Progestin-only birth control during adolescence linked to impaired fear regulation in adulthood

A new study suggests that hormonal contraceptive use during adolescence may impair the brain’s ability to retain fear extinction memories—a process thought to be important for regulating anxiety. In a series of experiments using female rats, researchers found that a progestin-only hormonal contraceptive disrupted fear extinction during adolescence and into adulthood, while a combined formulation containing synthetic estrogen did not have this effect.

These findings raise questions about how early exposure to certain hormonal contraceptives could influence vulnerability to anxiety-related difficulties later in life. The research has been published in the journal Hormones and Behavior.

Hormonal contraceptives are medications commonly used to prevent pregnancy, regulate menstrual cycles, or manage conditions such as endometriosis and acne. They often contain synthetic versions of sex hormones like estrogen and progesterone. These compounds suppress the natural production of hormones by interfering with the body’s reproductive signaling pathways. While generally considered safe and effective, researchers have increasingly examined whether hormonal contraceptives may influence brain development and mental health.

“There is a sex bias in preclinical research on anxiety. Despite anxiety disorders being nearly twice as common in women compared to men, data analyzed in the Graham lab showed that, as of a few years ago, only 32% of anxiety research included females, and only 7% studied females specifically,” explained study author Madison Brooke of the University of New South Wales.

“Preclinical research on anxiety disorders often examine extinction learning in rodents. Rodents will be trained to associate a neutral cue (like a tone), with something fearful (like a shock). After repetitive exposures to the tone and shock together, rodents become fearful of the tone itself. Extinction learning involves repetitively exposing the rodent to the tone alone, so that the tone is no longer associated with anything fearful. Extinction learning therefore demonstrates that ability to regulate fear.”

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“It’s important to correct this sex bias, as sex-specific factors like female sex hormones (estrogen and progesterone) are important for extinction learning. While we often think of these hormones in the context of their reproductive function, these hormones are synthesised in the brain, and during adolescence they are critical for the development of brain regions that are involved in fear and extinction learning.”

“Hormonal contraceptives lower the production of natural sex hormones, and studies in adults consistently demonstrate (in rodents and women) that these hormones are important for extinction learning, such that hormonal contraceptives impair extinction learning in adults,” Brooke explained. “But despite many hormonal contraceptive users starting during adolescence, no research had looked at their effects on extinction during this developmental period.”

Brooke and the senior author of the study, Bronwyn M. Graham, conducted four experiments using adolescent female rats. In these experiments, they tested the effects of two types of hormonal contraceptives: a high dose of levonorgestrel, which models a progestin-only contraceptive, and a combination of levonorgestrel with ethinyl estradiol, which represents a combined oral contraceptive.

The rats were treated with one of these two hormone formulations—or a control substance—for nine days starting on postnatal day 35, a developmental stage corresponding to early adolescence in rats. After treatment, some rats underwent fear conditioning and extinction training during adolescence, while others underwent the same procedures as adults, two weeks after the hormone treatment had ended.

Fear conditioning involved pairing a sound with a mild foot shock, teaching the rats to associate the sound with threat. During extinction training, the sound was played repeatedly without the shock, allowing the rats to learn that the stimulus was now safe. Retention of this extinction memory was later tested by measuring how much the rats froze—a common fear response—when hearing the sound again.

The research team also used hormonal assays and examined vaginal cytology to confirm whether the treatments disrupted natural hormone cycles. In additional experiments, they used a behavioral test known as the elevated plus maze to assess whether the hormone treatments influenced general anxiety-like behavior.

Across both adolescent and adult testing conditions, rats that received levonorgestrel alone showed impairments in extinction retention compared to controls. This means that these rats continued to freeze more in response to the conditioned sound, suggesting they had difficulty learning that the sound no longer signaled danger. These impairments persisted even after the levonorgestrel treatment had ended and natural hormone cycling had resumed.

In contrast, rats treated with the combined levonorgestrel and ethinyl estradiol formulation did not show these impairments. In some cases, these rats even exhibited improved extinction retention compared to controls, depending on when they were tested and the stage of their reproductive cycle.

“Adolescence appears to be a vulnerable window where hormonal contraceptives produce lasting extinction impairments,” Brooke told PsyPost. “As difficulties in regulating fear can increase the risk of developing anxiety disorders, this can have important implications for the development and persistence of anxiety disorders in adolescent hormonal contraceptive users (even beyond cessation). In addition, as extinction learning is the basis for exposure therapy – the gold standard treatment for anxiety disorders – this could have implications for treating anxiety in women who began hormonal contraceptives as adolescents.”

