Introduction

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Premenstrual syndrome is defined as the recurrence of psychological and physical symptoms in the luteal phase, which remit in the follicular phase of the menstrual cycle. It is estimated that up to 1.5 million women in the United Kingdom experience such severe symptoms that their quality of life and interpersonal relationships are greatly affected. Over 35% of these women will seek medical treatment.¹

The rationale for the use of progesterone and progestogens in the management of premenstrual syndrome is based on the unsubstantiated premise that progesterone deficiency is the cause.² There is no consistent evidence that low concentrations of progesterone are found in women with the premenstrual syndrome. ^{3 4} However, as premenstrual syndrome occurs in ovulatory cycles progesterone may be the underlying cause or at least the trigger for symptoms in susceptible women.⁵

Studies of prescribing patterns from the United Kingdom and the United States in the 1990s have shown that 60-70% of prescriptions for premenstrual syndrome are progesterone or progestogens based. ^{6 7}

View larger version (22K): [in this window] [in a new window]   Fig 1.   Standardised mean differences and 95% confidence intervals for proportion of patients who showed improvement in overall premenstrual syndrome (progesterone versus placebo). Negative values indicate reduction in symptoms, favouring active treatment

View larger version (10K): [in this window] [in a new window]   Fig 2.   Standardised mean differences and 95% confidence intervals for proportion of patients who showed improvement in overall premenstrual syndrome (progestogen versus placebo). Negative values indicate reduction in symptoms, favouring active treatment

Progestogens are also prescribed for premenstrual syndrome on the basis of their "progesterone-like" action. Dydrogesterone, norethisterone, and levonogestrel have pharmaceutical licences in the United Kingdom, despite the apparent paradox of claimed effectiveness of treatment versus their ability to generate side effects similar to those seen in the premenstrual syndrome.⁵ The continued popularity in prescribing these treatments for premenstrual syndrome led us to undertake a detailed review of clinical trials of all types of progestogens and progesterone therapy in the management of premenstrual syndrome.

	Methods

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Trials
We searched Embase (1988-2000), Medline (1966-2000), PsychINFO (1988-2000), and the Cochrane controlled trial register for reports of published clinical trials of progesterone and progestogens in the management of premenstrual syndrome. MeSH terms used were premenstrual syndrome, progesterone, and progestogen, as well as the individual drug names, together with title and abstract searches for keywords progesterone, progestogen, premenstrual syndrome, premenstrual tension, late luteal phase dysphoric disorder, premenstrual dysphoria, and premenstrual dysphoric disorder. References cited in all trials were searched to identify missing studies. All languages were included. Pharmaceutical companies who manufacture progesterone preparations and progestogens were contacted. We included only those trials that included patients with a pretreatment diagnosis of premenstrual syndrome.

Data extraction and outcome measures
All the data were extracted independently in duplicate. Disagreements were resolved by discussion with a third investigator. We collected data on the dosage and preparation of treatment. The main outcome measure was a reduction in overall symptoms of premenstrual syndrome. When possible we quoted results using intention to treat.

Quality assessment
We assessed trial quality using a scale developed by Jadad et al,⁸ which assesses the randomisation, double blinding, reports of drop outs, and withdrawals for the trials, and our own quality scale, which assesses the quality of the trials for study design, reproducibility, and statistical analysis.

Statistical analysis
When continuous data were presented we calculated a standardised mean difference. This is equivalent to an effect size, which is a dimensionless quantity representing the difference between two means as a number of SDs; 0.3 represents a small effect, 0.5 a medium effect, and 1.0 a large effect.⁹ A negative effect size means a reduction in symptoms. We calculated an overall standardised mean difference using random effects models. The overall standardised mean difference was converted to an odds ratio.¹⁰ Homogeneity was tested for with a ² test, with P<0.05 indicating significant heterogeneity. We used the method of Egger et al to detect bias.¹¹

	Results

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We identified 14 published trials that assessed the efficacy of progesterone in the management of premenstrual syndrome but excluded four from analysis. Ten trials remained, representing 531 women with data suitable for inclusion in the analyses.^12-21 One trial compared both progesterone suppositories and oral micronised progesterone with placebo, and the data were analysed as two studies.¹² We identified 15 published trials that assessed progestogen in the management of premenstrual syndrome but excluded 12 from analysis. Of the three remaining trials^22-24 one compared two different progestogens (each with their own placebo) and so this trial was treated as two separate studies.²² Table 1 gives details of the included trials for both treatments.

ProgesteroneThe overall standardised mean difference for a reduction in premenstrual syndrome symptoms with progesterone suppositories or pessaries was 0.04 (95% confidence interval 0.03 to 0.05) and hence was marginally in favour of placebo. This difference corresponds to an odds ratio of 0.93 (0.91 to 0.95). The figures for oral micronised progesterone were 0.15 (0.17 to 0.12), marginally in favour of oral micronised progesterone, corresponding to an odds ratio of 1.30 (1.25 to 1.36), showing a slight improvement for women taking oral micronised progesterone. When we combined all the trials of progesterone (by both routes of administration) the overall result showed no clinically significant difference between progesterone and placebo, although the result was statistically significant (0.028, 0.040 to 0.017; corresponding odds ratio 1.05, 1.03 to 1.08) in favour of progesterone. The pooled trials were statistically homogeneous (P=0.999) (figure 1).

