Opmaak07-prior:Opmaak 1 20/06/11 09:51 Pagina 109 F, V & V IN OBGYN, 2011, 3 (2): 109-120 Viewpoint Progesterone for Symptomatic Perimenopause Treatment –
Progesterone politics, physiology and potential for peri-
Professor, Endocrinology, University of British Columbia, and Vancouver Coastal Health Research. Institute, Vancouver,Canada V5Z 1M9. Scientific Director, Centre for Menstrual Cycle and Ovulation Research (www.cemcor.ubc.ca). Correspondence at: Professor J. C. Prior, Suite 4111, 2775 Laurel Street, Division of Endocrinology, Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC V5Z 1M9.
Telephone (604) 875-5927, Fax (604) 875-5915; email [email protected]; websites: www.cemcor.ubc.ca andwww.estrogenerrors.com Perimenopause, women's normal midlife reproductive transition, is highly symptomatic for about 20% of womenwho are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormonetherapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% havemenorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estra-diol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average26% higher and soar erratically – some women describe feeling pregnant! Also, ovulation and progesterone (P4) levelsbecome insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other's tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically(cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and pre-menstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance,metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines needdaily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk,increases bone formation and has beneficial cardiovascular effects. A controlled trial is testing OMP4 for peri-menopausal VMS – more evidence-based data are needed.
Key words: Perimenopause, vasomotor symptoms, night sweats, menorrhagia, sleep disturbance, anovulation, shortluteal phase, ovulatory disturbances, oral micronized progesterone, treatment, midlife women, estradiol levels, progesterone levels, infertility, nausea, migraine headaches, mastalgia, insulin resistance, osteoporosis, rapid boneloss, cardiovascular disease, breast cancer, estradiol-progesterone tissue interactions, self-actualization, feminism,history.
She is weeping and her normally attractive face has Your medical record shows that Emily, we'll call her, become twisted and swollen – almost inarticulate, she is 44 years old, apparently happily married, with a complains of extreme fatigue, flooding menstruation son in high school and a daughter in her early teens.
and night sweats robbing her of sleep. She is a social worker and a community leader in You have delivered her two babies and done her yearly your moderate-sized city. She has always been a Pap tests, but the woman in front of you seems a
stranger. What has changed? Why is she so miser-
vibrantly well woman in exceptional health who eats well, doesn't smoke and exercises regularly.
07-prior:Opmaak 1 20/06/11 09:51 Pagina 110 You're puzzled over Emily's current situation.
cultural and pharmaceutical reasons, perimenopause You inquire about her husband, her children – she and menopause came to be seen as a single, homo - mumbles and then vehemently snorts, "They're
genous downhill slide into waning hormones, loss of health and decreased attractiveness. "How are your periods besides the heavy flow?" Emily's symptoms don't make sense within this you ask. "Spot on regular!" she retorts, "That's current view of midlife's decreasing hormone levels what's so frustrating – maybe a bit shorter, about – with her shorter cycles and heavy flow she is highly unlikely to have deficient estradiol levels.
"I don't have a clue what's happening." She goes However, if her estradiol levels are not low, why is on. "I don't feel like myself – when do I get my life
she having night sweats? Before addressing these questions about what is causing Emily's symptoms let's start with current Midlife women all over the world are similarly official ideas. The North American Menopause challenging their gynaecologists. They want help to Society (NAMS) website says, "The years between understand the changes they are experiencing, some puberty (when periods start) and menopause are idea of the time course of these changes and, only called premenopause." (http://www.menopause.org/ occasionally, do they want and need some therapeu- expertadvice.asp). This statement totally eliminates tic intervention. The purpose of this review is to first any midlife transitional phase. identify the current concepts, policies and politics In the next sentence, however, NAMS contradicts that prevent many of us, as physicians, from under- that earlier sentence by saying: "Physical signs of standing our midlife patients' concerns. I will define menopause begin many years before the final and describe the phases of the long and varying per- menstrual period. This menopause transition phase imenopausal transition. Then I will reframe peri- is called perimenopause (literally meaning ‘around menopause physiology in a new and hormonally more accurate manner before embarking on my Did you notice? In that NAMS quotation the primary purpose – describing the evidence that oral word, "menopause," means two different things – in
micronized progesterone therapy is safe, appropriate the phrase, "physical signs of menopause," the word and effective for those (relatively few) symptomatic means (as the average woman defines menopause) perimenopausal women who require medical inter- everything changing and symptomatic in midlife.
