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Symptom Relief and Side Effects ofPostmenopausal Hormones: Results From thePostmenopausal Estrogen/ProgestinInterventions Trial

GAIL A. GREENDALE, MD, BETH A. REBOUSSIN, PhD, PATRICIA HOGAN, MS, MPH,

VANESSA M. BARNABEI, MD, PhD, SALLY SHUMAKER, PhD, SUSAN JOHNSON, MD,

AND ELIZABETH BARRETT-CONNOR, MD, FOR THE POSTMENOPAUSAL

ESTROGEN/PROGESTIN INTERVENTIONS TRIAL INVESTIGATORS

Objective: To assess pair-wise differences between placebo,estrogen, and each of three estrogen-progestin regimens onselected symptoms.

Methods: This was a 3-year, multicenter, double-blind,placebo-controlled trial in 875 postmenopausal women aged45–64 years at baseline. Participants were assigned ran-domly to one of five groups: 1) placebo, 2) daily conjugatedequine estrogens, 3) conjugated equine estrogens plus cycli-cal medroxyprogesterone acetate, 4) conjugated equine es-trogens plus daily medroxyprogesterone acetate, and 5)conjugated equine estrogens plus cyclical micronized pro-gesterone. Symptoms were self-reported using a checklist at1 and 3 years. Factor analysis reduced 52 symptoms to a setof six symptom groups.

Results: In intention-to-treat analyses at 1 year, each activetreatment demonstrated a marked, statistically significant,protective effect against vasomotor symptoms comparedwith placebo (odds ratios [ORs] 0.17–0.28); there was no

additional benefit of estrogen-progestin over estrogen alone.Only progestin-containing regimens were significantly asso-ciated with higher levels of breast discomfort (OR 1.92–2.27).Compared with placebo, women randomized to conjugatedequine estrogens reported no increase in perceived weight.Those randomized to medroxyprogesterone acetate reportedless perceived weight gain (OR 0.61–0.69) than placebo.Anxiety, cognitive, and affective symptoms did not differ bytreatment assignment. Analyses restricted to adherentwomen were not materially different than those using inten-tion-to-treat, except that women adherent to medroxyproges-terone acetate and micronized progesterone regimens re-ported fewer musculoskeletal symptoms (OR 0.62–0.68).

Conclusion: These results confirm the usefulness of post-menopausal hormone therapy for hot flashes, show convinc-ingly that estrogen plus progestin causes breast discomfort,and demonstrate little influence of postmenopausal hor-mones on anxiety, cognition, or affect. (Obstet Gynecol1998;92:982–8. © 1998 by The American College of Obste-tricians and Gynecologists.)

The decision to use hormone replacement therapy(HRT) is complicated. To help the decision-makingprocess, physicians are advised to counsel their patientsabout individual patient goals and concerns, the pres-ence or absence of menopausal symptoms, comorbidi-ties, family history, potential effects of estrogen onnumerous chronic diseases, possible symptom amelio-ration, and unwanted side effects.1 Knowledge aboutthe effects of HRT on symptoms and potential sideeffects is surprisingly limited, except for the well-established relief of hot flashes and night sweats.2 Theputative benefit of hormone treatment on other possibly

From the University of California, School of Medicine, Los Angeles,California; The Wake Forest University School of Medicine, Winston-Salem, North Carolina; George Washington University, School ofMedicine, Washington, DC; University of Iowa College of Medicine,Iowa City, Iowa; and the Department of Family and Preventive Medi-cine, University of California, San Diego, School of Medicine, La Jolla,California.

The Postmenopausal Estrogen/Progestin Interventions trial is sup-ported by cooperative agreement research grants (U01-HL40154, U01-HL40185, UL-HL40195, U01-HL40205, U01-HL40207, U01-HL40231, U01-HL40232 and U01-HL40273) from the National Heart,Lung, and Blood Institute; the National Institute of Child Health andHuman Development; the National Institute of Arthritis and Musculo-skeletal and Skin Diseases; the National Institute of Diabetes, Digestiveand Kidney Disease; and the National Institute on Aging. This investi-gation also was supported in part by PHS Grant No. 5 MO1 RR00865-24. Packaged medication and placebos for the trial were provided byWyeth-Ayerst Laboratories, Schering-Plough Research Institute, andThe Upjohn Company. Dr. Greendale also was supported for this workby the Iris Cantor-UCLA Women’s Center.

