Gynecological Endocrinology
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies Nicolas Mendoza, Tommaso Simoncini & Alessandro D. Genazzani To cite this article: Nicolas Mendoza, Tommaso Simoncini & Alessandro D. Genazzani (2014) Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies, Gynecological Endocrinology, 30:12, 850-860, DOI: 10.3109/09513590.2014.943725 To link to this article: http://dx.doi.org/10.3109/09513590.2014.943725
Published online: 25 Sep 2014.
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Date: 28 September 2017, At: 08:08
http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(12): 850–860 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.943725
POLYCISTIC OVARY
Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies Nicolas Mendoza1, Tommaso Simoncini2, and Alessandro D. Genazzani3 Departamento de Obstetricia y Ginecologı´a, Universidad de Granada, Granada, Spain, 2Dipartimento di Medicina Clinica e Sperimentale, Div. Ginecologia e Ostetricia, Universita` di Pisa, Pisa, Italy, and 3Clinica Ostetrica Ginecologica, University of Modena, Modena, Italy
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1
Abstract
Keywords
Introduction: This paper provides a critical review of the data concerning the effects of combined hormonal contraceptives (CHC) for polycystic ovary syndrome (PCOS). The aim is to determine the best treatment option for each PCOS phenotype. Study design: A literature search of the PubMed database was conducted for randomized clinical trials (RCTs) and observational studies published in any language prior to October 2013. Hyperandrogenism (HA) is the essential diagnostic criterion for PCOS and is frequently associated with insulin resistance (IR) or obesity. The combinations of these criteria define the different PCOS phenotypes and establish the scale of metabolic and cardiovascular risks. Results and conclusions: 19 RCTs and eight observational studies evaluated issues related to the current objectives. CHC represent an effective and safe treatment in women with any PCOS phenotype. In HA/PCOS patients, any CHC analyzed in this review can be used for symptom relief. For patients with metabolic risk, overweight or moderate IR that does not require metformin, a vaginal contraceptive ring appears to be preferred to oral EE/DRP. In these patients, the combination of CHC and myo-inositol may be more effective in controlling endocrine and metabolic profiles. However, further research is needed to define the optimal duration and to clarify the effects of treatment on long-term metabolic outcomes. Future research should also focus on new CHC.
Hirsutism, hormonal contraception, ovary, polycystic ovary syndrome
Introduction Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disease that involves reproductive and metabolic elements. An expert conference by the European Society for Human Reproduction and Embryology and the American Society for Reproduction Medicine determined that PCOS should be diagnosed when at least two of the following three features (Rotterdam criteria) are present [1]: oligo- and/or anovulation, hyperandrogenism (HA) and polycystic ovaries. This definition is more generic than the previous definition and increases the already high PCOS prevalence to the point that it is the most common endocrinopathy in women. Currently, PCOS has a worldwide prevalence of 7–14% of women of child-bearing age. Moreover, the additional phenotypes defined by the Rotterdam criteria identify women with primarily reproductive rather than metabolic dysfunction. The treatment choice for PCOS is partially determined by the scale of metabolic risk, defined by the presence of HA and the combination with obesity or insulin resistance (IR) [2]. Combined hormonal contraceptives (CHC) are the most common treatment for PCOS. However, there are doubts concerning their impact on the cardiovascular system and carbohydrate metabolism such that an ideal CHC does not seem to exist [3,4].
Address for correspondence: Prof. Nicolas Mendoza, University of Granada, Granada, Spain. E-mail: [email protected]
History Received 4 April 2014 Revised 6 May 2014 Accepted 8 July 2014 Published online 25 September 2014
The aim of this paper is to provide a critical review of the data concerning the effects of CHC in patients with PCOS to determine which option is best for each phenotype. There is a special focus on monotherapy strategies (CHC use without combination with other drugs for PCOS, e.g. metformin or flutamide) without and on the long-term health balance between the risks and benefits.
Methods Selection of studies Using the strategy described in Appendix A, we searched the PubMed database for all articles, in all languages, published in peer-reviewed journals through October 2013. First, we included articles concerning the choice of CHC in PCOS women. Articles describing the treatment or prevention of PCOS symptoms or the consequences of PCOS were also included. The inclusion criteria were the following: any randomized controlled trial (RCT), non-RCT or non-controlled studies focusing on CHC and PCOS. Papers that did not discuss CHC use in PCOS patients were excluded. Assessment of study quality and data synthesis We followed PRISMA guidelines for systematic reviews [5]. PICOS (population, interventions, comparators, outcomes, studies design) criteria were formulated a priori to guide the review’s scope and the search procedure, selection and synthesis of the literature. The selection criteria were as follows: (population)
Contraceptives and PCOS
DOI: 10.3109/09513590.2014.943725
PCOS patients of any age; (intervention) treatment with CHC; (outcome) efficacy and safety; (study design) RCTs non-RCT or non-controlled studies; no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. The authors independently conducted the search and screened studies for inclusion, extracted and checked the data, and synthesized the findings. The authors independently determined the adequacy of the design of the studies and their main methodological characteristics in order to ascertain the validity of eligible research. Disagreements were resolved by discussion and consensus. When duplicates of a study were found, we selected the more detailed or complete data from the multiple reports indicating the corresponding references.
Discussion Some of the most relevant weaknesses in the literature used for this study are due to limitations in the research designs. There are only a limited number of RCT and longitudinal studies with long-term follow-ups that occur after the completion of the intervention (see Table 1). In addition, data on effect sizes is often lacking. In many studies, the sample sizes are small and no information regarding power calculations to estimate the appropriate sample size is available. Furthermore, outcome measures are diverse, which makes it difficult to compare findings. Although components of combined interventions are usually described in detail, analyses of component-specific, separated effects are often not reported. Because the study designs, participants, interventions and reported outcome measures varied markedly, we focused on describing the studies, their main characteristics and results, and on qualitative synthesis rather than a meta-analysis. Nevertheless, several issues remain controversial or unknown, and future research should properly address these concerns. In addition to our reservations regarding the quality of the research included here, our review also suffers from several limitations. The most important limitation refers to the exclusion of reports due to the document type (e.g. non-peer-reviewed reports) or to their conditions (e.g. language, unavailability). PCOS phenotypes In the most recent implementation of the Rotterdam diagnostic criteria, different PCOS phenotypes have been defined. Severe PCOS, or the type I phenotype (HA, chronic anovulation and polycystic ovaries), is the most common. The type II phenotype (HA and chronic anovulation but normal ovaries) is much less
Records identified through database searching (n=167)
Records screened (n= 167)
Eligibility
Screening
Idenficaon
The literature search returned 167 studies; 129 were removed after reading titles or abstracts, leaving 38 studies of which 11 studies were excluded for various reasons (basically by the use of other treatments different than CHC), leaving 27 studies for final analysis. publications involving 19 RCT [6–32] (see flow diagram, Figure 1). Full articles that met the inclusion criteria were reviewed in detail. Data items to be considered were discussed by the review authors and appear in Table 1. Other relevant papers were used as a reference. When some of these informations were not available or clear, we treated it as missing data. Eleven RCTs were used to evaluate the best CHC method for women with hyperandrogenism (HA). One of the studies also evaluated women with idiopathic hirsutism [13], and we separated two RCTs that evaluated CHC in combination with anti-androgen drugs and therefore did not examine CHC monotherapy [13,14]. With the exception of the Battaglia study, which included a vaginal ring method, all of these RCTs compared oral CHCs [6]. Most of the RCTs used ethinyl-estradiol (EE) at a dose of 30 mcg as the estrogen component, while the progestin component varied between drospirenone (DRP), cyproterone acetate (CPA), chlormadinone acetate (CMA) and desogestrel (DSG). In general terms, when used as monotherapy, all CHC regimens were shown to relieve HA symptoms after 6 months. The study by Colonna et al. [12] in 2012, reported greater reductions in acne and seborrhea compared to DRP methods, while the only study that provided an assessment at 12 months indicated that CPA is the most potent drug for reducing HA symptoms and signs [11]. Most of the observational studies included in this review were limited to six months of intervention/follow-up and used CHC with 30 mcg EE. In a recent Italian study, an oral
Full text articles assessed for eligibility (n= 38)
Included
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CHC containing estradiol valerate plus dienogest (E2V/DNG) was tested [8]. When assessing patients with IR or any carbohydrate metabolism disorder, most RCTs have compared the above-mentioned CHC and metformin [17–23]. Among the treatment groups, CHC-metformin seems to be a more effective therapeutic option due to the additional beneficial effect on IR. Moreover, the CHC-metformin combination may be particularly beneficial in overweight women with PCOS because it improves vascular endothelial function. When CHC is compared in monotherapy, oral CHC containing DRP has a better lipid profile and a more favorable glycemic and hormonal profile than oral CHC with DSG. In one report, the vaginal ring appeared to be preferable to oral CHC with DRP in PCOS/hyperinsulinemic patients [6].
Limitations
Results
Figure 1. Flow diagram.
