Premenstrual syndrome

Irene Kwan; Joseph Loze Onwude

. 2009 Dec 21;2009:0806.

Premenstrual syndrome

Irene Kwan ^1,^#, Joseph Loze Onwude ^2,^#

PMCID: PMC2907788

Abstract

Introduction

Premenstrual symptoms occur in 95% of women of reproductive age. Severe, debilitating symptoms (PMS) occur in about 5% of those women. There is no consensus on how symptom severity should be assessed, which has led to a wide variety of symptoms scales, 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 review and aimed to answer the following clinical 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? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 56 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture; alprazolam; bright light therapy; buspirone; chiropractic manipulation; clomipramine; cognitive behavioural therapy (CBT); danazol; endometrial ablation; evening primrose oil; exercise; gonadorelin analogues; hysterectomy; laparoscopic bilateral oophorectomy; magnesium supplements; metolazone; non-steroidal anti-inflammatory drugs (NSAIDs); oestrogens; oral contraceptives; progesterone; progestogens; pyridoxine; reflexology; relaxation; selective serotonin reuptake inhibitors (SSRIs); spironolactone; and tibolone.

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.

Premenstrual symptoms occur in 95% of all women of reproductive age. Severe, debilitating symptoms (PMS) occur in about 5% of those women.
There is no consensus on how symptom severity should be assessed, which has led to a wide variety of symptoms scales, making it difficult to synthesise data on treatment efficacy. The cyclical nature of the condition also makes it difficult to conduct RCTs.
There is little good evidence for any of the wide range of treatments available, 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.

Drug treatments can be effective at reducing premenstrual symptoms, but some are associated with significant adverse effects.

There is good evidence that spironolactone improves mood and somatic symptoms in women with PMS.
Alprazolam (during the luteal phase), metolazone, and NSAIDs (such as mefenamic acid and naproxen sodium) may also be effective in treating the main physical and psychological symptoms of PMS.
Buspirone (luteal or continuous) and gonadorelin analogues seem to improve overall self-rated symptoms. Gonadorelin is effective in improving symptoms, but is associated with serious risks of osteoporosis when used for more than 6 months.
Other drug treatments such as clomipramine, danazol, and SSRIs may improve psychological symptoms, but are associated with serious adverse effects.

We don't know whetherprogesterone is effective in reducing symptoms of PMS. There is some evidence thatprogesterone-like drugs reduce premenstrual symptoms, but both progesterone and progesterone-like drugs are associated with several adverse effects.

We don't know whether other hormonal treatments such as oestrogen and tibolone are effective in reducing symptoms of PMS.
Oral contraceptives containing drospirenone (24/4 schedule [24 out of 28 days]) are likely to be effective in reducing symptoms of PMS.

There is not enough evidence for us to assess the efficacy of CBT in treating the psychological symptoms of PMS.

We also don't know how effective physical therapy techniques (bright light therapy, chiropractic manipulation, exercise, reflexology, relaxation, and acupuncture) are in relieving symptoms of PMS.

We found evidence that pyridoxine (vitamin B6) reduces the overall symptoms of PMS. Calcium supplements may also be effective.

We don't know whether other supplements, such as evening primrose oil or magnesium, are a useful treatment for PMS.

Surgery is indicated only if there are coexisting gynaecological problems.

There is a consensus that hysterectomy with bilateral oophorectomy or laparoscopic bilateral oophorectomy almost completely eradicate the symptoms of PMS, although we found no RCTs examining this.
We don't know whether endometrial ablation has the same effect.

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. This criteria is based on at least five symptoms, including one of four core psychological symptoms (from a list of 17 physical and psychological symptoms), 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

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Incidence/ Prevalence

Premenstrual symptoms occur in 95% of all women of reproductive age; severe, debilitating symptoms (PMS) occur in about 5% of those women.

Aetiology/ Risk factors

The cause is unknown, but hormonal and other factors (possibly neuroendocrine) probably contribute.

Prognosis

Except after oophorectomy, symptoms of PMS usually recur when treatment is stopped.

Aims of intervention

To improve or eliminate physical and psychological symptoms; to minimise the impact on normal functioning, interpersonal relationships, and quality of life; to minimise adverse effects of treatment.

Outcomes

Symptom severity: There is no consensus on how this should be assessed. One review of PMS outcomes found 65 different questionnaires or scales, measuring 199 different symptoms or signs. In describing outcomes, we refer to psychological, behavioural, and physical symptoms as described in table 1 . We also assess adverse effects of treatment.

Methods

Clinical Evidence search and appraisal July 2009. The initial search strategy was adapted from the Cochrane Collaboration's Menstrual Disorders and Subfertility Group. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2009, Embase 1980 to July 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 2 (1966 to date of issue). An additional search within the Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. For anxiolytics, diuretics, and non-SSRIs, we searched for all drugs within these classes and included all studies that met Clinical Evidence quality criteria. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people. There was no minimum length of follow-up required to include studies. 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 not possible. 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. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. The categorisation of the quality of the evidence (into 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). To aid readability of the numerical data in our reviews, 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). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of treatments for premenstrual syndrome

Important outcomes	Symptom severity (mood, somatic symptoms), adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of drug treatments in women with premenstrual syndrome?
3 (131)	Physical symptoms	Spironolactone v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and methodological flaws. Consistency point deducted for conflicting results
3 (131)	Mood	Spironolactone v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and methodological flaws. Consistency point deducted for conflicting results
2 (84)	Premenstrual symptoms	Alprazolam v placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor methodology, and poor follow-up
1 (185)	Premenstrual symptoms	Alprazolam v oral progesterone or placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (185)	Mood	Alprazolam v oral progesterone	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (63)	Mood	Buspirone v placebo	4	–1	–1	0	0	Low	Quality point deducted for sparse data. Consistency point deducted for conflicting results
1 (63)	Physical symptoms	Buspirone v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
5 (115)	Premenstrual symptoms	Gonadorelin analogues v placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and no ITT analysis
3 (66)	Premenstrual symptoms	Gonadorelin analogues plus hormonal add-back v gonadorelin analogues alone	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and no ITT analysis
1 (46)	Mood	Metolazone v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and poor follow-up
1 (46)	Physical symptoms	Metolazone v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and poor follow-up. Consistency point deducted for conflicting results
4 (114)	Mood	NSAIDs v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and poor follow-up. Consistency point deducted for conflicting results
4 (114)	Physical symptoms	NSAIDs v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and poor follow-up. Consistency point deducted for conflicting results
2 (93)	Mood	Clomipramine v placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results
2 (93)	Physical symptoms	Clomipramine v placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results
2 (68)	Premenstrual symptoms	Continuous danazol v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and poor follow-up
1 (100)	Premenstrual symptoms	Luteal-phase danazol v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
15 (2458)	Premenstrual symptoms	SSRIs v placebo	4	–2	0	0	0	Low	Quality points deducted for poor follow-up and incomplete reporting of results
15 (1806)	Physical symptoms	SSRIs v placebo	4	–2	0	0	0	Low	Quality points deducted for poor follow-up and incomplete reporting of results
9 (1023)	Mood	SSRIs v placebo	4	–2	0	0	0	Low	Quality points deducted for poor follow-up and incomplete reporting of results
What are the effects of hormonal treatments in women with premenstrual syndrome?
1 (49)	Mood	Oral contraceptives v placebo	4	–4	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, methodological flaws, and poor follow-up
1 (513)	Premenstrual symptoms	Oral contraceptives v placebo	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and methodological flaws
2 (181)	Premenstrual symptoms	Progesterone v placebo	4	–4	0	0	0	Very low	Quality point deducted for incomplete reporting of results, sparse data, poor follow-up, and analysis flaws
4 (344)	Premenstrual symptoms	Progestogens v placebo	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (40)	Premenstrual symptoms	Oestrogens v placebo	4	–1	–1	0	0	Low	Quality point deducted for sparse data. Consistency point deducted for different results before and after crossover
1 (18)	Premenstrual symptoms	Tibolone v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
What are the effects of psychological interventions in women with premenstrual syndrome?
2 (132)	Mood	CBT v waiting list control	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results
2 (100)	Premenstrual symptoms	CBT v waiting list control	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (42)	Physical symptoms; mood	CBT v HRT	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
What are the effects of physical therapy in women with premenstrual syndrome?
1 (35)	Premenstrual symptoms	Acupuncture v sham acupuncture	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and uncertainty about assessment methods. Directness point deducted because of uncertainty about diagnosis
4 (55)	Mood	Bright light therapy v dim light placebo	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and poor blinding. Directness point deducted for uncertain duration and details of intervention
1 (45)	Premenstrual symptoms	Chiropractic treatment v sham treatment	4	–3	–1	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and poor follow-up. Consistency point deducted for conflicting results before and after crossover
1 (50)	Mood	Reflexology v sham reflexology	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor blinding, poor follow-up, and incomplete reporting of results
1 (50)	Physical symptoms	Reflexology v sham reflexology	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor blinding, poor follow-up, and incomplete reporting of results
3 (185)	Premenstrual symptoms	Relaxation therapy v controls	4	–3	0	–1	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and poor follow-up. Directness point deducted for inclusion of different interventions
What are the effects of dietary supplements in women with premenstrual syndrome?
9 (940)	Premenstrual symptoms	Pyridoxine (vitamin B₆) v placebo	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
6 (756)	Mood	Pyridoxine (vitamin B₆) v placebo	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and poor follow-up
1 (160)	Physical symptoms	Pyridoxine (vitamin B₆) v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and poor follow-up
2 (557)	Premenstrual symptoms	Calcium supplements v placebo	4	–1	0	0	0	Moderate	Quality point deducted for methodological weaknesses in one study
4 (148)	Premenstrual symptoms	Evening primrose oil v placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and poor follow-up
3 (144)	Premenstrual symptoms	Magnesium supplements v placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results

