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 Although initial data suggest there to be abnormal concentrations of metabolites of progesterone (pregnanolone and allopregnanolone),³ there is no consistent evidence that low concentrations of progesterone are found in women with the premenstrual syndrome. Indeed, published studies have shown progesterone to be the same in women with and without premenstrual syndrome.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. Women taking hormone replacement therapy experience typical symptoms seen in premenstrual syndrome (progestogen induced premenstrual syndrome).⁵

In 1989 the National Association of Premenstrual Syndrome sent a questionnaire to general practitioners and found that over half prescribed progesterone pessaries or suppositories and over 60% prescribed progestogens⁶ for women with premenstrual syndrome. In the United States and Canada an earlier study found that 70% of prescriptions for premenstrual syndrome were for progesterone suppositories or pessaries.⁷ From 1993 to 1998 progestogens and progesterone remained the most widely prescribed treatments for premenstrual syndrome in the United Kingdom (unpublished data).

In the United Kingdom, the only licensed preparation of progesterone is Cyclogest, administered as a suppository or pessary. Oral micronised progesterone has been available for some time in Europe and the United States but not in the United Kingdom. Crinone, a vaginal progesterone gel, does not have a UK pharmaceutical licence, but it is listed for treatment of premenstrual syndrome in the Monthly Index of Medical Specialties (MIMS). Topical, "natural" progesterone cream has, without evidence, been extensively marketed through the internet and lay media as a reputedly effective treatment for premenstrual syndrome.⁸

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 This, together with the seeming lack of evidence from clinical trials for the efficacy of progesterone or progestogens, the known failure of transdermal preparations of progesterone to achieve measurable increase in blood concentrations of progesterone, ^{9 10} and 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 medical databases 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 (PMT), late luteal phase dysphoric disorder (LLPDD), premenstrual dysphoria (PMD), and premenstrual dysphoric disorder (PMDD). We searched Embase (1988-2000), Medline (1966-2000), PsychINFO (1988-2000), and the Cochrane controlled trial register. References cited in all trials were searched iteratively to identify missing studies. All languages were included. Pharmaceutical companies who manufacture progesterone preparations (oral micronised, intramuscular, vaginal gel, topical cream, or suppositories) and progestogens were contacted. We included trials that investigated the effect of progesterone or progestogens on premenstrual symptoms if they were randomised, placebo controlled, double blind studies that included patients with a pretreatment diagnosis of premenstrual syndrome, for which all data from the trials could be acquired.

Data extraction and outcome measures
All the data were extracted independently in duplicate by two investigators (PWD, KMW) by means of a standardised protocol and data collection form. Disagreements were resolved by discussion with a third investigator (SO'B). When there were insufficient data presented for inclusion, we contacted authors for further details. We collected data on the dosage and preparation of treatment. The main outcome measure was a reduction in overall symptoms of premenstrual syndrome. Combined or overall symptoms was chosen in an attempt to overcome the clinical heterogeneity associated with the measurement and scoring of symptoms used in individual trials. When possible we quoted results using intention to treat, as such results represent an accurate means of determining the efficacy of a drug. We undertook separate analyses of micronised oral progesterone and progesterone pessaries or suppositories versus placebo. We carried out a secondary analysis of the treatment of behavioural and physical symptoms. Withdrawals from treatment and side effects were recorded.

Quality assessment
We assessed trial quality using a scale developed by Jadad et al,¹¹ 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. This eight point scale comprised the following: confirmation that no other medications or oral contraceptives were being taken; a power calculation to justify patient numbers or more than 65 participants in each arm (enabling detection of a small effect size of 0.3, see below); a single, clearly stated dose of drug; reproducible measurement of premenstrual symptoms; clear presentation of results; a description of the number and reason for trial withdrawals; exclusion of, or a separate analysis of, participants with a major psychiatric disorder; and whether or not the trial was supported by independent funding. We awarded one point for each category present in the trial. Each trial was independently scored by two investigators and the third investigator arbitrated on any disagreements. We used predetermined criteria for the recognition of the highest quality trials. A score of 3 or more was required in the Jadad score for the trial to be designated "high quality" and included in the meta-analysis¹¹; a score of less than 3 meant that the trial was designated "low quality." We have given results for our quality score, but we did not use it as a criterion for inclusion because the score has not been validated.

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. The magnitude of an effect size has been described by Cohen¹²; 0.3 represents a small effect, 0.5 a medium effect, and 1.0 a large effect. A negative effect size means a reduction in symptoms. When medians and ranges were presented the values were converted to means (SD).¹³ When comparisons were made between pooled standardised mean differences for different subanalyses, we assessed statistical differences using a z test; P<0.05 was considered significant. We calculated an overall standardised mean difference using both fixed and random effects models. The overall standardised mean difference was converted to an odds ratio with the association described by Hassleblad and Hedges.¹⁴ Homogeneity was tested for with a ² test, with P<0.05 indicating significant heterogeneity.

