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CeMCOR Newsletter - March 2023 - Perimenopause and Menopause are NOT the same

If Perimenopause and Menopause are the SAME, so are COVID and Common Flu

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

Let’s start with two short stories.

In November, 2022, you go to your family doctor with 2 days of fever, tiredness and shortness of breath with coughing. You have diarrhea and don’t feel like eating. He checks your forehead, asks if you have a headache and says you have seasonal flu. He tells you to rest, drink a lot, take aspirin or acetaminophen and you’ll soon feel better. The next day your husband calls an ambulance because you are breathless and almost unconscious. You’re admitted to the hospital, a COVID-19 test is positive, and you end up on a ventilator in the intensive care unit.

Should your physician know the difference between COVID and influenza?

You are a 42-year old woman seeing your family doctor with night sweats, sleep problems, tiredness and mood swings. Because she doesn’t ask, she doesn’t learn of your recent heavy flow and regular cycles. She says: “You are having menopausal symptoms” and prescribes Menopausal Hormone Therapy (MHT) 1 with daily estrogen and progestin pills.

Two weeks later you faint while teaching. In the emergency department, doctors admit you to the hospital with an extremely low blood count requiring transfusion. Your legs are swollen. Your blood pressure is high and they treat it with diuretics. They stop MHT when you explain that heavy bleeding has worsened on it. You now feel more energy, but your daily night sweats and mood swings continue. Doctors tell you, “Since you had adverse reactions to MHT, the only night sweat treatment is an anti-depressant or a sleeping pill.

Should physicians know the difference between perimenopause and menopause?

Yes. But many do not.

The difference is simple—perimenopausal women have had flow in the last year.  Menopause, by contrast, is diagnosed when a full year has passed without further menstruation (and this is not explained by anything else), according to the World Health Organization  

Why don’t they know?

They may not have been taught in medical school!

Perimenopause and specific treatment of its night sweats/hot flushes is not covered in the current guidelines 1,2,3-6 . Yet perimenopausal hot flushes/night sweats (called vasomotor symptoms, or VMS) are both more frequent and more intense than menopausal VMS 7.

Heavy flow is also common in perimenopause (a third of women 8). In addition, premenstrual symptoms increase, like sore breasts, inappropriately increased appetite, fluid retention and increased depression 9. Menopause does not cause heavy flow, sore breasts, increased appetite, fluid retention or increased depression 9.

Perimenopause is rarely mentioned when describing “reproductive aging” 10, but even if it is, the assumption is still thatmenopausal symptoms” occur in both perimenopausal and menopausal women 1-6

What’s the main difference between perimenopause and menopause?

A perimenopausal woman has had flow within the last year.

That’s simple, but perimenopause is not. It is complex and unpredictable. The most symptomatic of perimenopausal people wake in the middle of night, have night sweats that may cluster around periods 11, and episodes of heavy flow 8,12. Some will also have breast tenderness, chest pain, palpitations, and report dreaming they are pregnant 13,14. Perimenopausal women also may admit they are struggling to cope, or no longer  feel like themselves 15.

Yes. There ARE similarities between perimenopause and menopause. Both share vasomotor symptoms. They also may share vaginal dryness. In menopausal women that is likely due to lower estrogen levels. In perimenopausal women vaginal dryness usually occurs because they are not interested in sex and don’t become aroused when they have it.  

Despite having VMS in common, these two normal life phases, are hormonally very different. Estrogen levels during regular, premenopausal menstrual cycles (Figure), differ from those in perimenopause.  Estrogen level average higher in perimenopause 16,17.  Most dramatically, estrogen levels are erratically swinging in perimenopause 18. The highs may be double the normal midcycle estrogen peak 19. As estrogen crashes down, it triggers a night sweat. 

Meanwhile, estrogen’s partner hormone, progesterone, has steadily decreasing levels across the many perimenopausal years 20,21. By the time a woman has reached menopause (Figure), her estrogen and progesterone levels are almost as low as in childhood.   


Figure: Mean Estradiol Levels and Variability in Premenopausal, Perimenopausal and Menopausal Women—showing ~one–month changes

Mean values and Standard Deviation (bars) are from the following sources: Premenopause—a meta-analysis in Table 1 published in Prior JC. Endo Reviews 1998; 19:397-428; Perimenopause—same as premenopause; Menopause—a mean of two population-based studies: Pardhe BD. Int J Women's Health 2017:9:781-788, Collins A. Maturitas 1995;20:101-111.


