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Progesterone (not Estrogen) for Hot Flushes in Perimenopausal and Menopausal Women

In less than a year, two influential articles reporting on consensus recommendations for therapy of “menopause-associated” and “menopausal” symptoms have been published (1) (JSOGC, February, 2006). Both of them conclude that estrogen (with or without progestin) is the optimal therapy. Both the Canadian (JSOGC, February, 2006) and the USA’s National Institutes of Health (1) statements recommend hormone therapy for symptomatic midlife women. The symptoms to which these statements primarily refer are hot flushes/night sweats (also called vasomotor symptoms or VMS) but the Canadian statement also specifically includes “mood swings.” Both statements recommend hormone therapy with as low a dose as possible and for as short a time as possible. I agree with that. However, I strongly disagree with estrogen therapy for hot flushes in perimenopause, when estrogen levels are still potentially high.

The purposes of this article are to propose that progesterone therapy is an equally or more effective hot flush/night sweat therapy than estrogen and to show that progesterone is safer than estrogen or estrogen with progestin (a synthetic cousin of progesterone) therapy.

However, before I can explain why estrogen therapy should not be used for symptoms in perimenopause, I need to clarify what those two consensus statements are really saying, to make clear distinctions between the hot flushes that are difficult in perimenopause and those that need therapy in menopause, to discuss what we know about the risk factors for and life pattern of hot flushes for the women who experience them, and finally, to present the evidence showing that progesterone is effective for hot flushes.

Who gets hot flushes and how long do they last?

First, what are the natural patterns of hot flushes? Almost two thirds of women have hot flushes/night sweats in the final year of perimenopause, these continue for two years on average, but have gone away for all except 10-20 percent in the five years following menopause (2). Women with the most hot flushes are those who are stressed (especially those who have trouble paying for basic needs like food and housing) and have lower education levels (3). Asian women living in the USA appear to have fewer hot flushes than Caucasian women and African American women to have more (3). Although, when occupation is similar for Caucasian and African American women, this racial difference disappears (4). It is now well documented that night sweats disturb sleep and that sleep problems worsen in perimenopause and may get better as women become menopausal (5). When sweats and flushes chronically waken a person, work effectiveness often suffers and there is a significant risk for developing depression (6).

A primer on midlife definitions and confusing language

With that background on night sweats and hot flushes, we can start to discuss the USA and Canadian consensus recommendations for “menopausal symptoms.” Both statements are (purposefully?) vague about what women should be treated for symptoms—“menopausal” and “menopause-associated” imply to most physicians, perimenopause as well as (post) menopause (one year without flow). What the consensus statements are saying is confusing because of the many meanings for the word “menopause.” Most women say they are “in menopause” when they start to experience anything that’s different. In other words, women say they are “in menopause” when they mean perimenopause. However, two official statements, define “menopause” as the literal final menstrual period (7;8). Yet, only when a year has passed without more flow is there a 95 percent probability that no more periods will occur (9). By that point, one year past the final period, estrogen levels are no longer thirty percent higher than normal, as they are in perimenopause, and have settled into their rather stable, normal low levels (10).

How does CeMCOR define perimenopause and menopause?

The Centre for Menstrual Cycle and Ovulation Research has adopted one year past the final menstrual period as the definition of menopause, and the time of changes before that as perimenopause (11;12). (See CeMCOR’s overviews of normal perimenopause and menopause characteristics.) To complete the definitions, official bodies call the time after the maybe-maybe not-final period as “postmenopause.” We don’t use “postmenopause” because it is a negative kind of double-speak and may totally overlap with the final year of perimenopause. We use the terms perimenopause and menopause as they are defined here.

Are hot flushes the same in perimenopausal and menopausal women?

Hot flushes are basically the same in perimenopausal and menopausal women but do show some differences in patterns. Women with the most severe VMS are those who were still menstruating before surgical menopause (removal of ovaries as well as uterus) (13), perhaps because the drop in estrogen levels is so major and so abrupt. In both perimenopausal and menopausal women, stress (from economic insecurity, environmental chaos) makes VMS worse (14;15). By contrast, in perimenopause, having current or past premenstrual symptoms and being heavier (3;16;17) are associated with more hot flushes. This probably because both premenstrual symptoms and higher body mass index are related to higher perimenopausal estrogen levels. In menopausal women, being skinny and smoking may make hot flushes more likely because, in women with these characteristics, menopausal estrogen levels drop to lower values.

Estrogen’s low in menopause, and high in perimenopause—why flushes in both?