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Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds 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.
Moderate-quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Reflexology: is defined as the application of manual pressure to reflex points on the ears, hands, and feet that somatotopically correspond to specific areas of the body.
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, Royal College of Obstetricians and Gynaecologists, London, UK.

Joseph Loze Onwude, The Portland Hospital, London, UK.

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BMJ Clin Evid. 2009 Dec 21;2009:0806.

Spironolactone

Summary

MOOD Compared with placebo: Luteal-phase spironolactone may improve mood ( very low-quality evidence ). SOMATIC SYMPTOMS Compared with placebo: Luteal-phase spironolactone may improve somatic symptoms (very low-quality evidence).

Benefits

Spironolactone versus placebo:

We found no systematic review, but found three RCTs comparing spironolactone 100 mg daily versus placebo. The first RCT (43 women; 12% withdrawal rate; crossover design) compared three interventions: spironolactone, medroxyprogesterone acetate, and placebo. It found that luteal-phase spironolactone significantly improved mood from baseline at 3 months compared with placebo (measured on a visual analogue scale [VAS] 0–75 mm, where 0 = extremely good mood: 65.1 mm with spironolactone v 37.4 mm with placebo; absolute difference 27.6 mm, 95% CI 7.0 mm to 48.3 mm). The RCT did not assess other outcomes.

The second RCT (35 women; 6% withdrawal rate; crossover design) found that, compared with placebo, luteal-phase spironolactone significantly reduced negative mood symptoms over 6 months (summarised VAS score for anxiety/tension, irritability, fatigue, and depression: 11.1 mm with spironolactone v 12.1 mm with placebo; P <0.01). It also found that spironolactone significantly reduced somatic symptoms over 6 months compared with placebo (summarised VAS score for headache, feeling of swelling, sweet craving, and breast tenderness: 4.7 mm with spironolactone v 6.2 mm with placebo; P <0.01). The RCT did not report results before crossover.

The third RCT (63 women; 11% withdrawal rate) found that luteal-phase spironolactone 100 mg daily significantly reduced the "general feeling of bloatedness" over two cycles compared with placebo (measured on a 3-point scale as "same", "better", or "worse": proportion of women who reported feeling better: 23/26 [88%] with spironolactone v 8/21 [38%] with placebo; P <0.001). It found no significant improvements in swollen abdomen, swollen hands and feet, breast discomfort, irritability, depression, anxiety, headaches, and levels of sexual interest (reported as not significant; P values not reported).

Harms

Spironolactone versus placebo:

The first and second RCTs gave no information on adverse effects. The third RCT gave little information on adverse effects, reporting similar rates with spironolactone and placebo, and that none of the withdrawals (11/63 [17%]) were caused by adverse effects.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Alprazolam

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: Luteal-phase alprazolam may improve physical and psychological symptoms of premenstrual syndrome after 3–6 months' treatment, including severe symptoms in women with premenstrual dysphoric disorder ( very low-quality evidence ). Compared with oral progestogens: Luteal-phase alprazolam may improve premenstrual symptoms ( moderate-quality evidence ). MOOD Compared with oral progestogens: Luteal-phase alprazolam improves premenstrual mood (moderate-quality evidence). ADVERSE EFFECTS Mild adverse effects are common with alprazolam. Benzodiazepines are associated with dependence.

Benefits

Alprazolam versus placebo:

We found no systematic review, but found two crossover RCTs (see table 2 ). Neither RCT reported results before crossover, and both had high withdrawal rates (54% in one RCT). The first RCT in women with premenstrual syndrome found that luteal-phase alprazolam significantly reduced overall symptoms after 4 months' treatment compared with placebo. The second RCT in women with late luteal premenstrual dysphoric disorder found that luteal-phase alprazolam significantly reduced overall premenstrual symptoms after 6 months' treatment compared with placebo.

Table 2.

