Cardiovascular Impact of the Menstrual Cycle and Contraception - Longitudinal Evaluation

Recently, Caroline Criado Perez highlighted gender bias in her book "Invisible Women: Exposing Data Bias in a World Designed for Men". Perez sheds light on the pervasive bias against women, affecting various aspects of their lives in a world predominantly shaped by male-centric data. Town planning, public transport, car seat belt design, toilet facilities, pension policies, and smartphone tracking apps are among the areas revealing systemic disadvantages for women.

Moreover, women are also disadvantaged in terms of their own health. Menstrual cycle effects have been found for antipsychotics, antihistamines, antibiotics, and heart medications, meaning that dosages can sometimes be inappropriate. Sex differences in pharmacodynamics may also affect cardiovascular medications. This is not without consequences; for example, digoxin therapy is associated with an increase in all-cause mortality among women.

These issues persist because scientific studies dedicated to women are significantly under-represented in research. Sport science research is no exception. While women's sport is slowly but increasingly becoming accessible and popular worldwide, women remain under-represented in scientific studies on sports performance. This is illustrated by the fact that among three major Sports and Exercise Medicine journals, 1,382 articles involve a total of 6,076,580 participants, including 2,366,968 (39%) female participants and 3,709,612 (61%) male participants, with only 4-13% of the articles incorporating female participants exclusively. A primary justification for the lack of female inclusion in sports science research is the limited understanding of hormonal variations during the menstrual cycle.

The gap in female representation in sports science must be addressed. The present study aims to improve understanding of the impact of the hormonal cycle on sports performance among women with and without hormonal contraception. A deeper understanding of hormonal effects on performance may offer widespread benefits for women globally. The menstrual cycle is the sequence of hormonal and physiological changes that occur in a woman's body from the start of one period to the start of the next. Four main hormones regulate this sequence, dividing the cycle into three phases.

Hormonal fluctuations influence numerous physiological systems, and their effects during exercise may have implications for performance. Although several studies have observed performance variation between menstrual phases, others report no effects. At present, the literature lacks consensus, with conflicting results across studies. Due to methodological challenges and constraints, many studies are not sufficiently reliable to be conclusive.

The first phase of the present study aims to conduct a well-structured investigation with minimal confounding factors, employing repeated testing at precise phases of the menstrual cycle. These initial results will also serve as a control condition for the second phase, which focuses on the effects of hormonal contraception on exercise performance.

One method of regulating the hormonal cycle is hormonal contraception, the most common being the pill. This altered hormonal environment differs significantly from that of eumenorrheic women and may impact exercise performance due to changes in ovarian hormone-mediated physiological processes. Studies on oral contraceptive pill (OCP) use and exercise are typically of moderate to low quality. OCP use may result in slightly diminished exercise performance on average compared to naturally menstruating women.

To gain a comprehensive understanding of the effects of the hormonal cycle and hormonal contraception on sports performance, the present study will incorporate multiple test protocols. Three validated approaches will be used: symptom tracking, daily urinary hormone measurement throughout the tested cycle, and blood hormone analysis on each test day. Based on these data, testing will be scheduled during the following three menstrual phases: menstruation, late follicular phase (FP), and luteal phase (LP).

The study will include 60 healthy women: 30 taking a monophasic hormonal pill and 30 not using any form of hormonal contraception. Participants will be matched by age, body mass index (BMI), and activity level. Eligibility criteria include being non-smokers, non-obese, drug-free, and free of any relevant pathologies. Informed consent will be obtained from all participants. The protocol, approved by an ethical review board, ensures participant privacy and data confidentiality. All procedures and potential risks will be clearly communicated, including those associated with physical exertion and blood sampling. Health will be closely monitored throughout participation. The investigators possess extensive experience in conducting similar studies and are trained to ensure participant safety.

Initial procedures will include resting assessments: blood sampling for hormone concentrations, inflammatory markers, and metabolomics, as well as a clinical examination. In a supine position, HRV will be measured under two conditions (controlled and free ventilation) with continuous blood pressure monitoring at the finger (Finapres), ergospirometry, and continuous ECG. These assessments will provide insight into metabolism and ventilation at rest, as well as baroreflex sensitivity and HRV.

Participants will also undergo a metaboreflex test involving dynamic contraction of the forearm flexors followed by three minutes of ischemia. Blood pressure will be monitored continuously at the opposite finger (Finapres), with simultaneous ergospirometry and ECG to assess ventilatory and baroreflex responses.

Following resting and metaboreflex testing, participants will undergo a complete echocardiographic examination at rest, followed by an exercise stress echocardiography (semi-supine left tilt position) and resting lung diffusion capacity measurements. Continuous blood pressure monitoring (Finapres) will be conducted during the cardiopulmonary exercise test (CPET). Upon reaching VO₂max, participants will rest for five minutes with HRV measurement and undergo a final blood draw to assess inflammatory and metabolic markers.

Following physiological testing, participants will complete questionnaires on daily activity, nutrition, sleep, symptoms and pain, menstrual cycle patterns, well-being, and mood. On the following day, a Wingate test will be conducted.

All tests will be repeated during the same three menstrual phases (menstruation, FP, and LP), at the same time of day and under standardized nutrition and sleep conditions.

This research addresses critical factors influencing cardiovascular health. Hormonal fluctuations-particularly those associated with the menstrual cycle-have been linked to variations in blood pressure, heart rate, and vascular responsiveness. Understanding these physiological changes is vital, as they may contribute to conditions such as hypertension, atherosclerosis, and cardiac arrhythmias. It is hypothesized that both natural hormonal cycles and hormonal contraception exert subtle but meaningful effects on the cardiovascular system.

Inclusion criteria

• Female, aged 18 to 35 years.
• Healthy participant.
• Either;

• Current user of hormonal oral contraception for at least 3 months prior to enrollment; or
• Naturally cycling woman not using hormonal contraception.
• Regular menstrual cycles between 26 and 34 days, with no more than 2-3 days variation between consecutive cycles.
• Evidence of ovulation during the menstrual cycle monitoring period.
• Nulliparous.
• Body mass index (BMI) between 18.5 and 25.0 kg/m².
• Able and willing to comply with all study procedures and visits.

Exclusion criteria

• Current smoker or use of nicotine-containing products.
• Pregnancy or breastfeeding.
• History or presence of gynecological disorders.
• History or presence of cardiovascular disease.
• History or presence of neurological disease.
• History or presence of respiratory disease.
• History or presence of musculoskeletal disorders that may affect exercise performance.
• Obesity (BMI >25.0 kg/m²).
• Use of medications known to affect cardiovascular, respiratory, autonomic, or hormonal function.
• Inability or unwillingness to abstain from alcohol and caffeine for 72 hours before each experimental session.