“Importantly, these effects do appear to be formulation dependent – that is, we found differences between a combined formulation (akin to the combined oral contraceptive) and a progestin-only formulation (akin to progestin-only contraceptives like the IUD or the minipill). More research needs to be done to determine whether these effects are specific to the type of synthetic hormones used in our study, the dose used, or both!”

“Ultimately our finding adds to a growing area of research highlighting the need to consider age of usage as a critical factor in research on hormonal contraceptives long-term effects.”

Both hormone treatments suppressed natural hormone levels during the treatment period, but neither produced lasting changes in hormone levels two weeks after the treatments ended. This suggests that the impairments in extinction retention caused by levonorgestrel were not simply due to lower hormone levels.

“The Graham lab has done extensive research demonstrating that sex hormones (estrogen and progesterone) are important for fear extinction,” Brooke said. “Hormonal contraceptives mainly work by administering synthetic versions of these sex hormones, which in turn hijacks females’ reproductive system and prevents the production of natural estrogen and progesterone. It was therefore previously assumed that hormonal contraceptives impair extinction via lowering natural sex hormone levels. However, as we found that both our contraceptive formulations similarly lowered natural sex hormones, but differentially impacted extinction, it suggests that extinction impairments are not simply impacted by natural sex hormones, but may result from exposure to specific synthetic hormones.”

The elevated plus maze results indicated that the hormone treatments did not affect general anxiety-like behavior. This suggests that the effects observed were specific to extinction learning rather than a broad increase in fearfulness or stress.

This study builds on previous work showing that hormone levels affect extinction learning. In adult rats, extinction retention is better when it occurs during high-hormone phases of the reproductive cycle. Similarly, in women, low estrogen levels have been linked to poorer outcomes in exposure-based therapy for anxiety. Hormonal contraceptives can lower natural estrogen levels by suppressing ovulation, raising concerns that they may interfere with this type of learning. The new findings extend this research by showing that the timing of hormone exposure matters.

“What is novel with our research is that we have shown that previous hormonal contraceptive exposure as an adolescent causes’ persistent impairments (beyond usage), whereas existing research has demonstrated that previous hormonal contraceptive exposure as adults, does not lead to persistent extinction impairments,” Brooke said. “Our findings fit with a growing body of research suggesting that adolescence may be a particularly vulnerable period where hormonal contraceptives can produce lasting effects (beyond their usage).”

The researchers suggest that the negative effects of levonorgestrel on extinction learning may not stem solely from hormone suppression but might also involve direct effects of the synthetic hormone on the brain. Levonorgestrel may influence the development of neural circuits involved in learning and emotional memory, such as those in the hippocampus and prefrontal cortex. Another possibility is that levonorgestrel interferes with the stress-regulation system (the hypothalamic-pituitary-adrenal axis), which also undergoes developmental changes during adolescence and plays a role in emotional learning.

But the study, like all research, includes some caveats. The study used animal models, and although rats are useful for studying brain development and behavior, results may not directly translate to humans. The hormone doses and duration of treatment in this study were designed to model specific contraceptive formulations, but human use patterns are more variable and typically involve much longer exposure.

“There are various formulations of hormonal contraceptives and the synthetic sex hormones used in different formulations vary largely according to chemical structure,” Brooke noted. “Here we compared two formulations, but it is likely that the type of progestin used may influence the effects hormonal contraceptives have on extinction. In addition, the window of adolescence in rodents is far shorter than the window of adolescence in humans. As such, it is important to confirm how these results translate to women.”

“Our next step is to translate these results to women. We want to confirm that these effects, observed in rodents, translates to extinction learning and exposure therapies in women. Ultimately, we would like to work out what is driving these effects. Discovering what drives these effects, whether that be identifying specific formulations and dosages, or identifying effects that hormonal contraceptives have on systems involved in extinction learning (e.g. fear circuitry), will allow women to make more informed choices when it comes to selecting hormonal contraceptives, and help develop more effective treatment options for women experiencing anxiety from hormonal contraceptives.”

“It’s important to note that though we found that hormonal contraceptives could impair extinction long-term (and extinction learning is important for the development, maintenance, and treatment of anxiety disorders) it is a small population of women who report experiencing anxiety as a side effect of hormonal contraceptives,” Brooke added. “Our research shows age of exposure, and formulation may be important factors in this, but it’s also important to consider that it is likely not all women who are vulnerable to developing anxiety as a function of dysregulated extinction learning. My hope is that our research will help improve treatment options for the women that are.”

The study, “Birth controlling your fears: The long-term effects of adolescent exposure to hormonal contraceptives on fear extinction in long-evans female rats,” was authored by Madison Brooke and Bronwyn M. Graham.