	Results

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We identified 14 published trials that assessed the efficacy of progesterone in the management of premenstrual syndrome.^16-29 We excluded four: two because of their low quality score on the Jadad scale, ^{26 27} one because the data could not be extracted,²⁹ and one because the trial failed to make a prospective diagnosis of premenstrual syndrome before randomisation.²⁴ Ten trials remained, representing 531 women with data suitable for inclusion in the analyses. One trial compared both progesterone suppositories and oral micronised progesterone with placebo, and the data were analysed as two studies.¹⁶

We identified 15 published trials that assessed progestogen in the management of premenstrual syndrome.^30-44 We excluded 12: three were open studies,^41-43 four did not include a prospective diagnosis of premenstrual syndrome, ^{34 36-38} three were preliminary reports of included trials, ^{35 40 44} and in two data could not be extracted. ^{33 39} Of the three remaining trials one compared two different progestogens (each with their own placebo) and so this trial was treated as two separate studies.³⁰

Table 1 gives details of the included trials for both treatments, and table 2 lists the excluded trials and their reason for exclusion.

Quality assessment of trials
All the included trials of progesterone and progestogens scored 3 on the Jadad scale. On our quality score four of the 10 progesterone trials ^{20 22 23 28} and two of the three progestogen trials ^{30 31} scored 6, five progesterone trials ^{16-18 21 25} and the other progestogen trial³² scored 7, and one trial of progesterone scored the maximum of 8.⁹

Data extraction
All the included trials for either treatment presented continuous data and so an overall standardised mean difference was calculated with both fixed and random effects models. Because we found only minimal differences between the fixed and random effects models we used the more conservative random effects model.

Progesterone
The 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, 0.017 to 0.0408; 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 shows the individual standardised mean difference for each trial, the type of preparation and dosage for that trial, and the pooled standardised mean difference with 95% confidence intervals for trials that used progesterone suppositories and those that used oral micronised progesterone. The inclusion of the data from the two low quality trials ^{25 26} did not significantly affect the overall result.

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

Progestogens
The 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.

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

Bias
We investigated bias using a funnel plot.¹⁵ Regression analysis of the plots indicated no significant asymmetry (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) and thus no evidence of bias.¹⁵

Subanalyses
We carried out a subanalysis of the effectiveness of the treatments in managing either physical or behavioural symptoms. Figure 3 shows the overall standardised mean difference for behavioural and physical symptoms from eight of the trials of progesterone, which represented 371 women. The overall standardised mean difference was 0.011 (0.003 to 0.024) for behavioural symptoms and 0.088 (0.061 to 0.115) for physical symptoms. There was no significant variation in the overall standardised mean differences (P=0.357). This was also true when the treatments were further divided into progesterone suppositories and oral micronised progesterone.

View larger version (22K): [in this window] [in a new window]   Fig 3.   Standardised mean differences and 95% confidence intervals for proportion of patients who showed improvement in behavioural and physical symptoms (progesterone versus placebo)

View larger version (18K): [in this window] [in a new window]   Fig 4.   Standardised mean differences and 95% confidence intervals for proportion of patients who showed improvement in behavioural and physical symptoms (progestogen versus placebo)

Side effects
We extracted data on side effects (when reported) from the included trials (table 3). The data in the trials were incomplete; five of the trials 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. We analysed withdrawals from progesterone trials due to side effects, comparing placebo with treatment. This showed an increased but not significant risk of drop out due to side effects in the treatment group (odds ratio 1.66, 0.43 to 6.79).

	Discussion

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The meta-analyses that we carried out in this systematic review show 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. This is based on the observation that symptoms are reduced or eliminated during pregnancy (when progesterone concentrations are high and non-cyclical) and are absent during non-ovulatory cycles and after the menopause.⁴⁴ As early as 1938 it was proposed that premenstrual syndrome was caused by relative, unopposed oestrogen during the luteal phase.⁴⁵ Dalton and Green developed this theory further in the 1950s, and Dalton still remains one of the main proponents of the progesterone deficiency theory. No research, however, has convincingly shown a progesterone deficiency in women with premenstrual syndrome.⁴⁶

Many therapeutic interventions have been claimed to be effective. This may be attributed 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 the known high placebo response associated with premenstrual syndrome that one of the stated inclusion criteria for our meta-analyses was that in all trials the women should have had premenstrual syndrome diagnosed before randomisation. We also considered only randomised, double blind placebo controlled trials suitable for analysis. It could be argued that women with self diagnosed premenstrual syndrome would, in fact, be the population that the clinician treats. However, in a meta-analysis it is essential that the trials have defined the disorder precisely before treatment to permit definitive statements on the efficacy of the given treatment to be made.

Progesterone
Of the ten trials of progesterone treatment that met the inclusion criteria, eight assessed progesterone suppositories and three used oral micronised progesterone (one trial compared both suppositories and oral micronised preparations and the two arms were treated as two separate trials). There are no published trials of topical progesterone cream, which has been popularised through the media and the internet.⁸ One trial of intramuscular progesterone was identified, but the data were presented in a textbook review chapter in a format that was not extractable.²⁹ This placebo controlled trial involved only 14 women with premenstrual syndrome and concluded that progesterone did not produce a significant beneficial effect. Of the eight adequately controlled 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.¹⁸ However, when we examined the data on an intention to treat basis, as opposed to an analysis of "completers," we could not show a beneficial effect.