COVER ARTICLE

OBGMANAGEMENT

Exercise reduces risk of breast cancer. Oral and transdermal EPT have different effects on risk of thromboembolism. EPT has no significant effect on gynecologic cancers. Update on An expert’s insight on pivotal studies

BY WULF H. UTIAN, MD, PHD Confusion about what to do—on the part of both physicians and patients—may be the greatest consequence of recent studies.

he past 2 years have witnessed a flurry 2003 Position Statement on use of of scientific publications on menopause and progestogen in peri- and postmenopausal Tand related therapies, particularly use women (www.menopause.org). Even as this of the sex hormones. In turn, attitudes Update on Menopause is being written, the about menopause and hormone therapy have report of the terminated estrogen-only arm of changed. Perhaps the greatest consequence of the Women’s Health Initiative (WHI) is in all the attention is the confusion about what to press and may further change clinical prac- do, on the part of both provider and patient. tice. NAMS will present an updated report on Many organizations responded with con- all these developments at the 2004 scientific sidered, evidence-based, practical guidelines. meeting in Washington, DC, October 6 to 9, The most detailed and practice-oriented of 2004. In the interim, the current recommen- these guidelines is the North American dations hold, and the following publications Menopause Society’s (NAMS’s) September are of clinical relevance.

60 OBG MANAGEMENT • May 2004 WHI COMMENT Higher levels of exercise Modest protection, reduce breast cancer risk but encourage exercise anyway his large, prospective cohort study per- McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in post- Tformed in the mid-1990s strengthens menopausal women: the Women’s Health Initiative Cohort the growing body of evidence that higher Study. JAMA. 2003;290:1331–1336. levels of physical activity afford modest pro- tection against breast cancer. Recreational ■ LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED TRIAL physical activity appears to be associated he risk of breast cancer in post- with reduced risk for breast cancer in post- Tmenopausal women who exercised menopausal women; longer exercise dura- moderately for only a few hours a week was tions showed only slightly greater reduction reduced by 18% compared with inactive in risk. women—and risk was reduced more in The strengths of this study are its large women who exercised moderately but for numbers, prospective nature, and detailed considerably more hours per week. reporting of breast cancer outcomes. A total of 74,171 postmenopausal Limitations include possible confounders women aged 50 to 79, with no history of such as prior oral contraceptive use, and use breast cancer, were enrolled. At a mean fol- of self-administered questionnaires to esti- low-up of 4.7 years, an increasing total cur- mate physical activity. rent physical activity score was associated One very important question is raised by with a statistically significant reduced risk this study: Given the low increase in for breast cancer (P = .03 for trend). The absolute risk of breast cancer reported by women in whom the 18% (95% confidence the WHI with estrogen plus progestin1— interval [CI], 0.68-0.97) reduced risk of which barely reached statistical significance breast cancer was observed exercised the (total breast cancer RR, 1.24; 95% CI, 1.02- equivalent of 1.25 to 2.5 hours per week of 1.50)—and given the statement in the brisk walking (5.1-10.0 metabolic hours). McTiernan study that “the reduced risk Women who exercised the equivalent of 10 associated with increased levels of total or more hours of brisk walking per week had physical activity was seen across all the cat- slightly greater reductions. egories of these variables” (including cur- The greatest benefit was in women with rent or past use, or no previous use of hor- a body mass index (BMI) below 24.1, but mone therapy), does the reduction of inci- benefits were seen in women with BMIs dence with physical activity in hormone ranging from 24.1 to 28.4. In evaluating the therapy users lower the level of risk to non- effect of previous strenuous-intensity exer- significance or to that of nonexercisers in cise, a statistically significant decreased risk the placebo group? The answer cannot be of breast cancer was seen for women who determined from this report, but it would had engaged in strenuous exercise at age 35 be illuminating. (relative risk [RR], 0.86; 95% CI, 0.78-0.95); These findings are preliminary, and no significant associations were found for confirming studies are needed. There is lit- strenuous exercise at ages 18 or 50. tle harm in encouraging women to exercise, however.

■ Dr. Utian is executive director, North American Menopause 1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal Society; professor emeritus, Case University, Cleveland; and women: the Women's Health Initiative Randomized Trial. JAMA. gynecologist, The Cleveland Clinic. 2003;289:3243–3253.

