estrogen vs. progesterone: have perimenopause treatments been wrong all along?
10 minute read
problematic symptoms in perimenopausal women usually begin with night sweats that can be more prominent than daytime hot flashes, at least early in perimenopause.
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dr. jerilynn prior vividly remembers her first night sweat – a common but highly disruptive occurrence for women whose hormones are fluctuating as their body changes over time.
“i was still regularly menstruating, and remember it was a dark and cold wee hour of a morning in november,” she says. “suddenly, i was awake and furious. i was ready to blame someone or something. but my bedroom was quiet, my partner wasn’t snoring. i was totally at a loss. and then this wave of heat swept over me and i began to sweat. i took a deep breath, laid back down and tried to get back to sleep.”
the impacts of hormonal changes and night sweats
these events also often mean sweat-soaked pjs and sheets as well, so not much fun when it happens on a regular basis. night sweats are severe hot flashes (also referred to as hot flushes) that can occur at any hour, prior explains.
they often start with a huge brain release of every kind of stress hormone and neurotransmitter we can measure. hot flashes and night sweats bother people (men get hot flashes, too, for example if they are taking testosterone-reducing medicines for prostate cancer) because of reactions to those high brain hormones.
“if you don’t understand what is happening, it is easy to be quite flustered and upset,” prior added. “hot flushes are just frustratingly mysterious, especially when they happen after a sip of wine, or when you are upset at a co-worker, or the clerk in a store.”
understanding perimenopause and its symptoms
prior, a professor of endocrinology at the university of british columbia and the scientific director at the centre for menstrual cycle and ovulation research, has spent years helping women understand and navigate the changing life phases that come with aging as the body shuts down its reproductive abilities. perimenopause usually starts a few years before a woman’s last menstrual cycle, most often for women in their 40s, but symptoms like hot flashes, insomnia, irregular periods, mood changes and vaginal dryness can begin even for women in their 30s. menopause starts a year after not having a period when the chaos of perimenopause hormones, anxiety and stress settle down.
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these distinct stages are important when it comes to treatment.
problematic symptoms in perimenopausal women usually begin with night sweats that can be more prominent than daytime hot flashes, at least early in perimenopause. that’s because the sleep disruption of the night sweats compounds other sleep difficulties common in perimenopause, so the double whammy leaves women exhausted and groggy.
prior has written her own take on perimenopause, estrogen’s storm season, to create awareness that perimenopause can be a physical and emotional rollercoaster that’s often dismissed by doctors.
now she has published a breakthrough study that shows the hormone progesterone, taken in capsule form at bedtime daily, is an effective way to decrease night sweats and improve sleep for perimenopausal women who have menstruated in the last year. results of the canada-wide, four-month trial of the therapy was published this june in scientific reports, turning the conventional, estrogen-based hormone therapy treatment on its head.
up to this point, the thinking has been that all aging women need an estrogen boost. but that is not the case every time, especially in perimenopause.
the two hormones crucial to a woman’s reproductive system are estrogen and progesterone. they are like dance partners, working in a coordinated pattern during the menstrual cycle to collaborate on ovulation and healthy cell function. for women in their late 30s, the body doesn’t produce as much progesterone, and the number and quality of follicles in the ovaries diminishes, which in turn results in a dip in estrogen production and fewer ovulations. when women are in their 40s, the menstrual cycle length and flow can be irregular and unpredictable. and estrogen can either drop or spike higher than normal.
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traditional menopausal hormone therapy (mht) and its limitations
current guidelines for menopausal hormone therapy (mht) reflect the long-held conviction that hot flashes and night sweats are caused by low estrogen levels. these symptoms, referred to vasomotor symptoms, were associated with menopause where estrogen must be low. prior believes that it makes sense to treat with estrogen when you think low estrogen levels cause them and multiple scientific randomized controlled studies have proven that estrogen-dominant therapy is highly effective for menopausal hot flashes.
but, a comprehensive 2019 paper in drugs in context on mht therapy in clinical practice outlines the science that estrogen therapy may not be suitable for women with a history of blood clots, high blood pressure, or history of breast, ovarian or uterine cancer. the paper also lists the risks of long-term use of estrogen linked to breast and other cancers and that blood clots can block the flow of blood to major organs.
and beyond the potential risks, giving more estrogen to someone whose estrogen levels are already high, with the dips and spikes in perimenopause, does not make clinical sense, prior included.
understanding the root cause of night sweats
in fact, prior and her colleagues in obstetrics and gynecology at peking union medical college in beijing reviewed studies focusing on vasomotor symptoms and discovered new evidence on what’s really behind hot flashes and night sweats.
it turns out they’re triggered, not by low estrogen levels, but by a sudden decrease in estrogen – from very high to normal, or from normal to low – all stemming from a brain that has gotten “addicted” to high estrogen levels.
the team published the findings in 2020 in drug discover today: disease models, suggesting a “paradigm shift” in how these symptoms are perceived by the medical community is needed. they also looked at cases where stopping estrogen therapy can create a rebound effect where women find their hot flashes and night sweats actually get worse.
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“when doctors prescribe estrogen therapy for hot flashes, rarely is a woman told that when she eventually gets over her hot flashes and night sweats and stops her estrogen treatment, they may suddenly get much worse,” prior said.
the effect of progesterone on night sweats
how progesterone reduces night sweats and hot flashes isn’t fully understood right now. prior’s theory is that it helps calm the brain. many of the brain chemicals released in a hot flash are stress-type hormones. the most significant stress hormone is norepinephrine, one of the “fight or flight” hormones that the brain makes as well as the adrenal glands (that fire up adrenaline). studies in rats show that when brain norepinephrine is increased, it causes the temperature where an animal is comfortable (not sweating or shivering) to become very narrow, she explains.
