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Update on menopause: An expert’s insight on pivotal studies

OBG Management. 2004 May;16(05):60-68
May 1, 2004|OBG Management
Wulf H. Utian, MD, PhD
Author and Disclosure Information

WULF H. UTIAN, MD, PHD
Dr. Utian is executive director, North American Menopause Society; professor emeritus, Case University, Cleveland; and gynecologist, The Cleveland Clinic.
Dr. Utian serves as an advisor/consultant for Eli Lilly, Pfizer, and Novartis. He has received research funding from Amylin, 3m, Barr, Berlex, BMS, Eli Lilly, Forest, Galen, Glaxo Smith Kline, Neurocrine Biosciences, Novartis, Novo Nordisk, Organon, Pharmacia, P & G, Pfizer, Roche, Sepracor, Solvay, Wyeth, and Yamanouchi.

Confusion about what to do—on the part of both physicians and patients—may be the greatest consequence of recent studies.

The reduced incidence of VTE in postmenopausal women on transdermal EPT does justify further randomized controlled clinical trials; however, given the low prevalence of VTE, conducting such a study would be nearly impossible. It would be interesting if data from the Million Women Study were analyzed for effects of different routes of ET/EPT administration on VTE.

3 RANDOMIZED, CONTROLLED TRIALSIsoflavones are no better than placebo for hot flashes

Soy 40%, placebo 40%

Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–1117.

  • LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
Soy-derived isoflavones are no more effective than placebo in reducing hot flashes, according to this 6-month, randomized, double-blind, placebo-controlled trial. In all, 62 postmenopausal women aged 45 to 60 years who had at least 7 hot flashes per day were randomized to either soyderived isoflavones (72 mg/day) or placebo. Primary endpoints were the daily number of hot flashes, endometrial thickness, and arterial pulsatility index. At study end, both the isoflavone and placebo groups had a 40% reduction in the number of hot flashes. Soy had no effect on either endometrial thickness or the arterial pulsatility index of either the uterine or cerebral arteries.

Effects in women with breast cancer

Nikander E, Kikkinen A, Metsa-Heikkila M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–1220.

  • LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
Phytoestrogen tablets do not effectively relieve menopause-related symptoms, including hot flashes, in postmenopausal women with breast cancer, according to this randomized, placebo-controlled, double-blind, crossover trial from Finland. Investigators enrolled 62 postmenopausal women (mean age, 54) who had been treated for breast cancer but were not currently taking tamoxifen. Subjects received phytoestrogen tablets (114 mg/day) or placebo for 3 months, and switched to the other treatment after a 2-month washout.

Menopause-related symptoms, including hot flashes, were recorded on the Kupperman index. At study end, the overall Kupperman index score was reduced by 15.5% in the phytoestrogen group (mean drop, 4.2) and by 14.7% in the placebo group (mean, 4.0); the between-group difference was not statistically significant.

When evaluated separately from the rest of the Kupperman index, the hot flash component was reduced more in the placebo group (14.3%) than in the study group (10%), although the difference was not statistically significant.

The quality of life parameters measured—capacity to work and mood changes—were not affected by phytoestrogen therapy.

Phytoestrogen treatment was well tolerated and caused no significant changes in liver enzymes, creatinine, body mass index, or blood pressure. In a subset analysis, investigators evaluated results based on high and low levels of endogenous equol; results did not differ between the groups.

Red clover vs placebo

Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) study. JAMA. 2003;290:207–214.

  • LEVEL I EVIDENCE: RANDOMIZED CONTROLLED TRIAL
Isoflavones derived from red clover were no more effective than placebo in reducing the incidence of hot flashes, in this randomized, double-blind, placebo-controlled trial. A total of 252 women were assigned either to placebo or active treatment with 1 of 2 red clover isoflavone products: Promensil (82 mg/day isoflavones) or Rimostil (57 mg/day isoflavones). Follow-up was 12 weeks. The primary outcome was frequency of hot flashes. Secondary outcomes were quality of life and side effects. After 12 weeks, the mean reduction in hot flash incidence was 41% for Promensil, 34% for Rimostil, and 36% for placebo, a significant reduction from baseline for all 3 groups (P .001 results in the isoflavone groups however were statistically no different from placebo even though promensil recipients had significantly more rapid reductions hot flashes than rimostil or recipients. quality of life improvements and side effects similar groups.>

COMMENT
The clinical implications

These 3 negative trials of isoflavones (2 extracted from soy, 1 from red clover) confirm previous reports of their essential inefficacy. The clinical implications:

  • Women with mild hot flashes might consider either no pharmacotherapy or low-dose selective serotonin-reuptake inhibitors.
  • Women with moderate to severe hot flashes that disrupt quality of life may continue to benefit from short-term, low-dose hormone therapy.

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