May 2004 • OBG MANAGEMENT 61 Update on menopause

WHI COMMENT Estrogen-progestin Bias against hormone therapy? has no significant effect he authors concluded that EPT may Tincrease the risk of ovarian cancer but on gynecologic cancers has no significant effect on the risk of Anderson GL, Judd HL, Kaunitz AM, et al, for the Women’s endometrial cancer. They commented, how- Health Initiative Investigators. Effects of estrogen plus ever, that, since the EPT arm of the trial was progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. prematurely stopped, the precision of the JAMA. 2003;290:1739–1748. results is limited and examination of longer- term exposure is precluded. ■ LEVEL I EVIDENCE: RANDOMIZED, CONTROLLED TRIAL This paper once again raises the question ontinuous combined estrogen plus prog- of whether the writers of the WHI trial have a Cestin therapy (EPT) does not have a sta- bias against hormone therapy. In this report, tistically significant effect on either ovarian the EPT arm of the WHI trial had an observed or endometrial cancer compared with place- annual incidence of 34 ovarian cancer cases per bo, according to this report. 100,000 person-years—somewhat less than the In this randomized, double-blind, place- anticipated population-based rate of 45 per bo-controlled trial, 16,608 women were 100,000 person-years. In the authors’ words, assigned to either EPT (0.625 mg/day conju- the ovarian cancer rate in the EPT group “was gated equine plus 2.5 mg/day elevated (HR 1.58; 95% CI 0.77-3.24 [adjusted medroxyprogesterone acetate) or placebo; 95% CI, 0.59-4.23]) but not statistically signif- none of the women had undergone a hys- icant.” The Kaplan-Meier estimates of cumu- terectomy. lative hazards also did not reach statistical sig- After an average follow-up of 5.6 years: nificance. Yet in the conclusion of the abstract, • There were 20 cases of invasive ovarian the authors state that continuous combined cancer in the EPT group (n = 8,506) and 12 EPT “may increase the risk of ovarian cancer cases in the placebo group (n = 8,102). while producing endometrial cancer rates sim- Compared with placebo, the hazard ratio ilar to placebo.” (HR) for invasive ovarian cancer among Regarding the conclusion on endometrial EPT recipients was a nonsignificant 1.58 cancer risk, the observed incidence for EPT (95% CI, 0.77-3.24 [adjusted 95% CI, 0.59- users was 62 per 100,000 person-years, which 4.23]). is also lower than the anticipated population- • For endometrial cancer, 27 and 31 cases based rate of 83 per 100,000 person-years. The occurred, respectively, which translated sta- authors state that this was a “small, nonsignif- tistically to a nonsignificant hazard ratio icant reduction” in endometrial cancer risk for EPT recipients of 0.81 (95% CI, 0.48- (HR 0.81; 95% CI, 0.48-1.36). Yet, in the con- 1.36). clusion, while claiming that the nonsignifi- No appreciable differences were found cant difference in ovarian cancer suggests an in the distributions of tumor histology, increased risk, the authors do not state that the stage, or grade for either cancer site. nonsignificant reduction in endometrial can- However, significantly more women using cer suggests a decreased risk. EPT required endometrial biopsies (33% What do the authors expect us to versus 6%; P <.001). believe, their data or their conclusions? • For cervical cancers, 8 and 5 cases were My interpretation of the data in this article is reported, respectively, with a nonsignificant that ovarian and uterine cancers need not be of HR of 1.44 (95% CI, 0.47-4.42). major concern when determining a woman’s

62 OBG MANAGEMENT • May 2004 risk-benefit ratio for hormone therapy. therapy alone (ET) or EPT. Primary end- A retraction. Of interest, when this issue was points were diagnosis of breast cancer and raised in subsequent JAMA correspondence, death from breast cancer. the WHI authors agreed—representing per- Current ET or EPT use (compared with haps the first time that a WHI report publicly nonuse) was associated with a statistically sig- retracted a potentially biased conclusion.1,2 nificant increased risk of both breast cancer Fewer biopsies will be needed with incidence (RR, 1.66; 95% CI, 1.58-1.75) and lower dosage. It is not surprising that breast cancer mortality (RR, 1.22; 95% CI, women taking hormonal therapy containing 1.00-1.48). Past use did not increase the risk of estrogen had more bleeding and, therefore, incident (RR, 1.01; 95% CI, 0.94-1.09) or fatal more endometrial biopsies than women taking disease (RR, 1.05; 95% CI, 0.82-1.34), and the placebo, because a known effect of estrogen is risk decreased with time since last use. proliferation of the endometrial lining. With The risks associated with ET and with the lower-dose hormonal preparations cur- EPT differed significantly. Current ET users rently available (which result in lower systemic had a 30% increased risk for breast cancer (95% estrogen levels and less endometrial stimula- CI, 1.21-1.40) while current EPT users had a tion), uterine bleeding episodes in menopausal 100% increased risk (95% CI, 1.88-2.12). hormone therapy users should diminish, along However, vaginal or other local EPT formula- with the number of endometrial biopsies. tions did not increase the risk (RR 0.67, 95%