851
Studies included in qualitative synthesis (n= 27)
Full text articles excluded (n= 11)
Records excluded on a title/abstract basic (N= 129)
Duplicated (n= 0)
Randomization
Allocation in a 1:1 ratio. Random number table. Double blind
Computer-generated randomization
Not described
Random number table
Computer-generated randomization table
Computer-generated randomization tables in a 1:1:1 ratio. Double blind
Reference
Battaglia et al. [6]
Kriplani et al. [7]
De Leo V et al. [8]
Harris-Glocker et al. [9]
Oner [10]
Bhattacharya et al. [11]
The treatment of hirsutism with both COC containing DRP offered comparable effects and was well tolerated. No difference in effects after 6 months. At 12 months, CPA showed the strongest antiandrogen activities (Ferriman Galwey score). Effects on metabolic parameters were identical. CPA significantly increased SHBG (change ¼ 142.91) compared with DSG (change ¼ 99.53); DRP significantly increased SHBG (change ¼ 131.52) compared with DSG; and CPA significantly decreased the Free Androgen Index (change ¼ 10.57) compared with DSG (change ¼ 5.58).
Hirsutism, Hormonal levels
COC (DRP 3 mg + EE 30 mg + metformin COC + placebo. 6 months DRP 3 mg + EE 30 mg DRP 3 mg + EE 20 mg 6 months DRP 3 mg + EE 30 mg CPA 2 mg + EE 30 mg DSG 150 mg + EE 30 mg 12 months
Endocrine and metabolic parameters
N. Mendoza et al.
50 women (no age data) with moderate to severe hirsutism 171 Women (18–35 years) with HA/PCOS Androgen Excess Society criteria
36 post-menarchal (12–18 years) with HA/PCOS NIH criteria
Quality-of-life
HA
3
40 women (35 years) with HA/PCOS Rotterdam criteria
DRP 3 mg + EE 30 mg CMA 2 mg + EE 30 mg GES 75 mg + EE 30 mg DSG 150 mg + EE 30 mg months
Endocrine and metabolic parameters
DRP 3 mg + EE 30 mg or DSG 150 mg + EE 30 mg 6 months
60 women (16–40 years) not desirous of conception + PCOS Rotterdam criteria
Both treatments improved hirsutism, hyperandrogenemia and ultrasound and color Doppler ovarian parameters. Both induced a slight but significant increase of diurnal and 24-hour blood pressure. Although both therapies worsened the lipid profile, the oral pill administration was associated with a more evident increase of circulating triglycerides. The 6-month treatment with the vaginal ring significantly improved the area under the curve for glucose, insulin, and Cpeptide, whereas the DRP-EE pill induced an increase in the insulinogenic index and homeostatic model assessment estimate for insulin resistance values. COC with DRP has better outcome in regular cycles, antiandrogenic effect, fall in BMI and BP, better lipid profile, favorable glycemic and hormonal profile than COC with DSG: BMI fell by 0.52 kg/m2; LDL was decreased (p50.01) and HDL was elevated (p50.05), Systolic BP reduced (1.6% fall) and diastolic BP (0.5% fall) (p50.05) A significant fall in fasting/postprandial blood sugar and insulin and total testosterone with both COC without differences between groups. In all groups, mean concentrations of free T, total T and A dropped by 40–60%, and concentrations of DHEAS dropped by 20–50%. Formulations with DRSP and CMA caused a greater reduction of androgens and a progressive increase in serum concentrations of SHBG than those with DSG and GSD (without significant differences). The addition of metformin does not add improvement to quality-of-life.
CVD risk, endocrine and metabolic parameters
DRP 3 mg + EE 30 mg Vaginal ring (EE 15 mg + ENG 120 mg) 6 months
Key results
40 women 418 years for treatment of HA/PCOS and contraceptive necessities Rotterdam criteria
Outcomes
Intervention
Participants*/PCOS criteria
Randomized controlled trial involved in hyperandrogenism (HA) PCOS patients.
Table 1. Summary of studies.
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852 Gynecol Endocrinol, 2014; 30(12): 850–860
Not described
Not described
Not described
Non-blind, based on patients’ chronological presence (indifferent of BMI and IR)
Computer-generated randomization tables
Colonna et al. [12]
Karakurt et al. [13]
Hadzˇiomerovic´Pekic´ et al. [14]
Panidis et al. [15]
Romualdi et al. [16]
Endocrine and metabolic parameters
AMH levels
Metformin (M) Naltrexone (N) COC (EE 35 mg + CPA 2 mg) + prednisolone (Pr) 3 month.
6
29 women (18–36 years) HA/PCOS + IR Rotterdam criteria
45 HA/PCOS NHI criteria
30 PCOS (19–30 years) Rotterdam criteria
DRP 3 mg + EE 30 mg DRP 3 mg + EE 20 mg 12 months
Endocrine and metabolic parameters
Hirsutism
COC (EE 35 mg + CPA 2 mg) + SPL 100 mg Flutamide 250 mg 6 months
29 with hirsutism (HA/ PCOS and idiopatic)
EE 35 mg + CPA 2 mg EE 30 mg + DRP 3 mg Metformine months
HA
59 women (19–29 years) HA/PCOS
DRP 3 mg + EE 30 mg CMA 2 mg + EE 30 mg 6 months
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Contraceptives and PCOS (continued )
Both treatments were well tolerated and showed a significant improvement of HA, although EE/ DRP showed a more potent effect on acne and seborrhea at the end of the study (p50.05 between treatments). Seborrhoea (mcg/cm2 of skin) 2412.26 ± 1692.03 versus 4076.69 ± 2497.66 p Ferryman–Gallwey score 9.43 ± 2.02 versus 11.24 ± 2.35 delta-4-androstenedione (ng/mL) 1.98 ± 0.72 versus 2.72 ± 0.64 total testosterone (nmol/L) 0.99 ± 0.37 versus 1.28 ± 0.37 Both treatments are effective in the treatment of hirsutism: A significant decrease in Ferryman– Gallwey score was observed with flutamide (from 11.2 ± 3.3 to 7.6 ± 4.0) and SPL + CPA/EE (from 9.9 ± 1.9 to 7.1 ± 2.0). However, there was no statistically significant difference between the two groups. A statistically significant decrease in free androgen index was seen in all groups. Testosterone concentrations declined significantly in the M and N groups after 3 months, and in the COC/Pr group, only after the first month. DHEAS decreased significantly only in the N group. SHBG levels more than doubled during COC use and was not affected by M or N. The only significant within-group changes in the metabolic state were an average decrease in total cholesterol by 10 mg/dL and BP by 9 mm Hg in the M group (p ¼ 0. 01, p ¼ 0.03, respectively). HDL cholesterol increased in the OC/Pr group by 7 mg/dL, whereas it remained unchanged in the other two groups (p ¼ 0.046). The diastolic BP increased in the OC/Pr group by 10.6 mm Hg, whereas it decreased in the M group and remained unchanged in the N group (p ¼ 0.02). AMH serum levels were significantly decreased under treatment with EE 35 mg + CPA 2 mg (p ¼ 0.002 at 3 months and p ¼ 0.001 at 6 months). EE/DRP and metformin did not significantly affect serum AMH levels. AMH was significantly decreased under COCs treatment compared to metformin (p ¼ 0.005). Both COC induced a significant improve in hirsutism score, testosterone, DHEAS and SHBG levels. Total Cholesterol, LDL, HDL and triglycerides
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853
Randomization
Participants*/PCOS criteria
Intervention
Case-control study followed by a RCT
Not described
Not described
Luque-Ramı´rez et al. [18]
Moran et al. [19]
Kebapcilar et al. [20]
48 women with PCOS Rotterdam criteria + IR
Overweight, age and BMImatched women with PCOS (no ¼ 80) or without PCOS (no ¼ 27)
40 PCOS patients and 20 non-HA women.
Blood clotting tests and endothelial function
Inflammatory markers, endocrine and metabolic parameters Endocrine and metabolic parameters
metformin EE 35 mg + CPA 2 mg 6 months A. COC (EE 35 mg + CPA 2 mg) B. Metformin C. COC + metformin D. COC + SPL 3 months
Outcomes CVD risk factor
Outcomes
COC (EE 35 mg + CPA 2 mg) metformin 24 weeks
Randomized controlled trial involved in PCOS patients with insulin resistance (IR) or obesity. Reference Randomization Participants*/PCOS criteria Intervention COC (35 mg EE + 2 mg Luque-Ramı´rez Randomized, open-label, 34 HA/PCOS patients and CPA) et al. [17] parallel clinical trial 40 non-HA control Metformin women NIH criteria
Reference
Randomized controlled trial involved in hyperandrogenism (HA) PCOS patients.
Table 1. Continued
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Key results Obesity is the main determinant of serum uric acid concentrations in PCOS patients, yet amelioration of androgen excess with an antiandrogenic contraceptive pill results in a significant decrease in these levels, an effect that is not observed with metformin. There were no statistically significant differences in uric acid levels between PCOS and non-hyperandrogenic control women. Obese women showed higher uric acid concentrations than lean and overweight women, In PCOS women, COC decreased in uric acid levels (p ¼ 0.018), whereas no changes were observed with metformin. COC and metformin may exert deleterious effects on blood clotting tests of PCOS women, yet the effects of metformin appear to be milder. Because smoking potentiates some of these effects and deteriorates endothelial function, smoking cessation should be promoted in PCOS patients. Alterations in leptin between women with and without PCOS and following pharmacological interventions are primarily related to adiposity and not IR. Aldosterone was reduced equivalently with metformin and the COC. In all treatment groups were observed reduced levels of coagulation parameters, improvement of hormonal, hematological and metabolical variables. by most probably reducing insulin levels. Among the treatment groups, EE/CA-metformin may be a more effective therapeutic option than the other protocols and this may be due to the beneficial effect of EE/CA-metformin on IR: All women lost weight significantly after the treatment (Group A: 3.5 kg, 4.8%; Group B: 2.8 kg, 3.6%; Group C: 2.7 kg, 3.7%; Group D: 2.6 kg, 3.4%). Lipid profiles: Group A: no change; Group B: significant decrease in total and LDL cholesterol and increase in HDL; there were no changes in triglycerides; Group C: triglycerides, total and LDL cholesterol levels were significantly reduced after the treatment whereas HDL concentrations
increased in both groups. Triglycerides more markedly increased with EE 30 mg.
