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CeMCOR Newsletter July 2024 - Key Concepts From Almost Five Decades of Clinical Research

Key Concepts From Almost Five Decades of Clinical Research

Jerilynn C. Prior BA, MD, FRCPC 

I'm excited to share insights from my (almost) five decades in clinical research, focusing on the importance of studying women's health. Here’s a look at our journey and why it matters.
The Early Days: Curiosity and Collaboration
I have been doing clinical research, meaning with people rather than rats or chemicals, for 47 years. I was curious about bone when I first arrived in Vancouver in 1976 and long before founding the Centre for Menstrual Cycle and Ovulation Research (CeMCOR). I sought out and volunteered to work with Dr. Bert Cameron. He was a trainee of Dr. Harold Copp who discovered calcitonin1 (a hormone from the parathyroid gland that lowers rather that raises serum calcium). Dr. Cameron was a kidney doctor and finding extreme bone problems in those with chronic kidney disease being treated by dialysis. I valued his humble mentorship. Only now, looking for his earlier work, I realized he had studied the accuracy and variability of the only two bone-revealing tools available at the time2.
The Complexity of Clinical Research
When you think about it, clinical research is highly varied and always complex. It involves engaging people, not necessarily with a vested interest, and asking them to do standardized and sometimes difficult things. Volunteers also need to keep careful records or show up at certain times. When you have gathered all the information, you must try to make sense out of often complex and chaotic data. 
It is not as hard to do a single measurement on a lot of people. But I believe that within-person changes over longer periods of time are the most revealing and thus important. That kind of prospective clinical study takes many times longer to do than most laboratory or animal-based experiments. Your “subjects” are ideally free-living humans who volunteer knowing they may be advancing knowledge that will only help someone else.
The Importance of Asking the Right Questions
The most important first step is asking a unique and important research question. That means you must find a question that no one else has asked, or that no one else has answered or studied as comprehensively as you will. That requires extensive reading and tracking of everything anyone has written. I learned early to use a reference manager program. I could read each paper, write key words and make short and important comments outlining the results and critique. By now I have over 25,000 such recorded manuscripts. Using such a programme meant I could find a study again, and instantly know what it was about, and how well or poorly it was done.
Tools and Techniques: Ensuring Accuracy and Reliability
Then you need appropriate research tools. These methods need to be safe for people, and they must be convenient for participants to do. In addition, the tool needs to be not too expensive for you or requiring costly or complex equipment. Once you’ve decided on a tool, you must assess its accuracy (how close it comes to telling you the “truth” that you want to know), and reliability (how variable the result is if you repeat it twice or three times). In addition, if I were asking a participant to do some test, I always did it myself first to experience what it was like. I was planning a bone study, so I once had a bone biopsy—no way was I asking a volunteer to have such a painful and invasive test! 
Initial Research and Tool Development: The Runner Study
My first independent Vancouver research was with women runners in the late 1970s. There was a North American “aerobics” fad at the time, plus women were rallying to be allowed to run longer races than 10 kilometers. I had to create the tools I needed. I don’t remember why, except for a sense of completeness, that I knew ovulation was important. Only after release of an egg was progesterone produced. I wanted to understand not only about cycle length—that would give me an idea of estrogen production—but also about progesteroneI needed to study ovulation. Other than a progesterone blood test that was expensive and very difficult to time right, there was no other way than basal body temperature (BBT) at that time.
I was also upset that the current women runner published studies were short-term, in very young and stressed women, often college/university students living in dorms, staying up all night to cram, and going out partying the next. Results of study after similar study declared that longer distance running caused amenorrhea (no flow for 3 or more months). These studies measured lots of hormones but didn’t assess ovulation or track the length of time progesterone was high, the luteal phase

I confirmed by studying the early literature that progesterone caused the morning temperature to increase3. I also realized early on, by asking university kinesiology student volunteers to plot their first morning temperatures, that BBT was full of errors (even in this educated, science-studying group). And also there was already research showing that the BBT method was inaccurate4

