Management of Premenstrual Syndrome: Green-top Guideline No. 48.

Abstract

BJOG: An International Journal of Obstetrics & GynaecologyVolume 124, Issue 3 p. e73-e105 RCOG Green-top GuidelineFree Access Management of Premenstrual Syndrome Green-top Guideline No. 48 First published: 30 November 2016 https://doi.org/10.1111/1471-0528.14260Citations: 55AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat This is the second edition of this guideline, which was first published in 2007 under the same title. Executive summary of recommendations How is premenstrual syndrome (PMS) diagnosed? When clinically reviewing women for PMS, symptoms should be recorded prospectively, over two cycles using a symptom diary, as retrospective recall of symptoms is unreliable. Grade of recommendation: ✓ A symptom diary should be completed by the patient prior to commencing treatment. Grade of recommendation: ✓ Gonadotrophin-releasing hormone (GnRH) analogues may be used for 3 months for a definitive diagnosis if the completed symptom diary alone is inconclusive. [New 2016] Grade of recommendation: ✓ What aspects are involved in delivering a service to women with PMS? When should women with PMS be referred to a gynaecologist? Referral to a gynaecologist should be considered when simple measures (e.g. combined oral contraceptives [COCs], vitamin B6, selective serotonin reuptake inhibitors [SSRIs]) have been explored and failed and when the severity of the PMS justifies gynaecological intervention. Grade of recommendation: ✓ Who are the key health professionals to manage women with severe PMS? Women with severe PMS may benefit from being managed by a multidisciplinary team comprising a general practitioner, a general gynaecologist or a gynaecologist with a special interest in PMS, a mental health professional (psychiatrist, clinical psychologist or counsellor) and a dietician. [New 2016] Grade of recommendation: ✓ How is PMS managed? Are complementary therapies efficacious in treating PMS? Women with PMS should be informed that there is conflicting evidence to support the use of some complementary medicines. Grade of recommendation: C An integrated holistic approach should be used when treating women with PMS. Grade of recommendation: ✓ Interactions with conventional medicines should be considered. Grade of recommendation: ✓ Is there a role for cognitive behavioural therapy (CBT) and other psychological counselling techniques? When treating women with severe PMS, CBT should be considered routinely as a treatment option. Grade of recommendation: A Hormonal medical management of PMS Which COC has the best evidence for managing PMS, including regimens delivering ethinylestradiol? When treating women with PMS, drospirenone-containing COCs may represent effective treatment for PMS and should be considered as a first-line pharmaceutical intervention. [New 2016] Grade of recommendation: B What is the optimum COC pill regimen, e.g. continuous, cyclical or flexible? When treating women with PMS, emerging data suggest use of the contraceptive pill continuously rather than cyclically. Grade of recommendation: ✓ How efficacious is percutaneous estradiol? Percutaneous estradiol combined with cyclical progestogens has been shown to be effective for the management of physical and psychological symptoms of severe PMS. Grade of recommendation: A When treating women with PMS, alternative barrier or intrauterine methods of contraception should be used when estradiol is used to suppress ovulation. Grade of recommendation: ✓ How can the return of PMS symptoms be avoided during estrogen therapy with progestogenic protection? When using transdermal estrogen to treat women with PMS, the lowest possible dose of progesterone or progestogen is recommended to minimise progestogenic adverse effects. [New 2016] Grade of recommendation: A Women should be informed that low levels of levonorgestrel released by the levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg can initially produce PMS-type adverse effects (as well as bleeding problems). [New 2016] Grade of recommendation: ✓ Micronised progesterone is theoretically less likely to reintroduce PMS-like symptoms and should therefore be considered as first line for progestogenic opposition rather than progestogens. [New 2016] Grade of recommendation: ✓ What is the optimum regimen for prevention of endometrial hyperplasia? When treating women with percutaneous estradiol, a cyclical 10–12 day course of oral or vaginal progesterone or long-term progestogen with the LNG-IUS 52 mg should be used for the prevention of endometrial hyperplasia. [New 2016] Grade of recommendation: ✓ When using a short duration of progestogen therapy, or in cases where only low doses are tolerated, there should be a low threshold for investigating unscheduled bleeding. [New 2016] Grade of recommendation: ✓ What is the safety of