Key results
854 N. Mendoza et al. Gynecol Endocrinol, 2014; 30(12): 850–860
Computerized random number generator using a 1:1 ratio
Not described
Not described
Essah et al. [21]
Orbetzova et al. [22]
Kilic et al. [23]
96 women (18–35 years) non-HA and oligoamenorrheic/
66 PCOS + overweight + IR Rotterdam criteria
18 women (no data of age) PCOS/HA Rotterdam criteria
CVD risk and carbohydrate metabolism
Adipose tissue hormones and hypothalamic neuropeptide Y
COC (CMA 2 mg + EE 30 mg) + metformin COC + rosiglitazone 3-months
1. Obese + metformin. 2. Obese + COC (DSG 150 mg + EE 30 mg) 3. Non-obese + metformin
Endocrine and metabolic parameters
COC (EE 35 mg + norgestimate 0.18– 0.25 mg) + metformin COC + placebo 3 months
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Contraceptives and PCOS (continued )
were increased significantly; Group D: LDL and total cholesterol were significantly reduced but there were no significant changes in triglycerides and HDL levels. Activated partial thromboplastin time, prothrombin time levels D-dimer, WBC and MPV were reduced significantly in all the groups (p50.05). HOMA-IR, insulin and androgen levels decreased in all treatment groups. EE/CA–metformin and metformin alone groups resulted in a higher proportional reduction of Ddimer levels. EE/CA–metformin group showed higher proportional reduction fasting insulin concentrations, HOMA-IR and free testosterone levels than metformin alone and EE/CA–SPL groups. DHEAs levels significantly decreased in group EE/ CA–metformin than EE/CA alone and EE/CA– SPL groups. In multiple stepwise regression analyses, reduction in proportional insulin levels was independently and positively associated with decrease of MPV, D-dimer, free testosterone levels. Both treatments had similar effects on androgen levels, lipid profile, insulin sensitivity, and serum inflammatory markers, but flow-mediated dilatation increased by 69.0% in the metformin plus COC group while it remained unchanged in the COC group. beneficial effects of the treatment on potential cardiovascular risk in IR PCOS women Significant decrease of leptin (p50.01; p ¼ 0.001, respectively), resistin (p50.01; p50.01, respectively), TNF a) (p ¼ 0.001; p50.001, respectively.), and neuropeptide Y (p50.05; p50.001, respectively) was observed in both groups after treatment. Decrease in the anthropometric parameters of body weight in the metformin group only. No significant changes in hormonal characteristics of the groups were found except for a decrease in androstenedione and DHEA-S (p50.05) in the metformin group and in 17-OH-progesterone (p50.05) in the rosiglitazone group. HDL-cholesterol rose and diastolic BP fell (p50.05) in the metformin group. A significant decrease was observed in ADMA, homocysteine and HOMA-IR levels in Groups 1 and 3. An increase in ADMA and hs-CRP levels was observed in Groups 2 and 4.
DOI: 10.3109/09513590.2014.943725
855
1:1 proportion using a randomizer program
Randomization
49 HA/PCOS women 20 PCOS who wanted HC 20 control required HC 20 control wanted nonHC 28 lean PCOS and 28 control. Rotterdam criteria
20 women (18–33 years) PCOS Rotterdam criteria
Banaszewska et al. [27]
Gomes et al. [28]
De Leo et al. [30]
Aydin et al. [29]
155 patients with PCOS prospective, open-label clinical study.
Participants*/PCOS criteria 50 non-obese women: 30 HA/PCOS and 20 control
50 women (18–35 years) Rotterdam criteria (no describe if HA or not)
PCOS + impaired glucose tolerance
Participants*/PCOS criteria
Minozzi et al. [26]
Observational studies involved in PCOS patients. Reference Uras et al. [25]
Vieira et al. [24]
Reference
Randomized controlled trial involved in hyperandrogenism (HA) PCOS patients.
Table 1. Continued
Endocrine and metabolic parameters Endocrine and metabolic parameters
EE 30 mg + GTD 75 mg EE/GTD + myo-inositol 12 months. COC (EE 20 mg + 150 DSG) 6 months. COC: CMA 2 mg + EE 30 mg 6 months
Anthropometric, endocrine and metabolic parameters
Anthropometric, and metabolic parameters
EE 30 mg/DRP 3 mg 6 months.
E2V/DNG 3 months
Plasma concentrations of Matrix metalloproteinases (MMPs)
Outcomes Endocrine and metabolic parameters
Arterial function
Outcomes
Intervention PCOS: CMA 2 mg + EE 30 mg 6 months
COC (CMA 2 mg + EE 30 mg) COC + SPL 100 mg 12 months
4. Non-obese + COC 6 months
Intervention
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After 6 months of treatment in the PCOS patients, total fat percentage increased from 24.5% ± 7.1% to 26.0% ± 6.1% (p ¼ 0.035) and trunk fat percentage increased from 20.2% ± 8.9% to 22.2% ± 7.1% (p ¼ 0.014), although weight, BMI and waist to hip ratio remained unchanged. Median values of insulin, Homeostasis model assessment of insulin resistance and oral glucose tolerance test after treatment were lower than values before treatment. No significant difference was observed in BMI
Reduced plasma MMP-2 concentrations in both healthy and PCOS women.
Key results In the EE/CMA group, androgen levels and bioavailability, hirsutism and acne score were significantly lower, whereas they did not change in the control group. In both groups, glucose-insulin metabolism and body composition parameters were not affected. Combination of COC and myo-inositol may be more effective in controlling endocrine, metabolic, and clinical profile in patients with PCOS than COC alone, and reduce insulin levels and IR. Decrease in the testosterone level but negative effect on total cholesterol and triglycerides level
In this study, metformin treatment leads to improvement in hormonal and metabolic parameters and decreases endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and homocysteine levels. COC impaired glucose tolerance, increases ADMA and high sensitive C-reactive protein levels and creates an increase in the metabolic risk. The increase in mean total cholesterol levels was greater in the COC + SPL group than in the COC group (27 versus 13%, respectively; p ¼ 0.02). The increase in SHBG levels was greater in the COC group than in the COC + SPL group (424 versus 364%, respectively; p ¼ 0.01).
Key results
856 N. Mendoza et al. Gynecol Endocrinol, 2014; 30(12): 850–860
Contraceptives and PCOS *All without contraindications for hormonal contraceptives. BMI: Body mass index; BP: blood pressure; CMA: chlormadinone acetate; COC: combined oral contraceptive; CPA: ciproterone acetate; CVD: cardio vascular disease; DNG: dienogest; DSG: desogestrel; DRP: drospirenone; E2V: estradiol valerate; EE: etinilestradiol; ENG etonogestrel; GSD: gestodene; HA: hyperandrogenism; IR: insulin resistance; MMPs: Matrix metalloproteinases; SHBG: sex hormone-binding globulin; NIH: National Institutes of Health; PCOS: polycystic ovary syndrome; SPL: spironolactone.
Endocrine and metabolic parameters 46 lean women: 23 PCOS and 23 control Harmanci et al. [32]
PCOS: EE-DRP + SPL 6 months
Anthropometric, endocrine and metabolic parameters EE/DRP (30 mg/3 mg) EE/DRP + metformin 6 months 45 lean HA/PCOS women Cinar et al. [31]
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EE/DRSP alone or in combination with metformin improves clinical and biochemical HA in lean PCOS. Both treatments similarly alter lipid profile. EE/DRSP alone does not affect insulin sensitivity, whereas combining EE/DRSP with metformin might improve it. Improves HA in lean PCOS without any adverse effects on adiposity, glucose tolerance status or lipid profile, and increases high-sensitivity Creactive protein and homocysteine levels.
