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CeMCOR Newsletter - May 2022 - If it is not Scientific it is NOT Ethical

If it is not Scientific it is NOT Ethical!
research about menstrual cycle phases

Jerilynn C. Prior BA, MD, FRCPC

Is a “Pill Cycle” the same as a usual menstrual cycle? Some think so!

I was flabbergasted while chairing an American College of Sports Medicine (ACSM) session in the early 1990s, to discover that many of the “menstrual cycle changes” reported during physical activity included participants who were using combined hormonal contraceptives (CHC, or “The Pill”). Worse, that key piece of information was revealed only when authors were specifically questioned. ACMS treated The Pill “cycle” the same as a natural menstrual cycle.

Result—although I continued to be keen to assess reproduction in physically active women1, I discontinued my membership at the ACSM. As well as confusing natural menstrual cycles with Pill cycles, it also promoted “the female athlete triad” that felt very prejudicial to me. Thankfully that is now replaced with the both-sexes-included Relative Energy Deficiency Sport2.

The question:
Can you learn
anything about normal, physiological changes during exercise (or any other experimental condition) in a woman on The Pill whose reproductive system is suppressed by high dose synthetic estrogen?  

The answer is No!

I thought that the problem of confusing a spontaneous menstrual cycle with a “Pill cycle” had disappeared. However, recently, as I participated in a UBC Clinical Research Ethics Board (CREB) session, I reviewed three research proposals, all about assessing complex physiological changes. Two included both young men and women; one studied only women. All were funded by highly competitive Canadian National Science and Engineering Research Council (NSERC) grants. All proposed very sophisticated experiments involving complex technologies in careful, well-referenced details. Given the Science in the physiology objectives, I was shocked to find that all three discussed recruiting women who were taking CHC.

In addition, none of these otherwise excellent research studies described a practical way to determine menstrual cycle phases. The methods need to realistic (taking into account known menstrual cycle variability 3), comprehensive (including a valid measure of luteal phase progesterone), cost-effective, and convenient-for-women. And cycle phase documentation is necessary because of the prevalence of ovulatory disturbances and the hormonally very different follicular and luteal phases of the spontaneous, endogenous menstrual cycle.

One study was examining a specific physiological effect of progesterone. It proposed to compare the outcome in women during the follicular phase (early part of the cycle when estrogen levels are rising but progesterone levels are low) with the luteal phase (following ovulation when progesterone levels are high). However, this study, like the other two, proposed recruiting women ages 19-35 who were healthy, not pregnant or nursing, but could be taking CHC.

In proposing their study design, the researchers made at least six scientifically false assumptions:

  1. A spontaneous menstrual cycle is the same as when a woman is taking The Pill. This is false because endogenous hormone levels will be low (because of high dose synthetic [non-measured] ethinyl estradiol levels) and will look like a woman is menopausal or has had no flow for months (amenorrhea). 
  2. All normal-length cycles are normally ovulatory (with at least 10 days of luteal phase length and normal progesterone levels) 4
  3. Progesterone and synthetic progestins behave the same in every tissue.
  4. Undergraduate women (the group they proposed to recruit) who are often less than 10 years from their first period, are consistently normally menstruating and ovulating 5.
  5. Ovulation always occurs on “cycle day 14” so a serum level on cycle day 21-22 will be “in the luteal phase” and therefore have a high progesterone level 3.
  6. Estradiol (estrogen)has no effect on the physiology they are measuring. Strong evidence supports collaborative or counterbalancing effects of both estradiol and progesterone on every cell and tissue in women’s bodies 6.

In reporting to CREB my assessment of this project, I protested that these researchers could not test what they set out to assess because “there is no progesterone in The Pill.” When I said that, I saw (from faces on Zoom), that some of my CREB colleagues were puzzled. Combined hormonal contraceptives include a synthetic estrogen, in a dose four times higher than in the normal menstrual cycle, and a progestin (a synthetic “knock-off” of progesterone). CHC does NOT include progesterone. Progestins are only required to act like natural progesterone in the uterus. Most progestins have undefined actions in non-reproductive body tissues.  

When I suggested we not approve this study, I was, again, surprised.

The response was: “Do you want to exclude young women from research?”

As a feminist who has sought increased research with and for women for decades, I responded, “No—of course not!”

I explained that we were able to recruit 125 women not using CHC to a menstrual cycle study during the pandemic (when research recruitment was very difficult). Only about a third of young woman, at any one time, are taking CHC today (95% CI 13.4-38.6), It is perfectly possible to recruit for and scientifically study menstrual cycles during use of effective non-hormonal contraception:  a condom or diaphragm, with full dose vaginal spermicide or a copper intra-uterine device. Also, some research participants may be sexually active only with women.

Despite those discussions, many CREB members still thought I was making an unjustifiable demand on the researchers.

The additional reason I felt that study needed to be rejected was because the authors, despite their good physiological science, had no practical plan for assessing the menstrual cycle. They were simply sending women to a biochemistry lab two different times for a blood test for estrogen and progesterone. The protocol did not even say on which cycle days women should be tested.

There is also confusion in the literature. One peer-reviewed paper, to my chagrin, even stated that there is no reason for documenting different menstrual cycle phases when studying vascular function 7.  Others, without scientific documentation of menstrual cycle phases, publish reviews or meta-analyses of “menstrual cycle effects” on everything from doing math, visual perceptions 8, appetite, food preferences 9, blood volume, and sense of smell 10, as well as numerous sport performance measures.  The literature has become littered with “menstrual cycle” nonsense.