estradiol on the premenopausal endometrium and breast tissue? When treating women with PMS using estradiol, women should be informed that there are insufficient data to advise on the long-term effects on breast and endometrial tissue. Grade of recommendation: ✓ For how long can estradiol be used safely and what is the risk of recurrence? Due to the uncertainty of the long-term effects of opposed estradiol therapy, treatment of women with PMS should be on an individual basis, taking into account the risks and benefits. [New 2016] Grade of recommendation: ✓ What is the evidence for efficacy and adverse effects of danazol in the treatment of PMS? Women with PMS should be advised that, although treatment with low dose danazol (200 mg twice daily) is effective in the luteal phase for breast symptoms, it also has potential irreversible virilising effects. [New 2016] Grade of recommendation: A Women treated with danazol for PMS should be advised to use contraception during treatment due to its potential virilising effects on female fetuses. [New 2016] Grade of recommendation: ✓ How effective are GnRH analogues for treating severe PMS? GnRH analogues are highly effective in treating severe PMS. [New 2016] Grade of recommendation: A When treating women with PMS, GnRH analogues should usually be reserved for women with the most severe symptoms and not recommended routinely unless they are being used to aid diagnosis or treat particularly severe cases. [New 2016] Grade of recommendation: ✓ How should women with PMS receiving add-back therapy be managed? When treating women with severe PMS using GnRH analogues for more than 6 months, add-back hormone therapy should be used. [New 2016] Grade of recommendation: A When add-back hormone therapy is required, continuous combined hormone replacement therapy (HRT) or tibolone is recommended. Grade of recommendation: A Women should be provided with general advice regarding the effects of exercise, diet and smoking on bone mineral density (BMD). Grade of recommendation: ✓ Women on long-term treatment should have measurement of BMD (ideally by dual-energy X-ray absorptiometry [DEXA]) every year. Treatment should be stopped if bone density declines significantly. [New 2016] Grade of recommendation: D Can GnRH analogues be useful in clarification of diagnostic category? When the diagnosis of PMS is unclear from 2 months’ prospective Daily Record of Severity of Problems (DRSP) charting, GnRH analogues can be used to establish and/or support a diagnosis of PMS. [New 2016] Grade of recommendation: ✓ What is the role for progesterone and progestogen preparations in treating PMS? There is good evidence to suggest that treating PMS with progesterone or progestogens is not appropriate. [New 2016] Grade of recommendation: A There is no evidence to support the use of the LNG-IUS 52 mg alone to treat PMS symptoms. Its role should be confined to opposing the action of estrogen therapy on the endometrium. Grade of recommendation: ✓ Non-hormonal medical management of PMS How do selective SSRIs work in PMS and how should they be given? SSRIs should be considered one of the first-line pharmaceutical management options in severe PMS. [New 2016] Grade of recommendation: A What is the efficacy of SSRIs in treatment of PMS? When treating women with PMS, either luteal or continuous dosing with SSRIs can be recommended. Grade of recommendation: B Is there any evidence on how SSRIs should be discontinued when used in PMS? SSRIs should be discontinued gradually to avoid withdrawal symptoms, if given on a continuous basis. Grade of recommendation: ✓ What are the risks and adverse effects of SSRIs? Women with PMS treated with SSRIs should be warned of the possible adverse effects such as nausea, insomnia, somnolence, fatigue and reduction in libido. [New 2016] Grade of recommendation: ✓ Is there evidence for improved efficacy with other SSRI regimens? When using SSRIs to treat PMS, efficacy may be improved and adverse effects minimised by the use of luteal-phase regimens with the newer agents. [New 2016] Grade of recommendation: A What preconception and early pregnancy advice should be given regarding SSRIs/serotonin–noradrenaline reuptake inhibitors (SNRIs)? Women should be provided with prepregnancy counselling at every opportunity. They should be informed that PMS symptoms will abate during pregnancy and SSRIs should therefore be discontinued prior to and during pregnancy. [New 2016] Grade of recommendation: ✓ Women should be informed how to safely stop SSRIs. [New 2016] Grade of recommendation: ✓ Women with PMS who become pregnant while taking an SSRI/SNRI should be aware of the possible, although unproven, association with congenital malformations. They should be reassured that if such an association does exist, it is likely to be extremely small when compared to the general population. [New 