VMS relate to estrogen down-swings, from high to not-quite-so-high 22, as well as from normal to low 23. These estrogen down-swings not only trigger a hot flush, they also release every known neurohormone, cytokine, and stress hormone we can measure 24. VMS are not caused by  “low estrogen levels” 22.

Do we know that MHT is effective for perimenopausal VMS?


No scientific study, such as a randomized, double-blind, placebo-controlled trial (RCT), has been published that showed MHT improved VMS more than placebo in perimenopausal women. Two other perimenopause VMS RCTs have been published. One study in 30 women who reported VMS at baseline, required a progestin-releasing IUD for 50 days followed by adding estrogen gel or placebo treatment for another 50 days. Although VMS significantly decreased within-woman randomized to estrogen, there was no significant VMS difference on estrogen versus placebo 25. This placebo comparison is the essence of an RCT.   A 132-woman strong, 6-month perimenopausal RCT tested low-dose Birth Control Pills 26. It showed no significant difference in VMS on The Pill compared with placebo.

Do we know that MHT is safe in perimenopause?


No RCT of VMS treatment has tested MHT for safety in perimenopausal women.

Yet all the guidelines ASSUME that Menopausal Hormone Therapy (MHT) is both effective and safe for perimenopause as well as menopause 1-6.

Why is MHT prescribed for night sweats in perimenopause when there are no data?

Good question.  Maybe you should ask regulatory bodies like Health Canada or the FDA.

Those who write “menopause symptoms” (seem to) be denying the proven perimenopausal hormonal changes:  higher and erratic estrogen levels 16,17,19, lower and decreasing progesterone levels 17,20,21 and higher stress hormone levels 27,28. They (seem to) believe that VMS are caused by lower estrogen levels. But how could they be, since VMS are happening to still-menstruating women?   

Not only do VMS require a dropping estrogen level, they require an estrogen-acclimatized (or addicted) brain. These estrogen levels repeatedly down-swinging cause higher brain levels of the stress hormone, norepinephrine. Increased central norepinephrine causes our ‘temperature comfort zone’ to become very narrow 29. As a consequence, any room temperature increase, or drinking a coffee, may make us feel hot and sweaty.

In short, hot flushes and night sweats resemble addiction. The brain is “high on estrogen” and goes through withdrawal when estrogen levels drop. Importantly, the same withdrawal may happen when MHT is stopped.  

How does giving the brain more estrogen help VMS? 

It helps the way heroin helps an opioid addict—it (temporarily) provides what the brain is missing. But over half of women who took hormone therapy in the huge American “Women’s Health Initiative (WHI)” menopausal hormone trials had worsened hot flushes/night sweats when they stopped MHT (estrogen alone or estrogen-progestin) 30.  This estrogen withdrawal worsening of VMS was most difficult for women stopping estrogen-only therapy; almost a quarter were so miserable they couldn’t stop 31,32.

Do the guidelines warn women that stopping MHT may make VMS much worse?


Does MHT suppress perimenopausal estrogen levels (as in premenopausal women)?   

No. That’s why perimenopausal estrogen levels are high and erratic—the normal feedback system is no longer working. In younger women taking The Pill or if they were to take MHT, that hormonal therapy will suppress body-made estrogen levels. But in perimenopause, the feedback system is disturbed. This disturbed hormonal feedback, I believe, is on purpose to allow us to “get rid of” the remaining ovarian follicles that could produce a period when we’re pushing 80 16.

In perimenopausal women, when taking placebo or MHT, hot flushes will typically improve, at least for a while, because of the strong effect of belief in treatment. (Placebo responses in VMS controlled trials range from 20-50% improvements 33,34). But perimenopausal women who have adverse effects from MHT may think those experiences are from perimenopause itself. Or they may blame MHT, stop it and never see the prescribing MD. If perimenopausal women do describe worsened symptoms while taking MHT (such as heavy flow, breast tenderness, headaches or migraines), doctors may not believe them. Women with the worst symptoms and the least perimenopausal education and support, may end up unable to work, going on long-term disability 35, and/or develop a deep distrust of physicians and/or Medicine. 

The good news is that severe perimenopausal VMS become better or go away completely (as does PMS), when they become menopausal 35. If hot flushes persist into menopause it is because the hyperactivity of the stress-brain system takes time to settle, or the higher brain norepinephrine levels are maintained by increased life stresses and/or lack of adequate support 28.

