Hormonal contraceptive effects on the brain: considering the dual impact of endogenous and exogenous hormone flux

Ultimately, HC neuroscience will need experimentation and longitudinal designs to capture differences in hormone-sensitive symptoms during transition periods such as initiation, withdrawal, and around the HFI. Because people may be differentially sensitive to progestin types, doses, and regimens, as well as associated endogenous hormone fluctuations, head-to-head comparisons of formulations (e.g., comparing those with distinct effects on ALLO) offer an opportunity to elucidate key triggers of COC sensitivity. However, further neurobiological profile characterization of individual progestins is needed. This will allow us to better understand underlying mechanisms of their brain effects, enabling precision prescribing of COCs to minimize adverse effects and maximize benefits.

COC regimen, referring to the schedule of active versus inactive pills (e.g., 21/7, 24/4, or continuous), is another underacknowledged source of variability. Although shortened hormone-free-intervals (HFI) of 24/4 achieve stronger ovarian suppression than 21/7, the HFI is associated with some follicular development (E2 surges) in both regimens relative to continuous use [ 3 ], thus determining the pattern of both exogenous and endogenous hormone exposure. Since studies of PMDD—which is characterized by surge-sensitive symptoms—demonstrate a delay of 1-2 weeks between surge and symptom peak, this introduces complexity in mapping hormone flux to symptoms [ 4 ]. A rare strength of this study’s design [ 5 ] was daily pill-use recording, allowing sensitivity analyses excluding those currently in the HFI. However, since hormone-surge-related symptoms are known to operate on a delay in susceptible individuals, more information is needed about effects of pill-pack transitions (e.g., how many days since the HFI start? How many days since the end? ) and associated measurements of endogenous and exogenous hormone changes. Of note, triphasic regimens introduce additional weekly variability.

Although often treated as a single category, progestins differ markedly in their pharmacologic profiles, impact on ovarian steroid production (i.e., preventing ovulation), and associated neurobiological effects. As reviewed by Pletzer et al. [ 1 ], progestins differentially influence neurosteroids (e.g., ALLO) and neurotransmitters (e.g., GABA, serotonin) that are central to mechanisms of behavioral hormone sensitivity [ 4 ]. For instance, preclinical studies show that levonorgestrel decreases hippocampal ALLO, whereas drospirenone has a neutral effect. This distinction is clinically salient: paradoxical adverse responses to luteal ALLO rise underlie PMDD, a hormone sensitivity disorder for which drospirenone-containing COCs are uniquely efficacious and FDA-approved [ 4 ]. Progestins vary in receptor binding affinities (e.g., desogestrel > levonorgestrel at the glucocorticoid receptor), leading to diverse off-target effects to which individuals may be more or less sensitive [ 1 ]. These differences highlight that progestins should not be considered a homogeneous group, and variability in type may critically shape various hormone-related behavioral symptoms in susceptible individuals.

The authors restricted the sample to individuals using COCs (containing EE + a progestin). This reduces route-related heterogeneity (i.e., excludes intrauterine, transdermal, subdermal methods), but COCs themselves remain highly diverse [ 1 ]. Below, we outline key sources of COC formulation variability that may interact with the findings [ 5 ] and individual differences in sensitivity [ 4 ].