ProgestogensThe overall standardised mean difference for reduction in symptoms showed a slight difference between progestogens and placebo in favour of progestogens (0.036, 0.059 to 0.014), the corresponding odds ratio being 1.07 (1.03 to 1.11). The pooled trials were statistically homogeneous (P=0.999). Figure 2 shows the individual standardised mean difference for each trial, the type of progestogen used in the trial, and the pooled standardised mean difference with 95% confidence intervals.

BiasRegression analysis of the plots indicated no evidence of bias (intercept=2.97, 3.88 to 9.82, P=0.45, for progesterone and intercept=0.80, 9.79 to 11.4, P=0.85, for progestogens).

Side effectsWe extracted data on side effects (when reported) from the included trials (table 2). The data in the trials were incomplete; five of the trials of progesterone did not give a detailed breakdown of side effects or the number of participants who suffered from them. The most commonly reported side effect for progesterone administered as a suppository or pessary was an increase or decrease in the length of the menstrual cycle; the most commonly reported side effect for oral micronised progesterone was fatigue or sedation. There was an increased but not significant risk of drop out due to side effects in the progesterone group (odds ratio 1.66, 0.43 to 6.79). None of the included trials gave a detailed breakdown of side effects for progestogens. We noted withdrawals from trials due to side effects, comparing placebo with progestogens. This showed a non-significant higher dropout rate in the treatment group due to side effects (1.65, 0.86 to 3.21).

	Discussion

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This systematic review shows that there is no published evidence to support the use of either progesterone or progestogens in the management of the premenstrual syndrome.

The premenstrual syndrome has been considered to be an endocrine disorder as symptoms are eliminated during pregnancy and are absent during non-ovulatory cycles and after the menopause.²⁵ No research, however, has convincingly shown a progesterone deficiency in women with premenstrual syndrome.⁴

Many therapeutic interventions have been claimed to be effective due to a high placebo effect and the large number of poorly controlled trials in women without a pretrial diagnosis of premenstrual syndrome. It is because of these factors that one of the stated inclusion criteria for this review was a diagnosis of premenstrual syndrome before randomisation. There are no published trials of topical progesterone cream, which has been popularised through the media and the internet.²⁶ Of the eight trials of progesterone suppositories, all but one showed a negative result. The only study that claimed to show a positive result was the study by Magill.¹⁴ When we examined the data on an intention to treat basis, however, we could not show a beneficial effect.

We found a small positive effect of progesterone over placebo in the three trials that assessed oral micronised progesterone. This may be due to the ability of this treatment to increase concentrations of allopregnanolone and pregnanolone (metabolites of progesterone), which have a positive effect on the central nervous system similar to that of GABA (-aminobutyric acid). Progesterone administered as a suppository or pessary does not increase concentrations of these metabolites. ^{13 27} This standardised mean difference (0.147) could be compared with that for selective serotonin reuptake inhibitors (SSRIs), which was 1.066 in favour of treatment. These standardised mean differences correspond to an odds ratio of 1.3 and 6.91, respectively.²⁸ It should also be noted that oral micronised progesterone is not available in the United Kingdom.

The published evidence for progestogen treatment is not of high quality. Of the 15 published trials, only three trials met quality criteria, representing 378 women in total. A sensitivity analysis on the three trials (266 women) that were excluded because of lack of a prospective diagnosis slightly improved the standardised mean difference (0.182, 0.044 to 0.320) but it did not make it clinically significant. Poorly controlled, low quality trials often have positive results, often due to an imprecise definition of premenstrual syndrome in the study population and a subsequent uncertainty as to what condition is being treated.

Of the four included studies, two used dydrogesterone, one used norethisterone, and one used medroxyprogesterone. Low numbers of participants and trials meant that a comparative analysis of individual progestogens could not be undertaken.

While the role of endogenous progesterone and its metabolites in the aetiology of premenstrual syndrome remains unclear, it is evident from this meta-analysis that exogenous administration of either progestogens or progesterone does not improve symptoms. This is not surprising as there are reliable data to refute the theory that premenstrual syndrome is caused by a progesterone deficiency. With this review, there is now no convincing evidence to support the continued prescription of progesterone or progestogens for the management of premenstrual syndrome.

	Footnotes

   Funding: No external funding.

Competing interests: SO'B has been reimbursed for lectures and conferences by Hoechst Marion Roussel, Shire Pharmaceuticals, SmithKline Beecham, Eli Lilly, Searle, Sanofi Winthrop, Zeneca, Galen Laboratories, Solvay Pharmaceuticals, and Novo Nordisk. He has also received funds for research staff from Searle, SmithKline Beecham, Eli Lilly, and Sanofi Winthrop. He is married to a member of the research department of Zeneca Pharmaceuticals.

The full version of this paper appears on the BMJ's website

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(Accepted 10 July 2001)