Lessons learned from the Women's Health Initiative study.

To the Editor: I read with great interest the views of the Editor (1) and those of different specialists regarding the results of Women's Health Initiative (WHI) study, (2) which showed an overall harm of using postmenopausal hormonal replacement therapy (HRT). I would like to comment on the implications &the previous study on the management of hot flushes, an important issue that was not addressed sufficiently by the six experts. Hot flushes occur in approximately 60% of women in the early postmenopausal period. (3) Their prevalence then declines gradually, and hot flushes resolve in most women within 4 or 5 years. (4) However, approximately 9% of women are still symptomatic at age 72 years. (3) Hot flushes frequently interfere with quality of life and sometimes can be disabling. Both estrogens and progesterone6 are highly effective in reducing the severity or eliminating hot flushes. It is not surprising therefore that the commonest indication of HRT is the control of postmenopausal vasomotor symptoms. After the release of the disturbing results of the WHI study, (2) the main concern among postmenopausal women is to find nonhormonal alternatives for the treatment of climacteric symptoms. It should be emphasized that in all studies that evaluated the effectiveness of various drugs on the severity of hot flushes, there was a substantial placebo effect ranging from 20 to 50%. Accordingly, the validity of results obtained from non-placebo-controlled trials is questionable. The two main agents that proved some efficacy in relieving hot flushes over placebo are clonidine and the selective serotonin reuptake inhibitors (SSRI). Clonidine has been used for that purpose since the early 1970s. (7) One hypothesis related to the pathogenesis of hot flushes is the hyperactivity of the sympathetic nervous system. (8) Thus, the reduction of sympathetic hyperactivity by clonidine, an [[alpha].sub.2]-adrenergic agonist, is associated with amelioration of hot flushes, Another abnormality described in women with vasomotor symptoms is the lowering of the threshold of core body temperature for sweating. (8) Both estrogen (8) and clonidine (9) have been shown to increase the sweating threshold in women with hot flushes.

SSRI medications have been used to control hot flushes on the basis of anecdotal reports rather than on a scientific basis. The best-studied SSRI medications for that purpose are venlafaxine (10) and fluoxetine, (11) mad trials with sertraline are underway. Venlafaxine is also an inhibitor of norepinephrine uptake. (10) Table 1 lists the nonhormonal agents proved to have some effectiveness in treating hot flushes based on data derived from randomized, double-blind, placebo-controlled trials. As shown in Table 1, the overall effectiveness of clonidine and SSRI drugs is mild to moderate at best, and these agents are not free of adverse effects.

In addition to clonidine and SSRI medications, claims have been made regarding various drags, vitamins, and botanic products. For instance, soy food containing phytoestrogens (or isoflavones) received a lot of public attention on the basis of their weak estrogenic and antiestrogenic properties. However, several randomized, double-blind, placebo-controlled trials Palled to show any advantage over placebo in relieving hot flushes with administration of isoflavone in daily doses ranging from 40 to 160 mg. (12,13) Similarly, vitamin E, (14) black cohosh, (15) mad primrose oil (16) were evaluated in well-designed studies, but none demonstrated better efficacy than placebo.

The increased risk of coronary heart disease and pulmonary emboli in patients randomized to HRT in the WHI trial was evident soon after randomization. (2) Therefore, it is worthwhile to try clonidine or one of the SSRI medications in symptomatic postmenopausal women. In those already taking HRT, it may be reasonable to taper the HRT over several months, and try the nonhormonal alternatives if tapering is unsuccessful. Tapering could be achieved by gradually decreasing the daily dose of HRT (dose taper) or by decreasing the number of days per week of HRT use (day taper). (4) If clonidine or an SSRI exerts a positive effect on hot flushes, this usually becomes evident from the first week of administration. (10,11,17,18) In patients with climacteric symptoms who do not tolerate or respond to clonidine or SSRI drugs, HRT can be initiated or resumed at the least possible doses. In fact, low doses of oral HRT are as effective as higher doses in reducing hot flushes, and they are accompanied by less frequent vaginal bleeding. (19) Likewise, low-dose transdermal estrogen has been used successfully for that purpose. (20)

The absolute risk associated with HRT administration in the WHI study is Small (2) but real and increases with years of use. Thus, every effort should be made to avoid the long-term use of HRT.