1. Utian WH. Hormone therapy and risk of gynecologic cancers [letter]. JAMA. CI, 0.30-1.49). No significant differences in 2004;291:42. risk were found between specific types or doses 2. Anderson GL, Judd HL, Kaunitz AM, et al. Hormone therapy and risk of gyne- cologic cancers—Reply. JAMA. 2004;291:43. of EPT or between continuous combined and continuous cyclic regimens. MILLION WOMEN STUDY Breast cancer risks increased COMMENT by estrogen plus progestogen Limitations of observational studies his extremely large observational study Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Tfound levels of breast cancer risk associ- Study. Lancet. 2003;362:419–427. ated with ET and EPT similar to those reported by the WHI and as predicted in ■ LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED 1997 by the Collaborative Group on urrent use but not past use of post- Hormonal Factors in Breast Cancer study.1 Cmenopausal hormone therapy is associat- The Million Women Study implicates an ed with an increased risk of incident and fatal expanded number of ET and EPT products breast cancer, especially for estrogen-progesto- and routes of administration. gen therapy (EPT), according to this large Acting as devil’s advocate, I will point out observational study from Britain. Risks that this is an observational study with large increased among current users as total dura- potential for error. The major weakness is tion of use increased. that it is a snapshot of hormone therapy use A total of 1,084,110 women aged 50 to 64 taken at the time of the women’s entry into were enrolled between May 1996 and March the study, which was at the time of their 3- 2001 and followed to the study finish (end of year mammogram. No further information 2002). Mean follow-up was 2.6 years for breast was gleaned from the women regarding sub- cancer incidence and 4.1 years for mortality. sequent changes in hormone therapy use, Nearly half of the women had used post- such as whether they terminated use or menopausal hormone therapy, either estrogen changed the dose or route.

64 OBG MANAGEMENT • May 2004 Update on menopause

Also, the patient-provided data at entry “Million Women” can be accepted only as showed a 96% agreement with the actual prescription written by the physician. The an observational confirmation of a small 4% variance, although it seems small, is of increase in absolute risk of breast cancer. some concern given the narrow difference in relative risks and the large number of study small increase in the absolute risk for breast participants. This is a weakness of any obser- cancer in women on hormone therapy. vational study; even if the prescription is Further implications. The suggestion that filled, evidence that it was actually taken is these results apply to products beyond those inadequate. tested in the WHI is in agreement with the Finally, the authors report that current NAMS Advisory Panel’s 2003 statement on use of hormone therapy at baseline increased Postmenopausal Hormone Therapy, which the risk of breast cancer, although the rela- supports the view that although it is not pos- tive risk was not as large as for disease inci- sible to make general conclusions about all dence. They were not able to come up with members of the estrogen and progestogen reliable estimates of mortality attributable to families, an improved benefit-risk profile of breast cancer. other EPT agents cannot be assumed.

In conclusion, the Million Women 1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and Study can be accepted only as an observa- hormone replacement therapy: collaborative reanalysis of data from 51 epidemio- logical studies of 52,705 women with breast cancer and 108,411 women without tional study providing confirmation of a breast cancer. Lancet. 1997;350;1047–1059. CONTINUED Transdermal estrogen/progestogen had no according to this hospital-based, case-con- effect on risk of venous thromboembolism trol study of postmenopausal women in France. in postmenopausal women. Investigators enrolled 155 women aged 45 to 70 years who had been diagnosed with ESTHER STUDY VTE, defined as either pulmonary embolism Oral and transdermal EPT or deep vein thrombosis, and 381 matched have different effects on risk controls. In women with VTE, 21% were using oral EPT and 19% were using transder- of thromboembolism mal EPT. In controls, 7% and 24% were using Scarabin PY, Oger E, Plu-Bureau G, for the EStrogen and oral or transdermal EPT, respectively. An THromboEmbolism Risk (ESTHER) Study Group. adjusted analysis showed that, compared with Differential association of oral and transdermal oestrogen- replacement therapy with venous thromboembolism risk. nonuse, current use of oral EPT significantly Lancet 2003;362:428–432. increased the VTE risk (adjusted odds ratio, [OR] 3.5; 95% CI, 1.8-6.8); transdermal EPT ■ LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED STUDY did not increase the VTE risk (OR, 0.9; 95% ral estrogen plus progestogen therapy CI, 0.5-1.6). A between-group comparison O(EPT) significantly increases the risk of showed that current oral EPT users had a sig- venous thromboembolism (VTE), but trans- nificantly increased VTE risk (OR, 4.0; 95% dermal EPT has no effect on the VTE risk, CI, 1.9-8.3) over transdermal EPT users.