2016] Grade of recommendation: B Are diuretics efficacious in the treatment of PMS? Spironolactone can be used in women with PMS to treat physical symptoms. [New 2016] Grade of recommendation: C How can PMS be managed surgically? Can surgical management of PMS be justified and is it efficacious? When treating women with severe PMS, hysterectomy and bilateral oophorectomy has been shown to be of benefit. Grade of recommendation: D When treating women with PMS, hysterectomy and bilateral oophorectomy can be considered when medical management has failed, long-term GnRH analogue treatment is required or other gynaecological conditions indicate surgery. [New 2016] Grade of recommendation: ✓ Should the efficacy of surgery always be predicted by the prior use of GnRH analogues? When treating women with PMS, surgery should not be contemplated without preoperative use of GnRH analogues as a test of cure and to ensure that HRT is tolerated. Grade of recommendation: ✓ What is the role of HRT after surgical management? Women being surgically treated for PMS should be advised to use HRT, particularly if they are younger than 45 years of age. [New 2016] Grade of recommendation: ✓ Is there a role for endometrial ablation, oophorectomy or hysterectomy alone? When treating women with severe PMS, endometrial ablation and hysterectomy with conservation of the ovaries are not recommended. [New 2016] Grade of recommendation: ✓ Bilateral oophorectomy alone (without removal of the uterus) will necessitate the use of a progestogen as part of any subsequent HRT regimen and this carries a risk of reintroduction of PMS-like symptoms (progestogen-induced premenstrual disorder). [New 2016] Grade of recommendation: ✓ Classification of PMS How PMS is treated – a decision-making algorithm 1 Purpose and scope The aim of this guideline is to review the diagnosis, classification and management of premenstrual syndrome (PMS). The evidence for pharmacological and nonpharmacological treatments is examined. 2 Introduction and background epidemiology Since the 2007 guideline, there has been considerable work by the International Society for Premenstrual Disorders (ISPMD) and the National Association for Premenstrual Syndrome (NAPS) to achieve consensus on the recognition, diagnosis, classification and management of PMS. Misdiagnosis of PMS (e.g. confusion with bipolar disorder) and the use of a wide range of treatments, often with little evidence for effectiveness and safety, demand that these issues are addressed. 2.1 Definition of PMS PMS encompasses a vast array of psychological symptoms such as depression, anxiety, irritability, loss of confidence and mood swings. There are also physical symptoms, typically bloatedness and mastalgia. It is the timing, rather than the types of symptoms, and the degree of impact on daily activity that supports a diagnosis of PMS. The character of symptoms in an individual patient does not influence the diagnosis. In order to differentiate physiological menstrual symptoms from PMS, it must be demonstrated that symptoms cause significant impairment to the individual during the luteal phase of the menstrual cycle.1 2.2 Classification of PMS (ISPMD consensus) Core premenstrual disorders (PMDs) are the most commonly encountered and widely recognised type of PMS. As with all PMDs, symptoms must be severe enough to affect daily functioning or interfere with work, school performance or interpersonal relationships. The symptoms of core PMDs are nonspecific and recur in ovulatory cycles. They must be present during the luteal phase and abate as menstruation begins, which is then followed by a symptom-free week. There is no limit on the type or number of symptoms experienced; however, some individuals will have predominantly psychological, predominantly somatic or a mixture of symptoms (Appendix II). There are also PMDs that do not meet the criteria for core PMDs. These are called ‘variant’ PMDs and fall into four subtypes. ‘Premenstrual exacerbation of an underlying disorder’, such as diabetes, depression, epilepsy, asthma and migraine. These patients will experience symptoms relevant to their disorder throughout the menstrual cycle. ‘Non-ovulatory PMDs’ occur in the presence of ovarian activity without ovulation. This is poorly understood due to a lack of evidence, but it is thought that follicular activity of the ovary can instigate symptoms. ‘Progestogen-induced PMDs’ are caused by exogenous progestogens present in hormone replacement therapy (HRT) and the combined oral contraceptive (COC) pill. This reintroduces symptoms to women who may be particularly sensitive to progestogens. Although progestogen-only contraceptives may introduce symptoms, as they are noncyclical they are not included within variant PMDs and are considered adverse effects (probably with similar mechanisms) of continuous progestogen therapy. ‘PMDs