982 0029-7844/98/$19.00 Obstetrics & GynecologyPII S0029-7844(98)00305-6

menopausal symptoms, such as memory and mood,remains uncertain.3–5 Many of the “known” side effectsof HRT have not been evaluated in placebo-controlledclinical trials.

Only a randomized, controlled, masked trial canobviate concerns regarding confounding by indication,treatment bias, and placebo effects.6,7 In one of theearliest placebo-controlled, randomized clinical trials ofestrogen, Campbell and Whitehead8 noted a remark-able placebo benefit for many symptoms.

The Postmenopausal Estrogen/Progestin Interven-tions Trial was a randomized, double-masked, placebo-controlled trial conducted in 875 postmenopausalwomen, to examine the effects of estrogen alone or incombination with three progestin regimens on selectedoutcomes. The study also was planned to collect infor-mation systematically on a wide range of self-reportedsymptoms at baseline and during the 3 years of treat-ment. We present here side effects and symptom reliefresulting from treatment with estrogen and each ofthree estrogen-progestin treatment regimens versusplacebo.

Materials and Methods

Between December 1989 and February 1991, the Post-menopausal Estrogen/Progestin Interventions Trial en-rolled 875 postmenopausal women at seven clinicalcenters in the United States in a randomized, double-blind, placebo-controlled trial of the effects of oralconjugated equine estrogen, 0.625 mg daily, or conju-gated equine estrogen plus one of three oral progestinregimens, on selected cardiac risk factors, other healthoutcomes, and symptoms. Sample size calculationswere based on the primary cardiac endpoints.9 Theprogestin regimens were medroxyprogesterone acetate,10 mg for 12 of 28 days (conjugated equine estrogen 1medroxyprogesterone acetate [cyc]); medroxyproges-terone acetate, 2.5 mg daily (conjugated equine estro-gen 1 medroxyprogesterone acetate [con]); and micron-ized progesterone, 200 mg for 12 of 28 days (conjugatedequine estrogen 1 micronized progesterone). All med-ication was identical in appearance, and tamper-proofrandomization was accomplished by computer. Subjectrecruitment, eligibility criteria, study design, and base-line characteristics of the sample have been reported indetail.9 Women were required to be between 45 and 64years of age; at least 1 year, but not greater than 10years, postmenopausal; not taking estrogen or proges-tin for at least 2 months before screening; if treated withthyroid replacement, to have been on a stable dose forat least 3 months before screening; and to be free ofmajor medical contraindications to hormone use. Fourwomen with self-defined severe menopausal symptoms

(characterized by a positive response to “Do you havesevere menopausal symptoms that cannot be toleratedwithout treatment?”) also were excluded because theywould have been unable to take placebo.

Demographic characteristics, medical history, physi-cal activity, and consumption of cigarettes and alcoholwere collected by standardized questionnaires. Symp-toms were assessed at baseline and 12 and 36 monthsusing a self-administered checklist. When the protocolwas developed, no validated checklist of menopausalsymptoms or estrogen side effects had been reported.Therefore, Postmenopausal Estrogen/Progestin Inter-ventions Trial investigators compiled a list of 52 possi-ble symptoms from the published literature, augmentedby the experience of the clinical investigators and avalidated instrument designed to assess the premen-strual syndrome.10 The order of the symptoms wasrandomized and formatted into a dichotomous (yes-no)checklist.

Women who took at least 80% of their pills during the6 months before each annual visit were defined asadherent, with 612 meeting this definition. Medicationswere blister-packed, and pill counts were performed ateach visit by clinic staff. The protocol required perma-nent drug interruption for the following conditions:possible estrogen-dependent tumors, stroke, transientischemic attack, pulmonary embolus, deep vein throm-bosis, or complex (adenomatous or atypical) hyperpla-sia. Other participants elected to discontinue studydrug permanently or temporarily for symptoms or forpersonal reasons. Narrative summaries of the reason(s)for treatment discontinuation were completed by clinicstaff, and the primary reason for each interruption wascoded. Women could not transfer between treatmentarms within the Postmenopausal Estrogen/ProgestinInterventions Trial. Those who chose to institute hor-mone therapy did so under the care of their personalhealth care provider.

