Low estradiol levels: a vulnerability factor for the development of posttraumatic stress disorder.

t a e t m l t r d s c t a P osttraumatic stress disorder (PTSD) affects millions of people who experience trauma in a given year and women are twice as likely to develop PTSD (1). Many preclinical and clinical studies have used fear conditioning and extinction paradigms to investigate the mechanisms underlying PTSD (2). This paradigm is thought to be a good model for PTSD because fear conditioning resembles the occurrence of a traumatic event and fear extinction forms the basis of exposure therapy, which is a commonly used treatment for anxiety. Elucidating the factors that lead to extinction deficits in PTSD may help to develop novel targets for treatment. Over the last decades, much progress has been made in defining the neural and molecular substrates of fear extinction (2). However, most preclinical studies have used male rodents as subjects, and most human studies have collapsed results across sex or not considered potential influences of menstrual cycle. Recent studies indicate that the natural variance of gonadal hormones across the estrous/menstrual cycle regulates fear responses during fear extinction in both female rats and healthy women (3). The aforementioned studies used healthy women to demonstrate the effect of gonadal hormones on fear extinction. In this issue of Biological Psychiatry, Glover et al. (4) took the important next step to ask: do stradiol levels influence fear extinction in women with PTSD? To answer this question, the authors exposed traumatized omen with and without PTSD to a fear conditioning and extincion paradigm. The conditioned stimuli were colored shapes preented on a monitor, the unconditioned stimulus (US) was an air last directed at the larynx, and fear potentiated startle of the eye link muscle contraction after presentation of the startle probe was sed as a measure of conditioned responding. Fear extinction trainng occurred 10 minutes after conditioning during which the conitioned stimuli were presented but no air blast US was delivered. lood samples were collected before startle testing to assess serum evels of estradiol. Women with PTSD were classified into highand ow-estradiol groups based on the median split of estradiol serum evels. The same was also conducted for the trauma-exposed omen without PTSD. Thus, there were a total of four experimental roups. The results showed that all groups acquired fear during onditioning and extinguished fear during extinction training. owever, PTSD women with low estradiol exhibited significantly levated conditioned responses during extinction training relative o all other groups. Moreover, among women with PTSD, those with ow estradiol had greater symptom severity relative to those with igh estradiol. The authors concluded that low levels of estrogen ight be a vulnerability factor for the development of PTSD in omen with trauma histories. This is an important and fundamenal study because it is the first to assess the involvement of estradiol n fear extinction in a clinically anxious population. The study by Glover et al. (4) extends recent findings demontrating a role for estradiol in fear extinction (3). For example, Chang