However, in the phrase, "around menopause," the My perspective is that of an endocrinologist who, gynaecological definition of menopause is used, herself, suffered a long, perplexing and highly meaning the literal last menstrual period. If this is symptomatic perimenopause. I am also a clinician- not confusing enough, there is yet a third, epidemi- scientist, doing epidemiological, clinical observa- ological, meaning of menopause (and this is how I tional and randomized controlled trial research on will consistently use the word in this paper) – perimenopause. In the early 1990s, despite my train- menopause is the normal woman's life phase that
ing and roles, I like Emily, struggled to understand begins one year after the last menstruation (and is the changes I personally experienced – I found the sometimes called "postmenopause"). Thus the hormonal changes to be the opposite of what I had confusing use of two key words (menopause and been taught and always thought; instead, estradiol perimenopause) in official documents, rather than erratically soared and progesterone progressively helping Emily understand what is happening to her, decreased. Before we get to that, however, we must illustrate the unhelpfully inconsistent messages first review how we got to a situation where Emily medicine and gynaecology are giving about is seeking yet not finding help. Historical and Medico-political Context of Peri-
Timelines and Definitions
I will clarify how I use language describing the With the discovery of estradiol in the mid-1920's transition between fertile cycles and menopause by came the concept that it was the female hormone
showing a diagram that incorporates the latest evi- (Oudshoorn, 1994; Baxter and Prior, 2009) and that dence defining the phases of this midlife transition.
all symptomatic women must be "estrogen defi- It uses the world-wide epidemiology/cohort-based cient." Given the model of puberty, we would expect data from the ReStage Collaboration to refine the a long biological transition between potentially re- onset of the Early Menopause Transition (Harlow et productive, menstruating premenopausal and al., 2008), and the onset of the Late Menopause ‘hormonally deficient' menopausal women. But for Transition (Harlow et al., 2006), of the Stages of F, V & V IN OBGYN
07-prior:Opmaak 1 20/06/11 09:51 Pagina 111 production within a shorter follicular phase (Landgren et al., 1980). The early menopause transition as shown in Figure 1 requires cycle variability of +/- 6 days (Harlow et al., 2008). Women often describe thisvariation as "irregular" cycles but they also may notnotice this degree of variability (given that 29% of apopulation-based sample of women experience atleast one cycle-to-cycle length variability of 14-daysa year (Munster et al., 1992) and some women maynever have established, nor learned to recognize, regular cycles. Fig. 1. — The ReSTAGE Collaboration refinements of the
Women begin the late menopause transition with Stages of Reproductive Aging Workshop (STRAW) definitions 60 days between flow episodes or what women of the phases of midlife. The estimated timelines are based onextensive clinical experience (Prior, 2010).
commonly call a "skipped period" (Harlow et al.,2006). Note that, in neither the early nor latemenopause transition did the ReStage investigatorsfind that the elevated FSH levels required by Reproductive Aging Workshop (STRAW) definitions STRAW (Soules et al., 2001) contributed to the (Soules et al., 2001) of the menopausal transition menstrual cycle-based classification (Harlow et al., and perimenopause. 2006; Harlow et al., 2008) and thus routine cycle day Early perimenopause, before the irregular or 3 FSH testing to determine perimenopausal status is skipped cycles of the menopause transition begin, is not cost-effective. The late perimenopause, meaning characterized by a several-year stretch of changes in the time from the final menstruation until experience without any cycle interval changes (Prior, menopause, is a year during which women's breast, 2005a). In my view, this is the most frustrating and heavy flow and premenstrual symptoms have symptomatic time for many women. Evidence shows improved but hot flushes and sleep problems are that hormone levels have already changed although commonly worsening, but alternatively may be regular cycling hasn't. For these reasons, a series of decreasing (Dennerstein et al., 2000).
experience-changes, any three of which a woman no-tices, can be used to make a "diagnosis" of the onset Current Evidence for the Hormonal Changes of
of early perimenopause (Table 1) (Prior, 2005a). Emily, the highly distraught woman whose story began this paper, is clearly in early perimenopause Symptomatic parous women often describe feeling because she is miserable with heavy flow (#1 in pregnant during perimenopause. I had such a vivid Table 1), has regular but shorter cycles (#2) and is dream in early perimenopause – when I described it suffering with night sweats (#6). Evidence suggests to an audience of midlife women someone at the that the shorter cycle lengths documented with re- back hollered, "That's not a dream, it's a night- productive aging (Vollman, 1977) are associated mare!" Likewise, a hunter-gatherer !Kung woman of with, and are likely caused by, higher cycle estradiol the Kalahari desert told her anthropologist inter-viewer: "Not long ago I had a dream that I was pregnant. I thought, ‘What? Haven't I stoppedmenstruating?'" (Shostak, 1981). At the time Nisawas thought to be in her early 50s and from her Table 1. — A ‘diagnosis' of early perimenopause can be
made in midlife women who continue to have regular
description, was in late perimenopause (Fig. 1).