RCTs comparing anxiolytics versus placebo

Ref	Intervention	Participants	Results	Adverse effects
Alprazolam v placebo
	Alprazolam 0.25–0.75 mg daily from day 20 of the cycle to the second day of menstruation v placebo	19 women with PMS, 26% withdrawal rate	Physical symptoms Mean PMS scores of the 7 most severe luteal days (0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe): Abdominal bloating:5.8 with alprazolam v 9.8 with placebo; P <0.05 Abdominal cramps:2.6 with alprazolam v 4.0 with placebo; P <0.05 Headaches:3.4 with alprazolam v 8.1 with placebo; P <0.005 Weight gain:4.2 with alprazolam v 7.8 with placebo; P <0.05 Psychological symptoms Mean PMS scores of the 7 most severe luteal days (0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe): Mood swings:3.4 with alprazolam v 10.7 with placebo; P <0.005 Irritability:4.5 with alprazolam v 13.4 with placebo; P <0.005 Anxiety:3.3 with alprazolam v 10.9 with placebo; P <0.005 Depression:3.5 with alprazolam v 8.8 with placebo; P <0.05 Forgetfulness:2.1 with alprazolam v 7.3 with placebo; P <0.005 Crying:2.2 with alprazolam v 7.6 with placebo; P <0.005 Behavioural symptoms Mean PMS scores of the 7 most severe luteal days where 0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe): Fatigue:6.3 with alprazolam v 10.3 with placebo; P <0.05 Cravings for sweets:5.5 with alprazolam v 10.7 with placebo; P <0.05	No major adverse effects of alprazolam except for minimal daytime sedation in 2/14 (14%) women, which was treated by decrease in dose of medication
	Alprazolam 0.25–0.75 mg daily 6–14 days before menstruation tapered at the onset of menses v placebo	65 women with premenstrual dysphoric disorder, 54% withdrawal rate	Overall premenstrual symptoms Measured by physician rated CGI severity scale (lower scores indicates less severity): Physician rated CGI severity scale (lower scores indicate less severity):2.6 with alprazolam v 3.4 with placebo; P <0.001 Physician rated CGI improvement:2.4 with alprazolam v 3.3 with placebo; P <0.002 Physician rated CGI overall efficacy:6.6 with alprazolam v 9.2 with placebo; P <0.02 Physician rated GAS for symptoms and functioning (higher scores indicate better functioning):80 with alprazolam v 73 with placebo; P <0.002	Mild adverse effects such as drowsiness, nausea, anxiety, and headache reported with alprazolam and headaches and nausea reported with placebo
Alprazolam v oral progesterone or placebo
	Alprazolam 0.75–2.5 mg daily v oral progesterone 900–2700 mg daily v placebo from day 18 of the menstrual cycle to day 2 after onset of menses	185 women with severe PMS, 19% withdrawal rate	Overall premenstrual symptoms Alprazolam significantly reduced overall premenstrual symptoms after 3 months compared with oral progesterone or placebo (measured by CGI severity scale [lower scores indicates less severity]): 1.96 with alprazolam v 2.45 with progesterone v 2.35 with placebo; P <0.02 for alprazolam v either intervention Psychological symptoms Measured by DSR scores (lower scores indicate less severity): Mental state:15 with alprazolam v 23 with progesterone v 25 with placebo; P <0.01 Mood:35 with alprazolam v 48 with progesterone v 48 with placebo; P <0.04 (P value for alprazolam v either intervention) Physical symptoms Measured by DSR scores (lower scores indicate less severity): Pain:9 with alprazolam v 13 with progesterone v 12 with placebo; P <0.008 for alprazolam v either intervention	Adverse effects such as sedation, dizziness, confusion, and headache: 79% of women with alprazolam v 88% with progesterone v 55% with placebo (unable to interpret significance assessment)
Buspirone v placebo
	Buspirone (10–40 mg) given during the luteal cycle for 2 months followed by 2 months of continuous treatment v nefazodone v placebo for 4 months	63 women with premenstrual syndrome, 20% withdrawal rate	Overall premenstrual symptoms Buspirone (luteal or continuous) was significantly better than placebo in improving self-rated global improvement (measured by CGI: P <0.001; absolute numbers NR) Physical symptoms No significant difference between buspirone and placebo in physical symptoms (reported as not significant; no further data reported) Psychological symptoms Irritability:Buspirone used continuously significantly better than placebo in reducing irritability (change in VAS from baseline: 83% with buspirone v 54% with placebo; P = 0.03) No significant difference between buspirone used in the luteal-phase only and placebo in reducing irritability (change in VAS from baseline: 72% with buspirone v 47% with placebo; P value reported as not significant) Depressed mood, affect lability, and tension:No significant difference between buspirone (continuous or intermittent) and placebo in depressed mood, affect lability, or tension, whether given intermittently in the luteal-phase or continuously (P values reported as not significant for all outcomes; absolute results tabulated)	Buspirone was associated with significantly more light-headedness (P <0.008), blurred vision (P <0.02), disturbance of balance (P <0.05), abnormal dreams (P <0.05), tactile hallucinations (P <0.004), and influenza-like symptoms (P <0.01)

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CGI, Clinical Global Impressions; DSR, Daily Symptom Rating; GAS, Global Assessment Scale; PMS, premenstrual syndrome; NR, not reported; Ref, reference; VAS, visual analogue scale.

Alprazolam versus oral progesterone or placebo:

We found no systematic review, but found one large RCT comparing three interventions in women with severe premenstrual syndrome: luteal-phase alprazolam, oral progesterone, or placebo for three cycles. It found that alprazolam significantly reduced overall premenstrual symptoms after 3 months compared with oral progesterone or placebo, and significantly improved mental state, pain, and mood (see table 2 ).

Harms

Benzodiazepines are associated with dependence.

Alprazolam versus placebo:

The RCTs reported mild adverse effects such as drowsiness, nausea, anxiety, and headache with alprazolam, and headaches and nausea with placebo (see table 2 ).

Alprazolam versus oral progesterone or placebo:

Adverse effects such as sedation, dizziness, confusion, and headache were reported in all women in the RCT, with higher rates in woman taking alprazolam and progesterone than women taking placebo (see table 2 ).

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Buspirone

Summary

PHYSICAL SYMPTOMS Compared with placebo: Buspirone (luteal or continuous) may not improve physical premenstrual symptoms ( low-quality evidence ). MOOD Compared with placebo: The effects of buspirone on premenstrual mood are unclear (low-quality evidence). ADVERSE EFFECTS Mild adverse effects of buspirone are common.

Benefits

Buspirone versus placebo:

We found no systematic review, but found one RCT comparing three interventions: buspirone (luteal or continuous), nefazodone, and placebo for 4 months. The RCT found that buspirone (luteal or continuous) was significantly better than placebo in improving self-rated global improvement at 4 months in women with premenstrual syndrome. Buspirone used continuously, but not in the luteal-phase, was significantly better than placebo in reducing irritability. The RCT found no significant difference between buspirone (continuous or intermittent) and placebo in depressed mood, emotional lability, and tension. It also found no significant difference between buspirone and placebo in physical symptoms (see table 2 ).

Harms

Buspirone versus placebo:

The RCT found that, compared with placebo, buspirone was associated with significantly more balance-related adverse effects, such as light-headedness and influenza-like symptoms (see table 2 ).

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Gonadorelin analogues (GnRHa; buserelin, goserelin, leuprorelin)

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: Gonadorelin analogues may reduce overall symptoms of premenstrual syndrome over 3 to 6 months ( very low-quality evidence ). Gonadorelin analogues plus hormonal add-back therapy versus gonadorelin analogues alone: Hormonal add-back therapy may neither improve nor decrease the effectiveness of gonadorelin analogue therapy ( very low-quality evidence ). ADVERSE EFFECTS Women taking gonadorelin analogues are three times more likely to have adverse effects (including hot flushes, aches, night sweats, nausea, and headaches) than women taking placebo. Treatment with gonadorelin analogues without hormonal add-back for more than 6 months carries a serious risk of osteoporosis, limiting their usefulness for long-term treatment.

Benefits

Gonadorelin analogues versus placebo:

We found one systematic review (search date 2002), which identified seven RCTs comparing gonadorelin analogues (GnRHa) with or without hormonal add-back (oestradiol, oestrogen, medroxyprogesterone, or tibolone) versus placebo. One of the RCTs compared three interventions (GnRHa alone, GnRHa plus add-back, and placebo) and is reported for all relevant comparisons. The review found that continuous or 1 monthly single-dose GnRHa alone significantly reduced overall premenstrual symptoms over 3 to 6 months compared with placebo (5 RCTs; analysis of 115 women who completed the study; OR 8.66, 95% CI 2.52 to 30.26).

Three RCTs (66 women completed the study) identified by the review compared GnRHa plus hormonal add-back versus GnRHa alone and found no significant difference in overall premenstrual symptoms between groups (SMD +0.12, 95% CI –0.34 to +0.59; OR not reported). The review did not report the total number of participants for all the RCTs it identified; it is therefore unclear how many participants withdrew from the trials. The review analysis was also limited as it was not by intention to treat.