Watch for UPDATE ON GYNECOLOGIC INFECTIONS

By Sebastian Faro, MD, PhD Professor and Chairman Department of Obstetrics and Gynecology University of Texas, Houston

Coming in June Watch for future UPDATES

July Gynecologic cancers

August Contraception

September Technology

October Pelvic floor surgery

November

December Urinary incontinence Update on menopause

COMMENT 3 RANDOMIZED, CONTROLLED TRIALS More studies needed but unlikely are no better prime consideration for nonoral EPT for than placebo for hot flashes Apostmenopausal women is avoidance of the first-pass hepatic effect of oral medica- Soy 40%, placebo 40% tions, thereby reducing potential for the Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, adverse effects associated with oral therapies. endometrial thickness, and the pulsatility index of the uter- This study demonstrates a difference between ine and cerebral arteries. Fertil Steril. 2003;79:1112–1117. oral and transdermal therapy, but the number ■ LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL of patients is small and, while promising, it is probably not a final answer to the problem. oy-derived isoflavones are no more effective The reduced incidence of VTE in post- Sthan placebo in reducing hot flashes, accord- menopausal women on transdermal EPT ing to this 6-month, randomized, double-blind, does justify further randomized controlled placebo-controlled trial. In all, 62 postmenopausal clinical trials; however, given the low preva- women aged 45 to 60 years who had at least 7 hot lence of VTE, conducting such a study would flashes per day were randomized to either soy- be nearly impossible. It would be interesting derived isoflavones (72 mg/day) or placebo. if data from the Million Women Study were Primary endpoints were the daily number of hot analyzed for effects of different routes of flashes, endometrial thickness, and arterial pul- ET/EPT administration on VTE. satility index. At study end, both the and Update on menopause

placebo groups had a 40% reduction in the num- Red clover vs placebo ber of hot flashes. Soy had no effect on either Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, endometrial thickness or the arterial pulsatility Cummings SR. supplements for the treatment index of either the uterine or cerebral arteries. of hot flashes: the Isoflavone Clover Extract (ICE) study. JAMA. 2003;290:207–214.

Effects in women with breast cancer ■ LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL Nikander E, Kikkinen A, Metsa-Heikkila M, et al. A ran- domized placebo-controlled crossover trial with phytoestro- soflavones derived from red clover were no gens in treatment of menopause in breast cancer patients. Imore effective than placebo in reducing the Obstet Gynecol. 2003;101:1213–1220. incidence of hot flashes, in this randomized,

■ LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL double-blind, placebo-controlled trial. A total of 252 women were assigned either to placebo hytoestrogen tablets do not effectively or active treatment with 1 of 2 red clover Prelieve menopause-related symptoms, isoflavone products: Promensil (82 mg/day including hot flashes, in postmenopausal isoflavones) or Rimostil (57 mg/day women with breast cancer, according to this isoflavones). Follow-up was 12 weeks. The pri- randomized, placebo-controlled, double-blind, mary outcome was frequency of hot flashes. crossover trial from Finland. Investigators Secondary outcomes were quality of life and enrolled 62 postmenopausal women (mean side effects. After 12 weeks, the mean reduction age, 54) who had been treated for breast cancer in hot flash incidence was 41% for Promensil, but were not currently taking . 34% for Rimostil, and 36% for placebo, a sig- Subjects received phytoestrogen tablets (114 nificant reduction from baseline for all 3 mg/day) or placebo for 3 months, and switched groups (P <.001). Results in the isoflavone to the other treatment after a 2-month washout. groups, however, were statistically no different Menopause-related symptoms, including from placebo, even though Promensil recipi- hot flashes, were recorded on the Kupperman ents had significantly more rapid reductions in index. At study end, the overall Kupperman hot flashes than Rimostil or placebo recipients. index score was reduced by 15.5% in the phy- Quality of life improvements and side effects toestrogen group (mean drop, 4.2) and by 14.7% were similar in the 3 groups. in the placebo group (mean, 4.0); the between- group difference was not statistically significant. COMMENT When evaluated separately from the rest of The clinical implications the Kupperman index, the hot flash compo- hese 3 negative trials of isoflavones (2 nent was reduced more in the placebo group Textracted from soy, 1 from red clover) (14.3%) than in the study group (10%), confirm previous reports of their essential although the difference was not statistically inefficacy. The clinical implications: significant. • Women with mild hot flashes might con- The quality of life parameters measured— sider either no pharmacotherapy or low-dose capacity to work and mood changes—were not selective serotonin-reuptake inhibitors. affected by phytoestrogen therapy. • Women with moderate to severe hot flashes Phytoestrogen treatment was well tolerated that disrupt quality of life may continue to and caused no significant changes in liver benefit from short-term, low-dose hormone enzymes, creatinine, body mass index, or blood therapy. ■ pressure. In a subset analysis, investigators eval- Dr. Utian serves as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. uated results based on high and low levels of He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli endogenous ; results did not differ Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P & G, Pfizer, Roche, Sepracor, Solvay, between the groups. Wyeth, and Yamanouchi.

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