flow if they are experiencing – any 3 of these nine Likewise, in the introduction to her book, "Under-
standing Menopause" activist Canadian sociologist
also reported feeling pregnant during perimenopause
1. New onset heavy and/or longer flow (O'Leary Cobb, 2005). Why did all of us, culturally, 2. Shorter menstrual cycles (≤ 25 days)3. New sore, swollen or lumpy breasts ethnically and economically very different midlife 4. New mid-sleep wakening women, report feeling pregnant? I believe it is 5. Increased cramps because we all were experiencing the sore breasts, 6. Onset of night sweats, in particular premenstrually weight gain, bloating and other high estrogen 7. New or markedly increased migraine headaches symptoms that are common in perimenopause and 8. New / increased premenstrual mood swings9. Weight gain without changes in exercise or eating in pregnancy. Our subconscious minds told us whatour physicians didn't. P4 FOR SYMPTOMATIC PERIMENOPAUSE – PRIOR 111 07-prior:Opmaak 1 20/06/11 09:51 Pagina 112 Fig. 2. — The cross-sectional mid-follicular phase estradiol levels by menstrual cycle characteristics in menstruating women ages 45-
55 randomly selected and enrolled in the Melbourne Midlife Women's Health Project baseline data – annotated by including the mean
E2 level for premenopausal follicular phase women from the Burger lab as the lower horizontal line (surrounded +/- one SD by yellow
colour), and the second horizontal line as the mean E2 peak level (orange). Above that are very high E2 levels importantly higher than
ever seen during normal premenopausal menstrual cycles (red). Reprinted from Burger et al. (1995) with adaptations by the author.
Reliable evidence about the hormonal changes of data and was flabbergasted and angry that the perimenopause was absent from the medical litera- authors did not see the high E2 levels in their data.
ture until the mid-1990s, not only because peri- So, with colleagues, I challenged in a letter to the menopause and menopause were subsumed into the editor "that the data be allowed to speak" (Prior et same process, but perhaps also because no question- al., 1996). Burger and colleagues responded by naires about "menopause" included questions about admitting that perimenopausal "estradiol levels are either flow or breast tenderness which are clinically preserved. ." (Burger, 1996). important and distinctive for perimenopause. The These illustrative but traditionally interpreted first, population-based data of follicular phase estra- population data, however, were quickly followed by diol (E2) levels in menstruating Melbourne Australia confirmatory cross-sectional data, this time urinary women ages 45-55 were cross-sectional with data hormone levels across one cycle in women younger segregated by menstrual cycle characteristics (I = than 37 years old with regular cycles compared with regular cycles, interpreted as "premenopausal"; II = symptomatic menstruating women older than age 37 changes in flow; III changes in cycle interval; IV (Santoro et al., 1996). These data showed that estro- changes in both flow and cycle interval; IV no flow gen excretion products were significantly higher and for 3-11.9 months) (Burger et al., 1995). Figure 2 pregnanediol levels were importantly lower in the shows that early follicular phase (cycle days 3-8) perimenopausal women. These authors recognized fasting E2 levels had a large variance but the majority the uniqueness of their observation and clearly re- fell outside of the plus/minus 1 SD of the fasting nor- ported the higher estradiol level they observed. mal range (yellow). Note the number of women in I subsequently performed a meta-analysis of all phases (I-V) whose E2 levels are extremely high within-centre pre- versus perimenopausal serum estradiol levels that showed, in perimenopausal In reporting these results, the authors did not women (n = 415) in the follicular phase E2 levels describe observing higher than expected estradiol were 225 pmol/L versus 175 pmol/L in premeno - levels (Burger et al., 1995). Moreover, their abstract pausal women (n = 276; Fisher's F = 16.12, says: "We conclude that an increase in serum FSH P = 0.041) (Prior, 1998). The premenstrual or luteal and decreases in E2 and Inhibin are the major en-
phase E2 levels were also significantly higher in docrine changes cross-sectionally during the perimenopausal and than in premenopausal women menopausal transition" (author's emphasis). I – in perimenopausal women (n = 69) mean E2 levels immediately recognized myself in these hormonal were 374 pmol/L compared with 300 pmol/L in F, V & V IN OBGYN 07-prior:Opmaak 1 20/06/11 09:51 Pagina 113 premenopausal women (n = 290; Fisher's F = 15.46, matic perimenopause it is necessary to see estradiol P = 0.016) (Prior, 1998). Most recently two reports and progesterone and their interactions as I do. Estra- from a systematic 2-cycle thrice weekly serum hor- diol has generally been considered the predominant, mone study in midlife women of every STRAW most important woman's reproductive hormone and stage compared with mid-reproductive aged women ‘what makes a girl, a girl' (Baxter and Prior, 2009).