with absent menstruation’ include women who still have a functioning ovarian cycle, but for reasons such as hysterectomy, endometrial ablation or the levonorgestrel-releasing intrauterine system (LNG-IUS) they do not menstruate.2 An additional term, premenstrual dysphoric disorder (PMDD) classified by the American Psychiatric Association in 19943 requires fulfilment of strict criteria. The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) demands five out of 11 stipulated symptoms, one of which must include mood.4 The symptoms must strictly occur in the luteal phase and must be severe enough to disrupt daily functioning. However, these restrictive criteria may exclude women with a narrow range of severe symptoms who should receive treatment. Care must be taken not to label women with underlying psychiatric or somatic disorders that do not appear to be influenced by the menstrual cycle as having PMS. 2.3 Prevalence and aetiology Four in ten women (40%) experience symptoms of PMS and of these 5–8% suffer from severe PMS.5 A cross-sectional survey of 929 women based in Southampton who completed a 6-week prospective symptom diary revealed a 24% prevalence of premenstrual symptoms.6 Although the aetiology remains uncertain, it revolves around the ovarian hormone cycle, which is reinforced by the absence of PMS prior to puberty, during pregnancy and after the menopause. Currently two theories predominate and appear interlinked. The first suggests that some women are ‘sensitive’ to progesterone and progestogens, since the serum concentrations of estrogen or progesterone are the same in those with or without PMS. The second theory implicates the neurotransmitters serotonin and γ-aminobutyric acid (GABA). Serotonin receptors are responsive to estrogen and progesterone, and selective serotonin reuptake inhibitors (SSRIs) are proven to reduce PMS symptoms. GABA levels are modulated by the metabolite of progesterone, allopregnanolone, and in women with PMS the allopregnanolone levels appear to be reduced.7 3 Identification and assessment of evidence This guideline was developed in accordance with standard methodology for producing RCOG Green-top Guidelines. The Cochrane Library (including the Cochrane Database of Systematic Reviews and DARE), EMBASE, Trip, MEDLINE, Psych INFO, CINAHL, the Allied and Complementary Medicine Database (AMED), and the British Nursing Index (BNI) were searched. The search was restricted to articles published between 2005 and March 2014 in the English language. The databases were searched using the relevant Medical Subject Headings (MeSH) terms, including all subheadings, and this was combined with a keyword search. Search words included ‘premenstrual syndrome’, ‘premenstrual tension’, ‘late luteal phase dysphoric disorder’, ‘premenstrual dysphoric disorder’, ‘PMDD’, ‘PMS’, ‘PMD’, ‘LLPDD’, ‘PMT’. The search was restricted to humans and there were no language restrictions. Where possible, recommendations are based on available evidence. In the absence of published evidence, these have been annotated as ‘good practice points’. Further information about the assessment of evidence and the grading of recommendations may be found in Appendix I. 4 How is PMS diagnosed? When clinically reviewing women for PMS, symptoms should be recorded prospectively, over two cycles using a symptom diary, as retrospective recall of symptoms is unreliable. Grade of recommendation: ✓ A symptom diary should be completed by the patient prior to commencing treatment. Grade of recommendation: ✓ Gonadotrophin-releasing hormone (GnRH) analogues may be used for 3 months for a definitive diagnosis if the completed symptom diary alone is inconclusive. Grade of recommendation: ✓ There are many patient-rated questionnaires available. However, the Daily Record of Severity of Problems (DRSP) remains the most widely used and is simple for patients to use.2 The DRSP has also been consistently shown to provide a reliable and reproducible record of symptoms (see Appendix III).8 The Premenstrual Symptoms Screening Tool (PSST)9 is another patient-rated questionnaire; however, it is retrospective and has been validated for screening but not diagnosis. Various attempts at electronic data capture have been attempted. Commercially available diagnostic apps are now available, but these require validation. Another easily accessible symptom diary exists on the NAPS website (www.pms.org.uk). This diary is not validated but is sufficient to be used in the context of clinical practice.10 Before any form of treatment is initiated, symptom diaries should be completed over at least two consecutive menstrual cycles. Treatment may improve symptoms, therefore masking underlying PMS, but it can also create a pattern of symptoms incompatible with a diagnosis of PMS, making the interpretation of DRSP charts confusing. These charts should be brought by the patient to any future appointments. Symptom diaries can sometimes be confusing and inconclusive: this is most likely to occur in those patients with variant PMDs. GnRH analogues, which are widely used within gynaecology, can be useful in separating those with and those without PMS by inhibiting cyclical ovarian function. These should be used for 3 months to establish a definitive diagnosis. This is to allow a month for the agonist to generate a complete hormonal suppressive effect, as well as providing 2 months’ worth of symptom diaries. 