Harms

The review found no significant difference between GnRHa alone and placebo in the proportion of women who withdrew because of adverse effects (5 RCTs; OR 1.95, 95% CI 0.71 to 3.63; absolute data not reported). However, women taking GnRHa were three times more likely to have adverse effects than women taking placebo.

The three RCTs assessing GnRHa plus hormonal add-back compared with GnRHa alone found that women taking hormonal add-back were more likely to withdraw from the trial because of adverse effects than women taking GnRHa alone, although the difference was not significant (OR 1.60, 95% CI 0.71 to 3.63; absolute results not reported). Adverse effects with both GnRHa alone and GnRHa plus add-back included hot flushes, aches, night sweats, nausea, and headaches. Without hormonal add-back, treatment with GnRHa for more than 6 months carries a serious risk of osteoporosis, limiting their usefulness for long-term treatment.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Metolazone

Summary

MOOD Compared with placebo: Luteal-phase metolazone may improve mood ( low-quality evidence ). PHYSICAL SYMPTOMS Compared with placebo: The effects of luteal-phase metolazone on physical premenstrual symptoms are unclear ( very low-quality evidence ).

Benefits

Metolazone versus placebo:

We found one crossover RCT (46 women with premenstrual fluid retention; 28% withdrawal rate), which found that luteal-phase metolazone (1, 2.5, or 5 mg daily) significantly reduced premenstrual weight gain compared with placebo over 6 months (mean: 0.36 kg with metolazone v 1.08 kg with placebo; P <0.001). It also found that, compared with placebo, luteal-phase metolazone significantly improved mood symptoms from baseline (measured on a scale from 0–4, where 0 = absent and 4 = very severe: total score for irritability in all participants: 63 with metolazone v 107 with placebo; depression: 47 with metolazone v 87 with placebo; tension: 48 with metolazone v 113 with placebo; nervousness: 49 with metolazone v 77 with placebo; anxiety: 37 with metolazone v 57 with placebo; P = 0.001 for all outcomes). There was also a significant improvement in back pain with metolazone (total score: 46 with metolazone v 62 with placebo; P = 0.027) but not in headaches, joint aches, or muscle pains (total sores, headache: 67 with metolazone v 78 with placebo; joint aches: 16 with metolazone v 17 with placebo; muscle pains: 26 with metolazone v 21 with placebo).

Harms

Metolazone versus placebo:

The RCT found that women taking metolazone (5 mg daily) had weakness (13%) and excessive diuresis (frequency not reported). The RCT did not assess adverse effects in women taking placebo.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Summary

MOOD Compared with placebo: Luteal-phase mefenamic acid or naproxen sodium may improve premenstrual mood over 3 to 6 months ( very low-quality evidence ). PHYSICAL SYMPTOMS Compared with placebo: Luteal-phase NSAIDs may reduce some, but not all, physical symptoms of premenstrual syndrome (very low-quality evidence).

Benefits

We found no systematic review.

Mefenamic acid versus placebo:

We found three crossover RCTs. All RCTs found that mefenamic acid improved physical and mood symptoms compared with placebo, although results differed slightly depending on methods of assessment. The first crossover RCT (19 women; 0% withdrawal rate) found that continuous mefenamic acid (1500 to 2000 mg daily) significantly improved self-reported physical and mood symptoms of premenstrual syndrome over 3 months after crossover compared with placebo (13/19 [68%] with mefenamic acid v 4/19 [21%] with placebo; P <0.05).

The second crossover RCT (19 women; 21% withdrawal rate) found that, after crossover at 6 months, luteal-phase mefenamic acid (0.75 g daily) significantly improved some physical symptoms (fatigue, general aches, pains, and headache P <0.001), mood symptoms (swings in mood P <0.005; irritability P <0.01; feeling unattractive P <0.01), and behavioural symptoms (bad performance P <0.05; absolute results not reported) compared with placebo. It found no significant difference between mefenamic acid and placebo in breast symptoms, abdominal fullness and discomfort, changes in appetite, craving for certain foods, and back ache (reported as not significant; no further data reported).

The third crossover RCT (42 women; 29% withdrawal rate) found that luteal-phase mefenamic acid (0.75 g daily) significantly increased the proportion of women with self-reported improvement over four cycles compared with placebo (16/30 [53%] with mefenamic acid v 3/30 [10%] with placebo; P <0.05). When assessing symptoms using analysis of daily symptom checklist, the RCT found no significant difference in symptoms (including bloating, irritability, and depression) between mefenamic acid and placebo, except for an improvement in GI symptoms (P <0.05; absolute results tabulated).

Naproxen sodium versus placebo:

We found one RCT (34 women; 18% withdrawal rate), which found that late-luteal naproxen sodium (550 mg twice daily) significantly reduced most physical and psychological premenstrual symptoms over 3 months compared with placebo (measured by mean Menstrual Distress Questionnaire [MDQ] score; pain: 3.2 with naproxen v 7.6 with placebo; P <0.006; behavioural changes: 1.9 with naproxen v 4.4 with placebo; P <0.015; arousal: 3.0 with naproxen v 1.2 with placebo; P <0.002). However, this benefit was not significant with regard to negative effects (mean MDQ score: 6.5 with naproxen v 10.7 with placebo; P <0.06).

Harms

Mefenamic acid versus placebo:

The first RCT was undertaken as part of a larger study of 80 women taking mefenamic acid; adverse effects were not reported separately for women in the RCT. Mefenamic acid was associated with GI disturbances in 21/80 (26%) of women in the study. In the second RCT, one woman taking mefenamic acid and one taking placebo withdrew because of nausea, and one woman taking mefenamic acid withdrew because of giant urticaria.

Naproxen sodium versus placebo:

The RCT gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Clomipramine

Summary

MOOD Compared with placebo: Clomipramine (luteal or continuous) may improve psychological symptoms of premenstrual syndrome over three treatment cycles ( very low-quality evidence ). PHYSICAL SYMPTOMS Compared with placebo: Clomipramine may not reduce physical symptoms of premenstrual syndrome ( very low-quality evidence ), but not physical symptoms. ADVERSE EFFECTS Adverse effects of clomipramine include drowsiness, nausea, vertigo, and headache.

Benefits

Clomipramine versus placebo:

We found no systematic review, but found two RCTs of clomipramine. The first RCT (55 women; 27% withdrawal rate) found that continuous clomipramine (25 to 75 mg daily) was significantly better than placebo in improving irritability (measured on a visual analogue scale [VAS] of 0–100 mm, where 0 = no symptoms: irritability: reduced to 16% with clomipramine v reduced to 62% with placebo; P <0.001) and dysphoria (reduced to 17% with clomipramine v reduced to 57% with placebo; P <0.001) from baseline over three treatment cycles. However, it found no significant difference in bloating between clomipramine and placebo (reduced to 50% with clomipramine v reduced to 69% with placebo; P >0.05). It found that clomipramine significantly increased the proportion of women with global improvement (measured on the author's own scale; P <0.001; absolute results tabulated).

The second RCT (38 women; 24% withdrawal rate) found that, compared with placebo, luteal-phase clomipramine (25 to 75 mg daily) significantly reduced premenstrual self-rated mean irritability rating (P = 0.02), depressed mood (P = 0.01), and tension (P = 0.04) after 3 months' treatment. It found no significant difference in increased appetite/carbohydrate craving (P = 0.07), breast tenderness (reported as not significant; P value not reported), or bloating (reported as not significant, P value not reported). Symptoms were assessed using a VAS of 0 mm to 100 mm (where 0 = no symptoms) and absolute results were presented graphically.

