Introduction: Endogenous ovarian hormones have been shown to contribute to modulations in cortical excitability (1) inhibition (2), and neuroplasticity (3). However, little is known about the physiological effects of the synthetic versions of these hormones (e.g., ethinyl oestradiol), despite morphological changes in brain grey matter volume occurring with long-term use (4). The contraceptive pill is used by 151 million people world-wide and creates a daily micro cycle of synthetic hormones (~ 4-fold changes, 5), but the neurophysiological effects of these acute changes are yet to be investigated. Accordingly, the aim of this study was to determine the effect of the combined monophasic contraceptive pill on corticospinal excitability and plasticity.

Methods: The study received institutional ethical approval. Seventeen female participants (age: 23 ± 5 years) volunteered to take part, all were long term (45 ± 46 months) combined contraceptive pill users. Participants visited the lab in two pill cycle phases: withdrawal and active. Visits comprised of baseline assessments of corticospinal excitability (motor evoked potential [MEP]/M_max), short-intracortical inhibition (SICI), and intracortical facilitation (ICF) measures, recorded in the resting first dorsal interosseous. Participants then took their pill and after 90 minutes rest assessments were repeated. This was followed by a paired associative stimulation (PAS) protocol, utilising ulnar nerve and transcranial magnetic stimulation (25 ms interstimulus interval) to induce spike-timing-dependent plasticity. To assess the time course of spike-timing-dependent plasticity, measurements were repeated at 15 and 30-minutes post PAS.

Results: Prior to taking the pill, corticospinal excitability (MEP/M_max) was 12 ± 9% lower in the active phase (p <0.001) compared to withdrawal, with no differences observed for SICI or ICF (p ≥ 0.203). 90 minutes after taking the pill, a further reduction in MEP/M_max was observed in the active phase (86 ± 3% pre-pill, p < 0.001), with no change in the withdrawal phase (98 ± 3% pre-pill, p = 0.526). ICF increased pre-to-post regardless of phase (p = 0.007), but there were no changes in SICI (p = 0.347). PAS elicited an increase in MEP/M_max in active only, whereby at 15-minutes (118 ± 5% pre-PAS, p < 0.001), and at 30-minutes responses were facilitated (119 ± 5% pre-PAS, p < 0.001). PAS failed to elicit any facilitation in the withdrawal phase at either 15 minutes (101 ± 5% pre-PAS) or 30 minutes (106 ± 5% pre-PAS, p ≥ 0.424).

Conclusion: The present data contains two novel findings. Firstly, the oral contraceptive has acute neuroactive effects, reducing corticospinal excitability. Secondly, that oral contraceptive users are only able to experience synaptic plasticity during the active pill consumption phase, with blunted responses when not taking the pill. This has potential implications for neurorehabilitation, with individuals potentially needing to consider timing their pill consumption around motor performance.