The short-term effects of estradiol, raloxifene, and a phytoestrogen in women with perimenopausal depression

Abstract

Objective: We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). Methods: Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. Results: Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE—15.3 (4.5), raloxifene—16.0 (3.7), Rimostil—14.0 (2.7), and placebo—15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE—5.2(1.1), raloxifene—5.8(1.2), Rimostil—11.2(1.4), and placebo—7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. Conclusions: This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).

Trifolium pratense L.: uma alternativa para o tratamento de sintomas vasoativos em mulheres pré e pós-menopausa

“…Embora seja usado como suplemento alimentar nesse país, nunca obteve aprovação para uso médico. Schmidt et al (2021) desenvolveram um estudo clínico randomizado para avaliar o efeito sobre a depressão de mulheres no período da menopausa, onde utilizaram 4 grupos: palacebo; estradiol; raloxifene (fitohormônio da classe das benzofenonas) e o suplemento rimostil (isolflavonas isoladas de Trevo vermelho). Neste estudo para avaliar a ação desses produtos na redução da depressão, os autores concluíram que nenhum dos produtos testados demonstraram efeito redutor da depressão peri-menopausa.…”

The effect of hormone replacement therapy on cognition and mood

“…Yalamanchili et al 75 studied older postmenopausal women (65–77‐year‐old) and found no effect of HRT compared to placebo on GDS ( n = 489). A more contemporaneous but small study ( n = 66) by Schimdt et al 76 in 2021 replicated these findings, finding no beneficial effect in any treatment arm when assessing transdermal E2, raloxifene (a selective oestrogen receptor modulator), phytoestrogen or isoflavone. Cohen et al 73 carried out a study on peri‐ or postmenopausal women with a known diagnosis of depression ( n = 22).…”

Hormonal Agents for the Treatment of Depression Associated with the Menopause

“…A study of 62 women with menopause-related depression with MHT randomized to four treatment groups (raloxifene 60 mg/day; a phytoestrogen, Rimostil; transdermal estradiol [TE; 100 μg/day]; or placebo). No improvement in depression was described after the 8-week study for the women in any treatment arm [ 112 ]. The authors concluded “No differences were observed between raloxifene and either TE or placebo in any scale score”.…”