Combined oral contraceptive pill compared with no medical treatment in the management of polycystic ovary syndrome: A systematic review

Abstract Objective As part of the update of the International Evidence‐Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was performed to inform evidence‐based recommendations. Design Systematic review. Only randomised controlled trial were included. Patients Women with PCOS; the use of combined oral contraceptive pills (COCP) was compared with no medical treatment. Measurements Outcomes were designed in collaboration with clinical experts, researchers, and consumers. Critical outcomes included hirsutism, irregular cycles, quality of life, body mass index (BMI), and weight. Results 1660 publications were identified, but only four studies were included. No studies could be combined for meta‐analysis. COCP treatment improved cycle regularity compared with no medical treatment (100% vs. 0%, with low certainty of evidence). COCP showed no difference in improvement of hirsutism or BMI compared with placebo or lifestyle; a lower weight after COCP compared with no treatment (mean difference [MD] −8.0 (95% confidence interval, CI −11.67); −4.33 kg); and improvement in quality of life (MD 1.2 [95% CI 0.96]; 1.44), but these results were all very low certainty of evidence. Conclusion Results show that COCP benefit cycle regulation, but other benefits or potential adverse effects were only identified with very low certainty of evidence. The COCP is frontline medical treatment in PCOS, but this is still based on established efficacy in the broader general population. Our results show that research in PCOS is seriously lacking and should be prioritised to capture core reproductive, metabolic and psychological outcomes important in PCOS.


| INTRODUCTION
Polycystic ovary syndrome (PCOS) is a common condition, affecting 8%-13% of women. 1 PCOS is characterised by complex genetic architecture with genes clustering around both reproductive and metabolic factors. 2 Clinical diagnosis is based on modified Rotterdam criteria, requiring two out of three of the following: clinical and or biochemical hyperandrogenism, oligo/anovulation with irregular menstrual cycles and polycystic ovarian morphology (PCOM) on ultrasound, in adults. In adolescents, both hyperandrogenism and ovulatory disturbance are required as PCOM is a nonspecific finding among adolescent girls. 3 PCOS is also a metabolic disorder with features including obesity, insulin resistance, pregnancy complications, hypertension, dyslipidemia, impaired glucose tolerance, diabetes, and cardiovascular disease. 3 Psychological aspects are also prominent and include anxiety, depression, and eating disorders. 4 Depending on the clinical manifestations, different treatments can be used. Primary treatment involves multicomponent lifestyle interventions, which should be recommended to all women with PCOS. 3 Combined oral contraceptive pills (COCP) is one of the most frequently used medical treatments in PCOS to ameliorate hyperandrogenism and manage irregular menstrual cycles. 3 A COCP contains both an oestrogen and a progestogen and is approved for contraceptive use. Most COCPs contain ethinyl estradiol (EE) as the oestrogen compound, however, during the recent years, products containing more natural-like oestrogens have also been introduced. Several different progestogens are available, across different generations with variable properties bringing potentially distinguishable side-effect profiles similar to different oestrogen components. 5,6 COCP provides hormone replacement therapy where the hypothalamus-pituitary axis is effectively down regulated by oestrogen/progestogen and thereby enabling regulation of menstrual cycles. When the COCP is ceased (usually for 4-7 days per month when not used continuously) a withdrawal bleed is induced, resulting in a regular monthly bleeding pattern. COCPs are key contraceptive agents, important for women with PCOS not currently seeking pregnancy. Even though women with PCOS can experience difficulties conceiving spontaneously, effective contraception is essential when a pregnancy is not desired. 7 COCP treatment can be administered cyclically or continuously.
Regardless, cyclic or continuous administration protects the endometrium from unopposed oestrogen in women with PCOS who do not ovulate as regularly and often lack adequate endometrial progesterone exposure. The longstanding unopposed oestrogen stimulation is the main hypothesis behind the potentially increased risk for endometrial cancer in women with PCOS. 8 From large studies in the general populations, it is well-known that COCP use is an effective long-term protection against endometrial cancer. 9 Importantly, COCP improves hyperandrogenism via different mechanisms, primarily by stimulation of sex hormone binding globulin (SHBG) production, the major binding protein for testosterone, thereby decreasing free circulating androgens. 10 COCP also decreases luteinizing hormone secretion, which leads to decreased ovarian androgen production. 11,12 In addition, some progestins has antiandrogenic properties via competition with endogenous androgens at androgen receptors (e.g., in skin and hair) and by inhibition of the 5-α-reductase type I enzyme expressed in skin. 13 In PCOS, COCP thus addresses two of the main symptoms in PCOS, namely irregular cycles and clinical signs of hyperandrogenism. These symptoms have also been shown to be associated with decreased health-related quality of life (HRQoL) in women with PCOS. 14 Here, we aimed to explore the effects of COCP compared with no treatment, placebo or lifestyle intervention in PCOS as a common reproductive, metabolic, psychological condition. We sought to capture the best available evidence in the treatment of women with PCOS to guide the 2023 International Guideline Update and inform future research priorities. 3,15 A number of outcomes were identified as important and were included in this systematic review, those identified a priori as critically important by clinical experts, researchers, and consumers were hirsutism, irregular cycles, quality of life, body mass index (BMI) and weight.