For analysis, the original set of 52 symptoms was firstreduced to a more manageable set of symptom groups.Each group consisted of symptoms that were correlatedhighly with each other, as determined by a factoranalysis at baseline.11 For each symptom group, a scorewas created for each subject by counting the number ofsymptoms she endorsed in each symptom group.Scores for each symptom group were calculated atbaseline and at 12 and 36 months. The effect of treat-ment at each visit on each symptom group score wasexamined using logistic regression models for ordinaldata.12 Specifically, we modeled the odds of having ahigher versus lower symptom score as a function oftreatment assignment, baseline symptom score, clinicalsite, and uterus status. (Clinical site and uterus statuswere randomization blocking variables.) The correla-

VOL. 92, NO. 6, DECEMBER 1998 Greendale et al Postmenopausal Hormones 983

tion between symptom group scores at 12 and 36months was accounted for using the statistical approachof Heagerty and Zeger.13 Each symptom group wasconsidered in a separate logistic regression analysis.Significant interactions between treatment assignmentand follow-up year and treatment assignment andbaseline symptom scores were included in final models.Pairwise comparisons between treatment effects weretested using two-sided generalized Wald tests. Becausethe changes in the effect sizes (odds ratios [ORs]) weresmall in the two cases in which baseline score interac-tions were significant, and because presenting ORs foreach baseline level would increase the number of tablesmany times over, all tables show the ORs calculatedwithout baseline symptom score interaction terms. Allanalyses were repeated restricted to adherent womenonly. The entire analysis also was done in the subsetof women (n 5 612) who were adherent to studymedication.

Results

The average age of the participants was 56.1 years atbaseline: 41% were between 45 and 54 years old, and theremainder were between 55 and 64 years old; 89% werewhite, and 32% had undergone hysterectomies. Amongwomen with a uterus (n 5 596), 52% were within 5years of their last menstrual period, and the remainderwere between 5 and 10 years postmenopausal. Partici-pation at the 1- and 3-year visits was 97% and did notvary by treatment assignment.

During the 3 years of follow-up, 210 women (24%)stopped treatment permanently; 51 (24%) of these wereprotocol-mandated, the majority (n 5 32) due to endo-metrial abnormalities. Among the remaining 159women, primary reasons for stopping treatment weresymptoms (n 5 127), concerns about health risks (n 511), and personal circumstances (n 5 21). The mostoften cited symptoms were vaginal bleeding (n 5 25);premenstrual-like symptoms (n 5 17); vasomotorsymptoms (n 5 11); headaches (n 5 10); anxiety-depression (n 5 10); and breast tenderness (n 5 7). Bythe year 3 visit, 19 women in the placebo group (11%)had begun taking privately prescribed hormones.

At the conclusion of the study, women were asked toguess what treatment they had received. Among place-bo-assigned women, 17.7% thought they were takingconjugated equine estrogens, and 23.8% believed theywere treated with conjugated equine estrogens plusprogestin. Of conjugated equine estrogen–assignedwomen, 13.6% guessed that they had taken placebo and40.1% guessed conjugated equine estrogen plus proges-tin. Among combination treated women, 10.6% guessedplacebo and 17.6% guessed conjugated equine estrogen.

Results of the factor analysis used to derive symptomgroups are displayed in Table 1. The six factors shownexplained 45.1% of the total variation in the baselinesymptoms. Symptom groups were similar in womenwith and without hysterectomy (data not shown). Va-somotor, musculoskeletal, increased appetite-perceivedweight gain, and cognitive-affective symptoms werecited most frequently; anxiety and breast discomfortsymptoms were less common (Table 1).

At 1 and 3 years, women in each active treatmentgroup had significantly lower vasomotor symptom lev-els compared with women in the placebo group, ad-justed for baseline vasomotor symptom level, clinic,and uterus status (Table 2). At year 1, the ORs compar-ing treatments to placebo (column 1 of Table 2) rangedbetween 0.17 and 0.28 (P , .001 for each comparison),indicating substantial protection against vasomotorsymptoms, but the ORs were between 0.26 and 0.53(P # .03 for each comparison) at follow-up year 3,indicating a less pronounced difference between treatedand untreated women.

