Ovarian steroid hormones exert myriad effects on the brain throughout the lifespan (see (McEwen, 2002, Pletzer et al., 2023, Schiller et al., 2016 for reviews). While these reproductive hormone fluctuations (such as puberty, pregnancy, the menstrual cycle, or menopause) do not lead to clinically significant symptoms in most cases, specific menstrual cycle-linked disorders are triggered by aberrant effects of ovarian hormones on the central nervous system (CNS).

Independent lines of research have established that an abnormal sensitivity to the normal hormone flux of the menstrual cycle drives clinical subtypes of three CNS-mediated disorders: premenstrual mood disorder, (PMD; Epperson et al., 2012); menstrual migraine, (MM; MacGregor, 2007); and catamenial epilepsy (CE; Foldvary-Schaefer & Falcone, 2003). As cyclical hormone levels and patterns do not generally differ in case-control studies between patients of each respective disorder (PMD, MM, CE) and healthy controls, the current best evidence points to some form of abnormal neuroendocrine sensitivity to the menstrual cycle—that is, they may be described as “hormone-sensitive” disorders, whereby individuals have heightened responsiveness or reactions to normal hormone changes. Given the diverse effects of hormones in the brain, the mechanisms of such hormone sensitivities are likely to differ both between and within these traditional diagnostic categories, and are probably best studied dimensionally rather than categorically (Insel et al., 2010). Prior work has reviewed possible shared sex steroid-based etiologies of PMD, CE, and MM, with a focus on the link between sex steroids and the GABAergic neurotransmitter system that modulates CNS excitability (Guille et al., 2008, Smith et al., 2007). Therefore, although PMD, MM, and CE are characterized by unique symptoms and pathophysiologies, they share the menstrual cycle as a temporal, within-person trigger that links reproductive hormones to their CNS disturbances.

Considering this fundamental overlap, we conducted a scoping review of experimental hormone research studies in PMD, MM, and CE in order to identify similarities and differences in research methodology used across these disorders. To our knowledge, while there is a strong body of literature reviewing the potential mechanisms that link menstrual cycle-linked neuroendocrine disorders (Bäckström et al., 2003, Finocchi and Ferrari, 2011, Guille et al., 2008, Reddy, 2022, Smith et al., 2007), there are no existing reviews to date summarizing the hormonal experiments that have been conducted across these topics. We utilize the scoping review format, as the broad goals of scoping reviews include identifying types of available evidence, examining the extent, range, and nature of how research is conducted across fields, identifying gaps in the literature, and assessing if a systematic review is warranted (Arksey & O’Malley, 2005). A scoping review allows us to chart the current state of the experimental clinical literature to inform future research goals, unlike a systematic review, which generally focuses on answering a specific research question and reviewing the quality of included research (Munn et al., 2018).

The structure of this scoping review is as follows: we briefly review clinical diagnosis and assessment practices of each disorder (Section 2), which is a necessary piece of the scoping review given the heterogeneity of methods used for studying menstrual cycle-based neuroendocrine disorders. The bulk of the scoping review (Section 3) will describe the hormone manipulation studies conducted in human subjects with PMD, MM, and CE, with the goal of understanding each field’s primary methods and leading hormone-related hypotheses. Where appropriate, we will identify methodological gaps in the literature (e.g., hormonal manipulations examined in one disorder but not another), and comment on areas where future systematic reviews or meta-analyses are warranted (Arksey and O’Malley, 2005, Pham et al., 2014, Tricco et al., 2016). Section 3 is organized by type of experimental manipulation: (1) trials of combined oral contraceptive (COC) agents, (2) trials of ovulation prevention with GnRH agonists (chemical menopause agents), and (3) trials of miscellaneous hormone manipulations. Finally, we provide a summary (Section 4). In line with the scoping review format, we focus primarily on describing the designs and number of experiments that have been presented in the literature, and do not provide a systematic discussion of the potential mechanisms or specific findings. In summary, our scoping review aims to assess the nature of the current literature in menstrual cycle-linked CNS disorders, highlighting methodological strengths and gaps within disciplines and areas for potential cross-disciplinary collaboration and future work.

The monthly female reproductive cycle (Figure 1), lasting an average of 28 days, is structured around ovulation, when an egg is released from the ovary for the purposes of possible fertilization (i.e., pregnancy), and menstrual bleeding, the shedding of the uterine lining that begins a new cycle (Welt et al., 2022). Hormonal feedback loops between the ovaries and the brain coordinate these recurring events.