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BCMJ /#47Vol10.wrap5 11/30/05 2:23 PM Page 538

Jerilynn C. Prior, MD, FRCPC

Clearing confusion about perimenopause

In an effort to improve health care for perimenopausal women, a study now under way looks at long-distance endocrine specialist consultation for symptomatic patients.

ABSTRACT: Of the 19% of women flushes. There is no consensus and urrently, there is confusion now between ages 45 and 60, 20% little evidence-based data about about how to describe the are experiencing perimenopausal treatment of symptomatic perimeno- state of midlife women symptoms and seeking medical help. pausal women. Oral contraceptives Cwho have menstruated in Primary health care is under eco- eventually improve flow but don’t the last year, yet are flushing, can’t nomic stress and specialists are help with hot flushes or quality of sleep, and have flooding periods. Are often not available. Furthermore, life. In this context, a University of they in , perimenopause, confusion reigns about the major British Columbia research group has or the menopausal transition? This is hormonal changes of perimeno- initiated a comprehensive long-dis- not an academic question because pause and the language used to tance endocrine specialist consulta- about 19% of all Canadian women are describe them. Menopause, for tion program called the Perimeno- currently in the midst of this linguistic example, can mean three different pause Experiences Project. The and conceptual midlife limbo because things—everything miserable from project aims to educate physicians of the baby boom demographic. Fur- midlife onward, the final menstrual about the physiology and manage- thermore, approximately 20% of these period, and a normal life phase be- ment of symptomatic women in peri- women will make repeated visits to ginning after 1 year without flow. menopause and to improve medical primary health care providers with The transition to menopause or peri- care for perimenopausal women. A urgent but perplexing problems. It is menopause was formerly thought to successful pilot has been completed not clear to these women why they are involve dropping levels. and health care providers are now having hot flushes if vasomotor symp- Estrogen levels are now known to being recruited to a 1-year study that toms are caused by estrogen “defi- average 30% higher, to be chaotic, will compare consultation with usual ciency.” Don’t their periods mean they and to be associated with less prog- care and the outcomes of both. The have enough estrogen? Further, there esterone. Perimenopause begins in study will involve physicians’ self- is confusion about whether therapies women with regular periods and assessment of their clinical compe- that are suitable for women after includes characteristic experiences tence and women’s self-assessment menopause are also appropriate for such as heavy flow or flooding, mid- of how perimenopause interferes menstruating midlife women. sleep disturbance, and cyclic hot with their usual activity. Dr Prior is a professor of internal medicine and at the University of British Columbia. She is affiliated with Van- couver General Hospital, the Vancouver Coastal Health Research Institute, and the Centre for and Research.

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Clearing confusion about perimenopause

