, 2008; Allen et al., 2009b; Mazure et al., 2011). However, other studies that used NRT observed improved smoking cessation outcomes in the follicular phase compared Bicalutamide chemical structure with the luteal phase (Carpenter et al., 2008; Franklin et al., 2008). Aside from differences in study methodology, one theory to explain these seemingly discordant observations is that among women smokers who did not use NRT, estradiol (which peaks in the late follicular phase) may enhance the reinforcing effects of nicotine and, therefore, favor relapse. The pre-clinical model has provided strong evidence for this theory indicating that estradiol is associated with the facilitation of drug self-administration, whereas progesterone reduces drug self-administration (Carroll & Anker, 2010; Lynch & Sofuoglu, 2010).

There is evidence indicating that changes in sex hormones may impact the pharmacokinetics of nicotine. This is illustrated by studies showing that exogenous administration of hormones (i.e., oral contraceptives) and clinical situations in which the concentrations of hormones are altered (i.e., pregnancy and menopause) impact nicotine metabolism (Benowitz, Lessov-Schlaggar, Swan, & Jacob, 2006; Berlin, Gasior, & Moolchan, 2007; Dempsey, Jacob, & Benowitz, 2000; Selby, Hackman, Kapur, Klein, & Koren, 2001). Conversely, in a small clinical study, nicotine metabolism did not differ by menstrual phase in non-smoking women (n = 11) who received an infusion of nicotine and cotinine (Hukkanen, Gourlay, Kenkare, & Benowitz, 2005). These conflicting data indicate additional research is needed to more fully characterize the role of sex hormones on nicotine pharmacokinetics.

Risk for relapse is further exacerbated in women who have a comorbidity of depression (Husky, Mazure, Paliwal, & McKee, 2008). Considerable evidence has been amassed to suggest that depression (including both depressive symptomatology and major depressive disorder [MDD]) also plays a significant role in undermining quit attempts in smokers. Numerous clinical studies and population-based surveys have confirmed that the presence of MDD (past or present) is associated with a decreased likelihood of smoking cessation (e.g., Hitsman, Borrelli, McChargue, Spring, & Niaura, GSK-3 2003; Killen, Fortmann, Schatzberg, Hayward, & Varady, 2003; Murphy et al., 2003). This association is of particular concern for women as depressive symptoms are more predictive of smoking behavior in women compared with men (Borrelli, Bock, King, Pinto, & Marcus, 1996; Husky et al., 2008; Pratt & Brody, 2010). The specific mechanisms involved in the increased risk for relapse among smokers with depressive symptoms, especially women, remain unknown.