A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy

Abstract

Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE.

Scoping review structured summary: Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms.

Objective: Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable.

Charting methods: After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial.

Results: Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders.

Conclusions: Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.

Keywords: Catamenial epilepsy; Menstrual cycle; Menstrual migraine; Premenstrual dysphoric disorder.

Figure 1.

Graphical depiction of ovarian and luteinizing hormones across an idealized 28-day menstrual cycle (Cycle Day represented on x-axis, where day 1 is the onset of menses, and there is no day 0). “M” represents menses onset, “O” represents ovulation day.

Figure 2.

PRISMA diagram. From three disorder-specific literature queries, we identified N=56, N=21, and N=8 studies for PMD, MM, and CE, respectively, to include in the present scoping review (total study N=85). Studies marked “out of scope” for MM utilize phytoestrogen compounds as the experimental manipulation. Studies marked “out of scope” for CE include two case studies of CE caused by cerebral endometriosis and one case study of C3-type CE.

Figure 3.

Conceptual framework linking PMD, MM, and CE. Premenstrual Mood Disorder, Menstrual migraine, and Catamenial Epilepsy represent three unique menstrual cycle-linked neuroendocrine phenomena. There are distinct pathophysiologies (blue, right-hand side) that can independently cause mood changes, migraines, and seizures. These disorders are not inherently linked to the menstrual cycle. However, they each have subtypes (PMD, MM, CE) that share a biological trigger: the menstrual cycle. In patients with any of these three disorders, we propose that the reproductive and central nervous systems interact abnormally, resulting in hormone sensitivity (red, left-hand side), or an abnormal responsiveness to normal estrogen and progesterone fluctuations.