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Progesterone in Ovulatory Cycles Likely Prevents Breast Cancer – January 2026 Newsletter

Jerilynn C. Prior BA, MD, FRCPC, Professor Emerita, Endocrinology/Medicine University of British Columbia

New information says that progesterone, decreases human breast cancer cell proliferation https://www.nature.com/articles/s43018-025-01087-x. This is the most cautious and timid of all study designs but dared to test a progesterone-receptor-acting progestin in menstruating women with early breast cancer.

Most of us know someone who has breast cancer and also who has died of it. Breast cancer, unlike heart attacks, affects women in their menstruating years. Yet the experts tell us that heart attacks are the biggest killer of women. But breast cancer often kills us before we are 60.

The problems about understanding the roles of progesterone and estrogen in breast cancer are that, for years, we have struggled with prominent scientists, mostly but not all, who study animals and cells or DNA, who assert that estrogen has nothing to do with breast cancer.

  • Is breast cancer more common in men or in women? In women.
  • Who has higher young adult estrogen levels, men or women? Women. 
  • And did the Women’s Health Initiative (WHI) randomized controlled trial (RCT) of estrogen-only in women who’d had a hysterectomy or bilateral ovariectomy, have the statistical power to show breast cancer risk? No1. That means it is totally irrelevant that that there was no change (not a decrease) in breast cancer risk on estrogen versus placebo in that RCT2.

Some, in a Trump-like inversion of reality, even assert that estrogen treatment saves women and prevents breast cancer3. Also, some basic science investigators still don’t fully realize that progesterone is dramatically different from all progestins (that are synthetic knock-offs of the natural hormone). Some even lump progesterone with progestins and call them all progestogens! I can’t think of a more scientifically and physiologically abhorrent labelling.

I confess for decades that I have thought that too much estrogen without enough progesterone was a risk for breast cancer. After all, we’ve shown Silent Ovulatory Disturbances in 25 to 40% of all studied regular menstrual cycles4 5 that has sufficient estrogen but do not have normal progesterone production. We have been able to study community-dwelling women+ prospectively using our Quantitative Basal Temperature© validated method to assess ovulation and the number of days of high progesterone in a cycle (called the luteal phase). However, no one has accurately studied both cycle lengths and ovulatory characteristics prospectively in population-based studies, and in women followed long enough to document breast cancer.

Here’s the reason for my hypothesis: estrogen and progesterone are essential ovarian hormones in partnership within menstrual cycles that occupy a huge portion in the middle of women’s lives. As early work showed, estrogens produce cell proliferation or growth and multiplication of cells; this cell growth continues as long as estrogen is present6. By contrast, progesterone’s main job is cell maturation, meaning it makes cells more ‘grown up’ and specialized while also controlling estrogen-based proliferation6.

Here’s my open-access review of the synergistic, collaborative and counterbalancing actions of estrogen and progesterone in their radical partnership7. I knew that medroxyprogesterone acetate (MPA) acted through the progesterone receptor (PR) in bone osteoblast cells8. I learned, to my chagrin, having used MPA as a progesterone stand-in before natural progesterone became available, that MPA in estrogen-treated women, increases the risk for breast cancer9. My French colleague and friend, Anne Gompel, discovered that MPA causes breast cell proliferation by acting through the cortisol (or the glucocorticoid) receptor10. This shows how the same progestin can act differently in different tissues. 

That is why it is important that a new, cautious but nevertheless exciting study has shown, in what should be the near-final necessary evidence—progesterone decreases breast cell proliferation—the killer characteristic of breast cancer https://www.nature.com/articles/s43018-025-01087-x. Here’s what these British scientists did—they recruited 198 menstruating women (average age 45) who had early breast cancer and invited them to a less-than-two-weeks RCT during the short window from breast cancer evaluation (assessing its estrogen receptors, making sure there were no metastases) until surgery or some therapy such as aromatase inhibitors (AI) that prevent adrenal and ovarian male-like hormones from being converted into estrogen.