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frequent but has similar clinical and endocrine characteristics as phenotype I. The Ovulatory PCOS, or type III, phenotype (HA and polycystic ovaries) is relatively common and presents milder clinical and endocrine alterations than phenotypes I and II. The normoandrogenic PCOS, or type IV, phenotype is relatively uncommon and characterizes patients with normal body mass index (BMI), insulin sensitivity and free androgen index with increased levels of LH and LH/FSH ratio [33,34]. All PCOS phenotypes display changes due to aging, suggesting an amelioration of ovarian dysfunction as indicated by the increase in number of regular menstrual cycles, decrease in serum androgen levels, and decrease in IR [35]. Apart from these signs and symptoms, a considerable proportion of women with PCOS display IR and overweight/obesity. The mechanisms responsible for IR are currently unknown, although it is likely a result of altered adipose and muscular cell glucose uptake due to a genetic defect that is independent of obesity. Although IR does not occur exclusively in overweight/ obese women with PCOS, IR is more frequent among these patients [36]. Similarly, a direct association between IR and HA has been observed although the cause-and-effect relationship is not well understood. Androgens have not been shown to alter the physiology or glucose homeostasis of adipocytes. In addition, tests have indicated that hyperinsulinism tends to be a cause rather than a result of excess androgens [37]. Other markers of cardiovascular disease (CVD) are increased in women with PCOS; however, whether this apparent risk translates into an increased incidence of CVD later in life remains to be elucidated [38,39]. Obesity likely plays a major role, but adjustments for BMI do not affect these findings, suggesting that the increased CVD risk is not exclusively related to a higher BM. Instead, the increased CVS risk may be due to excess androgen concentrations [28]. A common genetic origin of PCOS and diabetes mellitus has also been proposed [40]. A number of studies have linked PCOS with an increased risk of gestational diabetes, but a 2009 meta-analysis did not find sufficient evidence to confirm this hypothesis [41]. This is likely because the new definition of PCOS includes other phenotypes that are exempted from this risk. In this sense, the main link between PCOS and cardiovascular disease remains IR. Moreover, the risk for adverse obstetric or neonatal outcomes increases in patients with PCOS phenotypes with ovarian dysfunction plus biochemical HA, whereas no significant effect was detected for clinical HA without anovulation [42]. Thus, some clinicians prefer to delay fertility treatment until the patients have reached an appropriate weight or have leveled out their insulin levels [43]. In summary, HA serves as the essential diagnostic criterion of the syndrome and is frequently associated with IR or obesity. The combinations of these conditions define the different PCOS phenotypes and establish the scale of metabolic and CVD risk [44,45]. The long-term health risks of PCOS patients demand that their general health be monitored even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible [46]. To address this issue, the National Institutes of Health (NIH) Office for Disease Prevention-sponsored Evidence-based Methodology Workshop on Polycystic Ovary Syndrome recently proposed dividing the PCOS phenotypes into two distinct diseases. Those with primarily reproductive concerns should continue to be referred to as PCOS patients, and those with important metabolic consequences should have a new disease designation [47].
858
N. Mendoza et al.
PCOS phenotypes: hormonal contraception choice
PCOS with metabolic risk or obesity
To date, CHC have been the most common treatment for PCOS and its symptoms. However, there are no clinical guidelines that recommend a specific CHC for the different PCOS phenotypes. There are still doubts concerning the metabolic and cardiovascular effect of CHC in this population. In general terms, it has been recommended that the ideal contraceptive for women with PCOS should limit follicle development to reduce androgens synthesis, block the peripheral action of androgens and achieve good menstrual cycle control with minimal metabolic or thromboembolic risk.
There are doubts concerning the impact of CHC on cardiovascular function and carbohydrate metabolism, which hinders the choice of CHC method. Oral CHCs may worsen glucose tolerance in healthy users, but there is no finding indicating an increased risk of CVD in women with PCOS. These discrepancies could be due to inadequate adjustments for confounding factors that might influence body weight or IR (lifestyle, dietary composition, ethnicity, non-compliance, etc.) [56,57]. Although the metabolic effects of CHC in PCOS could be dependent on body weight, few studies have focused on the possible differences in the effect of CHC on lean versus obese patients. In lean-PCOS women, CHC do not change clinical anthropometric measures and do not exhibit adverse effects on adiposity, insulin sensitivity/glucose tolerance status and lipid profile [25,29,31,32]. In three meta-analyses that examined the effect of CHC on metabolic outcomes, the use of CHC was not associated with clinically significant adverse metabolic consequences. When changes in the lipid spectrum are compared, the vast majority of healthy users remain within reference limits, and it is unlikely that this could have a clinically significant effect on the risk of CVD [58–60]. In contrast, according to the World Health Organization’s recommendations, when arterial hypertension or an elevated risk of thromboembolism is present, levonorgestrelintrauterine system or progestogen-only hormonal contraceptives should be used instead of CHC [61]. Thus, the selected studies of this review suggest that progestogens with minimal metabolic side-effects, such as DRSP, could be more advantageous in overweight women or women whose glucose tolerance is a concern. In addition, the combination of CHC with myo-inositol may be more effective in controlling the endocrine, metabolic and clinical profiles in patients with PCOS than CHC alone, and may reduce insulin levels and IR [26]. With respect to estrogen, a recent European review indicates that the use of low-dose-oral CHC is preferable in patients with glucose intolerance or IR [62]. However, even though we have little evidence, it is interesting that the vaginal ring and oral E2V/DNG formulations seem to be preferred over CHC with EE/DRP [6,8].
HA/PCOS (type I, II and III phenotypes)
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As stated in the previous section, the key to defining the phenotype and severity of PCOS is HA. In HA/PCOS phenotypes, the CHC of choice would alleviate the HA without a negative impact on metabolism or cardiovascular risk. A recent practical guideline recommends CHC (oral, patch or vaginal ring) as firstline management for HA/PCOS patients, but there are insufficient data to define the optimal duration of treatment [48]. For the signs and symptoms of androgens excess, the most important parameter in CHC selection is the type of progestin. CPA, CMA, DNG and DRSP are progestogens with powerful anti-androgen activity. These progestogens mainly act by blocking androgen receptors in target organs; however, they also reduce 5 alpha-reductase skin activity. Studies on the efficacy of CHC containing DRSP or CPA in the treatment of hirsutism show a reduction in clinical manifestations of HA after 6–12 months of therapy, a significant reduction of circulating androgens and a significant increase in SHBG. Moreover, it is speculated that an interference with androgen synthesis may also reduce the risk of later metabolic disturbances and health complications [49]. In addition to this, estrogen increases SHBG, thereby reducing bioavailable androgens. However, there are no data providing direct comparisons regarding the type or dose of estrogen. Furthermore, research has shown a 2-fold increase in the risk of venous thromboembolism among women with PCOS who were taking oral CHC and a 1.5-fold increased risk among women with PCOS not taking oral CHC [50]. Therefore, it is recommended that women with PCOS use a CHC with the lowest effective estrogen dose. In addition, the dose of EE correlates with the concentration of SHBG, a critical factor in decreasing circulating free androgen. The residual follicular activity and adrenal steroidogenesis are more frequent with low estrogen dose. However, there are few studies comparing EE doses [10]. E2V/DNG has an impact on various metabolic and hemostatic parameters that is comparable to or less than that of EE/LNGcontaining oral CHC. The effects on prothrombin, D-dimer, HDL, LDL, insulin and carbohydrate metabolism are, in general, more favorable with E2V/DNG than with EE/LNG [51]. E2V/DNG could thus be recommended as an oral CHC in PCOS women with IR or overweight [8]. The specific CHC regimen does not appear to influence the metabolism of androgens; however, extended regimens improve follicular control and hormonal suppression [52]. One extended regimen consisting of 2 mg CMA plus 30 mcg EE showed an improvement in acne after 6 months [53,54], and another study evaluating 30 mcg EE plus 2 mg DNG reported increased SHBG and decreased testosterone levels, which is similar to previous observations with the conventional regimen [55]. Non-HA/PCOS phenotype Only one RCT analyzed PCOS women without HA; however, all of the participants had obesity or impaired glucose tolerance [23].
Conclusions CHC represent an effective and safe treatment in women with any phenotype of PCOS. In HA/PCOS patients, any CHC analyzed in this review can be used for symptom relief. In patients with metabolic risk, overweight or moderate IR that does not need metformin, a vaginal contraceptive ring appears to be preferred to oral EE/DRP. Moreover, a combination of CHC and myo-inositol may be more effective in controlling the endocrine and metabolic profile. However, further research is needed to define the optimal duration and to clarify the effects of treatment on long-term metabolic outcomes. Future research should also focus on new CHC.
Declaration of interest All authors participated in the review and approved the final version of the manuscript. None of them have conflict of interest with. No one is on speaker’s bureaus, received research funding or consulting.