Harms

Clomipramine versus placebo:

The first RCT found that daytime drowsiness occurred in 40% of women taking clomipramine compared with 30% taking placebo. Similar rates of women in both groups withdrew because of adverse effects (5/20 [25%] with clomipramine v 4/20 [20%] with placebo). These generally consisted of clusters of symptoms, such as nausea, vertigo, a feeling of being drugged, and a feeling of depersonalisation.

The second RCT found that more women taking clomipramine had dry mouth, fatigue, vertigo, nausea, sweating, and headaches compared with placebo (dry mouth: 67% with clomipramine v 7% with placebo; fatigue: 53% with clomipramine v 14% with placebo; vertigo: 33% with clomipramine v 0% with placebo; nausea: 27% with clomipramine v 14% with placebo; sweating: 13% with clomipramine v 7% with placebo; headaches: 13% with clomipramine v 7% with placebo). The RCT did not assess the significance of the difference between groups. Adverse effects leading to withdrawal occurred in 6/22 (27%) women in the clomipramine group compared with 1/15 (7%) in the placebo group.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Danazol

Summary

PREMENSTRUAL SYMPTOMS Continuous danazol compared with placebo: Continuous danazol may reduce overall premenstrual symptoms after 3 months' treatment ( low-quality evidence ). Luteal danazol compared with placebo: The effects of luteal-phase danazol are unclear ( very low-quality evidence ). ADVERSE EFFECTS Danazol has important adverse effects associated with masculinisation when used continuously in the long term.

Benefits

Danazol versus placebo:

We found no systematic review, but found three RCTs comparing danazol versus placebo.

Continuous danazol:

We found two RCTs, which both found that danazol given continuously significantly reduced symptoms compared with placebo. The first RCT (37 women; 24% withdrawal rate, crossover design) found that significantly more women had overall improvement in symptoms after 3 months' treatment with danazol (100 mg twice daily) compared with placebo (24/27 [89%] with danazol v 6/27 [22%] with placebo; P <0.001).

The second RCT (31 women with severe premenstrual syndrome; 10% withdrawal rate; crossover design) found that danazol (400 mg daily) significantly improved premenstrual symptoms after 1 month before crossover compared with placebo (reduction in Premenstrual Tension Self-Rating Scale score from baseline [36-point scale]: –14.0 points with danazol v –3.6 points with placebo; P <0.013). The RCT did not report results after crossover.

Luteal-phase danazol:

We found one RCT (100 women; 10% withdrawal rate) comparing danazol (200 mg) given in the luteal-phase versus placebo. It found that danazol significantly reduced premenstrual breast pain at 3 months (P = 0.01; absolute results presented graphically). It found no significant difference in any other premenstrual symptoms (irritability, depression, anxiety, or bloatedness) or in overall symptoms (reported as not significant; absolute results tabulated).

Harms

Danazol has been associated with irreversible male-type changes in the voice.

Continuous danazol:

The first RCT (crossover design) found that adverse effects such as altered menses, nausea, headaches, bloating, acne or oily skin, and increased appetite were reported in 21/33 (64%) women while taking danazol compared with 11/31 (33%) women while taking placebo. The RCT did not assess the significance of the difference between groups. The second RCT gave no information on adverse effects.

Luteal-phase danazol:

The RCT found similar rates of adverse effects between groups; one woman taking danazol and one taking placebo withdrew because of bloatedness.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Selective serotonin reuptake inhibitors (SSRIs)

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: SSRIs may improve premenstrual symptoms over two to six cycles ( low-quality evidence ). MOOD Compared with placebo: SSRIs may improve premenstrual mood (low-quality evidence). PHYSICAL SYMPTOMS Compared with placebo: SSRIs may improve physical symptoms (low-quality evidence). ADVERSE EFFECTS SSRIs cause frequent adverse effects. Current evidence indicates no clear relationship between SSRIs and increased risk for suicide, but there is concern that SSRIs may increase the risks of self-harm and suicidal ideation. Regulatory authorities in Europe, the UK, and the USA have issued warnings about the use of SSRIs in children and adolescents.

Benefits

SSRIs versus placebo:

We found one systematic review,one additional RCT,and one subsequent RCT (see table 4 ). The review (search date 2008; 40 RCTs; 2294 women with premenstrual syndrome; 0–42.5% withdrawal rate; analysis by intention to treat in 22 trials) compared an SSRI (fluoxetine [14 RCTs]; sertraline [11 RCTs]; citalopram [3 RCTs]; fluvoxamine [1 RCT]; paroxetine [9 RCTs]; or clomipramine [2 RCTs]) with placebo. It found that continuous or luteal-phase SSRIs significantly reduced overall premenstrual symptoms over two to six cycles compared with placebo. Fifteen RCTs identified by the review reported physical and behavioural symptoms separately, and found similar significant reductions with SSRIs compared with placebo. A separate analysis of results for fluoxetine and sertraline performed by the review found similar results.

Table 3.