5 What aspects are involved in delivering a service to women with PMS? 5.1 When should women with PMS be referred to a gynaecologist? Referral to a gynaecologist should be considered when simple measures (e.g. COCs, vitamin B6, SSRIs) have been explored and failed and when the severity of the PMS justifies gynaecological intervention. Grade of recommendation: ✓ General practitioners will manage the majority of cases of PMS; therefore, awareness of the condition together with up-to-date information on its management is essential. Referral to secondary care should be reserved for those with confirmed PMS in whom simple measures have failed to control symptoms. In women whose symptom diaries demonstrate noncyclical symptoms, an underlying psychiatric or somatic disorder should be considered. 5.2 Who are the key health professionals to manage women with severe PMS? Women with severe PMS may benefit from being managed by a multidisciplinary team comprising a general practitioner, a general gynaecologist or a gynaecologist with a special interest in PMS, a mental health professional (psychiatrist, clinical psychologist or counsellor) and a dietician. Grade of recommendation: ✓ While this set-up is desirable, it is not widely available or implemented within the National Health Service (NHS). There are specialist clinics within tertiary centres to which patients can be referred. However, it is likely that the general practitioner will remain key in facilitating potential treatments. A multidisciplinary team can offer women an individualised management plan utilising a range of treatments, such as cognitive behavioural therapy (CBT) and lifestyle interventions.11 6 How is PMS managed? 6.1 Are complementary therapies efficacious in treating PMS? Women with PMS should be informed that there is conflicting evidence to support the use of some complementary medicines. Grade of recommendation: C An integrated holistic approach should be used when treating women with PMS. Grade of recommendation: ✓ Interactions with conventional medicines should be considered. Grade of recommendation: ✓ Although there is limited evidence to support the use of complementary therapies, some women with PMS may benefit from a holistic approach.12 This is particularly important for women in whom hormonal therapy is contraindicated. It is important to evaluate evidence carefully for PMS as there is a 36–43% placebo response.13, 14 Evidence level 1− Table 1 summarises current research into the benefits of selected complementary therapies for the treatment of PMS. Table 1. Summary of evidence for selected complementary therapies Complementary therapy Benefit Types of studies Numbers in the study Note Exercise22-25 Some benefit Nonrandomised and randomised 72 (4 published studies) High quality studies recommended. Reflexology26 Some benefit Randomised 35 Vitamin B627-39 Mixed results Double-blind Randomised Cross-over 1067 (13 published studies) Peripheral neuropathy with high doses (most studies performed using higher doses). Department of Health restricts the daily dose to 10 mg. Magnesium37, 40, 41 Mixed results Double-blind Randomised Cross-over 153 (3 published studies) Used in premenstrual phase. Multivitamins42-45 Unknown – 400 (several published studies) Unclear which are the active ingredients. Calcium/vitamin D46, 47 Yes Double-blind Randomised Cross-over 499 (2 published studies) Isoflavones48, 49 Mixed results Double-blind Randomised Cross-over 72 (2 published studies) May benefit menstrual migraine. Vitex agnus castus L.19, 39, 50-54 Yes Double-blind Randomised 923 (7 published studies) There is no standardised preparation. St John's Wort20, 21, 55, 56 Mixed results Double-blind Placebo-controlled 401 (4 published studies) May benefit physical and behavioural symptoms. Many withdrew from one study due to adverse effects. Significant interactions with conventional medicines. The British National Formulary advises avoid concomitant use with SSRIs. Ginkgo biloba57, 58 Some benefit Double-blind Placebo-controlled 233 (2 published studies) Saffron59 Yes Double-blind Placebo-controlled 47 Further data before recommendation. Evening primrose oil15, 60-63 Some benefit Double-blind Placebo-controlled Cross-over 215 (4 published studies) May benefit women with cyclical breast symptoms. Acupuncture64-73 