This is the first study to assess daily fluctuations in waking cortisol, progesterone, and estradiol alongside changes in mood and craving across one complete menstrual cycle, in CD females over their first month of abstinence compared with HC females. CD females showed significantly higher levels of cortisol and progesterone, and significantly lower estradiol to progesterone (E2/P) ratios across their menstrual cycle compared with controls. Furthermore, these hormonal fluctuations were accompanied by higher ratings of negative mood in CD females compared to HCs.
Such increases in subjective and hormonal stress markers across the menstrual cycle may also be indicative of hormonal adaptations in response to cocaine withdrawal and abstinence in CD females. For example, the acute effects of progesterone and its metabolite allopregnanolone have been shown to exert anxiolytic and antidepressant-like properties via GABAA
receptors (for review, see Bitran et al. 1995
; Brot et al. 1997
; Rupprecht 2003
). In animal models, allopregnanolone has been shown to be stress responsive and play a homeostatic role in restoring normal GABAergic and HPA axis function. Notably, allopregnanolone has been shown to reduce alcohol withdrawal symptoms in voluntary and chronic alcohol-drinking rats (Martin-García et al. 2007
) as well as reduce prenatal stress (Zimmerberg and Blaskey 1998
) and cocaine-induced kindling in mice (Leskiewicz et al. 2003
). In humans, high levels of both progesterone and allopregnanolone have been observed in schizophrenia (Marx et al. 2006
) anxiety and panic disorders (Brambilla et al. 2003
) as well as after laboratory manipulated panic (Eser et al. 2005
It may be the case then, that increased levels of progesterone in early abstinent CD females potentially represent a compensatory adaptation to an enhanced distressed state, characterized in the current sample, by increased levels of cortisol and enhanced negative mood. Consistent with this explanation, recent preliminary data from our laboratory indicate that high luteal-phase progesterone levels in CD females is associated with lower stress and drug cue-induced craving (Sinha et al. 2007
). Moreover, previous human studies have shown that increased progesterone levels, achieved either by artificial exogenous administration or by testing women during different phases of their menstrual cycle, have attenuated subjective response to either acute administration of cocaine (Evans et al. 2002
; Evans and Foltin 2006
; Sofuoglu et al. 2002
) or stress response (Del Rio et al. 1998
). Clearly, although a more comprehensive assessment concerning the role of progesterone in modifying stress-related craving in CD females is warranted current findings do indicate that perturbations in steroid hormone levels continue after 1 month of abstinence and may be associated with relapse vulnerability.
CD females also demonstrated significantly lower E2/P ratios across their menstrual cycle compared with HCs, reflecting the significantly increased progesterone levels particularly during the follicular and ovulation phases. Although little is known regarding the specific pathophysiological consequences of low E2/P ratios, one possibility is that it may eventually culminate in progesterone deficiency and adrenal exhaustion (Studd 2006
). While stress-related increases in neurosteroids such as progesterone and allopregnanolone may be adaptive at first, the longer-term consequences of these agents may have opposing effects resulting in increased anxiety (Gulinello and Smith 2003
). Repeated biological adaptations to stress have also culminated in depleted basal levels of allopregnanolone as well as blunted response to stress in depressive disorders and premenstrual dysphoric disorder (PMDD; Girdler and Klatzkin 2007
; Romeo et al. 1998
). Importantly therefore, persistently high progesterone levels and low E2/P ratios may eventually predispose females to increased anxiety, reduced tolerance for stress, mood swings, and agitated depression (Fiad et al. 1996
; Kaplan and Manuck 2004
). As these stress-related behaviors are associated with abstinence symptoms and relapse susceptibility in recently abstinent CD patients (Kampman et al. 2004
; Sinha et al. 2006
), the current hormonal neuroadaptions may have important implications for relapse susceptibility in women.
