Impact of hormonal contraceptives on sex differences in fear conditioning and fear extinction in PTSD

Abstract

Sex differences in the neurobiological mechanisms involved in fear conditioning and extinction have been suggested to contribute to differential vulnerability for the development of posttraumatic stress disorder (PTSD) in women compared with men. Reproductive hormones, such as estradiol, have been shown to facilitate fear conditioning and extinction learning and may explain some of these differences. However, the effect of commonly used hormonal contraceptives on the neurobiological mechanisms of fear conditioning and extinction is poorly understood. A laboratory study was conducted in trauma-exposed men and women with and without full or partial PTSD to examine effects of sex and use of hormonal birth control on fear conditioning, fear extinction learning, and extinction retention. Participants underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later, and extinction retention was tested 1 wk after extinction. Women on hormonal contraceptives (HCs) demonstrated enhanced acquisition of fear conditioning and enhanced extinction of fear as compared with women off hormonal birth control and men. While clinical implications have yet to be determined, these results suggest that hormonal contraceptives may facilitate learning during both fear acquisition and extinction. Understanding the impact of sex and hormones on fear conditioning and extinction processes may lead to new insights into the pathophysiology of PTSD and result in advancements in treatment that may vary by sex.

Sex Hormones, Neurosteroids, and Glutamatergic Neurotransmission: A Review of the Literature

“…A negative relationship between salivary estradiol levels and the number of reported PTSD symptoms has been reported in a sample of trauma-exposed women, such that more estradiol was associated with less PTSD symptoms [50]. Exogenous estrogen administration in the form of birth control (synthetic estradiol) has been successfully utilized in order to increase the efficacy of extinction training (which has implications for exposure therapies) in women with PTSD [51]. Naturally occurring low estrogen levels seem to impair extinction learning among women with PTSD [52, 53].…”

Using Translational Models of Fear Conditioning to Uncover Sex-Linked Factors Related to PTSD Risk

“…Women in the low estradiol group did not display either discrimination or inhibition when measured via FPS. A study by Bartholomew and colleagues utilized a trauma-exposed sample and found that women on hormonal contraceptives (low levels of ovarian hormones but higher synthetic hormones) demonstrated a faster time course of fear learning when compared to naturally cycling women who were in the early follicular phase of their menstrual cycle (low estradiol and progesterone) and men [ 42 ]. This study is unique in its comparison of women on hormonal contraceptives and women with low endogenous estradiol and suggest there may be some enhancements in fear acquisition specifically due to synthetic hormones.…”

“…There were no differences in extinction based on PTSD diagnosis among those with high estradiol [ 44 ]. The afore-mentioned Bartholomew study that compared trauma-exposed women on hormonal contraceptives and women in the follicular phase of the menstrual cycle extinguished the previously conditioned fear 72 h after acquisition and found that women on hormonal contraceptives displayed a faster time course of extinction learning suggesting that synthetic hormones from hormonal contraceptives might be impacting both acquisition and extinction learning [ 42 ]. The results with fear acquisition, inhibition, and extinction in clinical samples contrasts with the lack of evidence for any hormonal impact on fear acquisition and extinction seen in community samples.…”

“…Although the differences in fear extinction learning with hormonal contraceptive use was shown using SCR in the Bartholomew study, differences in the learning outcome of acquisition or extinction were not found. The differences found were in the time course of fear and extinction learning which could explain this discrepancy [ 42 ]. Future work examining fear acquisition, inhibition, and extinction learning using FPS in community samples is needed as well as analyses on the time course of learning alongside specific learning outcomes to determine if study differences are responsible for these contradictory results.…”

“…In addition, the ratio of allopregnanolone/pregnanolone to dehydroepiandrosterone (DHEA) levels was positively associated with extinction recall only during the midluteal phase, with some evidence that this was more so in the PTSD group than the non-PTSD trauma-control group [ 46 ]. In the sample comparing women on or off hormonal contraceptives, extinction recall was tested 1 week after extinction, thus this compared women on hormonal contraceptives (low estradiol and low progesterone) to women in the late follicular phase (high estradiol and low progesterone [ 42 ]. Researchers detected an overall effect of sex in that women who were in the late follicular phase displayed lower overall SCR than men, but there was no impact of hormonal contraceptive status on extinction recall itself.…”