confirmed the higher estradiol levels, lower proges- Progesterone – only produced after a midcycle E2 terone levels (Hale et al. 2007) and showed atypical peak and the LH peak it subsequently triggers – is secondary estradiol peaks called "luteal out of present for fewer than half of all menstrual cycle phase" or LOOP events within the luteal phases of a days. However, P4 is secreted in extremely high quan- third of all cycles from women in the menopausal tities (reported as nmol versus estradiol's pmol), ris- transition (Hale et al., 2009). Therefore, evidence ing 1400 percent above its low follicular phase from multiple continents and many different re- levels; midcycle maximum E2 levels, by contrast, rise searchers confirms what perimenopausal women's only 220 percent above its low during flow (Nielsen experiences (shorter cycles, heavy flow, breast ten- et al., 1990). Progesterone production is dependent derness, weight gain, insulin resistance and feeling on preceding E2 production. However, nature does pregnant) are telling them – they are experiencing not spend energy making large quantities of non- higher estradiol levels.
essential hormones. Thus high levels of P4 for at least Why are these paradoxical increased estradiol lev- 10 days per cycle appear necessary to counter- els occurring in women whose ovaries are running balance or complement estradiol's powerful and out of follicles (Richardson et al., 1987)? Evidence essential growth-stimulating actions (Graham and suggests that inhibin B levels (Burger et al., 1998) Clarke, 1997). To provide a few reproductive decrease thus allowing small increases in FSH levels examples of estradiol-progesterone partnerships: E2 which, in turn, recruit more follicles each of which stimulates cervical gland production of slippery, can make estradiol and even stimulate non-typical clear mucus to aid sperm transit while P4 inhibits cer- additional waves of follicle maturation (as in LOOP) vical mucus production; E2 stimulates breast glandu- cycles (Hale et al., 2009). Furthermore, these higher lar development in puberty (Tanner stages I-III) estradiol levels do not reliably suppress FSH levels, while P4 (plus E2) is required for final breast matura- at least partly because of decreases in inhibin B tion to Tanner stages IV-V as the areolar diameter (Klein et al., 1996; Prior, 1998). expands and the ductal system and nipple mature The decreasing progesterone production across (Prior et al., 1989); both E2 and P4 induce intermedi- the menopausal transition (Santoro et al., 2008) ate cell vaginal maturation – 12-mo. following pre- (Prior, 2002b) is also related to disturbed hypo - menopausal ovariectomy during randomized thalamic-pituitary-ovarian feedback loops so that double-blind treatment with conjugated equine es- estradiol peaks can occur and not be followed by LH trogen (CEE, 0.6 mg/d) or medroxyprogesterone peak levels; both estradiol and LH peak levels can (MPA, 10 mg/d) the majority of cells were interme- also occur and not be followed by ovulation (Weiss diate cells, although CEE produced significantly et al., 2004) although the complete physiological more superficial cells (Prior et al., 1994). E2 and P4 reasons for these observations are not yet clear. In an work together in normal bone remodelling so that earlier as well as a recent study of daily urinary hor- estradiol reduces bone resorption while progesterone mone levels, perimenopause is a time of unopposed stimulates bone formation (Prior, 1990; Seifert- and higher estrogen production often without coun- Klauss and Prior, 2010). In two randomized terbalancing ovulatory progesterone production controlled human trials with breast biopsy cellular (Metcalf and MacKenzie, 1985; O'Connor et al., changes as the primary objective, topical estradiol caused breast epithelial cell proliferation while These multiple physiological ovarian hormonal progesterone decreased it (Chang et al., 1995; (higher estradiol and FSH levels, lower inhibin B and Foidart et al., 1998). In addition, the large French progesterone levels) and hypothalamic-pituitary- cohort study (E3N) shows estradiol treatment to be ovarian feedback disturbances to me represent a associated with a 29% increased risk for breast planned way of ending the potential for menstruation cancer compared with untreated menopausal and pregnancy as women become menopausal. women, estrogen plus progestin increased risk by69%, but estrogen with progesterone had no in- The Physiological Rationale for Progesterone
creased breast cancer risk (HR 1.0, 95% CI 0.82, Treatment of Symptomatic Perimenopause
1.22) (Fournier et al., 2008). In the vascular endothe-lium, both E2 and P4 similarly increase endogenous In order to understand why I consider progesterone nitric oxide activity to improve blood flow (Mather an important, safe and effective therapy for sympto- et al., 2000). In the brain, estradiol is neuroexcitatory P4 FOR SYMPTOMATIC PERIMENOPAUSE – PRIOR 113 07-prior:Opmaak 1 20/06/11 09:51 Pagina 114 and supported the probable safety of progesteronetherapy, I need to indicate why I consider the currentrecommendations that symptomatic perimenopausalwomen be treated with oral contraceptives ormenopausal type hormone therapy (National Insti-tutes of Health 2005) to be inappropriate and unsafe.