Development and Validation of the QBT© Method
If the temperature increase reflected progesterone, I needed to make it into something accurate and reliable. Working with an MD statistician, Michael Schulzer, we figured women could simply record the temperature (on a list), and if we developed a mathematical way to interpret it, we might have the ovulation tool we needed. The Quantitative Basal Temperature© (QBT©) method took all the temperatures in a single cycle and created a valid statistical way to analyze them. When we found the day at which there was the most difference between two average within-cycles temperatures, we confirmed that these were significantly different. As we were working to develop our ovulation test, I found the now-classical monograph by Rudolph Vollman5 in which he reported on thousands of cycles of rectal first-morning temperature data from about 600 women. He had also developed a quantitative way of analyzing a cycle’s data, called the “mean temperature method.” 
I knew we needed to validate our new quantitative tests of ovulation. At a Canadian sports medicine conference, I learned that a colleague in Halifax was studying running in young women and had funding to do daily mid-cycle blood tests to measure the luteinizing hormone (LH) peak that triggers ovulation. We agreed that they would provide their temperature data which we would analyze independently. We would then compare that quantitative temperature change information with the LH peak6. We found a strong relationship between the LH peak day and the temperature change day. We had validated our QBT© test!
Research Findings and Further Developments
Runner friends of mine and I worked together keeping track of our time and miles of running, and our temperature data. We found that the longest runs were associated with shortening of the luteal phases, although the lengths of cycles and the presence of ovulation stayed the same7. I was even able, with two women friends, one who was training to run her first marathon, and the other who was struggling to become pregnant again, to collect one-year records of changes in cycles and ovulation alongside running distances. We wrote up the data with the two runners as co-authors. When we couldn’t get this study published, we sent it as a letter to the Lancet8. This was “patient-reported data” long before that became a well-funded fad. 
I also got frustrated with the many “disease-suggesting” questions on premenstrual symptom (PMS) tools. I decided to make a simpler kind of daily Menstrual Cycle Diary©. We needed to record more objective cycle things like flow (as soaked normal-sized pads or tampons each day) and cramps on a 0-4 scale. This tool required writing something for each item for each day—a 0 was fine. We included other cycle-related things like fluid retention, frustration and breast tenderness also on a 0-4 scale. We also asked about other daily life experiences but that have no zero. These included changes in breast size, appetite, interest in sex, and feeling of self-worth and energy. Here we used a scale oriented around the woman’s usual (U) with letters higher and lower to show change. I also asked women to keep a record of how many minutes of running or other moderate-to-intense exercise each day plus minutes of things like walking.   
Commitment to Participants
From the start I committed to share results with participants. Interestingly ethics boards still do not require it; for-profit drug studies never reveal anything to “subjects.” We not only always share each participant’s data with them, but also disclose the whole study’s final results. That means long before the study is published, but asking them not to share, or today, not to put it on social media. In the early days we would share study results through a party: one such was a pot-luck spaghetti supper! Later we would hold a gathering just for participants. Currently we use a password protected study-specific section on the CeMCOR website. This sharing of results creates a feeling of teamwork since CeMCOR’s participants are really co-researchers. 
Publishing Challenges and Triumphs
As a recognition of the investment of participants, plus the public funding involved directly or indirectly, I never quit trying to get a research study published. My longest effort so far lasted almost 13 years and more than 25 rejections! We had completed a randomized comparative 1-year study of hot flushes in women who had undergone bilateral surgical removal of ovaries plus their uterus for non-cancer reasons when they were still menstruating. We compared treatment with estrogen (then PremarinÒ) and progestin (ProveraÒ) recording night sweats and daytime flushes daily over one year. Everyone then, and still, knew that estrogen would be far superior. However, the results showed that progestin was as effective at hot flush treatment as estrogen in these women at the very highest risk for severe symptoms. 
I have learned that to become a good clinical researcher requires a lot more than conventional academic smarts. It requires curiosity, determination, and the courage to try out new ideas you think are good. It also needs a commitment to share results with the people you engage as participants by treating them as responsible co-researchers. Finally, a successful researcher, whose results change the current concepts9 must have a stubborn determination to publish and widely share the new and controversial information they have learned, no matter what the barriers10.   
Thank you for being part of the CeMCOR community!
Dr. Jerilynn C. Prior

Reference List:

1. Copp DH, Cameron EC, Cheney BA, et al. Evidence for calcitonin--a new hormone from the parathyroid that lowers blood calciumEndocrinology 1962;70:638-49.

2. Cameron EC, Boyd RM, Luk D. Cortical thickness measurements and photon absorptiometry for determination of bone quality. Can Med Assoc J 1977;116:145-49.

3. Magallon DT, Masters WH. Basal temperature studies in the aged female: influence of estrogen, progesterone, and androgenJ Clin Endocrinol Metab 1950;10(5):511-18. doi: 10.1210/jcem-10-5-511 [published Online First: 1950/05/01]

4. Johansson ED, Larsson-Cohn U, Gemzell C. Monophasic basal body temperature in ovulatory menstrual cycles. American Journal Obstetrics Gynecology 1972;113:933-37.

5. Vollman RF. The menstrual cycle. In: Friedman EA, ed. Major Problems in Obstetrics and Gynecology, Vol 7. Toronto: W.B. Saunders Company 1977:11-193.

6. Prior JC, Vigna YM, Schulzer M, et al. Determination of luteal phase length by quantitative basal temperature methods: validation against the midcycle LH peakClinical & Investigative Medicine 1990;13:123-31.

7. Prior JC, Cameron K, Ho Yeun B, et al. Menstrual cycle changes with marathon training: anovulation and short luteal phaseCanadian Journal of Applied Sport Science 1982;7:173-77.

8. Prior JC, Ho Yeun B, Clement P, et al. Reversible luteal phase changes and infertility associated with marathon training. Lancet1982;1:269-70.

9. Kuhn TS. The structure of scientific revolution. Chicago: University of Chicago Press 1970.

10. Kalidasan D, Goshtasebi A, Chrisler J, et al. Prospective analyses of sex/genderrelated publication decisions in general medical journals: editorial rejection of population- based women’s reproductive physiologyBMJ Open 2022 doi: 10.1136/bmjopen-2021-057854

Estrogen’s Storm Season: Stories of Perimenopause

Estrogen's Storm Season

by Dr. Jerilynn C Prior

New second edition available

Estrogen’s Storm Season is now available in BOTH print and eBook (Mobi and ePUB) versions!

All royalties are recieved in our Endowment fund (overseen by UBC) and support CeMCOR's research and future.

It is full of lively, realistic stories with which women can relate and evidence-based, empowering perimenopause information. It was a finalist in 2006 for the Independent Publisher Book Award in Health.

Purchase your ebook copy via our Amazon Kindle or
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Paperback copies (with updated insert) still available here.

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