SAT-LB003 Nonsmokers Benefit from Lower Doses of an Estradiol/Progesterone Combination: Results of the REPLENISH Trial

• Published in: Journal of the Endocrine Society 2019-04, Vol.3 (Supplement_1)
• Main Authors: Constantine, Ginger, Graham, Shelli, Bernick, Brian, Mirkin, Sebastian
• Format: Article
• Language: English
• Subjects: Steroid Hormones and Receptors
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/js.2019-SAT-LB003

Smoking has previously been reported to result in decreases in estradiol exogenous metabolism 1,2,3 and may influence the efficacy of hormone therapy (HT) in postmenopausal women 2,3 . Importantly, differences in smoking rates among clinical trial populations may also contribute to differences in effects of HT observed across the trials. 2 The REPLENISH trial (NCT01942668) was a 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated 4 doses of TX-001HR (17β-estradiol and progesterone [E2/P4]; 1/100, 0.5/100, 0.5/50, 0.25/50) combined in a single, oral softgel capsule vs placebo in 1835 menopausal women (40−65 y; intact uterus) for the treatment of menopausal, moderate to severe vasomotor symptoms (VMS). The 1 mg E2/100 mg P4 dose is FDA approved as BIJUVA TM (TherapeuticsMD, Boca Raton, FL). In this trial, statistically significant improvements in the frequency and severity of moderate to severe VMS were observed for the two highest doses of TX-001HR (1/100 and 0.5/100) and is reported in detail elsewhere. 4 The objective of this analysis was to assess the impact of smoking on estradiol metabolism by analyzing estradiol and estrone concentrations measured throughout the study and to assess the potential impact on efficacy. The overall percentage of current smokers was higher in the Replenish trial (26%) than in many other trials of HT, making analysis of the impact of smoking on estrogen levels and efficacy possible. Estradiol and estrone concentrations at baseline were similar between current smokers and nonsmokers (former/never smokers) for all treatment groups (active and placebo). However, at Weeks 4 and 12, Months 6, 9, and 12, estradiol (25%-32%) and estrone (30%-36%) concentrations were statistically significantly lower in smokers than in nonsmokers for all active estradiol/progesterone treatment groups (1/100, 0.5/100, 0.5/50, 0.25/50). There were no significant differences at any time point in the placebo group. Efficacy in reducing the frequency and severity of VMS was greater in nonsmokers. When evaluating nonsmokers, the 0.25/50 dose also demonstrated statistically significant improvements at Weeks 4 and 12, with a weekly reduction of greater than 14 hot flushes compared to placebo beginning at Week 4 and sustained through week 12. Results from this large Phase 3 clinical trial demonstrated a significant impact of current smoking on estradiol and estrone concentrations and indicate that non-smokers may