The remaining columns of Table 2 show pairwisecomparisons between the active treatments. None of

Table 1. Symptom Groups and the Prevalence of EachSymptom at Baseline (n 5 875)

Symptom group Percent reporting

Cognitive-affectiveForgetfulness 34Easily distracted 25Difficulty concentrating 24Decreased efficiency 18Short temper 18Loss of interest in work 13Lowered work performance 13Avoidance of social affairs 8Confusion 7

Weight-appetiteWeight gain 32Increased appetite 22Decreased appetite 5Weight loss 4

MusculoskeletalAches-pains 48Joint pain 44Muscle stiffness 42Skull-neck aches 34

Breast discomfortBreast sensitivity 9Painful breasts 4

AnxietySuffocation 5Difficulty breathing 4Fuzzy vision 4

VasomotorHot flashes 46Night sweats 36Cold sweats 7

984 Greendale et al Postmenopausal Hormones Obstetrics & Gynecology

these comparisons were significant at year 1, indicatingthat conjugated equine estrogens plus progestin wasnot more effective than conjugated equine estrogensalone against vasomotor symptoms. Comparisons atyear 3 showed similar equivalence of treatments withone exception: conjugated equine estrogens appeared tobe less effective than conjugated equine estrogens plusmicronized progesterone (indicated by the OR of 2.05 inthe last column of Table 2), although conjugated equineestrogens and conjugated equine estrogens plus mi-cronized progesterone were each more effective thanplacebo. Women with more severe vasomotor symp-toms at baseline experienced a greater treatment effect(data not shown); this interaction was statistically sig-nificant only for conjugated equine estrogens plus me-droxyprogesterone acetate [con] (P 5 .001) and conju-gated equine estrogens (P 5 .056).

For vasomotor symptoms, results confined to adher-ent women paralleled those seen in the intent-to-treatanalysis (data not shown). All treated women had lowersymptom levels compared with those taking placebo;there were no differences between treatments, and theeffects of treatment in year 3 were weaker than those inyear 1. The effect of all active treatments on vasomotorsymptoms, however, was greater in the adherent com-pared with the intent-to-treat analysis. Compared withplacebo, the odds of having more severe vasomotorsymptoms ranged from 0.11 to 0.13 for women adherentto the active treatments in year 1 (P , .001 for eachcomparison) and 0.16 to 0.29 for the adherent women inyear 3 (P # .001 for each comparison).

Vasomotor symptoms were the sole symptom groupthat demonstrated differences in the effects of treat-ments at year 1 versus year 3. Notably, the crude

prevalence of any hot flash symptom in women as-signed to placebo declined over time; it was 55.7%,38.7%, and 29.5% at baseline, year 1, and year 3,respectively. Among placebo-adherent women, corre-sponding prevalence figures were 52.9%, 43.7%, and30.3%.

Women assigned to active treatment did not differ atyears 1 or 3 in the domains of cognitive-affective,anxiety, or musculoskeletal symptoms compared withplacebo-assigned women (ORs between 0.7 and 0.9,comparisons not statistically significant, data notshown). Among adherent participants, the effect ofestrogen on cognitive-affective symptoms was not sub-stantively different than was found for all women (datanot shown). With respect to anxiety symptoms, theresults of the adherent analysis also were similar to theintent-to-treat results, with the exception that anxietysymptom levels were lower in conjugated equine estro-gens–adherent women compared with those who re-ceived placebo (OR 5 0.52, P 5 .05). A protective effectof active treatment on musculoskeletal symptoms wasevident in the adherent analysis (ORs 0.62–0.68 com-pared with placebo). These results were statisticallysignificant for women adherent to cyclic (P 5 .02) andcontinuous (P 5 .04) medroxyprogesterone acetate reg-imens and of borderline significance for the womentaking conjugated equine estrogens (P 5 .08) and con-jugated equine estrogens 1 micronized progesterone(P 5 .06).

Breast discomfort was significantly more commonwith each combination estrogen-progestin treatmentcompared with both placebo and unopposed conju-gated equine estrogens treatments (Table 3); the odds ofhaving more severe breast discomfort compared with

Table 2. Adjusted Odds* of Having Higher Vasomotor Symptom Scores for Each Treatment Group (Row) Compared Withan Alternative Treatment Group (Column) at 1 and 3 Years

Treatment assignment†

and year

Comparison group‡,§

Placebo CEE 1 MPA (cyc) CEE 1 MPA (con) CEE 1 MP

Year 1CEE 0.28 (0.16, 0.48) 1.20 (0.63, 2.29) 1.62 (0.81, 3.25) 1.32 (0.69, 2.49)CEE 1 MPA (cyc) 0.23 (0.13, 0.40) 1.35 (0.67, 2.68) 1.09 (0.58, 2.06)CEE 1 MPA (con) 0.17 (0.09, 0.32) 0.81 (0.41, 1.60)CEE 1 MP 0.21 (0.12, 0.37)

