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

Abstract

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.

Tosun and colleagues (2019) found that progesterone aids smoking cessation among women smokers. Twice daily exogenous administration of 200mg oral micronized progesterone increased rates of abstinence at one month after the initiation of treatment and delayed relapse in women, but not men (1). 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 (2–4). However, the mechanism underlying beneficial treatment effects are unclear. Neurobiological findings have long identified that estradiol enhances drug reward and drug seeking behaviors, interacting with both the reward and stress systems (5–7). Conversely, progesterone has generally been found to attenuate drug reward and seeking (4). However, the translation of these findings to the human literature have been mixed.

Much of the prior work examining the relationship of ovarian hormones to drug use behavior categorized women into dichotomous menstrual phases (luteal vs. follicular) as a proxy for ovarian hormone levels, which was imprecise and led to conflicting findings (8). Recent recommendations have moved the field towards assessing ovarian hormone levels in plasma (9), and as a further refinement, investigators are now modeling dynamic change in ovarian hormone levels across the menstrual cycle. Such investigations have demonstrated that smoking behavior and cessation are associated with dynamic change (i.e., rising progesterone levels and falling estradiol levels) in addition to static levels of ovarian hormones (i.e., high progesterone to estradiol ratios) (10–11).

This raises an interesting hypothesis when considering the Tosun et al. findings. In their study, participants were maintained on stable levels of progesterone (ranging from 3 to 25ng/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 at their lowest. While repeated assessment of ovarian hormone levels were not obtained in Tosun et al (1), 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 progestins have quick clearance, requiring bi-daily administration to maintain stable hormone levels, several long-acting progestin-based contraceptives have been shown to create stable hormone levels (12–14), making them potential targets for further investigation. For instance, pharmacokinetic and pharmacodynamic studies of a single-rod etonogestrel implant have indicated that progesterone levels remain at subovulatory levels for over three years, while estradiol levels initially decrease, returning to normal levels following approximately 6 months (12). Additionally, a 12-week study of depo-medroxyprogesterone acetate demonstrated estradiol levels equivalent to those observed during the early follicular phase, with consistent, albeit low progesterone levels (13). These longer-term progestin-based medications may be especially advantageous for women smokers, given the stable levels of hormones over time combine with the initial suppression of estradiol, which has generally been shown to negatively impact cessation outcomes among women (15). To date, there has been little work examining the impact of oral contraceptives on smoking behavior (16).

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 (1). However, the role of dynamic hormonal changes and smoking has not yet been adequately studied in either preclinical or clinical experiments. This exciting avenue of research warrants further investigation, as such studies may elucidate the underlying mechanisms associated with ovarian hormones, including interactions with reward and stress systems.