RCTs comparing SSRIs versus placebo

Ref	Study type	Participants	Results	Adverse effects
Any SSRI v placebo
	SR, search date 2008, 40 RCTs, 0–42.5% withdrawal rate, analysis by ITT in 22 trials	3834 women with PMS	Overall premenstrual symptoms: SSRIs significantly reduced compared with placebo (22 RCTs, 2294 women; SMD: –0.54, 95% CI –0.68 to –0.39)Overall physical symptoms: SSRIs significantly reduced compared with placebo (14 RCTs, 1703 women; SMD –0.34, 95% CI –0.45 to –0.22) Overall behavioural symptoms: SSRIs significantly reduced compared with placebo (15 RCTs, 1892 women; SMD –0.57, 95% CI –0.74 to –0.40) Specific symptoms: Irritability: SSRIs significantly reduced compared with placebo (8 RCTs, 920 women; SMD –5.2, 95% CI –19.6 to –0.9)	The review found that significantly more people taking SSRIs withdrew because of adverse effects compared with placebo (27 RCTs; 3231 women; OR 2.11, 95% CI 1.58 to 2.83; absolute results not reported). It found that SSRIs were significantly associated with nausea (21 RCTs; 2780 women; OR 3.71, 95% CI 2.75 to 5.01), fatigue and sedation (10 RCTs; 763 women; OR 2.01, 95% CI 1.28 to 3.17), insomnia (23 RCTs; 2842 women; OR 1.97, 95% CI 1.46 to 2.66), and decreased libido (14 RCTs; 2001 women; OR 2.91, 95% CI 1.84 to 4.59). There was no significant difference in headache between SSRIs and placebo (21 RCTs; 2548 women, OR 1.19, 95% CI 0.93 to 1.52). The review did not report absolute numbers
Fluoxetine v placebo
	SR, search date 2008, 8 RCTs, 8–31% withdrawal rate	827 women with PMS	Overall premenstrual symptoms: Fluoxetine significantly reduced compared with placebo (SMD –0.57, 95% CI –0.88 to –0.26)	The review did not perform a separate analysis of adverse effects with fluoxetine v placebo
Sertraline v placebo
	SR, search date 2008, 8 RCT, 18–30% withdrawal rate	1049 women with PMS	Overall premenstrual symptoms: Sertraline significantly reduced overall premenstrual symptoms compared with placebo (SMD –0.43, 95% CI –0.56 to –0.31)	The review did not perform a separate analysis of adverse effects with sertraline v placebo
Paroxetine v placebo
	Subsequent RCT, 28% withdrawal rate	103 women with PMS	Psychological symptoms Irritability: Luteal-phase paroxetine 20 mg significantly improved VAS scores for irritability compared with placebo (difference in percentage change from baseline in the luteal-phase VAS irritability score at study endpoint: –23.9, 95% CI –51.3 to –6.2). There was no significant difference in irritability symptoms between luteal-phase paroxetine 10 mg and placebo (difference in percentage change from baseline in the luteal-phase VAS irritability score at study endpoint: –10.7, 95% CI –42.3 to +9.9)Depressed mood: Paroxetine 20 mg significantly improved VAS scores for depressed mood compared with placebo (difference in mean VAS score: –13.4, 95% CI –24.5 to –2.2). There was no significant difference between paroxetine 10 mg and placebo (difference in mean VAS score: –9.8, 95% CI –21.7 to +2.2)Tension: Paroxetine 20 mg significantly improved VAS scores for tension compared with placebo (difference in mean VAS score: –17.7, 95% CI –32.7 to –2.7). There was no significant difference between paroxetine 10 mg and placebo (difference in mean VAS score: –23.9, 95% CI –23.9 to +6.3)Depressed mood, affect lability, and tension:No significant difference between buspirone (continuous or intermittent) and placebo in depressed mood, affect lability, or tension, whether given intermittently in the luteal phase or continuously (P values reported as not significant for all outcomes, absolute results tabulated)Mood swings: Paroxetine 20 mg significantly improved VAS scores for mood swings compared with placebo (difference in mean VAS score: –20.1, 95% CI –34.3 to –6.0)Physical symptoms Bloatedness:There was no significant difference in VAS scores for bloatedness between paroxetine 20 mg and placebo (difference in mean VAS score: –9.1, 95% CI –23.0 to +4.9) or paroxetine 10 mg and placebo (difference in mean VAS score: –4.4, 95% CI –18.4 to +9.6)Depressed mood, affect lability, and tension:No significant difference between buspirone (continuous or intermittent) and placebo in depressed mood, affect lability, or tension, whether given intermittently in the luteal phase or continuously (P values reported as not significant for all outcomes, absolute results tabulated)Breast tenderness: There was no significant difference in VAS scores for breast tenderness between paroxetine 20 mg and placebo (difference in mean VAS score: –5.5, 95% CI –18.8 to +7.8) or paroxetine 10 mg and placebo (difference in mean VAS score: 4.9, 95% CI –8.61 to +18.3) Behavioural symptoms Food craving:Paroxetine 20 mg significantly improved VAS scores for food craving compared with placebo (mean difference in VAS score: –14.1, 95% CI –27.3 to –0.9). There was no significant difference between paroxetine 10 mg and placebo (mean difference in VAS score: –7.2, 95% CI –20.2 to +5.8)Depressed mood, affect lability, and tension:No significant difference between buspirone (continuous or intermittent) and placebo in depressed mood, affect lability, or tension, whether given intermittently in the luteal phase or continuously (P values reported as not significant for all outcomes, absolute results tabulated)Lack of energy: There was no significant difference in VAS scores for lack of energy between paroxetine 20 mg and placebo (difference in mean VAS score: –4.7, 95% CI –18.9 to +9.4) or paroxetine 10 mg and placebo (difference in mean VAS score: –6.9, 95% CI –21.5 to +7.7)	In the RCT, 8 women withdrew from the trial because of adverse effects (4/35 [11%] with paroxetine 20 mg v 2/31 [6%] with paroxetine 10 mg v 2/33 [6%] with placebo; significance assessment not performed). The most common adverse effects (>5% in either paroxetine group and at least twice the rate of placebo) were nausea, fatigue, decreased appetite, exacerbation of fatigue, exacerbation of insomnia, weight gain, dizziness, yawning, heartburn, light-headedness, cold symptoms, and cramps. There were similar rates of overall adverse effects among groups (proportion of women who experienced at least 1 adverse effect: 83% with paroxetine 20 mg v 81% with paroxetine 10 mg v 85% with placebo; significance assessment not performed)
Venlafaxine v placebo
	Additional RCT, 23% withdrawal rate	164 women with PMS	Overall premenstrual symptoms: Venlafaxine (50–200 mg/day for 4 cycles) significantly increased the proportion of women with 50% or more reduction in daily total symptom score compared with placebo (41/68 [60%] with venlafaxine v 26/75 [35%] with placebo; P = 0.003)	One RCT reported that 12/157 (7.6%) women withdrew from the study because of adverse events (7/77 [9%] with venlafaxine v 5/80 [6%] with placebo). Venlafaxine was associated with significantly more nausea, insomnia, and dizziness, and decreased libido than placebo (P <0.01 for all outcomes)

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DSR, Daily Symptom Rating; PMS, premenstrual syndrome; NR, not reported; Ref, reference; SR, systematic review; SSRI, selective serotonin reuptake inhibitors; VAS, visual analogue scale.

The additional RCT found that continuous venlafaxine significantly improved overall premenstrual symptoms over 4 months compared with placebo. The subsequent RCT compared the effects of paroxetine 20 mg and paroxetine 10 mg versus placebo on a number of specific symptoms in women with PMS. It found that luteal-phase paroxetine 20 mg significantly reduced specific psychological outcomes compared with placebo, although it was less effective for specific physical and behavioural symptoms. There was no significant difference between luteal-phase paroxetine 10 mg and placebo for any of the reported outcomes.

Harms

The review found a significantly higher number of withdrawals due to side effects and adverse effects in women taking SSRIs than women taking placebo. Common adverse effects associated with SSRIs were nausea, insomnia, headache, asthenia, and decreased libido. Less frequent side effects included dizziness, fatigue, anxiety, tremor, sweating, and dry mouth. Results in one additional RCT and one subsequent RCT were similar. For full details see table 4 .

Harms alerts:

There is concern that SSRIs may increase the risk of self-harm and suicide. Regulatory authorities for Europe, the UK, and the USA have issued warnings about the use of SSRIs in children and adolescents. The FDA also issued a public health advisory safety alert regarding the use of paroxetine in women during pregnancy, based on a retrospective epidemiological study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy. This study suggested an increase in the risk of overall major congenital malformations with paroxetine compared with other antidepressants (OR 2.20; 95% CI 1.34 to 3.63).

Comment

None.

Substantive changes

SSRIs: One systematic review and one subsequent RCT added to benefits and harms, both of which found that SSRIs improved premenstrual symptoms, but were associated with a number of adverse effects, including nausea, insomnia, headache, asthenia, and decreased libido. Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Contraceptives (oral)

Summary

MOOD Compared with placebo: Oral contraceptives containing drospirenone may be no more effective at improving mood ( very low-quality evidence ). PREMENSTRUAL SYMPTOMS Compared with placebo: Oral contraceptives containing drospirenone may improve the symptoms of premenstrual dysphoric disorder ( low-quality evidence ).

Benefits

Oral contraceptives containing drospirenone versus placebo

We found one systematic review (search date 2007; 5 RCTs; 1600 women with premenstrual syndrome (PMS); four of five trials had >20% loss to follow-up) assessing the effectiveness of oral contraceptives containing drospirenone for the treatment of PMS. Three of the included RCTs compared ethinyloestradiol plus drospirenone versus placebo. The systematic review performed a meta-analysis of two RCTs comparing ethinyloestradiol (20 micrograms) plus drospirenone (3 mg) versus placebo over three cycles on a 24/4 day schedule (24 out of 28 days). It found that oral contraceptives containing drospirenone improved symptoms of premenstrual dysphoric disorder (PMDD) compared with placebo (2 RCTs; 513 women with PMDD; mean change in daily rating of problem severity in the first 3 months: –7.9, 95% CI –11.2 to –4.7).