Confusion about perimenopause ing life cycle phase to menopause is Table. Experience changes characteristic can be cleared by defining women’s premenopause. A is premeno- of perimenopause onset in regularly reproductive life phases (premeno- pausal from her first period until she cycling women. pause, perimenopause, and menopause), enters perimenopause or the meno- discussing current debates about the pausal transition. The changes that Any three of the following can be used to onset of the menopausal transition or occur in perimenopause are best define perimenopause onset: perimenopause, and highlighting the defined in contrast to premenopausal • New heavy and/or longer menstrual new evidence and controversy over ovulatory menstrual cycle hormonal flow reproductive hormonal changes in changes. • Shorter menstrual cycle lengths (≤ 25 days) midlife women. Understanding the The time of change in midlife wo- ovarian hormonal changes of peri- men has been called everything from • New sore, swollen, and/or lumpy menopause leads to a physiology- “climacteric,”4 “change of life,”5 and • New or increased menstrual cramps based (if not yet evidence-based) “decline of life”6 to “perimenopause,”7 • New mid-sleep wakening approach to treatment of symptomatic “menopausal transition,”8 and “meno- midlife women. pause.”9 STRAWprefers the term meno- • Onset of night sweats, especially around flow pausal transition, which defines as Changing language and beginning when cycles vary in length • New or markedly increased migraine headaches definitions by ±7 days in a woman with a cycle • New or increased premenstrual mood Does menopause mean everything Day 3 follicle-stimulating swings that’s miserable and changing in the (FSH) level that is elevated.2 The • Notable weight gain without changes in life of women older than 40, the final menopausal transition officially ends exercise or food intake menstrual period, or a life phase that with the final menstrual flow. But starts a year after the final menstrual problems arise with such a definition period? The WHO 1996 guidelines1 because (1) clinicians and women night sweats,14 mood swings, and in- and a 2001 Stages of Reproductive have a hard time documenting cycle creased bloating.15 Aging Workshop (STRAW)2 both call variability with adequate specificity, These and other symptoms such as menopause the final menstrual period. (2) it is not clear what level of FSH intractable migraines, nausea, and mid- The question is, how does a woman, should be considered “elevated,” and sleep wakening in regularly cycling or her physician, know when a partic- (3) variability occurs in some peri- midlife women often don’t make sense ular flow is final? The answer comes menopausal women. This last is con- to us. If menopause means low estro- from large prospective studies indi- firmed by a recent retrospective gen levels and premenopause means cating that 12 months must pass for analysis in 100 women who had pro- high levels, then estrogen levels 90% of women to be confident they’ve spectively collected cycle-length data should be dropping in perimenopause. had their final flow.3 For women older and been without flow for 1 year. The We were taught that hot flushes result than 50 at the onset of , data indicated a high degree of vari- from lower estrogen levels. However, there’s a 95% chance that the flow is ability, with irregular or even regular we also know that shorter cycles, sore final—the younger the woman who cycles occurring after varying times breasts, and heavier flow can result has been without a period for 12 without flow. Although the most com- from higher estrogen levels.16,17 It’s months, the greater the likelihood of mon pattern was from regular to irreg- also confusing because menopause further flow. Therefore, increasingly ular to skipping cycles to amenorrhea, and perimenopause often share two menopause is being defined (in wo- a high proportion of women didn’t ful- common symptoms—hot flushes/night men over 40, without hysterectomy) fill expectations.10 sweats and decreased sexual interest. as beginning after 1 year without flow. Perimenopause, in contrast to the The paradox of perimenopause is It’s helpful to know that further flow menopausal transition, ends after a that estrogen levels soar and become is likely not caused by pathology if woman goes 1 year without flow1,2 and erratic before they eventually settle sore breasts, bloating, or premenstru- begins when she is still having regular into the low, stable levels of meno- al symptoms precede it. periods.11 Often these periods are be- pause.2,7,11 Therefore, a practical defin- For the purposes of this discus- coming shorter12 or flow is heavy or ition of perimenopause onset must be sion, menopause is defined as 1 year flooding,13 and commonly the flow is based on characteristic changes in without menstrual flow. The contrast- preceded by tenderness and experience that likely result from

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Clearing confusion about perimenopause

