Animal models for studying the impacts of hormonal contraception

In a recent study published in the Frontiers in Neuroendocrinology journal, researchers assessed the impact of hormonal contraceptives (HC) on the brain and stress.

Hormonal contraceptives have enabled unprecedented levels of reproductive control and various health benefits, including a reduction in premenstrual symptoms and protection from certain cancers. These alterations, including those on mood, are typically benign or even advantageous. However, hormonal contraceptives cause depression or anxiety symptoms in 4–10% of users or as many as 30 million people at any given time. Extensive research is needed to understand how hormonal contraceptives affect these reactions or who is most vulnerable to negative consequences.

Hormonal contraceptives, stress, and the brain: The critical need for animal models. Image Credit: Africa Studio / Shutterstock

The need for animal models

In the present study, the team discussed research on the use of hormonal contraceptives in humans and outlined how laboratory animal models of hormone exposure to contraceptives will be a crucial tool for extending knowledge of the precise mechanisms by which hormonal contraceptives affect the brain, stress responses, and depression risk.

The use of rat and mouse models is crucial for determining the precise cellular, molecular, and circuit-level mechanisms of hormonal effects on behavior and the brain. In laboratory animals, researchers can systematically change the HC formulations, age at which HC exposure begins, history of stress exposure, and interactions between stress and HC use. In addition, the function of individual variances in stress or hormone responsivity can be determined by specific genotypes, including various strains and transgenic animals.

Furthermore, researchers can investigate how HCs affect psychological processes using behavioral models representing anxiety- and depression-like behavior and cognitive processes. To ascertain the precise causative processes by which HCs alter the brain, researchers can directly monitor stress hormone levels in laboratory animals and perform pharmacological manipulations and molecular, invasive surgical, and imaging approaches.

Hormonal effects on the brain

Studies of women and freely cycling female rodents and exogenous interventions provide ample evidence for the physiological effects of estrogens and progesterone on the brain beyond sexual behaviors. For example, in rats and mice, there is significant hormone-dependent regulation of gene expression and chromatin, dendritic spines, plasticity, and cognitive processes like memory, as well as behaviors like motivation, anxiety, fear, and impulsivity throughout the estrous cycle. Similar changes in prefrontal and hippocampal activity, as well as in affective states like anxiety and cognitive tasks like fear extinction, are caused by the menstrual cycle in humans.

Therefore, the study findings that hormonal changes impact a range of measurements are constant across the human menstrual cycle and the rodent estrous cycle. This supports the validity of using animals as models to study the mechanisms underlying the effects of hormones, including HC, on the brain. Future models of mice exposed to contraceptive hormones will be based on the use of animal models to study specific hormone-mediated effects on the brain.

HC effects on mood, anxiety, and depression

Whether contemporary HCs influence changes in mood and raises risks for or rates of anxiety, panic attacks, or depression is still a subject of debate. On the one hand, a majority of people claim that the rates or risk for these diseases have not changed; on the other hand, many believe that using HCs has helped their mood, especially around menstruation. People stop using HC mainly because of the unpleasant emotional effects and mood changes. Depression and suicidality are some of the severe side effects people experience when using HCs.

Understanding the mechanisms behind HC effects on mood and the causality of HC effects found in human studies would require animal models. However, the impact of HCs during adolescence, how androgenic versus anti-androgenic progestins affect risk for depressive-like behaviors, and how known risk factors for depression, such as prior stress exposure, modify risk for depression while using HCs, are all questions that these models are particularly well-suited to address.

Hormonal Contraceptives and the Stress Response

Most studies of HC users showed a blunted stress response, while some had altered basal cortisol levels, which provided an indirect mechanism using which HCs could modulate mood, motivation, and cognition. To fully comprehend the advantages and disadvantages of HCs on the brain, it is essential to consider their function in HPA-axis control. Animal models of HC exposure are well equipped to determine how HCs mediate these effects as well as the molecular mechanisms involved in these alterations, both in the peripheral and in the brain.

Overall, the study highlighted that animal models are essential to address problems raised by studies of HC users and to provoke new questions that human studies can subsequently answer. As a result, animal models will be crucial for comprehending risk factors, variability, and the processes by which HCs influence the brain, formulating plans for more individualized approaches to HC prescribing, and providing a base for research on novel and evolving HCs. 

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.