by Dr. Jerilynn C. Prior BA, MD, FRCPC
This article originally appeared in the Centre for Menstrual Cycle and Ovulation Research's newsletter on January 23, 2024
We hear a lot about “estrogen deficiency” and all of the negative things that are supposedly related to it (1). We blame low estrogen levels for hot flushes and night sweats (together called vasomotor symptoms or VMS) (2,3), and also for bone loss (4). Some describe a state of “estrogen dominance” meaning estrogen is too high for the amount of progesterone, or that progesterone is too low. Or, we may accurately consider high estrogen levels to cause breast tenderness or increased stretchy cervical mucus. But did you know that dropping estrogen levels are now linked to perimenopausal depression?
My intent here is not to make concepts more complex but more accurate. For a start, all brain-directed hormones are released in pulses (similar to nerve impulses). That is why a single blood test for estrogen, progesterone, testosterone or prolactin may sometimes seem very strange. But the estrogen changes we will discuss here are big-time compared to those every-day, brain-pulse ones.
Downswings in estrogen of 50 to 100% cause major changes in our experiences and also in our health.
New evidence says that downward changing estrogen levels are perceived as threats. When estrogen levels drop, all manner of stress and brain hormones are released. The evidence is now that dropping estrogen levels are related to bone loss, vasomotor symptoms, and perimenopausal depression. We’ll briefly discuss each here.
Bone loss and down-swinging estrogen levels
The normal menstrual cycle has changing levels of estrogen; estrogen rises to a high mid-cycle peak (220% above baseline), a smaller peak after ovulation, and then decreases to low levels during flow (5). Sophisticated markers of bone resorption show that there is loss of bone during the second half of the menstrual cycle as estrogen levels decrease (6). That is why we need to ovulate (and thus release progesterone) to increase bone formation and prevent bone loss (7).
We learned in the 1960s and 1970s that estrogen treatment prevented bone loss (8). However, around that same time, one of the pioneers in osteoporosis, Dr. Robert Lindsay, showed that there was very rapid bone loss when estrogen treatment was stopped (9). That meant that, after eight years, a woman treated with estrogen for four years, then off estrogen for four more, would have the same bone density as if she hadn’t been estrogen-treated at all (9)!
Hot flushes/night sweats and dropping estrogen levels
Many describe low estrogen levels in perimenopause and menopause as causing night sweats or daytime hot flushes or VMS (2). However, children and younger men have “low estrogen” levels compared with menstruating women, yet they don’t get VMS. It turns out that women’s brains need to be exposed to high estrogen levels (as in the menstrual cycle, or on hormone therapy) before they get VMS. The best example of that is a study of women in England who were being treated for VMS with a shot of estrogen that was supposed to last six months (3). The doctors were mystified and frustrated when women started coming back after five months with “flushes, sweats, mood swings and irritability” they called “estrogen deficiency symptoms” (3). Investigating, they measured these women’s estrogen levels—they were as high as or higher than the mid-cycle estrogen peak (3)! Because the estrogen shot gave extremely high levels for a few months, VMS started again as estrogen levels dropped despite being at still-high levels.
Perimenopausal depression and skydiving estrogen levels
Not every perimenopausal woman becomes depressed, no matter how symptomatic she may be with sleep problems, heavy flow, night sweats or migraine headaches. However, we have known for decades that estrogen levels are highly variable in perimenopause (10,11). But the evidence is now secure that more perimenopausal women become depressed than in pre-menopause or menopause (starting a year after the last flow).
How do we know that depression in perimenopause is related to an estrogen dive? The best evidence is from a study by Peter Schmidt from the USA’s National Institutes of Health. He found a number of women who, for the first time, became depressed during perimenopause; these women were now non-depressed in menopause (12). With their permission, he decided to do an experiment—he treated two groups of women with estrogen. The first were those who had previously experienced perimenopausal depression and the others were similar-aged menopausal women who had never been depressed. After some weeks of estrogen treatment, he switched half of each group to placebo estrogen (that was inactive but looked the same). Those for whom estrogen levels dropped who had previously experienced perimenopausal depression reported significantly increased depressive symptoms, but the others on placebo did not (12). The women who stayed on estrogen therapy had no symptom changes (12). Another study in Canadian perimenopausal women showed that depressive symptoms were increased if the standard deviation (measuring estrogen variability) was greater (13).
