Estradiol levels may influence the success of exposure therapy in women, study finds

A recent study demonstrated that the ingestion of 2 mg of estradiol facilitates the extinction of a fear response but also contributes to its stronger return later. In contrast, the administration of progesterone did not show any effect on fear responses. The research was published in Translational Psychiatry.

Fear conditioning experiments in humans investigate how individuals learn to associate a neutral stimulus (e.g., a tone or light) with an aversive stimulus (e.g., a mild electric shock), leading to the development of a fear response. These experiments typically measure physiological responses, such as heart rate, skin conductance, or brain activity, to evaluate the conditioned fear response. Researchers believe that fear conditioning can help understand mechanisms underlying anxiety disorders, PTSD, and the processes of fear extinction, as these conditioned responses mimic how individuals with these disorders react to situations that trigger fear and anxiety.

In general, females are at a higher risk of developing anxiety and related disorders. Multiple studies suggest that the female sex hormones estradiol and progesterone may influence the development of fear and anxiety responses. These two hormones play key roles in regulating the female reproductive system and are primarily produced in the ovaries.

Estradiol is crucial for developing and maintaining secondary sexual characteristics, regulating the menstrual cycle, and preparing the uterine lining for pregnancy. Progesterone is essential for maintaining pregnancy by stabilizing the uterine lining and preventing contractions that could lead to miscarriage. During the menstrual cycle, estradiol levels peak before ovulation, stimulating the release of an egg, while progesterone rises in the second half of the cycle to support potential implantation.

Study author Michael Kaczmarczyk and his colleagues aimed to examine the effects of administering estradiol and progesterone on the development and extinction of fear responses in healthy women. They hypothesized that administering estradiol before extinction training (a process in which a participant learns to no longer react with fear to a previously fear-provoking stimulus) would enhance extinction learning and reduce the fear response in a later test designed to measure its return.

The study included 116 healthy premenopausal women with no psychiatric, gynecological, or endocrinological conditions. Their average age was 26 years. All participants were tested in the follicular phase of their menstrual cycle, and each received €120 for participation.

In the experiment, participants were seated in front of a monitor while two electrodes were attached to the back of their right hand. These electrodes delivered mild electric shocks, serving as an unconditioned stimulus (a stimulus that elicits a fear response) in the fear conditioning trials. Two additional electrodes were placed on the palm of the left hand to record skin conductance responses (changes in skin conductivity caused by sweating due to fear reactions). Researchers displayed photographs on the monitor showing a lamp that initially remained off. After a brief interval, the lamp would glow yellow, blue, or red for six seconds, followed by a black screen for 15 seconds.

During fear acquisition training on Day 1, participants received electric shocks after the lamp displayed two of the three colors. Through this process, they learned to associate these specific colors with the electric shock that followed, resulting in measurable fear responses, as detected by changes in skin conductance.

On the second day, participants were given three pills to take. There were four possible combinations of pills: placebo only, placebo + estradiol, placebo + progesterone, or estradiol + progesterone. All pills looked identical to ensure participants would not know which combination they received. Participants were randomly assigned to one of these combinations. The estradiol pill contained 2 mg of estradiolvalerat (Gynokadin®), while the progesterone dose was 400 mg, delivered in two pills (Utrogest®; 200 mg each). Two hours after taking the pills, participants underwent fear extinction training, during which lights previously associated with electric shocks were presented but no shocks were delivered.

On the final day, which focused on testing the return of fear, each of the lights was shown five times. This was followed by four electric shocks administered while participants sat in front of a gray monitor screen. Afterward, all three lights were presented again without shocks to assess whether fear reactions had returned. Before and after each training session, participants provided saliva samples, allowing researchers to measure estradiol and progesterone concentrations.

The results showed that participants successfully learned to associate certain lights with electric shocks, as indicated by increased skin conductance responses when presented with the conditioned lights. Estradiol administration on the day of fear extinction training accelerated the extinction process. In participants who received estradiol, the difference in skin conductance responses between lights associated with electric shocks and those not associated was reduced.

However, during the return of fear test on Day 3, participants who had received estradiol showed heightened skin conductance responses to the extinguished stimulus (lights) compared to the previous day. This indicated a stronger return of fear in the groups that received estradiol than in the other groups.

Progesterone administration had no significant effects on fear reactions.

“In our interpretation, exogenous estradiol administration affected the extinction of the conditioned fear response which led subsequently to a stronger return of fear. From a clinical perspective our findings suggest that estradiol levels may have an influence on the success of exposure therapy and could be taken into consideration when planning exposure sessions,” the study authors concluded.

The study sheds light on the effects of estradiol on fear responses. However, the participants were all young women and the study only included reactions to mild electric shock. Results on other demographic groups and looking at stronger fear reactions might differ.

The paper, “Effects of separate and combined estradiol and progesterone administration on fear extinction in healthy premenopausal women,” was authored by Michael Kaczmarczyk, Christian Eric Deuter, Hanna Deus, Anna Kallidou, Christian J. Merz, Julian Hellmann-Regen, Christian Otte, and Katja Wingenfeld.