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 https://www.who.int/news-room/fact-sheets/detail/menopause.
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 that “menopausal 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.
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