‘The time has come, the walrus said. . .’ to think about changes in estrogen levels, especially down-swinging ones, when we think about women’s health. We already know that dropping from the normal estrogen mid-menstrual cycle causes a small increase in bone loss. But what happens when women who have been treated with estrogen-dominant menopausal hormone therapy (MHT) suddenly stop treatment? About 25% have severe increases in VMS and often find themselves unable to stop MHT (14). When progesterone therapy was stopped following a randomized controlled menopausal hot flush trial, by contrast, over one full month VMS had not yet increased to pre-treatment levels (15).
Might premenstrual symptoms, and postpartum depression also relate to dropping estrogen levels? We don’t yet know.
Learn More
If you are interested and/or concerned, feel free to use CeMCOR’s Menstrual Cycle Diary© to track your experiences and take your morning temperature, analyzed by Quantitative Basal Temperature© to assess ovulation.
Support this Work
Why not help CeMCOR continue our important work! Donate: https://www.cemcor.ubc.ca/donate
Reference List
1 Prior, J. C. Is Estrogen Deficiency Really a Thing? The catch-all term plays into a cultural notion that estrogen is what makes a woman a woman. Sci Am (2021).
2 Marsh, M. S. & Whitehead, M. I. Management of the menopause. British Medical Bulletin 48, 426-457 (1992).
3 Gangar, K. F., Cust, M. P. & Whitehead, M. I. Symptoms of oestrogen deficiency associated with supraphysiological plasma estradiol concentrations in women with oestradiol implants. British Medical Journal299, 601-602 (1993).
4 Eastell, R. et al. Postmenopausal osteoporosis. Nat Rev Dis Primers 2, 16069 (2016). [https://doi.org:10.1038/nrdp.2016.69]https://doi.org:10.1038/nrdp.2016.69
5 Nielsen, H. K., Brixen, K., Bouillon, R. & Mosekilde, L. Changes in biochemical markers of osteoblastic activity during the menstrual cycle. Journal of Clinical Endocrinology and Metabolism 70, 1431-1437 (1990).
6 Kalyan, S. & Prior, J. C. Bone changes and fracture related to menstrual cycles and ovulation. Crit Rev.Eukaryot.Gene Expr. 20, 213-233 (2010).
7 Li, D., Hitchcock, C. L., Barr, S. I., Yu, T. & Prior, J. C. Negative Spinal Bone Mineral Density Changes and Subclinical Ovulatory Disturbances--Prospective Data in Healthy Premenopausal Women With Regular Menstrual Cycles. Epidemiol Rev 36, 137-147 (2014).
8 Meema, S., Bunker, M. L. & Meema, H. E. Preventive effect of estrogen on postmenopausal bone loss. A follow-up study. Archives Internal Medicine 135, 1436-1440 (1975).
9 Lindsay, R., Hart, D. M. & MacLean, A. Bone response to termination of oestrogen treatment. Lancet 1, 1325-1327 (1978).
10 Burger, H. G. et al. The endocrinology of the menopausal transition: a cross-sectional study of a population-based sample. Journal of Clinical Endocrinology and Metabolism 80, 3537-3545 (1995).
11 Prior, J. C. Perimenopause: The complex endocrinology of the menopausal transition. Endocrine Reviews 19, 397-428 (1998).
12 Schmidt, P. J. et al. Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial. JAMA Psychiatry 72, 714-726 (2015).
13 Gordon, J. L., Peltier, A., Grummisch, J. A. & Sykes Tottenham, L. Estradiol Fluctuation, Sensitivity to Stress, and Depressive Symptoms in the Menopause Transition: A Pilot Study. Front Psychol 10, 1319 (2019). [https://doi.org:10.3389/fpsyg.2019.01319]https://doi.org:10.3389/fpsyg.2019.01319
14 Grady, D., Ettinger, B., Tosteson, A. N., Pressman, A. & Macer, J. L. Predictors of difficulty when discontinuing postmenopausal hormone therapy. Obstet.Gynecol. 102, 1233-1239 (2003).
15 Prior, J. C. & Hitchcock, C. L. Progesterone for hot flush and night sweat treatment - effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. Gynecol.Endocrinol. 28 Suppl 2, 7-11 (2012).