Lemon balm74 Curcumin75 Wheat germ76 Some benefit Some benefit Some benefit Some benefit Case–control Double-blindPlacebo-controlledDouble-blind Placebo-controlledTriple-blind Placebo-controlled 235 (10 published studies) 100 (1 published study) 70 (1 published study) 84 (1 published study) High risk of bias. Further data before recommendation. PMS severity quantified by PSST. Further data before recommendation. PMS severity quantified by an unvalidated symptom score. Further data before recommendation. PMS severity quantified by an unvalidated symptom score. Further data before recommendation. Unsaturated fatty acids, as contained in evening primrose oil, have been shown in one prospective randomised trial15 to improve menstrual symptoms compared with placebo at both 1 g/day and 2 g/day dosages. There was no measurable change in cholesterol levels. Dante et al.16 conducted a systematic review into herbal remedies for PMS. Four of the trials, including almost 600 women, supported the use of Vitex agnus castus L. (also known as chasteberry). However, this study concluded that there were inadequate safety data to support its use. Whelan et al.17 conducted a systematic review of 29 randomised controlled trials (RCTs). Two of these studies (n = 499) revealed consistent evidence for calcium in alleviating both physical and psychological symptoms of PMS. The evidence for both vitamin B6 and Vitex was contradictory in this review and therefore advice could not be given for either. Due to the lack of power, reliable recommendations cannot be provided. A systematic review18 focusing on the use of Vitex illustrated that in four out of five discrete placebo-controlled trials and two comparator trials, Vitex was superior to placebo, pyridoxine and magnesium in the treatment of PMS. In another study, it appeared comparable to fluoxetine for PMDD.16 The safety of Vitex is described as excellent, with adverse effects being infrequent and mild.18, 19 Studies have shown a dose dependent treatment response; however, due to the variability in quality and content of preparations a dosage range to treat PMS cannot be recommended. RCTs including St John's Wort (Hypericum perforatum) show conflicting results. A trial20 including 36 women with mild PMS showed significant improvements in physical and behavioural symptoms but no improvement in mood or pain-related symptoms. Another trial21 including 125 women found no evidence of benefit but felt that this may be attributable to low statistical power. St John's Wort interacts with other medications, in particular it should not be used concurrently with SSRIs and can render low dose COCs ineffective. Evidence level 1− 6.2 Is there a role for CBT and other psychological counselling techniques? When treating women with severe PMS, CBT should be considered routinely as a treatment option. Grade of recommendation: A Hunter et al.77 conducted a randomised trial comparing fluoxetine, CBT and the combination of fluoxetine and CBT for the treatment of PMDD. After a 6-month treatment period, all three treatment groups showed evidence of benefit, which was similar for each group, with fluoxetine combined with CBT no more effective than the two component therapies used separately. Fluoxetine showed quicker improvements; however at follow-up CBT was associated with better maintenance of treatment effects compared with fluoxetine. Evidence level 1+ A meta-analysis identified five RCTs testing CBT against a control intervention. The evidence was poor due to a high risk of bias but demonstrated a significant reduction in depression, anxiety and behavioural problems. If CBT proves successful to a patient it would avoid pharmacotherapy and potential adverse effects.78 Evidence level 1− 6.3 Hormonal medical management of PMS 6.3.1 What is the role of cycle-modifying agents in managing PMS? 6.3.1.1 Which COC has the best evidence for managing PMS, including regimens delivering ethinylestradiol? When treating women with PMS, drospirenone-containing COCs may represent effective treatment for PMS and should be considered as a first-line pharmaceutical intervention. Grade of recommendation: B Despite the combined pill's ability to suppress ovulation, studies initially illustrated no benefit in the treatment of PMS.79 This may be attributed to the progestogens in second-generation pills (levonorgestrel or norethisterone) regenerating PMS-type symptoms. Further research has therefore been directed towards new combined contraceptives, in particular those containing the antimineralocorticoid and antiandrogenic progestogen, such as drospirenone. Evidence level 2+ A Cochrane review80 involving five RCTs and 1920 participants looked into the effectiveness of drospirenone (3 mg) and ethinylestradiol COCs against placebo or an alternative COC, where the progestogen was substituted for desogestrel (1