Hot flushes occur in both perimenopause and menopause, yet hormone levels are very different. Why? Hot flushes appear to be caused by dropping estrogen levels when the brain has been exposed to, and gotten “used to” higher estrogen levels. Therefore the hot flushes in perimenopause occur because of the big swings in estrogen from super- high to merely high, or even from high to normal. In menopause, hot flushes occur because estrogen levels have become low after the normal levels of the menstruating years and the higher levels of perimenopause. Although no one has tracked the life experience of hot flushes within a woman, as opposed to in categories of women, I suspect that most women who are going to get hot flushes—except those with surgical menopause or who stop estrogen therapy—start having them before they are officially menopausal.

What’s the evidence that progesterone is good for hot flushes?

Although estrogen is the strongest known therapy for hot flushes in menopausal women, decreasing their number by 77% (18), there is strong evidence that synthetic cousins of progesterone are also effective. Medroxyprogesterone, like estrogens, is effective for hot flush control in the best kind of scientific study, the randomized placebo-controlled trial (19;20). However, the literature contains very few reports in which estrogen is tested against progestin for hot flush control in the same trial. Two studies that were randomized but both women and scientists knew who was taking what, tested high levels of estrogen similar to those in birth control pills against male-hormone derived progestins (21;22). Estrogen and estrogen/norgestrel (a progestin) were more effective than norgestrel alone, but all of the therapies including any hormone were more effective than placebo (21). Norethindrone, another progestin, however, was less effective than either of two high estrogen doses and not different from placebo (22). In a better, blinded, randomized controlled trial we tested conjugated equine estrogen (Premarin 0.6 mg/day) against medroxyprogesterone (Provera, 10 mg/d) and showed that they were equally effective (23). The large study comparing all controlled trials of estrogen against placebo, also showed that estrogen with progestin was even stronger than estrogen alone—combined hormones decreased hot flushes by about 90% (18).

So far we have been discussing trials of progestins for hot flushes. However, two trials have tested natural progesterone as a cream, against placebo for hot flushes in menopausal women (24;25). The first tested 20 mg of progesterone cream twice a day against placebo and showed a significant reduction in hot flushes (24). The second tested 32 mg once a day of progesterone or placebo and found no significant improvement in hot flushes (25). That suggests that you need at least 40 mg of progesterone cream each day for effective menopausal hot flush control.

What about progesterone or progestin therapy for hot flushes in perimenopausal women?

Basically there is almost no evidence in treatment of hot flushes in perimenopause (18)! Given that hot flushes begin in perimenopause, this is astonishing. We do know that the Pill containing 20-ug of estrogen with progestin was not significantly better than placebo in one randomized controlled trial (26). No other trial of either estrogen or progesterone has clearly tested hot flush control in only perimenopausal women. However, we have personal, practical experience from treating a large number of perimenopausal women, that progesterone alone is effective for their hot flushes.

Problems with the consensus recommendations

Now, having discussed definitions of menopause and perimenopause, the life history and risks for hot flushes, and the evidences about treatment we can evaluate these consensus recommendations. The NIH consensus stated that “menopausal symptoms are higher in early and late perimenopause than in pre- or postmenopause” (1).What they mean by “menopausal symptoms” is not clearly defined but can be understood as anything that a symptomatic perimenopausal woman with 30 percent higher, erratic estrogen and lower progesterone levels may experience! The Canadian consensus statement made sure that we would understand that they were talking about perimenopausal as well as menopausal women when discussing “menopausal symptoms” because they mentioned both hot flushes/night sweats and mood swings (that don’t occur for menopausal women).

Progesterone therapy is effective for hot flushes and safer for menopausal women

I’ll discuss the different issues for perimenopause in the next section. There are at least four reasons why I think that progesterone is equally effective as estrogen and safer for treatment of hot flushes in menopausal women. It is very clear that pill forms of estrogen therapy are effective treatment for hot flushes in menopausal women (18).

The reasons I believe that progesterone is preferable to estrogen for menopausal women with hot flushes are detailed below.