Given the feedback disturbances of perimenopause,it is likely that exogenous estrogen will not reliablysuppress endogenous (often high) E2 levels. Oralcontraceptives have not proven more effective thanplacebo for hot flushes in a controlled trial (Casperet al., 1997). In addition, new retrospective clinicaldata suggest breast cancer in women who weretreated in perimenopause with menopausal-type hor-mone therapy show a trend toward decreased time tobreast cancer progression and decreased overall sur-vival (P = 0.06) (Baumgartener et al., 2011). Thusoral contraceptives and hormone therapy do not ap-pear to be effective nor safe in perimenopause. We can now begin to describe clinical data and minimal evidence-based material available suggest-ing that progesterone is an appropriate and effectivetherapy for symptomatic perimenopause. (I addedthe adjective, "symptomatic" because peri-menopause is a normal life phase and only a smallpercentage of women need or want any medicaltreatment.) Oral Micronized Progesterone Treatment for
Before describing specific uses for progesterone, it Fig. 3. — Bark painting by an aboriginal man in Australia
is useful to provide some general clinical guidelines.
depicts two stylized snakes intimately entwined. This is a photo I think of progesterone as counterbalancing the of art that the author purchased in Western Australia. The artist'sidentity is unknown.
tissue effects of high estrogen – given the feedbackdisturbances, it is not realistic to expect that proges-terone will suppress endogenous E2 production in while progesterone inhibits this action, improves perimenopause. When I say "progesterone" I mean sleep and decreases addictive behaviours and anxiety the molecularly identical hormone to that produced (Gibson et al., 2009). Thus my vision is that estradiol by the corpus luteum and not progestins. I always and progesterone are both important for normal recommend oral micronized progesterone (OMP), physiology; they act together in all reproductive and rather than transdermal progesterone for peri- non-reproductive tissues (bone, blood vessels, brain) menopausal women. The primary reason is that I and are as closely tied together as the two snakes in have experience with it – however I think trans - this Australian aboriginal bark painting (Figure 3). dermal progesterone may not be "strong enough" to In addition, based on the above physiology, oral effectively counterbalance the tissue effects of high micronized progesterone appears safe for peri- estrogen levels, and furthermore it has no beneficial menopausal women – it should decrease their risks effect on sleep disturbances that are common in for endometrial cancer, does not show any indication perimenopause. OMP can either be prescribed as a of increasing venous thromboembolism risk, causes formulary drug, or where that is not available, women to burn 300 more kilocalories/day so will compounding pharmacists can make it up in olive oil help prevent rather than causing weight gain (Barr (which is similarly well absorbed based on my et al., 1995b) and decreases anxiety and doesn't clinical serum tests). cause depression (Dennerstein et al., 1985). A physiological luteal phase dose of OMP is Having explained the changing physiology of peri - 300 mg at bedtime – this keeps the P4 blood level menopausal hormonal levels and feedback systems, above a luteal phase threshold for 24 hours (Simon F, V & V IN OBGYN
07-prior:Opmaak 1 20/06/11 09:51 Pagina 115 et al., 1992). OMP must be taken at bedtime because
its beneficial sleep enhancing effects (Schussler et
al., 2008) would cause drowsiness or almost "intox-
icated" feelings if taken when awake. To be cautious,
especially for sleep-deprived and thin women, I rec-
ommend they begin OMP on a night following
which they can sleep in. Otherwise catch-up rapid-
eye-movement sleep may make them feel that OMP
caused a "hang-over". These morning sleepy feel-
ings, if present, do not persist more than a few days.
Finally, the schedule of OMP depends on women's bleeding pattern, her desires for fertility,and whether or not she gives a history of migraine Fig. 4. — Graph depicting the idealized regular 28-day men-
headaches. (I'll discuss the use of cyclic OMP to aid strual cycle showing on which cycle days to prescribe 300 mg perimenopausal fertility later.) For women with daily of oral micronized progesterone at bedtime to provide "lutealphase replacement" progesterone therapy for treating sympto- symptoms such as night sweats or hot flushes, espe- matic perimenopausal women (http://www.cemcor.ubc.ca/ cially if they have irregular or skipped cycles, I pre- scribe OMP daily. For women with regular cycles, unless they have migraines, I always start with cyclicOMP as shown in Figure 4 (http://www.cemcor.ubc.
ca/help_yourself/articles/cyclic_progesterone therapy). Women with migraine headaches are sen- daily_diaries), I provide women with this practical sitive to a host of changes thus, although OMP does lay language handout: (http://www.cemcor.ubc.ca/ not cause migraines, its withdrawal can trigger them.
