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 gives details of the included trials for both treatments, and table lists the excluded trials and their reason for exclusion.
Characteristics of studies included in meta-analysis of treatment of premenstrual syndrome
Characteristics of studies excluded from meta-analysis of treatment of premenstrual syndrome
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 trials20,22,23,28
and two of the three progestogen trials30,31
scored 6, five progesterone trials16–18,21,25
and the other progestogen trial32
scored 7, and one trial of progesterone scored the maximum of 8.9
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.
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 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 trials25,26
did not significantly affect the overall result.
Figure 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 (more ...)
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 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.
Figure 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 (more ...)
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
We carried out a subanalysis of the effectiveness of the treatments in managing either physical or behavioural symptoms. Figure 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.
Standardised mean differences and 95% confidence intervals for proportion of patients who showed improvement in behavioural and physical symptoms (progesterone versus placebo)
Figure shows the individual standardised mean difference for the progestogen trials that reported behavioural and physical symptoms separately. The overall standardised mean difference was −0.06 (−0.04 to −0.07) for behavioural symptoms compared with −0.16 (−0.13 to −0.19) for physical symptoms. Progestogens seem to be more effective in alleviating physical symptoms than behavioural symptoms (P<0.0001), although the magnitude of the effect size for physical symptoms is not considered to be clinically significant.
Standardised mean differences and 95% confidence intervals for proportion of patients who showed improvement in behavioural and physical symptoms (progestogen versus placebo)
We extracted data on side effects (when reported) from the included trials (table ). 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).
Side effects reported in included studies of progesterone according to method of administration
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).