  1. Progesterone is probably similarly effective as estrogen for hot flushes. Ideally we would have a blinded randomized therapy trial directly comparing progesterone and estrogen for hot flushes. The first reason I prefer progesterone to estrogen for hot flush therapy is that it has been shown to be effective for hot flushes. Progesterone cream in a low dose of 20 mg twice a day effectively controlled hot flushes (24) although it is the only well designed study of bio-identical progesterone that has been published. (We are currently doing a double blind 5-month randomized placebo-controlled trial of Prometrium® 300 mg at bedtime versus an identical placebo.) However, progestins (synthetic hormones derived from progesterone) have repeatedly been shown to significantly improve hot flushes in randomized double blind placebo-controlled trials (19;20;27) and with similar 85-95 percent improvements as estrogen.
  2. Progesterone has a “side effect” that it significantly improves deep sleep (28) thus particularly helping night sweats and one of the major reasons VMS interfere with women’s well being. (Progesterone cream and progestins don’t help sleep).
  3. Stopping estrogen therapy causes a rebound increase in the number and severity of hot flushes and night sweats to greater than they were initially (29). There is no evidence from clinical experience (although the definitive study has not yet been done) that stopping progesterone or progestin leads to a similar rebound increase in VMS.
  4. Estrogen or estrogen with low dose medroxyprogesterone increases the number of abnormal mammograms and need for further investigation. It is likely, although not proven, that progesterone alone would not do that.
  5. Estrogen or estrogen/progestin increases the risk for many diseases such as blood clots and strokes, gall bladder disease, incontinence and dementia as well as the more publicized increased risk for heart attacks and breast cancer (30;31). By contrast, these adverse effects are not seen with progesterone or most progestins. In particular, progestins “caused only minor effects on coagulation and fibrinolysis” (Kuhl, Maturitas, 1996) meaning no risks for blood clots that estrogens, especially in a pill form, increase.

Therefore, progesterone therapy should be recommended for menopausal women with intense hot flushes not adequately improved by the many other strategies to decrease them. (See “Natural Help for Hot Flushes”.)

It is a bad idea to treat symptomatic perimenopause with estrogen in any form!

Why? Progesterone, not estrogen, should be used to treat symptomatic women in perimenopause for many reasons. The reasons I believe that progesterone is preferable to estrogen for perimenopausal women with hot flushes are detailed below.

  1. The first reason is the hormone levels in perimenopause. Progesterone levels tends to be lower in perimenopausal women (11;32) while estrogen levels are often too high (10).
  2. Taking estrogen in perimenopause doesn’t make sense because it is a time of higher than normal estrogen levels (10;32;33). Estrogen therapy could cause an estrogen overdose. Estrogen levels in perimenopause become elevated because the normal feedback system with the brain and pituitary is changed. That means that taking estrogen will likely not normally suppress your own estrogen. The result of perimenopausal estrogen therapy could well be a serious excess of estrogen (which is why I call it perimenopausal ovarian hyperstimulation (10).
  3. There is no clear evidence that estrogen therapy helps hot flushes in perimenopausal women (13), although many of the controlled trials did include a mixture of both perimenopausal and menopausal women (18). In fact there is good evidence that estrogen/progestin doesn’t effectively treat perimenopausal hot flushes from a randomized double blind placebo-controlled trial of a 20mg estrogen-containing oral contraceptive in perimenopausal women with heavy bleeding (26). It also showed no significant improvement in quality of life (26).
  4. Progesterone therapy, at least from clinical experience (34), is effective for treatment of hot flushes in perimenopausal women. It also helps with heavy flow (35) and breast tenderness. Clearly a randomized double blind comparative trial of progesterone and estrogen is needed in symptomatic perimenopausal women.

In summary

Progesterone therapy should be offered to women with severe night sweats/hot flushes who are either in perimenopause or menopause. Many lines of evidence, in contrast to the recent official statements (1) (JSOGC, February, 2006) suggest that progesterone will be safer than, and similarly effective, as estrogen for hot flush treatment.

