INFLUENCE OF MENSTRUAL CYCLE PHASE ON SMOKING CESSATION TREATMENT OUTCOME: A HYPOTHESIS REGARDING THE DISCORDANT FINDINGS IN THE LITERATURE

Based on the literature demonstrating that female smokers in the premenstrual phase of their menstrual cycle (MC) experience greater nicotine-induced withdrawal (WD) and craving, three investigations into the role of the MC phase in smoking cessation treatment were conducted, with the same initial hypothesis: women who attempt to quit smoking while in the pre-ovulatory phase of the MC will achieve greater success than women who make a quit attempt in the premenstrual phase [1-3].

In line with the initial hypothesis, study 1 (Franklin et al.) found that females who started smoking cessation treatment in the pre-ovulatory phase were more than twice as likely as females in the premenstrual phase to achieve an abstinent outcome [1]. Although non-significant, Carpenter et al. reported similar findings [3]. Contrary to the initial hypothesis and the findings of the other studies, a well-controlled, randomized, prospective study conducted by Allen et al. found that premenstrual females had better treatment outcome success compared to pre-ovulatory females [2]. Here we will discuss only the findings of study 1 (Franklin et al. [1]) and study 2 (Allen et al. [2]).

There were several differences between the two studies (see Table 1). However, one in particular may explain the discordant findings. Study 1 included both nicotine replacement (NRT) and behavioral components, while study 2 was strictly a behavioral study. We propose that protection from WD symptoms provided by NRT at treatment initiation may be at the crux of the apparently discrepant findings.

Table 1.

Characteristics of the two studies, examining the influence of menstrual cycle (MC) phase at initiation of smoking cessation treatment on treatment outcome

	Study 1: Franklin et al. 2008 [1]	Study 2: Allen et al. 2008 [2]
Design	Retrospective	Prospective
Treatment modality	NRT/behavioral	Behavioral
Timed quit attempts	No	Yes
PMS/PMDD excluded	No	No
Included males	Yes	No
End-points	3 days, 9 weeks	≤24 hours, 14 days, 30 days

	Females grouped by menstrual cycle phase at treatment start
	Pre-ovulatory	Premenstrual	Pre-ovulatory	Premenstrual
Subject number	16	21	106	96
Age (years)	33.8 (±8.9)	36.8 (±6.6)	29.0 (±6.4)	30.6 (±6.7)
Education (years)	14.3 (±2.6)	15.4 (±2.9)	13.7 (±2.2)	13.7 (±1.7)
Years smoking	16.2 (±9.2)	19.1 (±6.8)	12.6 (±7.6)	13.6 (±7.0)
Cigarettes per day	24.6 (±8.1)	24.6 (±8.6)	15.8 (±4.7)	17.5 (±6.5)a
Race
African American	25.0%	38.1%	6%	2%
Caucasian	69%	62%	79%	84%
Other
American Indian	0.0%	0.0%	11%	7%
Asian	0.0%	0.0%	2%	4%
Multi	6.4%	0.0%	0%	0%
Hispanicb	0.0%	0.0%	2%	2%
FTND scores	6.5 (±1.5)	7.2 (±1.3)	4.4 (±1.9)	3.8 (±2.1)a
% Abstinent at 1st end-point	81%	48%a	52%	56%
% Abstinent at EOT	69%	29%a	14%	34%a

Note that the percentage of premenstrual females abstinent at both end-points are similar between studies 1 and 2. NRT: nicotine replacement therapy;

PMS/PMDD: premenstrual symptoms/premenstrual dysphoric disorder; lapse, single puff on a cigarette; FTND: Fagerström Test for Nicotine Dependence.

^bReported separately from race.

^aDenotes significantly different between pre-ovulatory and premenstrual females within a study at P ≤ 0.04. EOT: end of treatment.

Our working hypothesis is based partially on the more abundant and consistent preclinical reports demonstrating that addictive drugs are more rewarding during proestrus/estrus, the animal equivalent of the human pre-ovulatory phase [4]. The animal data imply that giving up smoking during the pre-ovulatory phase, when smoking during a lapse would be more rewarding, would eventuate in less favorable treatment outcome. The findings of study 2 are consistent with the animal literature. In study 1, wherein women received NRT, initial lapse rates were reduced in pre-ovulatory females compared to premenstrual females. We suggest that the initial early protection from WD symptoms provided by NRT prevented a lapse from occurring in the pre-ovulatory females in study 1, and therefore prevented the experience of increased reward. In contrast, premenstrual females lapsed, even while protected from WD, possibly a function of the discomfort associated with premenstrual symptoms. In support, although premenstrual compared to pre-ovulatory females were less likely to lapse early in treatment in study 2, the percentage of premenstrual females who were abstinent at the first time-point was similar between studies 1 (48%) and 2 (56%). Further, the numbers of premenstrual females abstinent at end of treatment were similar between studies 1 (29%) and 2 (34%) (see Table 1).

In conclusion, the question may become not only ‘when’ is the best time to quit smoking (pre-ovulatory versus premenstrual) but also ‘how’ (protected from WD symptoms versus unprotected). We acknowledge that an empirical test of our working hypothesis is a double-blind placebo-controlled NRT study wherein females are randomized according to cycle phase. Nevertheless, the findings of these two studies warrant the attention of researchers and clinicians alike.

Continued study is crucial, as women suffer more severe health consequences from smoking than males [5] and have more difficulty in quitting [6], which may be a function of the circumstances surrounding a quit attempt.