Are any therapies proven safe and effective for perimenopausal VMS?


We knew from our menopausal progesterone RCT, published in 2012, that oral micronized progesterone (progesterone) was effective for VMS and improved sleep 33. It was also safe for heart health 36. Stopping progesterone did not increase VMS 37.

Based on that knowledge, and that perimenopausal progesterone levels are decreasing, we postulated that progesterone would be effective for perimenopausal VMS. We performed a Canadian Institutes of Health Research-funded RCT of 3-month’s continuous progesterone (300 mg at bedtime or identical placebo) to treat bothersome VMS. We studied 189 women ages 35-57 years who had menstruated within the last year 38.  That trial was completed in 2017, and showed significantly improved night sweats and sleep in data presented to the Endocrine Society in 2018 38. Progesterone caused no serious adverse events 38. The huge variability of perimenopausal VMS, however, meant that progesterone did not significantly improve overall hot flushes versus placebo—we would have needed to study about 250-300 women 38

In summary—"menopausal symptom” guidelines assume both menopausal and perimenopausal women experience them. They recommend estrogen-based MHT for all women younger than 60 with VMS. They do not mention that MHT has not been proven effective nor safe for perimenopausal VMS or the likely increased in VMS when stopping MHT.

This is not good enough. 

Reference List

1. Yuksel N, Evaniuk D, Huang L, et al. Guideline No. 422a: Menopause: Vasomotor Symptoms, Prescription Therapeutic Agents, Complementary and Alternative Medicine, Nutrition, and Lifestyle. J Obstet Gynaecol Can 2021;43(10):1188-1204 e1. DOI: 10.1016/j.jogc.2021.08.003.

2. Jina R, Rowe T, Dunne C. Managing menopause Part 1: Vasomotor symptoms. BC Med J 2022;64(8):344-349.

3. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2015;100(11):3975-4011. (10.1210/jc.2015-2236 doi) (PM:26444994).

4. Baber RJ, Panay N, Fenton A, Group IMSW. 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric 2016;19(2):109-50. DOI: 10.3109/13697137.2015.1129166.

5. Menopause ACotKSo, Lee SR, Cho MK, et al. The 2020 Menopausal Hormone Therapy Guidelines. J Menopausal Med 2020;26(2):69-98. DOI: 10.6118/jmm.20000.

6. Gynecologists ACoOa. Practice Bulletin - Management of Menopausal Symptoms. Obstet Gynecol 2014;123(1):202-216.

7. Williams RE, Kalilani L, DiBenedetti DB, et al. Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States. Climacteric 2008;11(1):32-43. (PM:18202963).

8. Kaufert PA. Menstruation and menstrual change: women in midlife. Health Care Women Int 1986;7(1-2):63-76. (10.1080/07399338609515724 doi) (PM:3635526).

9. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351-358.

10. Harlow SD, Gass M, Hall JE, et al. Executive summary of the Stages of Reproductive Aging Workshop +10: addressing the unfinished agenda of staging reproductive aging. Climacteric 2012;15(2):105-114. (10.3109/13697137.2011.650656 doi) (PM:22338612).

11. Hale GE, Hitchcock CL, Williams LA, Vigna YM, Prior JC. Cyclicity of breast tenderness and night-time vasomotor symptoms in mid-life women: information collected using the Daily Perimenopause Diary. Climacteric 2003;6(2):128-139. (PM:12841883).

12.  Moen MH, Kahn H, Bjerve KS, Halvorsen TB. Menometrorrhagia in the perimenopause is associated with increased serum estradiol. Maturitas 2004;47(2):151-155. (PM:14757274).

13. Shostak M. Nisa: the life and words of a !Kung woman. New York: Vintage Books, 1981.

14. O'Leary Cobb J. Understanding Menopause. Toronto: Key Porter Books, 2005.

15. Prior JC. Estrogen's Storm Season- Stories of Perimenopause (e-book) 2nd ed. Vancouver, BC: CEMCOR, 2018.

16. Prior JC. Perimenopause: The complex endocrinology of the menopausal transition. Endocrine Reviews 1998;19:397-428.

17. Santoro N, Rosenberg J, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. Journal of Clinical Endocrinology and Metabolism 1996;81:4:1495-1501.

