Beyond Birth Control: The Neuroscience of Hormonal Contraceptives

Abstract

Hormonal contraceptives (HCs) are one of the most highly prescribed classes of drugs in the world used for both contraceptive and noncontraceptive purposes. Despite their prevalent use, the impact of HCs on the brain remains inadequately explored. This review synthesizes recent findings on the neuroscience of HCs, with a focus on human structural neuroimaging as well as translational, nonhuman animal studies investigating the cellular, molecular, and behavioral effects of HCs. Additionally, we consider data linking HCs to mood disorders and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress response as a potential mediator. The review also addresses the unique sensitivity of the adolescent brain to HCs, noting significant changes in brain structure and function when HCs are used during this developmental period. Finally, we discuss potential effects of HCs in combination with smoking-derived nicotine on outcomes of ischemic brain damage. Methodological challenges, such as the variability in HC formulations and user-specific factors, are acknowledged, emphasizing the need for precise and individualized research approaches. Overall, this review underscores the necessity for continued interdisciplinary research to elucidate the neurobiological mechanisms of HCs, aiming to optimize their use and improve women's health.

Figure 1.

Hypothalamic-pituitary-gonadal (HPG) axis. The synthetic hormones in HCs are potent analogs of endogenous estradiol and/or progesterone. While the synthetic estrogen in most HCs is ethinyl estradiol, there are many synthetic progestins used in HCs, one of the more common being levonorgestrel. The primary mechanism of action of HCs is via negative feedback regulation of the HPG axis. HCs act on hormone receptors in the hypothalamus to decrease secretion of gonadotropin releasing hormone which subsequently reduces the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), from the anterior pituitary. Reduced release of gonadotropins in turn suppresses the formation of the follicles at the ovary and diminishes ovarian production of estradiol and progesterone. In doing so, many HCs produce a state of anovulation and acyclicity in the user. Created using BioRender.

Figure 2.

Schematic summarizing structural neuroimaging studies of women using HCs. HCs have effects throughout the brain characterized by macrostructural changes involving both increases and decreases in volume in various cortical and subcortical gray matter brain regions as well as effects on cortical thickness. Created using ggseg R package.