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Appendix A: Search strategy
‘‘contraceptives’’[All Fields])) OR ((‘‘polycystic ovary syndrome’’[MeSH Terms] OR (‘‘polycystic’’[All Fields] AND ‘‘ovary’’[All Fields] AND ‘‘syndrome’’[All Fields]) OR ‘‘polycystic ovary syndrome’’[All Fields] OR (‘‘polycystic’’[All Fields] AND ‘‘ovary’’[All Fields]) OR ‘‘polycystic ovary’’[All Fields]) AND (‘‘contraception’’[MeSH Terms] OR ‘‘contraception’’[All Fields]))
((‘‘polycystic ovary syndrome’’[MeSH Terms] OR (‘‘polycystic’’[All Fields] AND ‘‘ovary’’[All Fields] AND ‘‘syndrome’’[All Fields]) OR ‘‘polycystic ovary syndrome’’[All Fields]) AND hormonal[All Fields] AND (‘‘contraceptive agents’’[Pharmacological Action] OR ‘‘contraceptive agents’’[MeSH Terms] OR (‘‘contraceptive’’[All Fields] AND ‘‘agents’’[All Fields]) OR ‘‘contraceptive agents’’[All Fields] OR
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies Nicolas Mendoza, Tommaso Simoncini & Alessandro D. Genazzani To cite this article: Nicolas Mendoza, Tommaso Simoncini & Alessandro D. Genazzani (2014) Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies, Gynecological Endocrinology, 30:12, 850-860, DOI: 10.3109/09513590.2014.943725 To link to this article: http://dx.doi.org/10.3109/09513590.2014.943725
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http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(12): 850–860 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.943725
POLYCISTIC OVARY
Hormonal contraceptive choice for women with PCOS: a systematic review of randomized trials and observational studies Nicolas Mendoza1, Tommaso Simoncini2, and Alessandro D. Genazzani3 Departamento de Obstetricia y Ginecologı´a, Universidad de Granada, Granada, Spain, 2Dipartimento di Medicina Clinica e Sperimentale, Div. Ginecologia e Ostetricia, Universita` di Pisa, Pisa, Italy, and 3Clinica Ostetrica Ginecologica, University of Modena, Modena, Italy
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1
Abstract
Keywords
Introduction: This paper provides a critical review of the data concerning the effects of combined hormonal contraceptives (CHC) for polycystic ovary syndrome (PCOS). The aim is to determine the best treatment option for each PCOS phenotype. Study design: A literature search of the PubMed database was conducted for randomized clinical trials (RCTs) and observational studies published in any language prior to October 2013. Hyperandrogenism (HA) is the essential diagnostic criterion for PCOS and is frequently associated with insulin resistance (IR) or obesity. The combinations of these criteria define the different PCOS phenotypes and establish the scale of metabolic and cardiovascular risks. Results and conclusions: 19 RCTs and eight observational studies evaluated issues related to the current objectives. CHC represent an effective and safe treatment in women with any PCOS phenotype. In HA/PCOS patients, any CHC analyzed in this review can be used for symptom relief. For patients with metabolic risk, overweight or moderate IR that does not require metformin, a vaginal contraceptive ring appears to be preferred to oral EE/DRP. In these patients, the combination of CHC and myo-inositol may be more effective in controlling endocrine and metabolic profiles. However, further research is needed to define the optimal duration and to clarify the effects of treatment on long-term metabolic outcomes. Future research should also focus on new CHC.
Hirsutism, hormonal contraception, ovary, polycystic ovary syndrome
Introduction Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disease that involves reproductive and metabolic elements. An expert conference by the European Society for Human Reproduction and Embryology and the American Society for Reproduction Medicine determined that PCOS should be diagnosed when at least two of the following three features (Rotterdam criteria) are present [1]: oligo- and/or anovulation, hyperandrogenism (HA) and polycystic ovaries. This definition is more generic than the previous definition and increases the already high PCOS prevalence to the point that it is the most common endocrinopathy in women. Currently, PCOS has a worldwide prevalence of 7–14% of women of child-bearing age. Moreover, the additional phenotypes defined by the Rotterdam criteria identify women with primarily reproductive rather than metabolic dysfunction. The treatment choice for PCOS is partially determined by the scale of metabolic risk, defined by the presence of HA and the combination with obesity or insulin resistance (IR) [2]. Combined hormonal contraceptives (CHC) are the most common treatment for PCOS. However, there are doubts concerning their impact on the cardiovascular system and carbohydrate metabolism such that an ideal CHC does not seem to exist [3,4].
Address for correspondence: Prof. Nicolas Mendoza, University of Granada, Granada, Spain. E-mail: [email protected]
History Received 4 April 2014 Revised 6 May 2014 Accepted 8 July 2014 Published online 25 September 2014
The aim of this paper is to provide a critical review of the data concerning the effects of CHC in patients with PCOS to determine which option is best for each phenotype. There is a special focus on monotherapy strategies (CHC use without combination with other drugs for PCOS, e.g. metformin or flutamide) without and on the long-term health balance between the risks and benefits.
Methods Selection of studies Using the strategy described in Appendix A, we searched the PubMed database for all articles, in all languages, published in peer-reviewed journals through October 2013. First, we included articles concerning the choice of CHC in PCOS women. Articles describing the treatment or prevention of PCOS symptoms or the consequences of PCOS were also included. The inclusion criteria were the following: any randomized controlled trial (RCT), non-RCT or non-controlled studies focusing on CHC and PCOS. Papers that did not discuss CHC use in PCOS patients were excluded. Assessment of study quality and data synthesis We followed PRISMA guidelines for systematic reviews [5]. PICOS (population, interventions, comparators, outcomes, studies design) criteria were formulated a priori to guide the review’s scope and the search procedure, selection and synthesis of the literature. The selection criteria were as follows: (population)
Contraceptives and PCOS
DOI: 10.3109/09513590.2014.943725
PCOS patients of any age; (intervention) treatment with CHC; (outcome) efficacy and safety; (study design) RCTs non-RCT or non-controlled studies; no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. The authors independently conducted the search and screened studies for inclusion, extracted and checked the data, and synthesized the findings. The authors independently determined the adequacy of the design of the studies and their main methodological characteristics in order to ascertain the validity of eligible research. Disagreements were resolved by discussion and consensus. When duplicates of a study were found, we selected the more detailed or complete data from the multiple reports indicating the corresponding references.
Discussion Some of the most relevant weaknesses in the literature used for this study are due to limitations in the research designs. There are only a limited number of RCT and longitudinal studies with long-term follow-ups that occur after the completion of the intervention (see Table 1). In addition, data on effect sizes is often lacking. In many studies, the sample sizes are small and no information regarding power calculations to estimate the appropriate sample size is available. Furthermore, outcome measures are diverse, which makes it difficult to compare findings. Although components of combined interventions are usually described in detail, analyses of component-specific, separated effects are often not reported. Because the study designs, participants, interventions and reported outcome measures varied markedly, we focused on describing the studies, their main characteristics and results, and on qualitative synthesis rather than a meta-analysis. Nevertheless, several issues remain controversial or unknown, and future research should properly address these concerns. In addition to our reservations regarding the quality of the research included here, our review also suffers from several limitations. The most important limitation refers to the exclusion of reports due to the document type (e.g. non-peer-reviewed reports) or to their conditions (e.g. language, unavailability). PCOS phenotypes In the most recent implementation of the Rotterdam diagnostic criteria, different PCOS phenotypes have been defined. Severe PCOS, or the type I phenotype (HA, chronic anovulation and polycystic ovaries), is the most common. The type II phenotype (HA and chronic anovulation but normal ovaries) is much less
Records identified through database searching (n=167)
Records screened (n= 167)
Eligibility
Screening
Idenficaon
The literature search returned 167 studies; 129 were removed after reading titles or abstracts, leaving 38 studies of which 11 studies were excluded for various reasons (basically by the use of other treatments different than CHC), leaving 27 studies for final analysis. publications involving 19 RCT [6–32] (see flow diagram, Figure 1). Full articles that met the inclusion criteria were reviewed in detail. Data items to be considered were discussed by the review authors and appear in Table 1. Other relevant papers were used as a reference. When some of these informations were not available or clear, we treated it as missing data. Eleven RCTs were used to evaluate the best CHC method for women with hyperandrogenism (HA). One of the studies also evaluated women with idiopathic hirsutism [13], and we separated two RCTs that evaluated CHC in combination with anti-androgen drugs and therefore did not examine CHC monotherapy [13,14]. With the exception of the Battaglia study, which included a vaginal ring method, all of these RCTs compared oral CHCs [6]. Most of the RCTs used ethinyl-estradiol (EE) at a dose of 30 mcg as the estrogen component, while the progestin component varied between drospirenone (DRP), cyproterone acetate (CPA), chlormadinone acetate (CMA) and desogestrel (DSG). In general terms, when used as monotherapy, all CHC regimens were shown to relieve HA symptoms after 6 months. The study by Colonna et al. [12] in 2012, reported greater reductions in acne and seborrhea compared to DRP methods, while the only study that provided an assessment at 12 months indicated that CPA is the most potent drug for reducing HA symptoms and signs [11]. Most of the observational studies included in this review were limited to six months of intervention/follow-up and used CHC with 30 mcg EE. In a recent Italian study, an oral
Full text articles assessed for eligibility (n= 38)
Included
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CHC containing estradiol valerate plus dienogest (E2V/DNG) was tested [8]. When assessing patients with IR or any carbohydrate metabolism disorder, most RCTs have compared the above-mentioned CHC and metformin [17–23]. Among the treatment groups, CHC-metformin seems to be a more effective therapeutic option due to the additional beneficial effect on IR. Moreover, the CHC-metformin combination may be particularly beneficial in overweight women with PCOS because it improves vascular endothelial function. When CHC is compared in monotherapy, oral CHC containing DRP has a better lipid profile and a more favorable glycemic and hormonal profile than oral CHC with DSG. In one report, the vaginal ring appeared to be preferable to oral CHC with DRP in PCOS/hyperinsulinemic patients [6].
Limitations
Results
Figure 1. Flow diagram.