AI is important because estrogen causes breast proliferation; estrogen isn’t just made by the ovarian follicle but also can be made from adrenal stress hormones (DHEA or DHEAS) or from testosterone (made by theca cells in the ovary, and in the adrenal glands). The chemical process called ‘aromatization’ changes their chemistry. The strong AI most often used now as a breast cancer treatment is letrozole which is better at interfering with estrogen’s actions than tamoxifen that we used to use. In this trial, all women took letrozole but two-thirds also took a low or high dose of the progestin, megestrol (MegaceÒ).

The main goal of this study was to see if megestrol (the progestin) with AI would decrease a proliferation marker, called Ki67 more than AI alone. They also wanted to see if megestrol was safe. Letrozole (AI) reduced proliferation by 71%; with megestrol (either dose) it was reduced by 80% (P = .013). The lower megestrol dose (40 mg) was safer than the high (160 mg) dose.

The reason these investigators had the courage to study megestrol, that acts through the breast cell progesterone receptor11, was because cancer cell proliferation can somehow escape from suppression by AI. The current hope is that megestrol can prevent that recurrence of breast proliferation.

Progesterone or Megace will also likely make AI more tolerable. Why? Because AI causes hot flushes and night sweats in spades! It also causes muscle aches and pains—many women suffer and some stop it before they are adequately protected. Decades ago, megestrol, was proven to improve night sweats and hot flushes12.

My hopes are:

  • Someone will now finally do an RCT of AI plus oral micronized progesterone (300 mg at bedtime daily) versus megestrol (40 mg) with outcomes of tumor free survival and control of hot flushes, night sweat and disturbed sleep. 
  • Develop an at-home, inexpensive (less than the cost of a Tim’s coffee), and non-invasive (urine stick or finger prick) test of normal ovulation so that women could do it during flow, cycle by cycle, for years on end. This could finally provide the information needed to show ovulation characteristics cycle by cycle over time in a random sample of the whole population.
  • The British Columbia Generations Project could use a Test of Normal Ovulation to document conditions associated with disturbed ovulation; the British Columbia CARMA-CHIWOS Collaboration (BCC3) in women living with HIV could use the Test of Normal Ovulation to see if stress-related ovulatory disturbances explain their shorter life expectancy despite effective HIV therapies.

Then we would finally learn to prevent breast cancer.

Reference List
  1. Prentice RL, Anderson G, Cummings S, et al. Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 1998;19(1):61-109. DOI: 10.1016/s0197-2456(97)00078-0.
  2. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291(14):1701-1712. (PM:15082697).
  3. Bluming A, Tavris C. Estogen matters. Why taking hormones in menopause can improve women’s well-being and lengthen their lives – without raising the risk of breast cancer. New York: Little, Brown Spark, 2018.
  4. Prior JC, Vigna YM, Schechter MT, Burgess AE. Spinal bone loss and ovulatory disturbances. New Engl J Med 1990;323(18):1221-1227.
  5. Prior JC, Naess M, Langhammer A, Forsmo S. Ovulation Prevalence in Women with Spontaneous Normal-Length Menstrual Cycles – A Population-Based Cohort from HUNT3, Norway. PLOS One 2015;10(8):e0134473. (10.1371/journal.pone.0134473 doi ;PONE-D-15-07557 pii). DOI: 10.1371/journal.pone.0134473.
  6. Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocrine Reviews 1990;11:266-301.
  7. 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. DOI: https://doi.org/10.1016/j.ddmod.2020.11.005.
  8. Prior JC. Progesterone as a bone-trophic hormone. Endocrine Reviews 1990;11:386-398.
  9. Writing Group for the Women’s Health Initiative I. Risks and benefits of estrogen plus progestin in health postmenopausal women: prinicpal results from the Women’s Health Initiative Randomized Control trial. JAMA 2002;288:321-333.
  10. Courtin A, Communal L, Vilasco M, et al. Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells. Breast Cancer ResTreat 2012;131(1):49-63. (PM:21336598).
  11. Horwitz KB, Sartorius CA. 90 YEARS OF PROGESTERONE: Progesterone and progesterone receptors in breast cancer: past, present, future. J Mol Endocrinol 2020;65(1):T49-T63. DOI: 10.1530/JME-20-0104.
  12. Quella SK, Loprinzi CL, Sloan JF, et al. Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 1998;82(9):1784-1788.

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