However, it IS possible to assess differences in women’s hormonally documented menstrual cycle phases for things like food intake 11, interest in sex 12, and maximal oxygen uptake (VO2max) 13. It is also possible to recruit and retain women documenting cycle lengths and ovulation characteristics over as long as one-two years. These prospective studies have provided new and important information about the negative effects of frequent, silent ovulatory disturbances, that happen within perfectly regular cycles, on bone mineral density changes 4,14,15.

There is also menstrual cycle research guidance in the literature. Someone proposing to study menstrual cycle phases today can readily find information.  Recent peer-reviewed consensus documents clearly describe ways to scientifically document menstrual cycle phases when doing research in sports medicine and in other fields 16,17.        

Menstrual cycle phases and ovulation are fundamental to women’s reproduction, to general health and healthy aging 6. Think about the negative effects on women’s self-worth and on Science if this unique research is not accurate. My instinct says that it would be better to have no information related to women, if it is “Pseudo-Science.”

Women have a fundamental right to accurate scientific information about their unique physiologies. It is right to study both women, men, and those whose gender and/or sex are not binary. It is important to do valid women’s menstrual cycle and ovulation research. But to do shoddy (cycle day only) or totally inappropriate (on CHC) assessments and to call it “science” is unethical. To approve such studies promotes “Pseudo-Equity”.

In studying women’s menstrual cycles, it is NOT a trade-off between Pseudo-Science and Pseudo-Equity. It is unethical to perform physiological research with premenopausal women taking combined hormonal contraception and/or that does not accurately assess the natural menstrual cycle and ovulation.

Reference List

1. Prior JC. Endocrine "conditioning" with endurance training: a preliminary review. Canadian Journal of Applied Sport Science 1982; 7: 149-57.

2. Mountjoy M, Sundgot-Borgen J, Burke L, et al. The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in Sport (RED-S). Br J Sports Med 2014; 48(7): 491-7.

3. Shea AA, Vitzthum VJ. The extent and causes of natural variation in menstrual cycles: Integrating empirically-based models of ovarian cycling into research on women’s health. Drug Discovery Today: Disease Models 2020; 32: 41-9.

4. Prior JC, Vigna YM, Schechter MT, Burgess AE. Spinal bone loss and ovulatory disturbances. New Engl J Med 1990; 323: 1221-7.

5. Nagata I, Kato K, Seki K, Furuya K. Ovulatory disturbances. Causative factors among Japanese student nurses in a dormitory. Journal of Adolescent Health Care 1986; 7: 1-5.

6. Prior JC. Women’s Reproductive System as Balanced Estradiol and Progesterone Actions—a revolutionary, paradigm-shifting concept in women’s health. Drug Discovery Today: Disease Models 2020; 32: 31-40.

7. Stanhewicz AE and Wong BJ. Counterpoint: Investigators should not control for menstrual cycle phase when performing studies of vascular control that include women. J Appl Physiol 1985; 129(5):1117-1119.

8. Peters M, Simmons LW, Rhodes G. Preferences across the menstrual cycle for masculinity and symmetry in photographs of male faces and bodies. PLOS One 2009; 4(1): e4138.

9. Arnoni-Bauer Y, Bick A, Raz N, et al. Is It Me or My Hormones? Neuroendocrine Activation Profiles to Visual Food Stimuli Across the Menstrual Cycle. Journal of Clinical Endocrinology and Metabolism 2017; 102(9): 3406-14.

10. Stanic Z, Pribisalic A, Boskovic M, et al. Does Each Menstrual Cycle Elicit a Distinct Effect on Olfactory and Gustatory Perception? Nutrients 2021; 13(8).

11. Barr SI, Janelle KC, Prior JC. Energy Intakes Are Higher During the Luteal-Phase of Ovulatory Menstrual Cycles. American Journal of Clinical Nutrition 1995; 61(1): 39-43.

12. Macbeth AB, Goshtasebi A, Mercer GW, Prior JC. Does Interest in Sex Peak at Mid-Cycle in Ovulatory Menstrual Cycles of Healthy, Community-Dwelling Women? An 11-month Prospective Observational Study. Women's Reproductive Health 2021; 8(2): 79-91.

13. Lebrun CM, McKenzie DC, Prior JC, Taunton JE. Effects of menstrual cycle phase on athletic performance. Medicine and Science in Sports and Exercise 1995: 437-44.

14. Bedford JL, Prior JC, Barr SI. A prospective exploration of cognitive dietary restraint, subclinical ovulatory disturbances, cortisol and change in bone density over two years in healthy young women. JCEM 2010; 95(7): 3291-9.

15. Li D, Hitchcock CL, Barr SI, Yu T, Prior JC. Negative Spinal Bone Mineral Density Changes and Subclinical Ovulatory Disturbances--Prospective Data in Healthy Premenopausal Women With Regular Menstrual Cycles. Epidemiol Rev 2014; 36(137): 147.

16. Elliott-Sale KJ, Minahan CL, de Jonge X, et al. Methodological Considerations for Studies in Sport and Exercise Science with Women as Participants: A Working Guide for Standards of Practice for Research on Women. Sports Med 2021; 51(5): 843-61.

17. De Jonge XJ, Thompson B, Han A. Methodological Recommendations for Menstrual Cycle Research in Sports and Exercise. Med Sci Sports Exerc 2019; 51(12): 2610-7.

Estrogen’s Storm Season: Stories of Perimenopause

Estrogen's Storm Season

by Dr. Jerilynn C Prior

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