To the editor: Twenty-seven years since the Revitalization Act and females remain underrepresented in biomedical research due to the complexities of the menstrual cycle and hormonal contraceptives (HC) (1, 4). In the Point argument, Drs. Wenner and Stachenfeld (6) stressed the importance of considering HC when studying vascular physiology in women. Oral contraceptives (OC) were introduced in 1960 (3) and have rapidly become the most prevalent HC in the United States (∼9 million fertile women; 17%) (2). However, little is known regarding the effects of synthetic sex hormones in human physiology and metabolism. To expand on the concerns raised previously (6), below are key considerations for experimental trials involving OC that aim to uncover sex-specific physiological outcomes:

• Formulation: Progestin-only versus combination pill

• Interactions: Ethinyl estradiol in combination with various progestins

• Acute Dosing: Timing of ingestion

• Chronic Dosing: Monophasic versus biphasic versus triphasic pills? Duration of use?

Due to the unanswered complexities with OC, it remains difficult to conduct highly controlled studies, and effectively one might argue that until more is known about confounding factors related to OC, these women should be studied separately from non-OC users. Since our knowledge of OC is negligible and the vast majority of women are non-OC users (83%) (2), this would enable researchers to better generalize biomedical findings to a larger sample, which is in line with the Counterpoint raised by Stanhewicz and Wong (5). Collectively, unravelling the effects of OC may supersede controlling for menstrual cycle phase when designing experiments to accurately assess physiology in women.