Abstract
Introduction
A woman has premenstrual syndrome (PMS) if she complains of recurrent psychological and/or physical symptoms occurring during the luteal phase of the menstrual cycle, and often resolving by the end of menstruation. Symptom severity can vary between women. Premenstrual symptoms occur in 95% of women of reproductive age. Severe, debilitating symptoms occur in about 5% of those women. There is no consensus on how symptom severity should be assessed for PMS, which has led to the use of a wide variety of symptom scores and scales, thus making it difficult to synthesise data on treatment efficacy. The cyclical nature of the condition also makes it difficult to conduct RCTs.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of continuous hormonal treatments in women with premenstrual syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
At this update, searching of electronic databases retrieved 132 studies. After deduplication and removal of conference abstracts, 132 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 102 studies and the further review of 30 full publications. Of the 30 full articles evaluated, one systematic review and three RCTs were added to this overview. We performed a GRADE evaluation for three PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for three interventions based on information relating to the effectiveness and safety of continuous combined oral contraceptives, continuous transdermal estradiol, and continuous subcutaneous estradiol implants.
Key Points
A woman has premenstrual syndrome (PMS) if she complains of recurrent psychological and/or physical symptoms occurring during the luteal phase of the menstrual cycle, and often resolving by the end of menstruation. Symptom severity can vary between women.
Psychological symptoms of PMS include irritability, depression, crying/tearfulness, and anxiety. Physical symptoms of PMS include abdominal bloating, breast tenderness, and headaches.
Premenstrual symptoms occur in 95% of all women of reproductive age. Severe, debilitating symptoms occur in about 5% of those women.
The cyclical nature of PMS makes it difficult to conduct RCTs. Furthermore, the lack of consensus on how premenstrual symptom severity should be assessed has meant that RCTs use different symptom scores and scales, which makes it difficult to synthesise data.
There is little good quality evidence for any of the wide range of treatments available for PMS, and the selection of treatment is mainly governed by personal choice. The clinician plays a key role in facilitating this choice, and in reassuring women with PMS without coexisting gynaecological problems that there is nothing seriously wrong.
We don't know whether continuous daily oral levonorgestrel plus ethinylestradiol is more effective than placebo at improving premenstrual symptoms because we only found one trial and this specifically studied women with premenstrual dysphoric disorder.
We found no evidence in women with PMS who did not have premenstrual dysphoric disorder.
Adverse effects that may occur with continuous daily oral levonorgestrel plus ethinylestradiol include vaginal haemorrhage, metrorrhagia, and flu-like symptoms. There is also a concern that the combined contraceptive pill is associated with more serious adverse events, such as deep vein thrombosis (DVT), breast cancer, pulmonary embolism, and stroke.
We found insufficient evidence (only one RCT with small numbers) to judge the effectiveness of continuous transdermal estradiol plus cyclical oral norethisterone for treating PMS in women with an intact uterus.
Continuous subcutaneous estradiol implant plus cyclical norethisterone may be more effective than placebo at improving premenstrual symptoms in women with an intact uterus, but this is based on one RCT.
We found no RCTs on the effectiveness of continuous transdermal estradiol or continuous subcutaneous estradiol implant for treating PMS in women who had had a hysterectomy without bilateral salpingo-oophorectomy.
Clinical context
General background
Premenstrual symptoms are common, occurring in 95% of women of reproductive age. A woman has premenstrual syndrome (PMS) if she complains of recurrent psychological and/or physical symptoms occurring during the luteal phase of the menstrual cycle, and often resolving by the end of menstruation. Symptom severity can vary between women. At the extreme severe end of the spectrum, PMS can present as premenstrual dysphoric disorder.
Focus of the review
This evidence overview aims to identify effective treatments for managing PMS, with minimum adverse effects. There are many different types of treatment that have been used. For this update, we have focused on investigating the evidence for hormonal treatments, as these are interventions that are probably more acceptable to women compared with other options.
Comments on evidence
Surprisingly for such a common condition, there have been very few RCTs comparing different hormonal interventions. Therefore, it is difficult to draw firm conclusions. The cyclical nature of PMS makes it difficult to conduct RCTs. Furthermore, the lack of consensus on how premenstrual symptom severity should be assessed has meant that RCTs use different symptom scores and scales, which makes it difficult to synthesise data. Confidence in the findings of the trials that have been done may be increased if these trials are repeated.
Search and appraisal summary
The literature search was carried out in April 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 132 studies. After deduplication and removal of conference abstracts, 132 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 102 studies and the further review of 30 full publications. Of the 30 full articles evaluated, one systematic review and three RCTs were added at this update.
Additional information
There is a need for further high-quality trials in this field as the current available evidence is limited.