18. Hale GE, Hughes CL, Burger HG, Robertson DM, Fraser IS. Atypical estradiol secretion and ovulation patterns caused by luteal out-of-phase (LOOP) events underlying irregular ovulatory menstrual cycles in the menopausal transition. Menopause 2009;16(1):50-59. (PM:18978637).

19. Burger HG, Dudley EC, Hopper JL, et al. The endocrinology of the menopausal transition: a cross-sectional study of a population-based sample. Journal of Clinical Endocrinology and Metabolism 1995;80:3537-3545.

20. Santoro N, Crawford SL, Lasley WL, et al. Factors related to declining luteal function in women during the menopausal transition. J Clin EndocrinolMetab 2008;93(5):1711-1721. (PM:18285413).

21. Prior JC. The ageing female reproductive axis II: ovulatory changes with perimenopause. In: Chadwick DJ, Goode JA, eds. Endocrine Facets of Ageing. Chichester, UK: John Wiley and Sons Ltd; 2003:172-186.

22. Gangar KF, Cust MP, Whitehead MI. Symptoms of oestrogen deficiency associated with supraphysiological plasma estradiol concentrations in women with oestradiol implants. British Medical Journal 1993;299:601-602.

23. Freedman RR. Physiology of hot flashes. Am J Human Biol 2001;13(4):453-464. (PM:11400216).

24. Kronenberg F, Cote LJ, Linkie DM, Dyrenfurth I, Downey JA. Menopausal hot flashes: thermoregulatory, cardiovascular and circulating catecholamine and LH changes. Maturitas 1984;6:31-43.

25. Santoro N, Teal S, Gavito C, Cano S, Chosich J, Sheeder J. Use of a levonorgestrel-containing intrauterine system with supplemental estrogen improves symptoms in perimenopausal women: a pilot study. Menopause 2015;22(12):1301-1307. (10.1097/GME.0000000000000557 doi) (PM:26575111).

26. Casper RF, Dodin S, Reid RL, Study I. The effect of 20 ug ethinyl estradiol/1 mg norethindrone acetate (Minestrin TM),  a low-dose oral contraceptive, on vaginal bleeding patterns, hot flashes, and quality of life in symptomatic perimenopausal women. Menopause 1997;4:139-147.

27. Woods NF, Mitchell ES, Smith-Dijulio K. Cortisol levels during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. Menopause 2009;16(4):708-18. DOI: 10.1097/gme.0b013e318198d6b2.

28. Fan Y, Tang R, Prior JC, Chen R. Paradigm shift in pathophysiology of vasomotor symptoms: Effects of estradiol withdrawal and progesterone therapy. Drug Discovery Today: Disease Models 2020;32:59-69. DOI: 10.1016/j.ddmod.2020.11.004.

29. Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid BiochemMol Biol 2014;142:115-120. (S0960-0760(13)00153-2 pii ;10.1016/j.jsbmb.2013.08.010 doi) (PM:24012626).

30. Brunner RL, Aragaki A, Barnabei V, et al. Menopausal symptom experience before and after stopping estrogen therapy in the Women's Health Initiative randomized, placebo-controlled trial. Menopause 2010;17(5):946-954. (10.1097/gme.0b013e3181d76953 doi) (PM:20505547).

31. Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA 2005;294(2):183-193. (PM:16014592).

32. Grady D, Ettinger B, Tosteson AN, Pressman A, Macer JL. Predictors of difficulty when discontinuing postmenopausal hormone therapy. ObstetGynecol 2003;102(6):1233-1239. (PM:14662209).

33. Hitchcock CL, Prior JC. Oral Micronized Progesterone for Vasomotor Symptoms in Healthy Postmenopausal Women--a placebo-controlled randomized trial. Menopause 2012;19:886-893.

34. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database SystRev 2004(4):CD002978. (PM:15495039).

35. Prior JC. Perimenopause lost - reframing the end of menstruation. Journal of Reproductive and Infant Psychology 2006;24  (4):323-335.

36. Prior JC, Elliott TG, Norman E, Stajic V, Hitchcock CL. Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women. PLOS One 2014;9:e84698-e84698.

37. Prior JC, Hitchcock CL. Progesterone for hot flush and night sweat treatment - effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. GynecolEndocrinol 2012;28 Suppl 2:7-11. (PM:22849758).

38. Prior JC, Cameron A, Hitchcock CL, et al. Oral Micronized Progesterone Beneficial for Perimenopausal Hot Flushes/Flashes and Night Sweats. Endocrine Reviews 2018;39(2).

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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