Table 2.
Differences in least squares mean (Δ LSM) and standard error of difference (SE) in women with PMDD who responded to Leuprolide (n=12) and then received combined estradiol and progesterone addback: PMDD symptom severity during each of the three months of E/P addback compared with the last month of Leuprolide alone when PMDD symptoms were in remission
| Study Month (M): | M3 V M5 | M3 V M6 | M3 V M7 | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Symptom Rating Scale | leuprolide - E/P(1) | leuprolide - E/P(2) | leuprolide - E/P(3) | ||||||
| Δ LSM | SE | p value | Δ LSM | SE | p value | Δ LSM | SE | p value | |
| PMTS (self) (p = 0.0013) | −3.792 | 0.971 | 0.0003 | −0.458 | 0.971 | 0.6392 | −0.009 | 1.03 | 0.9928 |
| PMTS (rater) (p < 0.0001) | −4.625 | 0.907 | <0.0001 | −0.5833 | 0.907 | 0.5236 | 0.223 | 0.932 | 0.8119 |
| Daily Rating Form | |||||||||
| Sadness (p = 0.0158) | −0.272 | 0.09 | 0.0036 | −0.148 | 0.09 | 0.1051 | −0.004 | 0.091 | 0.9684 |
| Irritability (p = 0.0017) | −0.394 | 0.112 | 0.0008 | −0.212 | 0.112 | 0.0634 | 0.027 | 0.114 | 0.8132 |
| Anxiety (p = 0.3851) | −0.196 | 0.116 | 0.0969 | −0.189 | 0.116 | 0.1085 | −0.058 | 0.118 | 0.6266 |
| Mood Swings (p = 0.5370) | −0.116 | 0.075 | 0.1272 | −0.073 | 0.075 | 0.3351 | −0.077 | 0.076 | 0.3114 |
| Cravings (p = 0.1893) | −0.181 | 0.09 | 0.0484 | −0.038 | 0.09 | 0.6768 | 0.022 | 0.092 | 0.8138 |
| Bloating (p = 0.0445) | −0.306 | 0.131 | 0.0224 | −0.164 | 0.131 | 0.2145 | −0.397 | 0.133 | 0.004 |
| Breast Pain (p = 0.2697) | −0.225 | 0.153 | 0.1484 | −0.255 | 0.153 | 0.102 | −0.324 | 0.154 | 0.0405 |
| Plasma Hormone levels | |||||||||
| Estradiol (pg/ml) (p < 0.0001) | −45.854 | 12.04 | 0.0004 | −52.571 | 12.04 | <.0001 | −72.718 | 12.352 | <.0001 |
| Progesterone (ng/ml) (p < 0.0001) | −12.021 | 1.529 | <.0001 | −12.617 | 1.529 | <.0001 | −12.392 | 1.571 | <.0001 |
Abbreviations: E/P = combined estradiol and progesterone replacement; PMTS = Rating for Premenstrual Tension
Legend to Table 2:
PMDD symptom severity was compared during each of the three months of E/P addback with symptom severity during the last month of Leuprolide alone when PMDD symptoms were in remission. 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.
Month 3 is the last month of leuprolide alone, month 5 is the first month of combined estradiol and progesterone replacement E/P(1), and months 6 and 7 represent the second and third months of E/P(2) and E/P(3) (i.e., stable estradiol/progesterone levels).
Both PMTS-self and –rater scores were significantly increased (more symptomatic) during the first month of E/P addback (month 5) compared with leuprolide alone, whereas 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 the second-third months of E/P (month 6 and month 7).
DRF scores: A pattern similar to that observed in PMTS scale scores was observed for the DRF symptom of irritability. Irritability scores during the first month of E/P addback were significantly increased compared with leuprolide alone, whereas there were no significant differences in symptom severity scores in irritability between the last month of leuprolide (month 3) and scores during the second and third months of E/P (month 6 and month 7). Daily Rating Form severity scores for sadness during the first month of E/P addback were significantly increased compared with the last month of leuprolide. There were no significant differences in the severity scores of any month for the symptoms of anxiety, mood swings, bloating (except between E/P addback month 3 and last month of leuprolide), breast pain and cravings.
Plasma progesterone and estradiol levels were measured by electrochemiluminescence immunoassay at the NIH Clinical Center Department of Laboratory Medicine. The lower limits of detectability for the progesterone and estradiol assays were 0.03 – 0.2 ng/ml and 5.0 – 10.0 pg/ml, respectively.
The Rating Scale for Premenstrual Tension (PMTS) scale consists of both an observer/rater-completed and a self-report rating that measures mood, behavior and physical symptoms on a 36-point scale, with scores > 10 consistent with PMDD symptoms and scores < 5 consistent with the absence of significant PMDD symptoms (51).
Daily Rating Form scores for the core PMDD symptoms of irritability, sadness, and anxiety were evaluated throughout the study. Each evening during the 2–3 months of baseline and during the three menstrual cycles on treatment, all women completed the daily rating form. All women were instructed that the ratings should represent a composite score for the previous 12 hours.