| Search strategy
The search was done as part of the PCOS guideline update and included three medical treatments (COCP, metformin and anti-androgens). The search for studies published until 2017 had been done for the previous international guidelines and thus captured there. 17 All included and excluded studies from that search were re-evaluated here. The search was updated on July 8, 2022, using the same search string, but limited to publications from 2017 and forward. The search was conducted using the following databases: Medline, EMBASE, All EBM, CINAHL, and PsychInfo, and was thus again performed for three medical treatments (COCP, metformin, and antiandrogens) as part of the evidence for the updated guidelines. The relevant overall question for COCP was: "Is the oral contraceptive pill alone or in combination effective for management of hormonal and clinical PCOS features in adolescents and adults with PCOS?" This publication is limited to comparisons between COCP compared with controls, placebo and/or lifestyle treatment. Supporting Information: Table 1 presents the search strategy in detail.

| Selection criteria
The PICO was defined with input from women and experts as noted Interventions included all types of COCP with a treatment duration of at least 3 months, however, to assess the outcome hirsutism, a minimum of 6 months treatment was required. Comparisons were no medical treatment, including controls (no treatment), placebo or lifestyle intervention.
The outcomes that a priori had been prioritised 3  A.), using study selection and appraisal criteria established a priori, in the tool Covidence (www.covidence.org). The articles were first reviewed by title and abstract by two reviewers. If no decision could be reached based on title and abstract alone, the full text was also retrieved. Only studies that were unsuitable for the PICO for any of the three medical treatments were excluded. Full-text screening was done by two reviewers (M. F., J. M., S. A.). Conflicts were resolved by discussion. In addition to the studies included in previous guidelines, the excluded list from that search was reviewed, and studies were included if they met PICO criteria, for comprehensiveness. Systematic reviews and evidence-based guidelines were not included but screened manually for additional references.

| Statistical analysis
All biochemical outcomes were converted to SI units when appropriate. When standard errors (SE) were reported, this was recalculated to standard deviation (SD) using conventional methods.

| Characteristics of included studies
Four RCTs were identified for these three comparisons, with a study duration between 6 and 24 months. These studies had been published between 2008 and 2021. Countries of origin were Turkey FORSLUND ET AL. | 81 (n = 1), 21 Egypt (n = 2), 22,23 and the United States (n = 1). 24 Characteristics of included studies are shown in Table 1. Two of the RCTs included adults with PCOS and two were restricted to adolescents.
Three of the studies had a high RoB and one had moderate risk. RoB assessments are shown in Figure 2.
El Maghraby et al. 22 included adolescent girls, 15-20 years, presenting with hirsutism, acne and menstrual disturbances. PCOS was defined as a combination of oligomenorrhea and biochemical hyperandrogenism, mean BMI or age at menarche was not reported.
Treatment with COCP (30 μg EE + 15 mg progestogen, type not reported), n = 40, was compared with no treatment (control group), n = 39. The study duration was 24 months, with 18% dropout rate in the COCP group and 36% dropout rate in the control group. The study was not blinded, baseline characteristics were only shown for a few outcomes, and the dropout rate was not the same in the two groups, thus the study was assessed as high RoB.
Bodur et al. 21 Table 2. One study 24 compared COCP with placebo, and the same study 24 also compared COCP with lifestyle, these results are shown in Tables 3 and 4. Results are summarised here according to outcome group, and reasons for GRADE assessments of the different outcomes are given in Table 2

| Anthropometry
Weight was lower after COCP treatment [mean difference, MD −8.0 (95% confidence interval, CI −11.67; −4.33 kg)] compared with notreatment controls, with very low certainty of evidence. BMI did not differ between COCP and placebo or between COCP and lifestyle, with very low certainty of evidence.