For migraneurs I always also prescribe daily OMP I always begin therapy with an over-the-counter non- even if they are regularly cycling – daily OMP will steroidal anti-inflammatory (NSAID) drug such as make perimenopausal flow light but usually doesn't ibuprofen. NSAIDs restore a normal balance of en- entirely prevent periods.
dometrial prostaglandins and thus cause a 25-50%decrease in flow (Lethaby et al., 2002) – I believe Progesterone for heavy or prolonged flow
NSAIDs should be taken on all heavy flow days bywomen of all ages. For ibuprofen, the dose is 200 mg In my experience, heavy flow occurs in all phases of (with food) every 4-6 hours while awake. perimenopause and is experienced by about 25% of In addition to ibuprofen I use cyclic OMP (Fig- all midlife women. (Heavy flow was not included in ure 4) treatment for all perimenopausal women with the questions asked in the Melbourne Midlife regular cycles and the recent onset of heavy flow. I Women's Health Study therefore we have no popu- would continue ibuprofen and cyclic OMP for at lation-based prospective data). The usual gynaeco- least three cycles. If, as often happens, flow starts logical approach to heavy bleeding is to assume while the 14 days of OMP therapy are still being fibroids or other pathology – it is far more likely, taken, the full OMP duration should always be com- however, that heavy flow is related to the disturbed pleted. The flow-start day is called a new Day 1 – ovarian hormonal physiology of perimenopause.
OMP is started on the next cycle day 14, even if that Therefore, for perimenopausal women I don't rec- gives only a few days off progesterone each cycle. ommend endometrial biopsies or ultrasounds or However, if I see a perimenopausal woman who screening for bleeding disorders unless at least three has had heavy flow for months, in addition to assess- cycles of ibuprofen plus progesterone therapy have ing for and treating anemia, I will usually start long- not importantly improved the abnormal bleeding. All cycle OMP – this means prescribing OMP for cycle evidence, especially this case-control clinical study days 4-28, along with ibuprofen as described above.
(Moen et al., 2004) ] strongly suggest that the higher In my clinical experience, even in women with doc- E2 and lower P4 levels typical in perimenopause umented bleeding disorders, long-cycle OMP plus cause the heavy flow. This suggests that OMP, which ibuprofen therapies are usually effective. The natural stabilizes the endometrium and, when given in long history of heavy flow in perimenopause is that it im- cycles, thins it, would be a beneficial therapy. proves over time and the closer a woman becomes Once I have a clear understanding of a woman's to menopause. Therefore OMP and ibuprofen are heavy flow experience (hopefully from Daily Peri- temporizing measures. If these are not sufficient, my menopause Diary records (Hale et al., 2003) that are next approach is to recommend the levonorgestrel downloadable from the CeMCOR website impregnated IUD (LNG-IUD) (Irvine et al., 1998).
P4 FOR SYMPTOMATIC PERIMENOPAUSE – PRIOR 115 07-prior:Opmaak 1 20/06/11 09:51 Pagina 116 Obviously the LNG-IUD would be an earlier choice disturbance typically occurs in three different pat- if the perimenopausal woman with heavy flow had terns: increased trouble falling asleep, early morning no night sweats, breast tenderness or other experi- wakening or, as is most common, abrupt waking ences that may be helped by the physiological ac- after a few hours of deep sleep. Perimenopausal tions of OMP, and she also had practical access to it women commonly, as did Emily, describe disturbed (despite its high cost in some jurisdictions). sleep as something that is troublesome for them and One or all of the above mentioned measures to for which they seek treatment.
treat perimenopausal menorrhagia are almost always Oral micronized progesterone is rapidly converted successful – in my practice, perimenopausal women in the brain into allopregnanolone which acts with heavy menstrual flow or flooding almost never through the GABAA receptors to decrease anxiety needed endometrial ablation or hysterectomy. Al- and induce sleep (Friess et al., 1997). Randomized though Cochrane reviews and randomized controlled double blind cross-over trials in men (Friess et al., trials support the use of ibuprofen and cyclic or long- 1997) and menopausal women (Schussler et al., cycle progestins for heavy flow, there are no data of 2008) clearly document significant increases in early which I'm aware that have studied OMP for peri- rapid-eye movement sleep, decreased sleep interrup- menopausal heavy flow.
tion and no changes in morning neurocognitive func-tion (Schussler et al., 2008). Therefore, OMP is an effective and evidence-based treatment for sleep dis-turbances, although it has not yet been proven effec- Unless cycles become consistently less than 21 days tive in perimenopause. Note that usually sleep apart, these usually do not require any therapy. How- disturbances are associated with other experience ever, often the shorter cycles are associated with in- changes such as night sweats. I usually don't pre- creased premenstrual symptoms, breast tenderness scribe OMP only for sleep problems.
