Exogenous progesterone for smoking cessation in men and women: a pilot double‐blind, placebo‐controlled randomized clinical trial

Abstract

Background and Aims In some clinical studies men and women have been found to differ in their ability to quit smoking, perhaps as a result of progesterone. The primary aim of this study was to provide a preliminary test of whether progesterone (PRO), compared with placebo (PBO), was more effective for smoking cessation in men and women. Design Pilot double‐blind, placebo‐controlled randomized clinical trial. Setting Minneapolis/St Paul metro area, Minnesota, USA. Participants A total of 216 participants were randomized, including 113 men (18–60 years; PRO = 56, PBO = 57) and 103 women (18–50 years, pre‐menopausal with self‐reported regular menstrual cycles; PRO = 51, PBO = 52). Intervention Participants were randomized (1 : 1 within sex group) to either PRO (200 mg twice daily) or PBO. Participants were assigned a quit date approximately 7 days after starting medication (luteal phase for women) and were followed for 12 weeks to assess relapse. Measurements The primary outcome was self‐reported 7‐day point prevalence abstinence (PPA) at week 4. Secondary outcomes included 7‐day PPA at weeks 8 and 12, prolonged abstinence, continuous abstinence, urine cotinine < 50 ng/ml, expired carbon monoxide ≤ 5 parts per million (p.p.m.) and days to relapse. Findings There was a significant difference in 7‐day PPA at week 4 among women [PRO: 18 (35.3%) versus PBO: 9 (17.3%), odds ratio (OR) = 2.61, 95% confidence interval (CI) = 1.04, 6.54, P = 0.041], but not among men [PRO: 13 (23.2%) versus PBO: 12 (21.1%), 1.13 (0.47, 2.76), P = 0.782]. There was some evidence that PRO delayed relapse in women (days to relapse; PRO: 20.5 ± 29.6 versus PBO: 14.3 ± 26.8, P = 0.03) but not in men (PRO: 13.4 ± 25.9 versus PBO: 13.3 ± 23.8, P = 0.69). Conclusions Oral micronized progesterone may aid smoking cessation in women.

Commentary on Tosun et al. (2019): Dynamic changes in sex hormones and smoking cessation

“…Tosun and colleagues (2019) found that progesterone aids smoking cessation among women smokers. Twice‐daily exogenous administration of 200 mg oral micronized progesterone increased rates of abstinence at 1 month after the initiation of treatment and delayed relapse in women, but not men . These results add to a growing literature identifying that the administration of exogenous progesterone may serve as a novel intervention for substance use disorders, including tobacco use .…”

“…In their study, participants were maintained on stable levels of progesterone (ranging from 3 to 25 ng/ml), similar to levels observed during the mid‐luteal phase of the menstrual cycle when naturally occurring progesterone levels are at their highest and estradiol levels are low. While repeated assessments of ovarian hormone levels were not reported in Tosun et al , it is possible that the administration of exogenous progesterone lead to an absence of dynamic hormone change (while maintaining a high progesterone to estradiol ratio), and this may be beneficial for cessation outcomes among women smokers .…”

“…While levels of oral micronized progesterone have quick clearance, requiring bi‐daily administration to maintain the stable hormone levels observed in Tosun et al , several long‐acting progestin‐based contraceptives have been shown to create stable hormone levels without daily administration , making them potential targets for further investigation. For instance, a study of progestin‐based implants has indicated that progesterone levels are typically maintained below 16 nmol/L, while estradiol levels initially decrease to levels observed in the early follicular phase and eventually rise over the course of treatment with the implants .…”

“…The study by Tosun et al . highlights the emerging evidence that sex hormones, specifically progesterone, may have utility in the development of interventions for substance use among women . However, the role of dynamic hormonal changes and smoking has not yet been adequately studied in either pre‐clinical or clinical experiments.…”

Hormonal contraceptive use in smokers: Prevalence of use and associations with smoking motives

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Commentary on Tosun et al (2019): Dynamic changes in sex hormones and smoking cessation There is growing evidence suggesting that exogenous progesterone may improve smoking cessation outcomes among women. We hypothesize that exogenous progesterone administration can result in stable progesterone levels, and that it is the absence of dynamic hormone change that may lead to improved smoking cessation outcomes.

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