In view of this, it is also notable that reduced E2/P ratios in the premenstrual or late luteal phase were associated with increased cocaine craving. While lower ratios were also associated with increased negative mood in the HC females, this was not observed in the CD sample. One tentative explanation for such associations during the premenstrual phase may be because of the fact that the late-luteal phase has been characterized by endogenous progesterone withdrawal in humans (Herzog 1995
; Moran et al. 1998
) and associated with both increased anxiety (Gallo and Smith 1993
; Smith et al. 1998
) and insensitivity to the potentiating effects of GABA-modulatory drugs (Gulinello et al. 2001
). Hence, GABAergic neuromodulatory mechanisms specific to the late-luteal phase may enhance E2/P ratios and craving during early cocaine abstinence.
Notably, limited associations were observed between craving, negative mood, and hormonal changes across the menstrual cycle in both CD and HC females. Disparity between subjective and biological data, particularly across numerous time points, is a common issue and consistent with previous findings (Back et al. 2005
; Cohen et al. 1995
) and may reflect the existence of semi-independent behavioral and neurovegetative stress systems which impact different aspects of adaptation to distressing situations (Fox et al. 2006a
; Sinha et al. 2003
CD females in the current sample experienced cocaine craving at equivalent levels across all four menstrual phases. It is interesting to note that the levels of cocaine craving did co-vary with negative mood as evidenced by the strong positive correlations between mood and craving in the follicular and luteal phases. As such, increased levels of progesterone, cortisol, and negative mood may represent important hormonal and emotional adaptations underpinning the cocaine abstinence state during the initial 4 weeks of abstinence. Most importantly, elevations in morning basal cortisol may represent overactivity of the CRF-HPA axis and subsequent impaired HPA and emotional response to stressors and drug-related cues, both of which have been shown to be gender-specific (Back et al. 2005
; Fox et al. 2006a
) and predict relapse factors in cocaine-abusing populations (Sinha et al. 2006
Some limitations of the current study should be noted. Compared with HC females, CD females reported a higher prevalence of lifetime alcohol dependence as well as mood and anxiety disorders. Findings may therefore reflect the combined effects of alcohol and cocaine use and psychiatric comorbidity on hormonal fluctuations. It is important to note, however, that CD females receiving any type of prescribed medication for either detoxification purposes or any current
psychiatric/medical condition were excluded from the study. Another caveat pertains to the fact that while the CD females were tested in a highly controlled environment across the 28 days, this was not the case for the HC females. Although CD females stayed on a locked hospital unit and were largely protected from day-to-day hassles and stressors, there may have been some aspects of inpatient units that could also be considered stressors. It is therefore conceivable that these differences in context could have contributed to the group differences observed in neuromodulatory function. In the present study, no hormonal verification of MC day was used to corroborate the self-report data; however, our subsequent findings show that the daily pattern of progesterone reflects the normal pattern of variation observed across the menstrual cycle (Gandara et al. 2007
). Current findings are also preliminary due to the small participant sample and may account for the lack of menstrual cycle effect on subjective ratings of craving and mood. Future research may also benefit from daily, rather than weekly assessment of mood to provide a more sensitive marker of hormonal modulation of affect across the menstrual cycle.
Previous human and preclinical studies have shown that both acute (Mantsch et al. 2003
; Quiñones-Jenab et al. 2000
) short-term (Zhou et al. 1999
) and, in some cases, long-term (Sarnyai et al. 1998
) cocaine use culminates in increased progesterone and HPA axis activity. As such, secondary analysis was performed in the current study to investigate more clearly the impact of both cocaine consumption and abstinence on hormonal fluctuations first, by correlating drug consumption variables in the three months before in-patient entry with hormonal changes and second, by examining hormonal changes as a function of study day rather than MC day. It is interesting to note that changes in hormonal levels in the current sample of CD females were not significantly correlated with drug consumption variables in the 3 months before in-patient entry. Moreover, no effect of study day was observed in relation to hormonal changes in cortisol, progesterone, or E2/P ratios.
It is clear therefore that further research is warranted to fully examine the nature of these neuroendocrine perturbations in early abstinence from cocaine and ascertain whether the hormonal and emotional elevations observed in the current study are reflective of excessive cocaine use or represent adaptive markers of a protracted abstinent state. Nonetheless, the current findings highlight alterations in the daily fluctuation of sex and stress steroid hormones in recently abstinent CD females compared with HC females. Most importantly, these neuroadaptations could have important implications for understanding cocaine abstinence symptomatology and relapse susceptibility in women.