or heavy flow, and these need treatment. If cycles areroutinely less than 21 days apart I suggest cyclic Increased Dysmenorrhea or Cramps
OMP as described above but beginning two days earlier and taken on cycle days 12-25. In my experience perimenopausal cramps respondwell to intense ibuprofen prophylaxis in women Breast Tenderness and/or Swelling and Nodular-
without a history of persistent severe cramps or en- dometriosis. This handout for women describes theearly and repeated use of ibuprofen to stay ahead of Breast tenderness is a symptom for 33% of early the symptoms and thus prevent the pain-causing perimenopausal women and decreases as cycles build-up of prostaglandins (http://www.cemcor.ubc.
become irregular (Dennerstein et al., 2000). Clinical evidence based on daily diary records suggests that if perimenopause causes a flair of endometriosis breast tenderness does not occur unless E2 levels ex- symptoms, then I have found that daily OMP is ef- ceed the usual midcycle peak values. Some non-pub- fective along with ibuprofen therapy. As opposed to lished data show that women with breast tenderness premenopausal women, daily OMP will not suppress have increased breast cell proliferation (Anne estradiol levels and therefore inducing rapid bone Gompel, 2011, personal communication). Given that loss is not a concern. progesterone decreases breast cell proliferation(Chang et al., 1995; Foidart et al., 1998), cyclic Night Sweats and Hot Flushes
OMP is likely to be effective therapy for breast tenderness occurring, as it commonly does, premen- Ten percent of women ages 45-55 with regular men- strually (Hale et al., 2003). Unfortunately, no con- struation report night sweats and ten percent hot trolled trial data are available to document that OMP flushes (Dennerstein et al., 2000). Often these night causes significant symptomatic improvement of sweats have a cyclic pattern and cluster around flow breast tenderness although the trend in a small cross- (Hale et al., 2003). However, at present it is unclear over trial was toward less tenderness (Dennerstein et how to treat vasomotor symptoms (VMS) in peri- al., 1985). menopausal women – estrogen-based treatments arethe gold standard for menopausal women (MacLen- Mid-sleep Wakening or Sleep Disturbances
nan et al., 2004) but perimenopause has a differentphysiology. Although oral contraceptives and Sleep disturbances occur in 31% of early peri- menopausal type ovarian hormone therapy are both menopausal women and increase to 38% in late currently advocated for VMS treatment (National perimenopause (Dennerstein et al., 2000). This sleep Institutes of Health, 2005), a randomized controlled F, V & V IN OBGYN 07-prior:Opmaak 1 20/06/11 09:51 Pagina 117 trial of 20 mg ethinyl estradiol oral contraceptive or tricyclic anti-depressants that are often used). In showed no meaningful improvement versus placebo addition, most perimenopausal women with mi- in perimenopausal women (Casper et al., 1997). Al- graines are also symptomatic with other experience though there are no such controlled trial data for the changes that OMP will likely help.
use of menopausal ovarian hormone therapy forVMS in perimenopause, epidemiological data sug- Perimenopausal Premenstrual and Mood Symp-
gest VMS don't improve during estrogen-based treatment until women become menopausal (Jo-hannes et al., 1994). Premenstrual symptoms are of obscure etiology in A recent randomized controlled trial showed that premenopausal women (Harvey, 2009) but clearly OMP was effective for both daytime and night VMS increase in perimenopause, and typically become in healthy early menopausal women (Prior and most evident in women with regular cycles. Approx- Hitchcock, 2010). The mechanisms through which imately 30 percent of women across perimenopause OMP helps VMS are not known, but probably in- reported depression and "nervous tension" experi- volve actions in the hypothalamus, on temperature ences in the last two weeks (Dennerstein et al., centres and by decreasing neuroexcitotoxicity and 2000). What is even more fascinating is that women inflammation in the brain (Gibson et al., 2009). The who reported PMS when they still had regular cycles Centre for Menstrual Cycle and Ovulation Research were more likely to later experience night sweats and has just secured Canadian Institutes for Health Re- VMS (Morse et al., 1989). It makes most sense to search funding to perform a similar trial in 175 per- me that women with a genetic or other predisposition imenopausal women. This trial will use daily OMP to estrogen sensitivity will develop increased breast (to avoid the problems of heavy bleeding or need to tenderness, bloating, inappropriately increased exclude migraneurs) and stratify women into "early appetite and mood symptoms premenstrually in perimenopause" if they have not had a 60-day cycle perimenopause as they experience higher E2 and and "late perimenopause" if they have. Results are lower P4 levels (Prior, 2002a). Calcium carbonate not expected until at least 2014. supplementation is the only evidence-based treat- In the mean time, extensive clinical evidence says ment for premenopausal premenstrual symptoms that OMP is effective for perimenopausal VMS. In (Thys-Jacobs and Alvir, 1995; Douglas, 2002). How- addition, it improves the sleep disturbances with ever, women with severe depression that has a pre- which night sweats are often associated. Cyclic menstrual exacerbation will be helped by serotonin OMP is effective for cyclic night sweats in regularly reuptake inhibitors (Douglas, 2002). Cyclic OMP cycling early perimenopausal women. However, may be an appropriate treatment for women who once VMS occur more consistently across the cycle, have become unable to cope because of combined as often happens by the early menopause transition, sleep disturbances, night sweats and breast tender- daily OMP is then necessary. ness with or without premenstrual mood swings.