Year 3CEE 0.53 (0.31, 0.93) 1.25 (0.68, 2.30) 1.36 (0.73, 2.51) 2.05 (1.08, 3.90)CEE 1 MPA (cyc) 0.43 (0.24, 0.75) 1.09 (0.58, 2.03) 1.64 (0.86, 3.15)CEE 1 MPA (con) 0.39 (0.22, 0.69) 1.51 (0.78, 2.91)CEE 1 MP 0.26 (0.14, 0.47)

* Odds ratios are adjusted for baseline symptom level, clinical site, and uterus status.† CEE 5 0.625 mg conjugated equine estrogens (daily); CEE 1 MPA (cyc) 5 0.625 mg conjugated equine estrogens (daily) and 10 mg

medroxyprogesterone acetate (days 1–12); CEE 1 MPA (con) 5 0.625 mg conjugated equine estrogens (daily) and 2.5 mg medroxyprogesteroneacetate (daily); CEE 1 MP 5 0.625 mg conjugated equine estrogens (daily) and 200 mg micronized progesterone (days 1–12).

‡ Entries in table are odds ratios with 95% confidence intervals from generalized Wald tests in parentheses.§ N 5 858–862 (due to missing data); N randomized to each arm: placebo (174); CEE (175); CEE 1 MPA (cyc) (174); CEE 1 MPA (con) (174);

CEE 1 MPA (178).


placebo were roughly equal among all of the progestinformulations and did not differ by year of follow-up.Women assigned to conjugated equine estrogens (OR 51.16, Table 3) and women adherent to conjugatedequine estrogens (OR 5 1.09, P 5 .82) had no higherlevels of breast discomfort than the placebo group.Compared with the intention-to-treat analysis, womenadherent to any progestin regimen had even greaterlevels of breast discomfort compared with those in theplacebo group (ORs $ 2.26; P # .006).

The perceived weight-appetite symptom group in-cluded the self-reported symptoms of perceived weightgain, increased appetite, perceived weight loss, anddecreased appetite (Table 1). Women assigned to con-tinuous medroxyprogesterone acetate reported signifi-cantly less perceived weight gain and appetite increasecompared with those in the placebo group (Table 3).Women reporting more perceived weight gain andincreased appetite at baseline were less likely to reportperceived weight gain 12 and 36 months, as a result ofany active treatment (data not shown). Few womenreported weight loss-decreased appetite; women as-signed to conjugated equine estrogens 1 micronizedprogesterone were significantly more likely to perceiveweight loss-decreased appetite compared to placeboassigned women (Table 3). A similar but marginallystatistically significant effect was also apparent for con-tinuous conjugated equine estrogens 1 medroxypro-gesterone acetate [con]. None of the perceived weight-

appetite symptoms differed between years 1 and 3among all participants and adherent participants.

Two symptoms, headache and forgetfulness, wereanalyzed separately. There was an interaction betweenbaseline headache score and treatment for conjugatedequine estrogens only (P 5 .06). If headache was absentat baseline, the conjugated equine estrogens group wasmore likely to develop headache than placebo or pro-gestin-treated groups. Conversely, if headache waspresent at baseline, the conjugated equine estrogensgroup reported less headache than placebo or proges-tin-treated women. Among women reporting no forget-fulness at baseline, there was no effect of treatment. Incontrast, for those who reported forgetfulness at base-line, conjugated equine estrogens treatment was asso-ciated with more forgetfulness than combination treat-ments (data not shown).

Discussion

Previous clinical trials have shown near-complete ame-lioration of hot flashes after hormone therapy.2 Becausemonotherapy with medroxyprogesterone acetate14 de-creases vasomotor symptoms, combination therapywith estrogen and progestin might be more effectivethan either treatment individually. We found convinc-ing evidence that conjugated equine estrogens with theprogestins tested is not more effective than conjugatedequine estrogens alone in hot flash reduction. The single

Table 3. Adjusted Odds* of Having Higher Symptom Scores for Each Treatment Group (Row) Compared With anAlternative Treatment Group (Column)