851
Studies included in qualitative synthesis (n= 27)
Full text articles excluded (n= 11)
Records excluded on a title/abstract basic (N= 129)
Duplicated (n= 0)
Randomization
Allocation in a 1:1 ratio. Random number table. Double blind
Computer-generated randomization
Not described
Random number table
Computer-generated randomization table
Computer-generated randomization tables in a 1:1:1 ratio. Double blind
Reference
Battaglia et al. [6]
Kriplani et al. [7]
De Leo V et al. [8]
Harris-Glocker et al. [9]
Oner [10]
Bhattacharya et al. [11]
The treatment of hirsutism with both COC containing DRP offered comparable effects and was well tolerated. No difference in effects after 6 months. At 12 months, CPA showed the strongest antiandrogen activities (Ferriman Galwey score). Effects on metabolic parameters were identical. CPA significantly increased SHBG (change ¼ 142.91) compared with DSG (change ¼ 99.53); DRP significantly increased SHBG (change ¼ 131.52) compared with DSG; and CPA significantly decreased the Free Androgen Index (change ¼ 10.57) compared with DSG (change ¼ 5.58).
Hirsutism, Hormonal levels
COC (DRP 3 mg + EE 30 mg + metformin COC + placebo. 6 months DRP 3 mg + EE 30 mg DRP 3 mg + EE 20 mg 6 months DRP 3 mg + EE 30 mg CPA 2 mg + EE 30 mg DSG 150 mg + EE 30 mg 12 months
Endocrine and metabolic parameters
N. Mendoza et al.
50 women (no age data) with moderate to severe hirsutism 171 Women (18–35 years) with HA/PCOS Androgen Excess Society criteria
36 post-menarchal (12–18 years) with HA/PCOS NIH criteria
Quality-of-life
HA
3
40 women (35 years) with HA/PCOS Rotterdam criteria
DRP 3 mg + EE 30 mg CMA 2 mg + EE 30 mg GES 75 mg + EE 30 mg DSG 150 mg + EE 30 mg months
Endocrine and metabolic parameters
DRP 3 mg + EE 30 mg or DSG 150 mg + EE 30 mg 6 months
60 women (16–40 years) not desirous of conception + PCOS Rotterdam criteria
Both treatments improved hirsutism, hyperandrogenemia and ultrasound and color Doppler ovarian parameters. Both induced a slight but significant increase of diurnal and 24-hour blood pressure. Although both therapies worsened the lipid profile, the oral pill administration was associated with a more evident increase of circulating triglycerides. The 6-month treatment with the vaginal ring significantly improved the area under the curve for glucose, insulin, and Cpeptide, whereas the DRP-EE pill induced an increase in the insulinogenic index and homeostatic model assessment estimate for insulin resistance values. COC with DRP has better outcome in regular cycles, antiandrogenic effect, fall in BMI and BP, better lipid profile, favorable glycemic and hormonal profile than COC with DSG: BMI fell by 0.52 kg/m2; LDL was decreased (p50.01) and HDL was elevated (p50.05), Systolic BP reduced (1.6% fall) and diastolic BP (0.5% fall) (p50.05) A significant fall in fasting/postprandial blood sugar and insulin and total testosterone with both COC without differences between groups. In all groups, mean concentrations of free T, total T and A dropped by 40–60%, and concentrations of DHEAS dropped by 20–50%. Formulations with DRSP and CMA caused a greater reduction of androgens and a progressive increase in serum concentrations of SHBG than those with DSG and GSD (without significant differences). The addition of metformin does not add improvement to quality-of-life.
CVD risk, endocrine and metabolic parameters
DRP 3 mg + EE 30 mg Vaginal ring (EE 15 mg + ENG 120 mg) 6 months
Key results
40 women 418 years for treatment of HA/PCOS and contraceptive necessities Rotterdam criteria
Outcomes
Intervention
Participants*/PCOS criteria
Randomized controlled trial involved in hyperandrogenism (HA) PCOS patients.
Table 1. Summary of studies.
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852 Gynecol Endocrinol, 2014; 30(12): 850–860
Not described
Not described
Not described
Non-blind, based on patients’ chronological presence (indifferent of BMI and IR)
Computer-generated randomization tables
Colonna et al. [12]
Karakurt et al. [13]
Hadzˇiomerovic´Pekic´ et al. [14]
Panidis et al. [15]
Romualdi et al. [16]
Endocrine and metabolic parameters
AMH levels
Metformin (M) Naltrexone (N) COC (EE 35 mg + CPA 2 mg) + prednisolone (Pr) 3 month.
6
29 women (18–36 years) HA/PCOS + IR Rotterdam criteria
45 HA/PCOS NHI criteria
30 PCOS (19–30 years) Rotterdam criteria
DRP 3 mg + EE 30 mg DRP 3 mg + EE 20 mg 12 months
Endocrine and metabolic parameters
Hirsutism
COC (EE 35 mg + CPA 2 mg) + SPL 100 mg Flutamide 250 mg 6 months
29 with hirsutism (HA/ PCOS and idiopatic)
EE 35 mg + CPA 2 mg EE 30 mg + DRP 3 mg Metformine months
HA
59 women (19–29 years) HA/PCOS
DRP 3 mg + EE 30 mg CMA 2 mg + EE 30 mg 6 months
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Contraceptives and PCOS (continued )
Both treatments were well tolerated and showed a significant improvement of HA, although EE/ DRP showed a more potent effect on acne and seborrhea at the end of the study (p50.05 between treatments). Seborrhoea (mcg/cm2 of skin) 2412.26 ± 1692.03 versus 4076.69 ± 2497.66 p Ferryman–Gallwey score 9.43 ± 2.02 versus 11.24 ± 2.35 delta-4-androstenedione (ng/mL) 1.98 ± 0.72 versus 2.72 ± 0.64 total testosterone (nmol/L) 0.99 ± 0.37 versus 1.28 ± 0.37 Both treatments are effective in the treatment of hirsutism: A significant decrease in Ferryman– Gallwey score was observed with flutamide (from 11.2 ± 3.3 to 7.6 ± 4.0) and SPL + CPA/EE (from 9.9 ± 1.9 to 7.1 ± 2.0). However, there was no statistically significant difference between the two groups. A statistically significant decrease in free androgen index was seen in all groups. Testosterone concentrations declined significantly in the M and N groups after 3 months, and in the COC/Pr group, only after the first month. DHEAS decreased significantly only in the N group. SHBG levels more than doubled during COC use and was not affected by M or N. The only significant within-group changes in the metabolic state were an average decrease in total cholesterol by 10 mg/dL and BP by 9 mm Hg in the M group (p ¼ 0. 01, p ¼ 0.03, respectively). HDL cholesterol increased in the OC/Pr group by 7 mg/dL, whereas it remained unchanged in the other two groups (p ¼ 0.046). The diastolic BP increased in the OC/Pr group by 10.6 mm Hg, whereas it decreased in the M group and remained unchanged in the N group (p ¼ 0.02). AMH serum levels were significantly decreased under treatment with EE 35 mg + CPA 2 mg (p ¼ 0.002 at 3 months and p ¼ 0.001 at 6 months). EE/DRP and metformin did not significantly affect serum AMH levels. AMH was significantly decreased under COCs treatment compared to metformin (p ¼ 0.005). Both COC induced a significant improve in hirsutism score, testosterone, DHEAS and SHBG levels. Total Cholesterol, LDL, HDL and triglycerides
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853
Randomization
Participants*/PCOS criteria
Intervention
Case-control study followed by a RCT
Not described
Not described
Luque-Ramı´rez et al. [18]
Moran et al. [19]
Kebapcilar et al. [20]
48 women with PCOS Rotterdam criteria + IR
Overweight, age and BMImatched women with PCOS (no ¼ 80) or without PCOS (no ¼ 27)
40 PCOS patients and 20 non-HA women.
Blood clotting tests and endothelial function
Inflammatory markers, endocrine and metabolic parameters Endocrine and metabolic parameters
metformin EE 35 mg + CPA 2 mg 6 months A. COC (EE 35 mg + CPA 2 mg) B. Metformin C. COC + metformin D. COC + SPL 3 months
Outcomes CVD risk factor
Outcomes
COC (EE 35 mg + CPA 2 mg) metformin 24 weeks
Randomized controlled trial involved in PCOS patients with insulin resistance (IR) or obesity. Reference Randomization Participants*/PCOS criteria Intervention COC (35 mg EE + 2 mg Luque-Ramı´rez Randomized, open-label, 34 HA/PCOS patients and CPA) et al. [17] parallel clinical trial 40 non-HA control Metformin women NIH criteria
Reference
Randomized controlled trial involved in hyperandrogenism (HA) PCOS patients.
Table 1. Continued
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Key results Obesity is the main determinant of serum uric acid concentrations in PCOS patients, yet amelioration of androgen excess with an antiandrogenic contraceptive pill results in a significant decrease in these levels, an effect that is not observed with metformin. There were no statistically significant differences in uric acid levels between PCOS and non-hyperandrogenic control women. Obese women showed higher uric acid concentrations than lean and overweight women, In PCOS women, COC decreased in uric acid levels (p ¼ 0.018), whereas no changes were observed with metformin. COC and metformin may exert deleterious effects on blood clotting tests of PCOS women, yet the effects of metformin appear to be milder. Because smoking potentiates some of these effects and deteriorates endothelial function, smoking cessation should be promoted in PCOS patients. Alterations in leptin between women with and without PCOS and following pharmacological interventions are primarily related to adiposity and not IR. Aldosterone was reduced equivalently with metformin and the COC. In all treatment groups were observed reduced levels of coagulation parameters, improvement of hormonal, hematological and metabolical variables. by most probably reducing insulin levels. Among the treatment groups, EE/CA-metformin may be a more effective therapeutic option than the other protocols and this may be due to the beneficial effect of EE/CA-metformin on IR: All women lost weight significantly after the treatment (Group A: 3.5 kg, 4.8%; Group B: 2.8 kg, 3.6%; Group C: 2.7 kg, 3.7%; Group D: 2.6 kg, 3.4%). Lipid profiles: Group A: no change; Group B: significant decrease in total and LDL cholesterol and increase in HDL; there were no changes in triglycerides; Group C: triglycerides, total and LDL cholesterol levels were significantly reduced after the treatment whereas HDL concentrations
increased in both groups. Triglycerides more markedly increased with EE 30 mg.