The third RCT identified by the review (49 women with PMS) compared ethinyloestradiol (30 micrograms) plus drospirenone (3 mg) with placebo over three cycles on a 21/7 day schedule (21 out of 28 days). The RCT found no significant difference between ethinyloestradiol plus drospirenone versus placebo in depressed mood (mean change in luteal-phase scores for Beck Depression Inventory: –6.8, 95% CI –15.0 to +1.4) and mood changes (mean change in luteal-phase scores for Profile of Mood States: –7.90, 95% CI –38.3 to +22.5).

Harms

The systematic review combined the results of two RCTs comparing ethinyloestradiol (20 micrograms) plus drospirenone (3 mg). It found that intermenstrual bleeding, nausea, and breast pain were significantly more common with ethinyloestradiol plus drospirenone compared with placebo (bleeding: 66/285 [23%] with ethinyloestradiol plus drospirenone v 11/267 [4%] with placebo; OR 4.92, 95% CI 3.03 to 7.96; nausea: 53/285 [19%] with ethinyloestradiol plus drospirenone v 16/267 [6%] with placebo; OR 3.15, 95% CI 1.90 to 5.22; breast pain: 37/285 [13%] with ethinyloestradiol plus drospirenone v 13/267 [5%] with placebo; OR 2.67, 95% CI 1.50 to 4.78). There was no significant difference in the frequency of headaches and abdominal pain between ethinyloestradiol plus drospirenone and placebo (headaches: 53/285 [19%] with ethinyloestradiol plus drospirenone v 51/267 [19%] with placebo; OR 0.97, 95% CI 0.63 to 1.49; abdominal pain: 13/285 [5%] with ethinyloestradiol plus drospirenone v 9/267 [3%] with placebo; OR 1.36, 95% CI 0.58 to 3.20).

The review did not report adverse effects for the RCT comparing ethinyloestradiol (30 micrograms) plus drospirenone (3 mg) versus placebo, commenting that the RCT did not provide sufficient adverse effects data for analysis by the review.

Comment

The RCT comparing ethinyloestradiol (30 micrograms) plus drospirenone (3 mg) with placebo assessed symptoms using the Calendar of Premenstrual Symptoms (COPE). The RCT did not report sufficient data for analysis of COPE scores and adverse effects by the review. The three RCTs identified by the review were either funded by the manufacturer of the medication, or were co-authored by manufacturer employees.

Substantive changes

Oral contraceptives: One systematic review found that ethinyloestradiol plus drospirenone may reduce the symptoms of premenstrual syndrome. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Progesterone

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: We don't know whether progesterone is more effective at improving overall premenstrual symptoms over 2 to 4 months compared with placebo ( very low-quality evidence ). ADVERSE EFFECTS A wide range of adverse effects are associated with progesterone, including excessive bleeding, dysmenorrhoea, abdominal pain, nausea, and headache.

Benefits

We found one systematic review (search date 2008; 2 RCTs; 181 women aged 18–45 years; 41% loss to follow-up), which compared progesterone (suppositories, pessaries, or tablets used during the luteal phase) versus placebo for 2 to 4 months. The results were not combined for meta-analysis because of differences in study design, drug dosage and delivery, and participants.

The first RCT (141 women) identified by the review found no significant difference in premenstrual symptoms between vaginal or pessary progesterone and placebo (review reported that data not suitable for reporting; see comment below). Similarly, the second RCT (40 women) identified by the review found no significant difference in premenstrual symptoms in women taking oral or vaginal progesterone compared with placebo (review reported that data not suitable for reporting; see comment below).

Harms

The review reported that 4/141 (3%) women withdrew from the first RCT because of minor adverse effects, such as irregular menstruation, an ovarian cyst in the group of women taking progesterone, and respiratory infection and depression in the women taking placebo. In this RCT, other adverse effects reported included menstrual disorders, vaginal pruritus, headache, nausea, abdominal pain, influenza syndrome, dysmenorrhoea, breast pain, rectal pain, and diarrhoea (total number of adverse events: 101 in 41/80 [51%] women with progesterone v 53 in 26/61 [43%] women with placebo; significance assessment not reported by review).

In the second RCT, 3/39 (8%) women withdrew because of minor adverse effects including depression and relapse of thyrotoxicosis in women taking progesterone, and nausea in the women taking placebo. In this RCT, tiredness was the most common adverse event, but was not significantly different between progesterone and placebo; drowsiness and dizziness was more frequent with oral progesterone, and vaginal irritation was more common with vaginal progesterone (absolute numbers and significance assessment not reported by the review). The authors of the review stated that it was not clear whether the reported adverse effects in both RCTs were caused by treatment.

Comment

The review reported that evidence for effectiveness of progesterone in the treatment of PMS was equivocal and gave several reasons for this. The two included RCTs both had methodological limitations and one presented data on outcomes incompletely. The data presented in both studies were ordinal data but were analysed as interval data, limiting their use. In addition, there was high loss to follow-up in both RCTs.

Substantive changes

Progesterone: One systematic review (2 RCTs; 281 women) found no overall improvement in premenstrual symptoms in women taking luteal-phase progesterone for 2 to 4 months compared with placebo. Categorisation changed from Trade-off between benefits and harms to Unknown effectiveness.

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Progestogens (synthetic progesterone-like drugs)

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: Progestogens seem more effective at reducing premenstrual symptoms over three or four cycles ( low-quality evidence ). ADVERSE EFFECTS The most common adverse effects associated with progestogens are nausea, breast discomfort, headache, and menstrual irregularity. Progestogen may induce premenstrual syndrome symptoms in some women.

Benefits

We found one systematic review and one subsequent RCT. The systematic review (search date 2000; 3 RCTs; 319 women; see comment below) compared progestogens versus placebo for 3 to 4 months. The review found that progestogens significantly reduced premenstrual symptoms compared with placebo (SMD –0.036, 95% CI –0.059 to –0.014; OR 1.07, 95% CI 1.03 to 1.11; absolute results presented graphically; see comment below). The subsequent RCT (25 women with premenstrual dysphoric disorder) found that a 5-day gradual reduction regimen of chlormadinone in the luteal phase significantly reduced daily symptom scores of premenstrual dysphoric disorder over three cycles compared with placebo (P <0.02; absolute results presented graphically).

Harms

None of the RCTs identified by the review reported a detailed analysis of adverse effects. The review found no significant difference between progestogens and placebo in withdrawals caused by adverse effects (OR 1.65, 95% CI 0.86 to 3.21; absolute results not reported). The most common adverse effects associated with progestogens are nausea, breast discomfort, headache, and menstrual irregularity. The subsequent RCT reported that two women had menstrual irregularities and one woman withdrew from the trial with dyspepsia (further data not reported).

Progestogen may induce premenstrual syndrome symptoms in some women. To avoid this systemic effect, progestogen may be given locally (using a levonorgestrel IUD or progesterone gel). We found no systematic review or RCTs evaluating this approach.

Comment

One RCT compared three interventions: medroxyprogesterone, norethisterone, and placebo, and was analysed as if it were two RCTs.

Substantive changes

Progestogens: One new RCT added, which found that a 5-day regimen of chlormadinone reduced symptoms of premenstrual syndrome. Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Oestrogens

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: The effects of continuous oestradiol on symptoms of premenstrual syndrome are unclear ( low-quality evidence ). ADVERSE EFFECTS Important adverse effects of oestrogen include increased risk of breast cancer, endometrial cancer, stroke, and venous thromboembolic disease.

Benefits

Oestrogens versus placebo:

We found no systematic review but found one RCT (40 women; 12.5% withdrawal rate; crossover design) comparing transdermal oestradiol patches (200 micrograms changed every 3 days throughout the cycle) versus placebo for 6 months. Oral norethisterone (5 mg daily) was added from day 19 to 26 for all women (see comment below). The RCT found that both groups improved during the first three cycles. After crossover at 3 months, it found that symptoms in women switching from placebo to active treatment significantly improved, but the symptoms of women switching from active treatment to placebo deteriorated to the level they were at the start of the RCT (measured on the Moos Menstrual Distress Questionnaire; reported as significant; absolute results tabulated).