these hormonal changes and occur in pausal levels were about menorrhagia, but no significant im- women with regular flow. What are 30% higher (F = 16.12, P = 0.041).11 provement in hot flushes or quality of these characteristic experience changes? Higher estradiol and lower proges- life.22 Likewise, a couple of poor-qual- They include shorter cycles, the onset terone levels help explain many of wo- ity studies suggest oral contraceptives of cyclic night sweats, new mid-sleep men’s perimenopausal experiences.11 can prevent perimenopausal wakening, and several other experi- For example, in a recent case-control loss.23,24 Acting on the assumption that ences listed in theTable . Women with study high estradiol levels and endo- menopause and perimenopause in- any three of these experience changes metrial were associated volve similarly low estrogen levels, can be diagnosed as perimenopausal. with heavy flow.17 and that hot flushes are effectively Hot flushes and night sweats in treated with estrogens,25 it is common Confusing endocrine menopausal women are understood to practice to treat perimenopause with changes of mean estrogen “deficiency.” Howev- estrogens or oral contraceptives. This perimenopause er, women with who treatment comes from the recommen- There are at least three hormonal have early menopause and have never dation to “consider extrapolating data changes in perimenopause. The first been treated with estrogen don’t have from postmenopausal women” and and most important is higher estrogen hot flushes. Also, menopausal women from “clinical experience when con- levels.7,11 The second major change is being treated with estradiol implants sidering management recommenda- lower levels7 and luteal every 6 months had severe hot flush- tions” for perimenopause.26 phase lengths that are shorter with es, irritability, and sleep disturbances The suggestion to treat perimeno- more common anovulation.18 The final at a time when their estradiol levels pausal symptoms like those of meno- change involves disruption of the were higher than mid-cycle estrogen pause, however, ignores the differing hypothalamic-pituitary-ovarian feed- peak levels.19 All of this evidence sug- hormonal dynamics of the two, back system. There is less reliable gests that vasomotor symptoms arise especially the higher estrogen levels suppression of FSH by higher estradi- because the has be- and disturbed hypothalamic-pituitary- ol levels and less likelihood that a lu- come used to higher estrogen levels— ovarian feedback in perimenopause.11,27 teinizing hormone (LH) mid-cycle hot flushes develop just as readily Treatment with estrogen could cause peak will follow high estrogen levels. when estrogen levels decrease from heavier flow, worsening mood swings, The practical results of these changes high to normal as from normal to low. and more breast tenderness. Instead, are higher estradiol and lower proges- Estrogen withdrawal from previously simple measures are often quite effec- terone levels, but also exogenous es- higher levels likely explains why night tive. These include explaining about trogen that doesn’t reliably suppress sweats and hot flushes occur in 37% perimenopausal hormone changes endogenous estrogen levels. of perimenopausal women.20 Mood and the characteristic experiences ac- The idea that estrogen levels are swings likely result because estradiol companying them, giving some idea dropping or low in perimenopause amplifies the stress hormone respons- of the perimenopause timeline,18 and was so common in the past that from es to life stresses.21 Other symptoms providing patients with a self-report the 1950s to the 1990s many studies such as waking after a few hours of form such as the Daily Perimenopause didn’t comment on the high estrogens deep sleep as yet have no hormonal Diary14 in which they can track their they found in some perimenopausal explanation. experiences. In addition, maintaining women.8 The same was true in seven or increasing exercise, increasing cal- studies comparing hormone levels A therapeutic approach cium and intake, paying early in the cycle and premenstrually to symptomatic more attention to healthy eating guide- in premenopausal versus perimeno- perimenopause lines, and taking relaxation training pausal women.11 A meta-analysis of Treatment of symptoms in perimeno- can all be beneficial. these comparative studies, which pause is problematic because few ran- These simple and practical sug- included 292 control premenopausal domized controlled trials have been gestions can allow the majority of women and 415 perimenopausal wo- conducted or published. One random- perimenopausal women to cope. How- men, showed that ized controlled trial of 20 µg ethinyl ever, the 20% who are highly symp- estradiol levels were 175 ± 57 pmol/L estradiol-containing oral contracep- tomatic will likely need additional compared with 225 ± 98 pmol/L in tive in perimenopausal women with therapy. At present, no perimenopause perimenopausal women. Perimeno- heavy flow showed some benefit for therapies have been adequately vali-

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Clearing confusion about perimenopause