Again, although there are numerous negative trials of cyclic progesterone for premenstrual symptomsin premenopausal women with premenstrual symp- Headaches are common in perimenopause and 32- toms (Douglas, 2002), none to my knowledge have 36% of perimenopausal women across all phases re- been performed in perimenopause. However, I have port their experience in the last two weeks never prescribed cyclic OMP only for premenstrual (Dennerstein et al., 2000). Migraine headaches may mood symptoms.
occur for the first time in perimenopause. However,typically a woman will have experienced them at pu- Weight Gain Despite Appropriate Diet and
berty or when first using oral contraceptives. What Exercise
is unique about perimenopausal migraines is thatthey seem more refractory to management with acute Before I experienced perimenopausal weight gain therapies, and often occur at midcycle and peri-men- and perpetual hunger (that a patient once aptly strually, thus twice a month. This can be debilitating described as, "my teeth feel hungry"), I was a skeptic if each migraine episode lasts for 3-5 days. To my that overweight could be increased by perimeno - knowledge there are no data on OMP for migraine pausal metabolic change and not simply by over- therapy however, it has multiple anti-oxidative, anti- eating and/or under-exercising. However, there are apoptotic effects and decreases neuroexcitotoxicity clearly changes in metabolic rate that occur in (Gibson et al., 2009). Therefore it appears to be an midlife women based on the 1.5 BMI unit gain in the appropriate therapy to try as a neuromodulating 45-54 decade in population based data from treatment (rather than the less specific beta blockers Canadian women; men experienced a more gradual P4 FOR SYMPTOMATIC PERIMENOPAUSE – PRIOR 117 07-prior:Opmaak 1 20/06/11 09:51 Pagina 118 0.5 BMI gain per decade starting in their 30s yet isn't getting restful sleep and is having night (Hopman et al., 2007). Perimenopausal women with sweats as well as heavy flow. "Lack of energy," al- a past history of gestational diabetes, those with a though non-specific, is the most prevalent experience Type 2 diabetes mellitus family history and those of perimenopausal women. It occurs for 38-43% of who are most generally symptomatic seem to be at women and is equally likely throughout all phases increased risk for weight gain. Obviously, before of perimenopause (Dennerstein et al., 2000). After doing anything else, the health care provider must assessing and treating for anemia or hypothyroidism, review actual exercise and food records and work to I would treat her sleep disturbance and night sweats ensure that both of these are optimal with at least with cyclic OMP. She also needs ibuprofen 200 mg 30 minutes of moderate exercise daily. There is some every 4-6 hours on every heavy flow day. In my ex- rationale for treatment with OMP given that proges- perience, once Emily understands the hormonal terone increases core temperature and requires changes she is experiencing and has an idea of 300 kcal/d to do that in weight stable premenopausal what's ahead for her, effective treatment of night women (Barr et al., 1995). However, I have rarely sweats and sleep disturbances will allow her to re- treated women with OMP only to assist them in gain her ability to cope. But, given the unpredictabil- weight control. Instead I have found that metformin, ity of perimenopause, she needs a skilled and a drug which makes insulin more effective and thus empathetic physician to work with her through this decreases insulin resistance, is a very helpful therapy protracted and sometimes difficult "estrogen's storm for women who have an increasing waist circumfer- season" of perimenopause (Prior, 2005b). ence (normal for Caucasians is less than 88 cm) or arising hemoglobin A1C level to values of 6.0 or References
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F, V & V IN OBGYN
The Celestial by Magda Streicher It is only appropriate to conclude the Image source: Starry Night Pro IYA2009 by considering one of the most vital parts of the telescope – the reticle – immortalised by the constel- lation Reticulum. Reticulum is Latin for ‘net'. One can imagine astronomers fishing out the discoveries from among rhomboidal crosshairs which he used to
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