Harms

The RCT found that four women had skin reactions (2 in each group) and 10 women in the trial had skin pigmentation at the site of patch application. The most important long-term adverse effects with oestrogens are increased risk of venous thromboembolic disease (see HRT in review on Secondary prevention of ischaemic cardiac events), endometrial cancer, and breast cancer (see oestrogens alone in review on Menopausal symptoms).

Comment

Clinical guide:

Unopposed oestrogens may cause endometrial hyperplasia. To avoid this, a 12-day progestogen course is needed every 28 days.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Tibolone

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: Continuous tibolone may improve premenstrual symptom score over 6 months ( low-quality evidence ).

Benefits

Tibolone versus placebo:

We found no systematic review, but found one crossover RCT (18 women; 0% withdrawal rate) comparing tibolone (2.5 mg) daily versus placebo (multivitamins) for 6 months. It found that tibolone significantly improved premenstrual symptoms before crossover at 3 months (measured by a 16-point visual linear analogue scale; P <0.05; absolute results reported graphically). Similar results were found after crossover.

Harms

The RCT gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

CBT

Summary

MOOD Compared with waiting list control: The effects of CBT on mood in women with premenstrual syndrome are unclear ( very low-quality evidence ). Compared with HRT: There may be no significant difference in mood scores with CBT ( low-quality evidence ). PHYSICAL SYMPTOMS Compared with waiting list control: There may be no difference in physical symptoms in women given CBT (low-quality evidence). Compared with HRT: There may be no significant difference in physical symptoms in women given CBT (low-quality evidence).

Benefits

CBT versus control treatments:

We found no systematic review. Four RCTs (204 women) compared a treatment with cognitive behavioural content versus control (relaxation, HRT, drug placebo, or waiting list control). The first RCT (42 women; 85% with severe premenstrual syndrome; 40% withdrawal rate) compared three interventions: coping skills training, relaxation training, and dydrogesterone for 3 months. The RCT was not able to assess the effects of relaxation, owing to the withdrawal of 75% of participants after 2 months' treatment. It found no significant difference in overall physical and psychological symptoms at 3 months between coping skills training and dydrogesterone (reported as not significant; P value reported incorrectly; absolute figures presented graphically).

PREMENSTRUAL SYMPTOMS Compared with controls: Relaxation treatment may be more effective than control interventions (including reading leisure material, charting symptoms, or massage) in reducing premenstrual symptoms over 5 months ( very low-quality evidence ).

Benefits

We found one systematic review (search date 2000), which identified two RCTs of relaxation in women with premenstrual syndrome. We found one additional RCT. The review reported no quantitative results. The first RCT (107 women randomised; 43% withdrawal rate) identified by the review compared three interventions: relaxation response, reading leisure material, and charting. Participants in the relaxation response group received tape instructions on how to do deep breathing and relax all muscles to elicit the relaxation response. The RCT found weak evidence that relaxation response (15–20 minutes twice daily for 3 cycles) significantly improved physical symptoms at 5 months compared with reading leisure material or charting symptoms (46 women: reported as significant absolute results; P value for each comparison not reported). The RCT found that in the subgroup of women with severe premenstrual symptoms, relaxation response also improved emotional symptoms and social withdrawal symptoms compared with reading leisure material or charting symptoms (absolute results presented graphically).

The second RCT (24 women; no withdrawals reported) identified by the review compared progressive muscle relaxation versus massage (2 sessions weekly for 5 weeks). In the progressive muscle relaxation group, participants received written instructions how to tense and relax major muscle groups, starting with the feet to calves, legs, hands, arms, back, and face. The RCT did not directly compare treatments, but assessed, within groups, changes before and after treatment.

Harms

The review and RCTs gave no information on adverse effects.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Pyridoxine (vitamin B₆)

Summary

PREMENSTRUAL SYMPTOMS Compared with placebo: Luteal-phase or continuous pyridoxine (vitamin B 6 ) is more effective in relieving overall symptoms of premenstrual syndrome over 2 to 6 months ( moderate-quality evidence ). MOOD Compared with placebo: Pyridoxine may be more effective at improving depressive symptoms ( low-quality evidence ). PHYSICAL SYMPTOMS Compared with placebo: Pyridoxine may be no more effective at improving physical symptoms ( low-quality evidence ). ADVERSE EFFECTS Pyridoxine has been associated with reversible peripheral neuropathy both at high (2000–6000 mg/day) and standard (>200 mg/day) doses.

Benefits

Pyridoxine versus placebo:

Benefits

We found no systematic review or RCTs. Cohort studies have described a reduction in the symptoms of premenstrual syndrome after hysterectomy.

Harms

We found no systematic review or RCTs, but potential risks include those associated with major surgery. Cohort studies have found almost complete eradication of the symptoms of premenstrual syndrome after hysterectomy plus bilateral oophorectomy and continuous oestrogen placement.

Comment

Clinical guide:

Cohort studies have found almost complete eradication of the symptoms of premenstrual syndrome after hysterectomy plus bilateral oophorectomy and continuous oestrogen placement. Surgery is rarely used, but may be indicated if there are coexisting gynaecological problems.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Laparoscopic bilateral oophorectomy

Summary

We found no clinically important results about the effects of laparoscopic bilateral oophorectomy in women with premenstrual syndrome.

Benefits

We found no systematic review or RCTs; an RCT is unlikely to be performed. Cohort studies have found almost complete eradication of the symptoms of premenstrual syndrome after hysterectomy plus bilateral oophorectomy and continuous oestrogen placement.

Harms

We found no RCTs.

Comment

Clinical guide:

After bilateral oophorectomy, oestrogen replacement treatment and cyclical progesterone (to prevent endometrial hyperplasia) are often used in women who still have a uterus. Surgery is rarely used, but may be indicated if there are coexisting gynaecological problems.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Dec 21;2009:0806.

Endometrial ablation

Summary

We found no clinically important results about the effects of endometrial ablation in women with premenstrual syndrome.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

Surgery is rarely used, but may be indicated if there are coexisting gynaecological problems.

Substantive changes

No new evidence

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PERMALINK

Premenstrual syndrome

Irene Kwan

Joseph Loze Onwude

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

About this condition

Definition

Table 1.

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table.

Glossary

Disclaimer

Contributor Information

References

Spironolactone

Summary

Benefits

Spironolactone versus placebo:

Harms

Spironolactone versus placebo:

Comment

Substantive changes

Alprazolam

Summary

Benefits

Alprazolam versus placebo:

Table 2.

Alprazolam versus oral progesterone or placebo:

Harms

Alprazolam versus placebo:

Alprazolam versus oral progesterone or placebo:

Comment

Substantive changes

Buspirone

Summary

Benefits

Buspirone versus placebo:

Harms

Buspirone versus placebo:

Comment

Substantive changes

Gonadorelin analogues (GnRHa; buserelin, goserelin, leuprorelin)

Summary

Benefits

Gonadorelin analogues versus placebo:

Harms

Comment

Substantive changes

Metolazone

Summary

Benefits

Metolazone versus placebo:

Harms

Metolazone versus placebo:

Comment

Substantive changes

Non-steroidal anti-inflammatory drugs (NSAIDs)

Summary

Benefits

Mefenamic acid versus placebo:

Naproxen sodium versus placebo:

Harms

Mefenamic acid versus placebo:

Naproxen sodium versus placebo:

Comment

Substantive changes

Clomipramine

Summary

Benefits