dated in randomized controlled trials. relate with the number of symptomatic However, based on the endocrine midlife women they reported seeing FPs and perimenopausal changes of perimenopause, cyclic or in a week but not with years in clini- women needed for study daily oral micronized progesterone in cal practice. Final results for women doses of 300 to 400 mg at bedtime show a significant lessening of peri- Family doctors and primary care appears to help with heavy flow, hot menopausal mood interference with practitioners from the Greater flushes, breast tenderness, and sleep their daily activities. Although final Victoria region can now participate (J.C.P., unpublished data, 2001). results from physician interviews are in a randomized controlled trial of In an effort to understand the con- not yet available, data collected so far specialist consultation for sympto- cerns of primary health care providers, shows that such a long-distance con- to provide patient-specific education sultation is feasible, is valuable to wo- matic perimenopausal women. If and consultation, and to determine men, and may assist family physicians. you are interested or need more whether suggested therapies such as The randomized controlled trial information, contact Ms Marjorie progesterone are acceptable and effec- set to follow the pilot study will test Tighe, nurse practitioner, at tive, the Centre for Menstrual Cycle whether active participation in PEP or [email protected] or phone and Ovulation Research at the Uni- usual care results in superior out- 250 388-7844 local 335, or versity of British Columbia began a comes for health care providers and 250 477-7284. unique long-distance consultation women. All women in both arms of project. the controlled trial will view “The Puzzle of Perimenopause,” an educa- Perimenopause tional video28 that teaches them how to three perimenopausal women within Experiences Project complete the Daily Perimenopause 3 months of joining. The PEP re- The Perimenopause Experiences Pro- Diary.14 Data from the women’s diary searchers invite family physicians and ject (PEP) began as a pilot study in records for three cycles, family physi- nurse clinicians in the Greater Victo- 2002 with 14 women and 9 health care cian referral forms, and interviewer- ria region to participate. Anyone inter- providers from the Greater Victoria administered questionnaires will then ested can send an e-mail message to area. The purpose of the 1-year pilot be used to write the consultation let- [email protected] or phone 250 388-7844 study was to test the feasibility of ter. A letter using the same informa- (extension 335) or 250 477-7284. long-distance, endocrine specialist tion, but written in nontechnical lan- consultation for symptomatic women guage, will go to each participating Summary in perimenopause. The two outcome woman. Communication from the spe- Language and definitions related to variables were (1) change over the cialist consultant and staff in Vancou- midlife women have changed. Most year in how much women felt peri- ver will go by coded computer files to importantly, perimenopause is now menopausal symptoms were interfer- the Victoria nurse-coordinator, who understood to involve higher and ing with their daily activities, and (2) will print and deliver the letters to both more chaotic estrogen levels and to change over the year in the degree of women and their physicians. Physi- begin in regularly cycling women. competence physicians felt while - cians and women in the active partic- Increasing numbers of symptomatic aging highly symptomatic perimeno- ipation arm will receive their consul- perimenopausal women are present- pausal women. The pilot PEP study is tation about 4 months into the study, ing with puzzling and intense symp- currently wrapping up. Physicians have while those in the usual care arm will toms for which there is no consensus proven willing to refer their patients not receive their consultation until the on causes or therapy. This is happen- and have expressed appreciation for end of the year. Women from both ing as primary health care is under the consultation letters from special- arms will have regular support and economic stress and specialist referral ists. The researchers have determined counseling from the Victoria nurse- has become more difficult. The Peri- that the women’s self-assessed mood coordinator. menopause Experiences Project is symptoms are reproducible over time, So far PEP researchers have re- performing a randomized controlled while the physician’s baseline self- cruited 12 family physicians and 13 trial of long-distance specialist con- assessed competence is not signifi- women for the study. They anticipate sultation for family physicians and cantly reproducible (r = 0.77). The needing a total of 30 physicians, who their symptomatic perimenopausal physicians’ scores did positively cor- will each be expected to refer one to patients. This study will help determine