Treatment assignment†

and symptom group

Comparison group‡,§

Placebo CEE 1 MPA (cyc) CEE 1 MPA (con) CEE 1 MP

Breast discomfortCEE 1.16 (0.70, 1.93) 0.52 (0.33, 0.82) 0.61 (0.38, 0.98) 0.50 (0.32, 0.79)CEE 1 MPA (cyc) 2.27 (1.39, 3.56) 1.17 (0.76, 1.81) 0.97 (0.63, 1.46)CEE 1 MPA (con) 1.92 (1.16, 3.09) 0.83 (0.53, 1.26)CEE 1 MP 2.33 (1.46, 3.74)

Perceived weight gainCEE 0.80 (0.54, 1.19) 1.15 (0.78, 1.71) 1.31 (0.87, 1.95) 0.92 (0.63, 1.35)CEE 1 MPA (cyc) 0.69 (0.47, 1.03) 1.13 (0.87, 1.70) 0.80 (0.54, 1.18)CEE 1 MPA (con) 0.61 (0.41, 0.91) 0.70 (0.47, 1.05)CEE 1 MP 0.87 (0.60, 1.26)

Perceived weight lossCEE 1.22 (0.61, 2.46) 0.80 (0.41, 1.55) 0.66 (0.35, 1.26) 0.55 (0.29, 1.02)CEE 1 MPA (cyc) 1.52 (0.78, 2.97) 0.82 (0.45, 1.49) 0.68 (0.38, 1.20)CEE 1 MPA (con) 1.85 (0.97, 3.56) 0.83 (0.47, 1.45)CEE 1 MP 2.22 (1.17, 4.30)

* Odds ratios are adjusted for baseline symptom level, clinical site, and uterus status.† CEE 5 0.625 mg conjugated equine estrogens (daily); CEE 1 MPA (cyc) 5 0.625 mg conjugated equine estrogens (daily) and 10 mg

medroxyprogesterone acetate (days 1–12); CEE 1 MPA (con) 5 0.625 mg conjugated equine estrogens (daily) and 2.5 mg medroxyprogesteroneacetate (daily); CEE 1 MP 5 0.625 mg conjugated equine estrogens (daily) and 200 mg micronized progesterone (days 1–12).

‡ Entries in table are odds ratios with 95% confidence intervals from generalized Wald tests in parentheses.§ N 5 858–862 (due to missing data); N randomized to each arm: placebo (174); CEE (175); CEE 1 MPA (cyc) (174); CEE 1 MPA (con) (174);

CEE 1 MPA (178).


pairwise comparison of conjugated equine estrogensversus conjugated equine estrogens 1 micronized pro-gesterone at year 3 suggested that the latter combina-tion was more effective, but this is likely artifact due toprotocol-mandated estrogen discontinuations in theconjugated equine estrogens–only arm. Not surpris-ingly, vasomotor symptom reduction was more pro-nounced in women who had more severe hot flashes atbaseline.

Most studies of hot flashes have been 1 year or less inlength,2 such that the natural history of hot flashes in anuntreated group has not been examined well. In thePostmenopausal Estrogen/Progestin InterventionsTrial, the difference in hot flash symptom–reportingbetween treated and untreated women diminished be-tween years 1 and 3, compatible with the observedpattern of diminishing hot flashes over time in theplacebo group.

The etiology of mastalgia in both premenopausal andpostmenopausal women is obscure.15 Most attentionhas focused on estrogens rather than progestins as thepotential cause,16,17 and lower starting doses of estrogenare recommended to minimize this side effect.18 How-ever, norethisterone also is reported to cause breast painwith HRT.19 In the Postmenopausal Estrogen/ProgestinInterventions Trial, worsened symptoms of breast painand discomfort were confined to the combination estro-gen-progestin treatment groups, suggesting that thecombination is responsible for the mastalgia associatedwith postmenopausal hormones. Neither a smallerdaily progestin dose (as in the 2.5-mg medroxyproges-terone acetate daily arm) nor use of micronized proges-terone was less likely to produce mastalgia than thetraditional cyclic dose of medroxyprogesterone acetate(10 mg). Because there was no progestin-only treatmentin the Postmenopausal Estrogen/Progestin Interven-tions Trial, we cannot determine whether estrogen mustbe present to observe progestin-related mastodynia.

