Table 3.
Differences in least squares mean (Δ LSM) and standard error of difference (SE) in women with PMDD: PMDD symptom severity during first month of estradiol and progesterone addback (E/P 1) compared with placebo addback, and the second and third months of estradiol and progesterone addback; leuprolide alone compared with placebo addback; and differences between PMDD symptom severity between the second and third months of estradiol and progesterone addback.
| Study Month (M): | M4 V M5 | M3 V M4 | M5 V M6 | M5 V M7 | M6 V M7 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Symptom Rating Scale | Placebo - E/P(1) | leuprolide - Placebo | E/P(1) - E/P(2) | E/P(1) - E/P(3) | E/P(2) - E/P(3) | ||||||||||
| Δ LSM | SE | p value | Δ LSM | SE | p value | Δ LSM | SE | p value | Δ LSM | SE | p value | Δ LSM | SE | p value | |
| PMTS (self) (p = 0.0013) | −3.292 | 0.971 | 0.0015 | −0.500 | 0.971 | 0.6092 | 3.333 | 0.971 | 0.0014 | 3.782 | 1.03 | 0.0006 | 0.449 | 1.03 | 0.6649 |
| PMTS (rater) (p < 0.0001) | −3.125 | 0.907 | 0.0013 | −1.500 | 0.907 | 0.1055 | 4.042 | 0.907 | <0.0001 | 4.848 | 0.932 | <0.0001 | 0.806 | 0.932 | 0.3915 |
| Daily Rating Form | |||||||||||||||
| Sadness (p = 0.0158) | −0.100 | 0.09 | 0.2723 | −0.172 | 0.09 | 0.0604 | 0.125 | 0.09 | 0.1702 | 0.268 | 0.091 | 0.0046 | 0.144 | 0.091 | 0.1200 |
| Irritability (p = 0.0017) | −0.347 | 0.113 | 0.0031 | −0.047 | 0.113 | 0.6773 | 0.182 | 0.112 | 0.1105 | 0.421 | 0.114 | 0.0005 | 0.239 | 0.114 | 0.0397 |
| Anxiety (p = 0.3851) | −0.099 | 0.117 | 0.3981 | −0.097 | 0.117 | 0.4105 | 0.007 | 0.116 | 0.9547 | 0.138 | 0.118 | 0.2441 | 0.132 | 0.118 | 0.2671 |
| Mood Swings (p = 0.5370) | −0.0004 | 0.077 | 0.9955 | −0.115 | 0.076 | 0.1356 | 0.043 | 0.075 | 0.5671 | 0.039 | 0.076 | 0.6142 | −0.005 | 0.076 | 0.9511 |
| Cravings (p = 0.1893) | −0.167 | 0.09 | 0.0704 | −0.015 | 0.09 | 0.8725 | 0.143 | 0.09 | 0.1157 | 0.203 | 0.091 | 0.0304 | 0.059 | 0.091 | 0.5195 |
| Bloating (p = 0.0445) | −0.120 | 0.131 | 0.3633 | −0.186 | 0.131 | 0.1599 | 0.143 | 0.131 | 0.2797 | −0.091 | 0.133 | 0.4977 | −0.233 | 0.133 | 0.084 |
| Breast Pain (p = 0.2697) | −0.095 | 0.153 | 0.5392 | −0.130 | 0.153 | 0.4005 | −0.030 | 0.153 | 0.8435 | −0.099 | 0.154 | 0.5216 | −0.069 | 0.154 | 0.6559 |
| Plasma Hormone levels | |||||||||||||||
| Estradiol (pg/ml) (p < 0.0001) | −44.204 | 12.045 | 0.0007 | −1.650 | 12.045 | 0.8917 | −6.717 | 12.045 | 0.5800 | −26.864 | 12.352 | 0.0351 | −20.147 | 12.352 | 0.1101 |
| Progesterone (ng/ml) (p < 0.0001) | −12.063 | 1.529 | <.0001 | 0.042 | 1.529 | 0.9784 | −0.596 | 1.529 | 0.6987 | −0.371 | 1.5701 | 0.8142 | 0.225 | 1.571 | 0.8870 |
Abbreviations: E/P = combined estradiol and progesterone replacement; PMTS = Rating for Premenstrual Tension
Legend to Table 3:
To evaluate the presence or absence of placebo effects on PMDD symptoms, we compared PMDD symptom severity between the one month of single-blind placebo with both the first month of E/P addback (Month 4 v 5), and the last month of leuprolide alone (Month 3 v 4). Additionally, we evaluated differences in PMDD symptom severity during the first month of addback (initial change in E/P levels) compared with symptoms during the subsequent months of addback (when stable levels of E/P had been established) (Month 5 v 6 and 5 v 7). Finally, we compared the last two months of E/P replacement to examine potential differences in PMDD symptom severity during the months when stable levels of E/P had been established (Month 6 v 7). To adjust for multiple comparisons, results with p-values less than 0.005 are considered statistically significant. This is an informal adjustment given the exploratory nature of this study. Values above this threshold are reported but were considered not significant.
Both Premenstrual Tension-self and –rater (PMTS-self and PMTS-rater) scores were significantly increased (more symptomatic) during the first month of E/P addback (month 5) compared with placebo addback (Month 4), as well as with scores during the second and third months of addback (Months 6 and 7). There were no significant differences in symptom severity scores in either PMTS-self or –rater scores between the last month of leuprolide (month 3) and scores during placebo (month 4), and the second-third months of E/P (month 6 and month 7). Finally, PTMS scores in the second month of E/P addback (month 6) and the third month of E/P addback (month 7) also were not significantly different.
Daily Rating Form scores: A pattern similar to that observed in PMTS scale scores was observed for the symptom of irritability. Irritability scores during the first month of E/P addback were significantly increased (more symptomatic) during the first month of E/P addback (month 5) compared with placebo addback (Month 4), as well as with scores during the third month of addback (Month 7). There were no significant differences in irritability symptom severity scores between the last month of leuprolide (month 3) and scores during placebo (month 4), and the second-third months of E/P (month 6 and month 7). Daily severity scores for sadness during the first month of E/P addback were significantly increased compared with the third month of E/P addback (Month 5 v 7). Symptom severity scores in no other months differed significantly.