About this condition
Definition
A woman has premenstrual syndrome (PMS) if she complains of recurrent psychological and/or physical symptoms occurring specifically during the luteal phase of the menstrual cycle, and often resolving by the end of menstruation. The symptoms can also persist during the bleeding phase (for details of psychological, behavioural, and physical symptoms commonly reported in women with PMS, see table 1 ). Severe premenstrual syndrome The definition of severe PMS varies among RCTs, but in recent studies standardised criteria have been used to diagnose one variant of severe PMS — premenstrual dysphoric disorder (PMDD). The criteria are based on at least five symptoms, including one of four core psychological symptoms (from a list of 17 physical and psychological symptoms) and being severe before menstruation starts and mild or absent after menstruation. The 17 symptoms are depression, feeling hopeless or guilty, anxiety/tension, mood swings, irritability/persistent anger, decreased interest, poor concentration, fatigue, food craving or increased appetite, sleep disturbance, feeling out of control or overwhelmed, poor coordination, headache, aches, swelling/bloating/weight gain, cramps, and breast tenderness.
Table 1.
Commonly reported symptoms in women with premenstrual syndrome
| Commonly reported symptoms in women with premenstrual syndrome | |
| Psychological symptoms | Irritability, depression, crying/tearfulness, anxiety, tension, mood swings, lack of concentration, confusion, forgetfulness, unsociableness, restlessness, temper outbursts/anger, sadness/blues, loneliness |
| Behavioural symptoms | Fatigue, dizziness, sleep/insomnia, decreased efficiency, accident prone, sexual interest changes, increased energy, tiredness |
| Physical symptoms: pain | Headache/migraine, breast tenderness/soreness/pain/swelling (collectively known as premenstrual mastalgia), back pain, abdominal cramps, general pain |
| Physical symptoms: bloatedness and swelling | Weight gain, abdominal bloating or swelling, oedema of arms and legs, water retention |
| Appetite symptoms | Increased appetite, food cravings, nausea |
Incidence/ Prevalence
Premenstrual symptoms occur in 95% of all women of reproductive age; severe, debilitating symptoms occur in about 5% of those women.
Aetiology/ Risk factors
The cause is unknown but hormonal and other factors (possibly neuroendocrine) probably contribute.
Prognosis
Symptoms of PMS can recur after treatment is stopped, except after oophorectomy and menopause.
Aims of intervention
To improve or eliminate physical and psychological symptoms with minimal adverse effects; and to minimise the impact on normal functioning, interpersonal relationships, and quality of life.
Outcomes
Premenstrual symptoms There is no consensus on how premenstrual symptom severity should be assessed. One review of PMS outcomes found 65 different questionnaires or scales, measuring 199 different symptoms or signs. Adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal April 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2014, Embase 1980 to April 2014, and The Cochrane Database of Systematic Reviews 2014, issue 2 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing more than 20 individuals. For continuous combined oral contraceptives, and continuous transdermal estradiol, we only included RCTs with minimum treatment duration of 3 months. For continuous subcutaneous estradiol implants, we only included RCTs with minimum treatment duration of 6 months. There was no minimum length of follow-up. Many of the RCTs we retrieved had problems with retaining participants throughout follow-up; this may be because of the cyclical nature of PMS. We, therefore, did not exclude RCTs on the basis of high withdrawal rates or high loss to follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included systematic reviews and subsequent RCTs that: (1) diagnosed PMS by validated scales before randomisation; (2) used a pre-randomisation placebo cycle to exclude women with a non-specific response; and (3) contained sufficient cycles to allow for symptom variability between cycles. Few trials fulfilled these criteria. The wide range of diagnostic scales, outcome criteria, and dosing schedules made comparison between trials difficult. We excluded reviews that systematically searched electronic databases but did not use overt criteria to appraise the results. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: What are the effects of drug treatments in women with premenstrual syndrome? What are the effects of hormonal treatments in women with premenstrual syndrome? What are the effects of psychological interventions in women with premenstrual syndrome? What are the effects of physical therapy in women with premenstrual syndrome? What are the effects of dietary supplements in women with premenstrual syndrome? What are the effects of surgical treatments in women with premenstrual syndrome? from this overview. We have added the following question: What are the effects of continuous hormonal treatments in women with premenstrual syndrome? Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Premenstrual syndrome.
| Important outcomes | Premenstrual symptoms | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of continuous hormonal treatments in women with premenstrual syndrome? | |||||||||
| 1 (at least 328) | Premenstrual symptoms | Continuous combined oral contraceptives (with no break in treatment) versus placebo | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results; directness points deducted for restricted population and high attrition |
| 1 (40) | Premenstrual symptoms | Continuous transdermal estradiol (with no break in treatment) versus placebo in women with an intact uterus | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (68) | Premenstrual symptoms | Continuous subcutaneous estradiol implant (with no break in treatment) versus placebo in women with an intact uterus | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data; directness points deducted for high attrition |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Premenstrual dysphoric disorder (PMDD)
An intense form of premenstrual syndrome occurring exclusively during the 2 weeks before menses. It often has more psychological symptoms than physical ones. Symptoms may include feelings of hopelessness, anxiety and depression, lethargy, irritability, and low self-esteem.
- Salpingo-oophorectomy
The removal of the fallopian tube (salpingectomy) and ovary (oophorectomy).
- Very low-quality evidence
Any estimate of effect is very uncertain.
Breast pain
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Irene Kwan, University of London, London, UK.
Joseph Loze Onwude, The Croft, Warley Road, Brentwood, UK.
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