In practice, many women are concerned that hor-mone use leads to weight gain.18 Although weight gainoccurs at menopause,20 studies have not found thatpostmenopausal hormones cause or prevent weightgain.21,22 In the Postmenopausal Estrogen/ProgestinInterventions Trial, measured weight gain was notcaused by conjugated equine estrogens only or conju-gated equine estrogens–progestin regimens.23 Thisstudy finds that women who used unopposed conju-gated equine estrogens did not perceive weight gaincompared with placebo. Those using conjugated equineestrogens–progestin sensed weight loss.

Prior studies of cognition and estrogen use have beeninconsistent. Barrett-Connor and colleagues24 found noeffects of estrogen on numerous complex tests of memoryand cognitive function, as did Ditkoff and colleagues25 in

a randomized controlled trial among women of similarage to the Postmenopausal Estrogen/Progestin Inter-ventions Trial sample. In contrast, other interventionstudies have found memory benefit from estrogen useamong women of varied ages and using different mea-sures.26 Reports that estrogen may protect against de-mentia also are contradictory,26 but dementia is quitedistinct from the outcomes assessed in the Postmeno-pausal Estrogen/Progestin Interventions Trial. Symp-toms such as forgetfulness and difficulty concentratingare common, but not sensitive for specific measures; ourresults do not support a relationship between HRT andthese symptoms.

In the United States and Europe, musculoskeletalcomplaints are not prominent during menopause.27,28

In Japan, however, muscle and neck pain may beconcomitants of the menopause.29 The PostmenopausalEstrogen/Progestin Interventions Trial was not de-signed to determine the symptoms that characterize themenopause transition, because women were postmeno-pausal at entry. It is notable that adherence to treatmentwas associated with less muscle and joint pain, provoc-ative findings that warrant further investigation.

The higher frequency of migraine among women andits relation to menses and, in some reports, menopausesuggests the hypothesis that these vascular events aremediated by changing estrogen levels.30 The Postmeno-pausal Estrogen/Progestin Interventions Trial symp-tom checklist did not distinguish headache types. Cu-riously, women in the study with headache at baselinewho took conjugated equine estrogens were less likelyto have headache at follow-up, whereas those withoutheadache at the beginning of the study were more likelyto develop headache in conjugated equine estrogenstreatment. This interaction might explain why previousstudies produced inconsistent results with respect toHRT and headache symptoms.

Even in a randomized controlled trial, it is difficult tointerpret side effect data because the symptoms beingevaluated as outcomes also could cause discontinuationor institution of treatment. The effect of treatmentcrossovers, relatively uncommon in the Postmeno-pausal Estrogen/Progestin Interventions Trial, wouldbe to diminish the difference between active treatmentand placebo for both beneficial (eg, vasomotor) anddeleterious (eg, breast tenderness) effects. Thus, neitherintention-to-treat nor adherent analyses characterizesymptom relief or side effects perfectly. To address thepotential problems of symptom-related discontinua-tions and crossovers, we presented both adherent andassigned treatment results. In most instances, the resultswere not affected materially, suggesting that the flawsof each analysis are not large.

This study assessed only those items that were in-


cluded on the symptom checklist, which was not avalidated scale of menopause symptoms. We also didnot assess symptom severity or the effects of improve-ment or worsening of symptoms on functional status.Unfortunately, standard tests of cognitive functionwere not obtained. Symptoms were not measured uni-formly during the estrogen-only or estrogen-progestinportion of the cyclical treatments, which could dilutebetween-group differences. We expect this error to berandom and not to introduce bias into the results.

We confirmed a beneficial effect of estrogen on vaso-motor symptoms with no additional advantage ofadded progestins. Breast discomfort was restricted tothe three estrogen-progestin treatment groups. Neitherestrogens nor estrogens and progestins caused per-ceived weight gain. Postmenopausal hormone therapydid not affect self-reported cognitive, affective, or anxi-ety symptoms but may have improved muscular achesand joint pains. This information will help clinicianscounsel women more effectively about benefits of hor-mone use and will assist in managing treatment-relatedside effects, such as mastalgia.

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Address reprint requests to:Gail A. Greendale, MDUniversity of California, Los AngelesSchool of Medicine10945 Le Conte Avenue, Suite 2339Los Angeles, CA 90095-1687E-mail: [email protected]

Received March 3, 1998.Received in revised form June 2, 1998.Accepted June 19, 1998.

Copyright © 1998 by The American College of Obstetricians andGynecologists. Published by Elsevier Science Inc.