Table 1. Nonhormonal treatment modalities for patients with hot flushes

Series (ref. no.)                Agent             Dose

Goldberg et al. 1994 (18)    Transdermal       0.1 mg qd
                               clonidine
Loprinzi et al. 2000 (10)    Venlafaxine       37.5, 75, or
                               (Effexor)         150 mg qd
Pandya et al, 2000 (17)      Oral clonidine    0.1 mg qd
Loprinzi et al, 2002 (11)    Fluoxetine        20 mg qd
                               (Prozac)

Series (ref. no.)                          Effectiveness

Goldberg et al. 1994 (18)    27% decrease in hot flush score (a)
                               compared with placebo
Loprinzi et al. 2000 (10)    Decrease in hot flush score (a) by 27, 37,
                               and 61% with placebo, 37.5, 75, and 150
                               mg, respectively
Pandya et al, 2000 (17)      38% decrease in hot flush frequency vs.
                               24% decrease with placebo
Loprinzi et al, 2002 (11)    50% decrease in hot flush score (a) with
                               fluoxetine vs. 36% with placebo

Series (ref. no.)                       Adverse effects

Goldberg et al. 1994 (18)    Dry mouth, constipation, drowsiness,
                               itchiness under the patch
Loprinzi et al. 2000 (10)    Dry mouth, decreased appetite, nausea,
                               constipation
Pandya et al, 2000 (17)      Difficulty sleeping
Loprinzi et al, 2002 (11)    Dry mouth

(a) Hot flush scare = hot flush fequenry x severity.

Nasser Mikhail, MD, MSc

Endocrinology Division

Department of Medicine

Olive View-UCLA Medical Center Sylmar, CA

References

(1.) Hamdy RC. Lessons learned from the Women's Health Initiative study. South Med J 2002;95:951-952 (editorial).

(2.) Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled Trial. JAMA 2002;288:321-333.

(3.) Rodstrom K, Bengtsson C. Lissner L, et al. A longitudinal study of the treatment of hot flushes: The population study of women in Gothenburg during a quarter of a century. Menopause 2002;9:156-161.

(4.) Grady D. A 60-year-old woman trying to discontinue hormone replacement therapy. JAMA 2002;287:2130-2137.

(5.) MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: A systematic review. Climacteric 2001;4:58-74.

(6.) Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347-352.

(7.) Clayden JR, Bell JW. Pollard P, Menopausal flushing: Double-blind trial of a non-hormonal medication. Br Med J 1974;1:409-412.

(8.) Freedman RR. Hot flash trends and mechanisms. Menopause 2002;9:151-152 (editorial).

(9.) Freedman RR, Dinsay R. Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. Fertil Steril 2000;74:20-23.

(10.) Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer. A randomised controlled trial. Lancet 2000;356:2059 2063.

(11.) Loprinzi CL, Sloan JA, Perez EA. et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-1583.

(12.) Knight DC, Howes JB, Eden JA. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84.

(13.) Kotsopoulos D, Dalais FS, Liang YL, et al. The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women, Climacteric 2000;3:161-167.

(14.) Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors, J Clin Oncol 1998;16:495-500.

(15.) Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh fur the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001; 19:2739-2745.

(16.) Chenoy R, Hussain S, Tayob Y, et al. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ 1994; 308:501-503.

(17.) Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: A University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Infern Med 2000; 132:788-793.

(18.) Goldberg RM, Lopriozi CL, O'Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994;12:155-158.

(19.) Utian WH, Shoupe D, Bachmann G, et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001;75:1065-1079.

(20.) Utian WH, Burry KA, Archer DF, el al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients: The Esclim Study Group. Am J Obstet Gynecol 1999; 181:71-79.