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what treatment strategies are helpful gram on Women’s Health. Women’s pathetic responses to psychosocial for highly symptomatic women and Health Issues 2004;14:220-226. stress in healthy young men. J Clin their health care providers. 11. Prior JC. Perimenopause: The complex Endocrinol Metab 1996;81:3639-3643. endocrinology of the menopausal transi- 22. Casper RF, Dodin S, Reid RL, Study Inves- Competing interests tion. Endocr Rev 1998;19:397-428. tigators. The effect of 20 µg ethinyl estra- None declared. 12. Treloar AE, Boynton RE, Behn BG, et al. diol/1 mg norethindrone acetate (Mines- Variation of the human menstrual cycle trin), a low-dose oral contraceptive, on References through reproductive life. Int J Fertil patterns, hot flashes, 1. Research on the menopause in the 1967;12:77-126. and quality of life in symptomatic peri- 1990s: Report of a WHO Scientific 13. Kaufert PA, Gilbert P, Tate R. Defining menopausal women. Menopause 1997; Group. Geneva: World Health Organiza- menopausal status: The impact of longi- 4:139-147. tion; 1996. 107 pp. tudinal data. Maturitas 1987;9:217-226. 23. Shargil AA. Hormone replacement thera- 2. Soules MR, Sherman S, Parrott E, et al. 14. Hale GE, Hitchcock CL, Williams LA, et py in perimenopausal women with a Executive summary: Stages of reproduc- al. Cyclicity of breast tenderness and triphasic contraceptive compound: A tive aging workshop (STRAW). Fertil night-time vasomotor symptoms in mid- three-year prospective study. Int J Fertil Steril 2001;76:874-878. life women: Information collected using 1985;30:15-28. 3. Wallace RB, Sherman BM, Bean JA, et the Daily Perimenopause Diary. Climac- 24. Gambacciani M, Spinetti A, Taponeco F, al. Probability of menopause with in- teric 2003;6:128-139. et al. Longitudinal evaluation of peri- creasing duration of amenorrhea in mid- 15. Prior JC. Premenstrual symptoms and menopausal vertebral bone loss: Effects dle-aged women. Am J Obstet Gynecol signs. In: Rakel RE, Bope ET (eds). Conn’s of a low-dose oral contraceptive prepara- 1979;135:1021-1024. Current Therapy 2002. New York: W.B. tion on bone mineral density and metab- 4. Hagstad A, Janson PO. The epidemiolo- Saunders Company; 2002:1078-1080. olism. Obstet Gynecol 1994;83:392-395. gy of climacteric symptoms. Acta Obstet 16. Landgren BM, Unden AL, Diczfalusy E. 25. MacLennan A, Lester S, Moore V. Oral Gynecol Scand Suppl 1986;134:59-65. Hormonal profile of the cycle in 68 nor- estrogen replacement therapy versus 5. Greer G. The Change: Women, Aging, mally menstruating women. Acta placebo for hot flushes: A systematic and the Menopause. London: Hamish Endocrinol (Copenh) 1980;94:89-98. review. Climacteric 2001;4:58-74. Hamilton; 1991. 17. Moen MH, Kahn H, Bjerve KS, et al. 26. Consensus Opinion. Clinical challenges 6. Tilt EJ. The change of life in health and Menometrorrhagia in the perimeno- of perimenopause: Consensus opinion disease. A practical treatise on the ner- pause is associated with increased of the North American Menopause Soci- vous and other afflictions incidental to serum estradiol. Maturitas 2004;47:151- ety. Menopause 2000;7:5-13. women at the decline of life. 3rd ed. 155. 27. Park SJ, Goldsmith LT, Weiss G. Age- Philadelphia, PA: Lindsay and Blakiston, 18. Prior JC. The ageing female reproductive related changes in the regulation of 1871. axis II: Ovulatory changes with perimeno- by estro- 7. Santoro N, Brown JR, Adel T, et al. Char- pause. In: Chadwick DJ, Goode JA (eds). gen in women. Exp Biol Med (Maywood) acterization of reproductive hormonal Endocrine Facets of Ageing. Chichester, 2002;227:455-464. dynamics in the perimenopause. J Clin UK: John Wiley and Sons; 2002:172-186. 28. Prior JC. The puzzle of perimenopause— Endocrinol Metab 1996;81:4,1495-1501. 19. Gangar KF, Cust MP, Whitehead MI. Using the Daily Perimenopause Diary 8. Burger HG, Dudley EC, Hopper JL, et al. Symptoms of oestrogen deficiency asso- [videocassette]. JC Prior/UBC Media Ser- The endocrinology of the menopausal ciated with supraphysiological plasma vices, 1999. Distributed by BC Endocrine transition: A cross-sectional study of a oestradiol concentrations in women with Research Services. population-based sample. J Clin Endo- oestradiol implants. BMJ 1989;299:601- crinol Metab 1995;80:3537-3545. 602. 9. Kaufert PA. Menopause as a process or 20. Guthrie JR, Dennerstein L, Hopper JL, et event: The creation of definitions in bio- al. Hot flushes, menstrual status, and hor- medicine. In: Lock M, Gordon D (eds). mone levels in a population-based sam- Biomedicine Examined. Durdrecht: Klu- ple of midlife women. Obstet Gynecol wer Academic Press; 1988:331-349. 1996;88:437-442. 10. Mansfield PK, Carey M, Anderson A, et 21. Kirschbaum C, Schommer N, Federenko al. Staging the menopausal transition: I, et al. Short-term estradiol treatment Data from the TREMIN Research Pro- enhances pituitary-adrenal axis and sym-

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