Key results
854 N. Mendoza et al. Gynecol Endocrinol, 2014; 30(12): 850–860
Computerized random number generator using a 1:1 ratio
Not described
Not described
Essah et al. [21]
Orbetzova et al. [22]
Kilic et al. [23]
96 women (18–35 years) non-HA and oligoamenorrheic/
66 PCOS + overweight + IR Rotterdam criteria
18 women (no data of age) PCOS/HA Rotterdam criteria
CVD risk and carbohydrate metabolism
Adipose tissue hormones and hypothalamic neuropeptide Y
COC (CMA 2 mg + EE 30 mg) + metformin COC + rosiglitazone 3-months
1. Obese + metformin. 2. Obese + COC (DSG 150 mg + EE 30 mg) 3. Non-obese + metformin
Endocrine and metabolic parameters
COC (EE 35 mg + norgestimate 0.18– 0.25 mg) + metformin COC + placebo 3 months
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Contraceptives and PCOS (continued )
were increased significantly; Group D: LDL and total cholesterol were significantly reduced but there were no significant changes in triglycerides and HDL levels. Activated partial thromboplastin time, prothrombin time levels D-dimer, WBC and MPV were reduced significantly in all the groups (p50.05). HOMA-IR, insulin and androgen levels decreased in all treatment groups. EE/CA–metformin and metformin alone groups resulted in a higher proportional reduction of Ddimer levels. EE/CA–metformin group showed higher proportional reduction fasting insulin concentrations, HOMA-IR and free testosterone levels than metformin alone and EE/CA–SPL groups. DHEAs levels significantly decreased in group EE/ CA–metformin than EE/CA alone and EE/CA– SPL groups. In multiple stepwise regression analyses, reduction in proportional insulin levels was independently and positively associated with decrease of MPV, D-dimer, free testosterone levels. Both treatments had similar effects on androgen levels, lipid profile, insulin sensitivity, and serum inflammatory markers, but flow-mediated dilatation increased by 69.0% in the metformin plus COC group while it remained unchanged in the COC group. beneficial effects of the treatment on potential cardiovascular risk in IR PCOS women Significant decrease of leptin (p50.01; p ¼ 0.001, respectively), resistin (p50.01; p50.01, respectively), TNF a) (p ¼ 0.001; p50.001, respectively.), and neuropeptide Y (p50.05; p50.001, respectively) was observed in both groups after treatment. Decrease in the anthropometric parameters of body weight in the metformin group only. No significant changes in hormonal characteristics of the groups were found except for a decrease in androstenedione and DHEA-S (p50.05) in the metformin group and in 17-OH-progesterone (p50.05) in the rosiglitazone group. HDL-cholesterol rose and diastolic BP fell (p50.05) in the metformin group. A significant decrease was observed in ADMA, homocysteine and HOMA-IR levels in Groups 1 and 3. An increase in ADMA and hs-CRP levels was observed in Groups 2 and 4.
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1:1 proportion using a randomizer program
Randomization
49 HA/PCOS women 20 PCOS who wanted HC 20 control required HC 20 control wanted nonHC 28 lean PCOS and 28 control. Rotterdam criteria
20 women (18–33 years) PCOS Rotterdam criteria
Banaszewska et al. [27]
Gomes et al. [28]
De Leo et al. [30]
Aydin et al. [29]
155 patients with PCOS prospective, open-label clinical study.
Participants*/PCOS criteria 50 non-obese women: 30 HA/PCOS and 20 control
50 women (18–35 years) Rotterdam criteria (no describe if HA or not)
PCOS + impaired glucose tolerance
Participants*/PCOS criteria
Minozzi et al. [26]
Observational studies involved in PCOS patients. Reference Uras et al. [25]
Vieira et al. [24]
Reference
Randomized controlled trial involved in hyperandrogenism (HA) PCOS patients.
Table 1. Continued
Endocrine and metabolic parameters Endocrine and metabolic parameters
EE 30 mg + GTD 75 mg EE/GTD + myo-inositol 12 months. COC (EE 20 mg + 150 DSG) 6 months. COC: CMA 2 mg + EE 30 mg 6 months
Anthropometric, endocrine and metabolic parameters
Anthropometric, and metabolic parameters
EE 30 mg/DRP 3 mg 6 months.
E2V/DNG 3 months
Plasma concentrations of Matrix metalloproteinases (MMPs)
Outcomes Endocrine and metabolic parameters
Arterial function
Outcomes
Intervention PCOS: CMA 2 mg + EE 30 mg 6 months
COC (CMA 2 mg + EE 30 mg) COC + SPL 100 mg 12 months
4. Non-obese + COC 6 months
Intervention
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After 6 months of treatment in the PCOS patients, total fat percentage increased from 24.5% ± 7.1% to 26.0% ± 6.1% (p ¼ 0.035) and trunk fat percentage increased from 20.2% ± 8.9% to 22.2% ± 7.1% (p ¼ 0.014), although weight, BMI and waist to hip ratio remained unchanged. Median values of insulin, Homeostasis model assessment of insulin resistance and oral glucose tolerance test after treatment were lower than values before treatment. No significant difference was observed in BMI
Reduced plasma MMP-2 concentrations in both healthy and PCOS women.
Key results In the EE/CMA group, androgen levels and bioavailability, hirsutism and acne score were significantly lower, whereas they did not change in the control group. In both groups, glucose-insulin metabolism and body composition parameters were not affected. Combination of COC and myo-inositol may be more effective in controlling endocrine, metabolic, and clinical profile in patients with PCOS than COC alone, and reduce insulin levels and IR. Decrease in the testosterone level but negative effect on total cholesterol and triglycerides level
In this study, metformin treatment leads to improvement in hormonal and metabolic parameters and decreases endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and homocysteine levels. COC impaired glucose tolerance, increases ADMA and high sensitive C-reactive protein levels and creates an increase in the metabolic risk. The increase in mean total cholesterol levels was greater in the COC + SPL group than in the COC group (27 versus 13%, respectively; p ¼ 0.02). The increase in SHBG levels was greater in the COC group than in the COC + SPL group (424 versus 364%, respectively; p ¼ 0.01).
Key results
856 N. Mendoza et al. Gynecol Endocrinol, 2014; 30(12): 850–860
Contraceptives and PCOS *All without contraindications for hormonal contraceptives. BMI: Body mass index; BP: blood pressure; CMA: chlormadinone acetate; COC: combined oral contraceptive; CPA: ciproterone acetate; CVD: cardio vascular disease; DNG: dienogest; DSG: desogestrel; DRP: drospirenone; E2V: estradiol valerate; EE: etinilestradiol; ENG etonogestrel; GSD: gestodene; HA: hyperandrogenism; IR: insulin resistance; MMPs: Matrix metalloproteinases; SHBG: sex hormone-binding globulin; NIH: National Institutes of Health; PCOS: polycystic ovary syndrome; SPL: spironolactone.
Endocrine and metabolic parameters 46 lean women: 23 PCOS and 23 control Harmanci et al. [32]
PCOS: EE-DRP + SPL 6 months
Anthropometric, endocrine and metabolic parameters EE/DRP (30 mg/3 mg) EE/DRP + metformin 6 months 45 lean HA/PCOS women Cinar et al. [31]
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EE/DRSP alone or in combination with metformin improves clinical and biochemical HA in lean PCOS. Both treatments similarly alter lipid profile. EE/DRSP alone does not affect insulin sensitivity, whereas combining EE/DRSP with metformin might improve it. Improves HA in lean PCOS without any adverse effects on adiposity, glucose tolerance status or lipid profile, and increases high-sensitivity Creactive protein and homocysteine levels.
