia organised by industry and received honoraria including compensation for travel and accommodation. Angela Aguilar does not own stocks or have investments in pharmaceutical or medical device companies.

Ali Kubba speaks at meetings sponsored by pharmaceutical companies including Bayer AG and undertakes occasional consultancies for which he receives expenses and honoraria.

Alfred Mueck has received financial support for his research, speaks at meetings sponsored by various pharmaceutical companies, including Bayer AG, and undertakes occasional consultancies for which he receives expenses and honoraria. Alfred Mueck does not own stocks or have investments in pharmaceutical or medical device companies.

Xiangyan Ruan has no financial support or conflicts of interest to declare.