“the best evidence we have is that progesterone decreases central norepinephrine levels,” she affirmed, allowing the body to regulate a normal temperature.
the evidence: results from the progesterone study
prior’s study in scientific reports followed 189 women for one month on no treatment and then for another three months with either progesterone (300 mg at bedtime daily) or a placebo. the researchers recorded hot flashes and night sweats, and at the end of the trial, asked women about what changes they perceived in daytime hot flashes, night sweats and sleep.
those responses revealed that night sweats and sleep disturbances were less severe on progesterone. the women also perceived that daytime hot flashes were less intense. in addition they were asked about their periods and didn’t notice a difference on progesterone compared with the placebo.
the researchers included a depression questionnaire at the study start and end, finding that progesterone did not cause depression, something that has been linked with progesterone for decades, prior said. interesting, too, the women on progesterone showed a much bigger decrease in perimenopausal life-interference than women on the placebo.
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the history of estrogen use in menopause
study co-author christine hitchcock, a research consultant in oakville, ont., says the acceptance of estrogen for hot flashes and night sweats hasn’t been widely challenged until this point.
“i think it’s important to know that estrogen was synthesized and commercialized about 60 years before progesterone was synthesized in a format that could be taken by mouth. so there is over half a century of experience and folklore around what estrogen can do for the female body,” she said.
progesterone in oral micronized form (taken by mouth) has been available in europe for medical use since 1980, but it wasn’t available for medical use in canada until 1995 and 1998 in the united states.
based on the fact that women start having heart attacks later than men, at a time when they’re no longer menstruating, one popular idea was that female hormones are protective. the coronary drug project was conducted between 1966 and 1975 to assess the effectiveness and safety of five drugs – two of which were different daily doses of estrogen – to prevent heart attacks.
the estrogen trial was actually cut short because of adverse effects. “the practice was discontinued when it was found that men receiving estrogen had an elevated incidence of myocardial infarction, a finding that suggests that estrogen may promote heart disease,” noted a paper on hormones and heart disease in geriatrics in 1979.the irony, as hitchcock states, is that the researchers didn’t think to consider that maybe that was true in women, too.
instead, she asserts the belief in much of the medical community was that female reproductive hormones, predominantly estrogen, were what made reproductive-age women vital, attractive and healthy. hormone therapy for women who were no longer menstruating was promoted for good health and preventing heart disease, cancer and osteoporosis.
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“it was a huge money-maker because the idea was that women would spend a third of their life paying for hormones to take by mouth in order to prevent hypothetical disease. so it was a preventative therapy and everyone should take it,” hitchcock said.
by 1990, women’s health researchers and women’s health advocates insisted that there be data and evidence before this therapy was prescribed across the board to women who were no longer menstruating. the women’s health initiative was launched in 1991 to look at some of the most common diseases that affect women after menopause (cardiovascular disease, breast cancer, osteoporosis) and find out how to reduce the incidences. more than 160,000 post-menopausal women ages 50 to 79 participated in the 15-year study, making it one of the largest prevention studies involving women in the u.s.
“there had never been a study that big and there will never be another study that big,” hitchcock asserted. “what they did was randomize women so that they could demonstrate what everybody knew, which was that taking hormones was going to make you healthier. and instead, they had to discontinue the study early because they found that taking hormones caused strokes. and it caused blood clots. it actually caused harm. there’s still ongoing cognitive dissonance. people still don’t want to believe it.”
the validation of women’s perimenopause experiences
hitchcock says the other part of these changing life phases for women is validating that what they’re experiencing in perimenopause is real and can be extremely debilitating. she sees women blaming themselves for managing their stress less well because they’re waking up in the middle of the night and they’re feeling rattled by stress in a way that they didn’t used to be. or they’re dealing with the unpredictability of menstrual flow that can be almost unmanageable in quantity and might lead to iron deficiency. “there’s this whole constellation of experiences for a minority of women who may or may not talk to their doctor,” she said.
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and estrogen deficiency should never have been a foregone conclusion for causing these symptoms.
“what we didn’t realize when we were telling ourselves stories about hormones is that women in their reproductive years have them and post-reproductive women don’t have them,” she said. “so we drew a straight line and described perimenopause as a time of declining estrogen, and blamed all of the symptoms on estrogen deficiency. “
progesterone: a solution for perimenopause?
so, is progesterone the potential saviour for women in menopause?
as prior and hitchcock’s study shows, there’s an argument to be made that during perimenopause, adding progesterone as a hormone replacement is replacing the progesterone your body might have made if your ovulation system wasn’t being shut down. it’s helping to reduce symptoms and doesn’t have adverse side effects, study authors say.
“i would just say that progesterone is pretty darned helpful for symptomatic perimenopausal women struggling with heavy flow, sleep problems and premenstrual symptoms,” prior said. progesterone also provides an effective treatment option for the menopausal woman with hot flushes and night sweats who shouldn’t or can’t take estrogen because she has a blood clot, for example. “progesterone makes more sense to me than an antidepressant the flushing menopausal feels she doesn’t need.”
empowering women with knowledge and options
bottom line, prior wants to help women live happy, full lives.
“i really hope that struggling midlife women, when learning results of our study, will ask their health-care providers for a prescription for progesterone. physicians change slowly, so i think the main change in practice will be driven by women themselves. women can now be much happier and more productive during their transitional years.”
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karen hawthorne is a toronto-based writer.
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