| Menstrual cycles
In the comparison COCP versus no-treatment controls, COCP treatment resulted in improved cycle regularity (100% vs. 0%) with F I G U R E 1 PRISMA flowchart. The search was performed for the update of the international evidence-based guidelines for the assessment and management of PCOS, and covered three questions (treatment with COCP, metformin and antiandrogens). In this systematic review, results comparing COCP with no medical treatment is included. *384 studies were excluded; an additional 33 studies were included in metformin and/or antiandrogen questions, but not in COCP. COCP, combined oral contraceptive pills; PCOS, polycystic ovary syndrome; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

| Clinical and biochemical hyperandrogenism
Hirsutism did not differ between COCP-treated women and women treated with placebo or lifestyle, respectively, with very low certainty of evidence. Total testosterone levels were lower after COCP treatment compared with no-treatment controls, placebo, and lifestyle, respectively, with very low certainty of evidence. SHBG was higher after COCP compared with placebo, but no difference was seen compared with lifestyle, with very low certainty. FAI was lower after COCP treatment compared with placebo, but did not differ when comparing COCP and lifestyle, with very low certainty of evidence.

| Insulin and glucose
Insulin levels were lower after COCP treatment, compared with notreatment controls, with very low certainty of evidence, but the COCP group had higher after-load insulin levels after an oral glucose tolerance test, also with very low certainty. HOMA-IR did not differ between COCP and no-treatment controls, with very low certainty.
Insulin levels did not differ compared with placebo or lifestyle, with very low certainty. Glucose did not differ in any of the comparisons with very low certainty.

| Metabolic lipids, PAI and CRP
Only Hoeger et al. examined lipid profile with COCP use compared with no medical treatment. 24 Cholesterol, LDL, HDL and triglycerides did not differ between COCP and placebo, with very low certainty.
LDL and triglycerides were higher after COCP treatment compared with lifestyle with very low certainty of evidence, whereas HDL and cholesterol did not differ.
Higher levels of CRP were seen after COCP treatment compared with no-treatment controls, and compared with the placebo group, but not compared with lifestyle, with very low certainty of evidence.
Levels of PAI-1 were higher after COCP treatment compared with controls, but there was no difference in PAI-1 levels when compared with lifestyle or placebo, with very low certainty.  12 However, COCP treatment is also associated with an increased risk of venous thrombosis (VTE)

| HRQoL and psychological outcomes
in the general population, with an estimated incidence of 1-6 per 10,000 women years in nonusers, compared with 8-10 per 10,000 women years in COCP users. 26 Second-generation progestogen COCPs are associated with less risk, even though the absolute differences are small. 26 Elevated high-sensitivity CRP levels are associated with an elevated risk of cardiovascular disease events, and CRP levels are often measured in studies as a metabolic risk marker. 27 COCP, especially those containing EE, seem to increase thromboinflammatory proteins, including CRP levels, 28,29 although the significance of this finding is still unknown. However, interestingly, a recent national case-control study from Finland, including almost 600,000 women, found that the increased risk was associated with COCPcontaining EE, whereas no increased risk of VTE was seen with COCP-containing estradiol combined with progestins other than cyproterone acetate. 6 COCP use are also associated with an increased risk of arterial thrombosis, that is, myocardial infarction or ischaemic stroke, relative risk 1.6. 30 There has also been a concern that COCP would have an unfavourable effect on glucose metabolism, but this has not been seen in healthy women. 28,31 In women with PCOS, results regarding effects on glucose metabolism are contradictory, potentially due to the diverse effects of the different progestins. Many patients are anxious about potential effects on weight, but this has not been shown in the general population. 32 Nevertheless, an association between COCP use and mood alterations is suspected, despite limited evidence. In a Swedish cohort study, the use of both COCP and progestin-only pills was associated with an increased risk of suicidal behaviour, with the greatest risk occurring 1 month after initiation of use (hazard ratio 1.7 and 2.8, respectively, after 1 month). 33 In a Danish cohort study, COCP users had a higher risk of starting antidepressive treatment, compared with nonusers, relative risk 1.2, 34 although a recent register study from Sweden was not able to confirm depression with COCP use. 35

| Evidence in women with PCOS
Women with PCOS differ from the general population since they are more hyperandrogenic and PCOS is associated with inherent metabolic disturbances including hyperinsulinemia and insulin resistance. Women with PCOS have higher BMI, are more prone to gain weight and also have an increased risk of psychiatric comorbidity. 36,37 In this systematic review involving women with PCOS T A B L E 2 (Continued)

| COCP versus lifestyle
Regarding the comparison COCP versus lifestyle, only one small study was identified in our review, with a total of 18 participants. 5  Note: All results had a very low certainty of evidence due to serious risk of bias, and very serious imprecision.

| Strengths and weaknesses
The strengths of this systematic review include the well-defined and clinically relevant question regarding COCP treatment in PCOS, with outcomes that have been defined and prioritised by multiple international stakeholders including consumers, clinicians and researchers. These results will directly inform the updated international PCOS guidelines. Limitations include the lack of RCTs precluding meta-analysis, small participant numbers, as well as the high RoB of the included studies.