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frequent but has similar clinical and endocrine characteristics as phenotype I. The Ovulatory PCOS, or type III, phenotype (HA and polycystic ovaries) is relatively common and presents milder clinical and endocrine alterations than phenotypes I and II. The normoandrogenic PCOS, or type IV, phenotype is relatively uncommon and characterizes patients with normal body mass index (BMI), insulin sensitivity and free androgen index with increased levels of LH and LH/FSH ratio [33,34]. All PCOS phenotypes display changes due to aging, suggesting an amelioration of ovarian dysfunction as indicated by the increase in number of regular menstrual cycles, decrease in serum androgen levels, and decrease in IR [35]. Apart from these signs and symptoms, a considerable proportion of women with PCOS display IR and overweight/obesity. The mechanisms responsible for IR are currently unknown, although it is likely a result of altered adipose and muscular cell glucose uptake due to a genetic defect that is independent of obesity. Although IR does not occur exclusively in overweight/ obese women with PCOS, IR is more frequent among these patients [36]. Similarly, a direct association between IR and HA has been observed although the cause-and-effect relationship is not well understood. Androgens have not been shown to alter the physiology or glucose homeostasis of adipocytes. In addition, tests have indicated that hyperinsulinism tends to be a cause rather than a result of excess androgens [37]. Other markers of cardiovascular disease (CVD) are increased in women with PCOS; however, whether this apparent risk translates into an increased incidence of CVD later in life remains to be elucidated [38,39]. Obesity likely plays a major role, but adjustments for BMI do not affect these findings, suggesting that the increased CVD risk is not exclusively related to a higher BM. Instead, the increased CVS risk may be due to excess androgen concentrations [28]. A common genetic origin of PCOS and diabetes mellitus has also been proposed [40]. A number of studies have linked PCOS with an increased risk of gestational diabetes, but a 2009 meta-analysis did not find sufficient evidence to confirm this hypothesis [41]. This is likely because the new definition of PCOS includes other phenotypes that are exempted from this risk. In this sense, the main link between PCOS and cardiovascular disease remains IR. Moreover, the risk for adverse obstetric or neonatal outcomes increases in patients with PCOS phenotypes with ovarian dysfunction plus biochemical HA, whereas no significant effect was detected for clinical HA without anovulation [42]. Thus, some clinicians prefer to delay fertility treatment until the patients have reached an appropriate weight or have leveled out their insulin levels [43]. In summary, HA serves as the essential diagnostic criterion of the syndrome and is frequently associated with IR or obesity. The combinations of these conditions define the different PCOS phenotypes and establish the scale of metabolic and CVD risk [44,45]. The long-term health risks of PCOS patients demand that their general health be monitored even after their reproductive needs have been fulfilled. Metabolic and cardiovascular risk prevention in women with PCOS should start as early as possible [46]. To address this issue, the National Institutes of Health (NIH) Office for Disease Prevention-sponsored Evidence-based Methodology Workshop on Polycystic Ovary Syndrome recently proposed dividing the PCOS phenotypes into two distinct diseases. Those with primarily reproductive concerns should continue to be referred to as PCOS patients, and those with important metabolic consequences should have a new disease designation [47].
858
N. Mendoza et al.
PCOS phenotypes: hormonal contraception choice
PCOS with metabolic risk or obesity
To date, CHC have been the most common treatment for PCOS and its symptoms. However, there are no clinical guidelines that recommend a specific CHC for the different PCOS phenotypes. There are still doubts concerning the metabolic and cardiovascular effect of CHC in this population. In general terms, it has been recommended that the ideal contraceptive for women with PCOS should limit follicle development to reduce androgens synthesis, block the peripheral action of androgens and achieve good menstrual cycle control with minimal metabolic or thromboembolic risk.
There are doubts concerning the impact of CHC on cardiovascular function and carbohydrate metabolism, which hinders the choice of CHC method. Oral CHCs may worsen glucose tolerance in healthy users, but there is no finding indicating an increased risk of CVD in women with PCOS. These discrepancies could be due to inadequate adjustments for confounding factors that might influence body weight or IR (lifestyle, dietary composition, ethnicity, non-compliance, etc.) [56,57]. Although the metabolic effects of CHC in PCOS could be dependent on body weight, few studies have focused on the possible differences in the effect of CHC on lean versus obese patients. In lean-PCOS women, CHC do not change clinical anthropometric measures and do not exhibit adverse effects on adiposity, insulin sensitivity/glucose tolerance status and lipid profile [25,29,31,32]. In three meta-analyses that examined the effect of CHC on metabolic outcomes, the use of CHC was not associated with clinically significant adverse metabolic consequences. When changes in the lipid spectrum are compared, the vast majority of healthy users remain within reference limits, and it is unlikely that this could have a clinically significant effect on the risk of CVD [58–60]. In contrast, according to the World Health Organization’s recommendations, when arterial hypertension or an elevated risk of thromboembolism is present, levonorgestrelintrauterine system or progestogen-only hormonal contraceptives should be used instead of CHC [61]. Thus, the selected studies of this review suggest that progestogens with minimal metabolic side-effects, such as DRSP, could be more advantageous in overweight women or women whose glucose tolerance is a concern. In addition, the combination of CHC with myo-inositol may be more effective in controlling the endocrine, metabolic and clinical profiles in patients with PCOS than CHC alone, and may reduce insulin levels and IR [26]. With respect to estrogen, a recent European review indicates that the use of low-dose-oral CHC is preferable in patients with glucose intolerance or IR [62]. However, even though we have little evidence, it is interesting that the vaginal ring and oral E2V/DNG formulations seem to be preferred over CHC with EE/DRP [6,8].
HA/PCOS (type I, II and III phenotypes)
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Gynecol Endocrinol, 2014; 30(12): 850–860
As stated in the previous section, the key to defining the phenotype and severity of PCOS is HA. In HA/PCOS phenotypes, the CHC of choice would alleviate the HA without a negative impact on metabolism or cardiovascular risk. A recent practical guideline recommends CHC (oral, patch or vaginal ring) as firstline management for HA/PCOS patients, but there are insufficient data to define the optimal duration of treatment [48]. For the signs and symptoms of androgens excess, the most important parameter in CHC selection is the type of progestin. CPA, CMA, DNG and DRSP are progestogens with powerful anti-androgen activity. These progestogens mainly act by blocking androgen receptors in target organs; however, they also reduce 5 alpha-reductase skin activity. Studies on the efficacy of CHC containing DRSP or CPA in the treatment of hirsutism show a reduction in clinical manifestations of HA after 6–12 months of therapy, a significant reduction of circulating androgens and a significant increase in SHBG. Moreover, it is speculated that an interference with androgen synthesis may also reduce the risk of later metabolic disturbances and health complications [49]. In addition to this, estrogen increases SHBG, thereby reducing bioavailable androgens. However, there are no data providing direct comparisons regarding the type or dose of estrogen. Furthermore, research has shown a 2-fold increase in the risk of venous thromboembolism among women with PCOS who were taking oral CHC and a 1.5-fold increased risk among women with PCOS not taking oral CHC [50]. Therefore, it is recommended that women with PCOS use a CHC with the lowest effective estrogen dose. In addition, the dose of EE correlates with the concentration of SHBG, a critical factor in decreasing circulating free androgen. The residual follicular activity and adrenal steroidogenesis are more frequent with low estrogen dose. However, there are few studies comparing EE doses [10]. E2V/DNG has an impact on various metabolic and hemostatic parameters that is comparable to or less than that of EE/LNGcontaining oral CHC. The effects on prothrombin, D-dimer, HDL, LDL, insulin and carbohydrate metabolism are, in general, more favorable with E2V/DNG than with EE/LNG [51]. E2V/DNG could thus be recommended as an oral CHC in PCOS women with IR or overweight [8]. The specific CHC regimen does not appear to influence the metabolism of androgens; however, extended regimens improve follicular control and hormonal suppression [52]. One extended regimen consisting of 2 mg CMA plus 30 mcg EE showed an improvement in acne after 6 months [53,54], and another study evaluating 30 mcg EE plus 2 mg DNG reported increased SHBG and decreased testosterone levels, which is similar to previous observations with the conventional regimen [55]. Non-HA/PCOS phenotype Only one RCT analyzed PCOS women without HA; however, all of the participants had obesity or impaired glucose tolerance [23].
Conclusions CHC represent an effective and safe treatment in women with any phenotype of PCOS. In HA/PCOS patients, any CHC analyzed in this review can be used for symptom relief. In patients with metabolic risk, overweight or moderate IR that does not need metformin, a vaginal contraceptive ring appears to be preferred to oral EE/DRP. Moreover, a combination of CHC and myo-inositol may be more effective in controlling the endocrine and metabolic profile. However, further research is needed to define the optimal duration and to clarify the effects of treatment on long-term metabolic outcomes. Future research should also focus on new CHC.
Declaration of interest All authors participated in the review and approved the final version of the manuscript. None of them have conflict of interest with. No one is on speaker’s bureaus, received research funding or consulting.
References 1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003, consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome (PCOS). Human Reprod 2004;19:41–7.
Contraceptives and PCOS
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DOI: 10.3109/09513590.2014.943725
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Appendix A: Search strategy
‘‘contraceptives’’[All Fields])) OR ((‘‘polycystic ovary syndrome’’[MeSH Terms] OR (‘‘polycystic’’[All Fields] AND ‘‘ovary’’[All Fields] AND ‘‘syndrome’’[All Fields]) OR ‘‘polycystic ovary syndrome’’[All Fields] OR (‘‘polycystic’’[All Fields] AND ‘‘ovary’’[All Fields]) OR ‘‘polycystic ovary’’[All Fields]) AND (‘‘contraception’’[MeSH Terms] OR ‘‘contraception’’[All Fields]))
((‘‘polycystic ovary syndrome’’[MeSH Terms] OR (‘‘polycystic’’[All Fields] AND ‘‘ovary’’[All Fields] AND ‘‘syndrome’’[All Fields]) OR ‘‘polycystic ovary syndrome’’[All Fields]) AND hormonal[All Fields] AND (‘‘contraceptive agents’’[Pharmacological Action] OR ‘‘contraceptive agents’’[MeSH Terms] OR (‘‘contraceptive’’[All Fields] AND ‘‘agents’’[All Fields]) OR ‘‘contraceptive agents’’[All Fields] OR
