Sex, steroids, and fear.

Psychiatric illness is not an “equal opportunity” disease. For example, the lifetime prevalence of posttraumatic stress disorder (PTSD) is twice as high in women than in men. In recent years, gonadal steroids have moved into the spotlight as a potential key to understanding this sex difference in vulnerability to trauma-related and stress-related disorders (1,2). Many preclinical and clinical studies have implicated ovarian hormones, including estrogen and progesterone, in the modulation of fear and anxiety in women (2). In particular, these hormones play an important role in fear extinction, a form of learning thought to underlie therapeutic interventions that reduce fear in patients with PTSD (1). Ovarian steroids and their metabolites are targets for the development of novel therapeutics for stressrelated disorders (ClinicalTrials.gov Identifier: NCT01339689). As discussed by Glover et al. (1), ovarian hormones play an important role in modulating fear extinction, a form of learning involved in the suppression of learned fear responses. For example, extinction of contextual and auditory fear conditioning is facilitated by estrogen in rodents and humans (2,3). Women in the luteal phase (high circulating estrogen) of the menstrual cycle have stronger extinction recall compared with women in the early follicular phase or on oral contraceptives (low circulating estrogen) (2). In addition to estrogen, progesterone and its neuroactive metabolite, allopregnanolone, have been shown to modulate anxiety and fear. Progesterone treatment in intact female rats facilitates extinction recall (2). A synthetic analogue of allopregnanolone, ganaxolone, has also been shown to facilitate extinction in mice (4). Although progesterone in women has not been linked to enhanced extinction recall (2), it has been implicated in various psychiatric disorders, including major depressive disorder and premenstrual dysphoric disorder (5). The fact that estrogen and progesterone can regulate extinction learning is of particular relevance to PTSD, insofar as patients with PTSD exhibit exaggerated conditioned fear responses (6). Yet there is an enigma: Sex differences in vulnerability to PTSD do not directly correspond to sex differences in estrogen levels. Low estrogen is correlated with deficits in extinction in women but not in men (2). Glover et al. suggest that the key is not absolute levels of estrogen, but rather fluctuations in estrogen levels, that give rise to sex-specific susceptibility. The regulation of fear conditioning and extinction by ovarian steroids in women may account for sex differences in these forms of learning (Figure 1). For example, female rodents exhibit lower levels of conditioned fear and more rapid fear extinction than male rodents, and this effect is mitigated by ovariectomy and restored by estrogen administration (3). However, at least in rodents, sex differences in fear conditioning and extinction are limited to shock-paired contexts. Discrete conditioned stimuli or “cues” support similar levels of fear in male and female rats (2,7,8) and in humans (2), although high estrogen states during extinction training result in weaker extinction recall (Figure 1). A critical gap in the