Reference List

  1. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann.Intern.Med 2005;142(12 Pt 1):1003-13.
  2. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351-8.
  3. Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am.J.Epidemiol. 2000;152:463-73.
  4. Wilbur J, Miller AM, Montgomery A, Chandler P. Sociodemographic characteristics, biological factors, and symptom reporting in midlife women. Menopause. 1998;5(1):43-51.
  5. Li C, Wilawan K, Samsioe G, Lidfeldt J, Agardh CD, Nerbrand C. Health profile of middle-aged women: The Women's Health in the Lund Area (WHILA) study. Hum.Reprod. 2002;17(5):1379-85.
  6. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989;262(11):1479-84.
  7. WHO Technical Report Series. Research on the menopause in the 1990's. A report of the WHO Scientific Group. 866, 1-107. 1996. World Health Organization, Geneva, Switzerland, World Health Organization. Ref Type: Report
  8. Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W et al. Executive summary: stages of reproductive aging workshop (STRAW). Fertil.Steril. 2001;76:874-8.
  9. Wallace RB, Sherman BM, Bean JA, Treloar AE, Schlabaugh L. Probability of menopause with increasing duration of amenorrhea in middle-aged women. Am J Obstet Gynecol 1979;135(8):1021-4.
  10. Prior JC. Perimenopause: The complex endocrinology of the menopausal transition. Endocr.Rev. 1998;19:397-428.
  11. Prior JC. The ageing female reproductive axis II: ovulatory changes with perimenopause. In: Chadwick DJ, Goode JA, editors. Endocrine Facets of Ageing. Chichester, UK: John Wiley and Sons Ltd; 2002. p. 172-86.
  12. Prior JC. Clearing confusion about perimenopause. BC.Med.J. 2005;47(10):534-8.
  13. Collins A, Landgren B. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population-based study. Maturitas 1995;20:101-11.
  14. Gold EB, Bromberger JT, Crawford S, Samuels S, Greendale GA, Harlow SD et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am.J.Epidemiol. 2001;153:865-74.
  15. Swartzman LC, Edelberg R, Kemmann E. Impact of stress on objectively recorded menopausal hot flushes and on flush report bias. Health Psychology 1990;9:529-45.
  16. Guthrie JR, Dennerstein L, Hopper JL, Burger HG. Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women. Obstetrics and Gynecology 1996;88(3):437-42.
  17. Whiteman MK, Staropoli CA, Langenberg PW, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet.Gynecol. 2003;101(2):264-72.
  18. MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric. 2001;4(1):58-74.
  19. Albrecht BH, Schiff I, Tulchinsky D, Ryan KJ. Objective evidence that placebo and oral medroxyprogesterone acetate therapy diminish menopausal vasomotor flushes. Am.J.Obstet.Gynecol. 1981;139:631-5.
  20. Schiff I, Tulchinsky D, Cramer D, Ryan KJ. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. Journal of the American Medical Association 1980;244:1443-5.
  21. Dennerstein L, Burrows GD, Hyman G, Wood C. Menopausal hot flushes: a double blind comparison of placebo ethinyl estradiol and norgestrel. Br.J.Obstet.Gynaecol. 1978;85:852-6.
  22. Nordin BEC, Jones MM, Crilly RG, Marshall DH, Brooke R. A placebo-controlled trial of ethinyl oestradiol and norethisterone in climateric women. Maturitas 1980;2:247-51.
  23. Prior, J. C., Alojado, N., Vigna, Y. M., Barr, S. I., and McKay, D. W. Estrogen and progestin are equally effective in symptom control post-ovariectomy—a one-year, double-blind, randomized trial in premenopausal women. Program of the 76th Annual Meeting of the Endocrine Society, Anaheim, Ca. Abstract 12H, 411. 1994.
  24. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstetrics and Gynecology 1999;94:225-8.
  25. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause 2003;10(1):13-8.
  26. Casper RF, Dodin S, Reid RL, Study Investigators. The effect of 20 ug ethinyl estradiol/1 mg norethindrone acetate (Minestrin™), a low-dose oral contraceptive, on vaginal bleeding patterns, hot flashes, and quality of life in symptomatic perimenopausal women. Menopause 1997;4:139-47.
  27. Loprinzi CL, Michalak JC, Quella SK, O'Fallan JR, Hatfield AK, Nelimark RA et al. Megesterol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347-52.
  28. Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R. Progesterone-induced changes in sleep in male subjects. Am.J.Physiol. 1997;272:E885-E891.
  29. Ockene JK, Barad DH, Cochrane BB, Larson JC, Gass M, Wassertheil-Smoller S et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA 2005;294(2):183-93.
  30. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in health postmenopausal women: prinicpal results from the Women's Health Initiative Randomized Control trial. JAMA 2002;288:321-33.
  31. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291(14):1701-12.
  32. Santoro N, Rosenberg J, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996;81:4,1495-501.
  33. Moen MH, Kahn H, Bjerve KS, Halvorsen TB. Menometrorrhagia in the perimenopause is associated with increased serum estradiol. Maturitas 2004;47(2):151-5.
  34. Prior JC. Estrogen's Storm Season- Stories of Perimenopause. Vancouver, BC: CeMCOR; 2005.
  35. Irvine GA, Campbell-Brown MB, Lumsden MA, Heikkila A, Walker JJ, Cameron IT. Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia. Br.J Obstet.Gynaecol. 1998;105(6):592-8.
Type: 
Articles
Life Phase: 
Perimenopause, Menopause
Updated Date: 
April 8, 2014

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