Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone

American Journal of Obstetrics

and Gynecology Founded in 1920

volume 170

number 5 part

MAY

1994

CLINICAL SECTION

Clinical Articles

Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone J. Donald Woodruff, MD, and James H. Pickar, MD, for The Menopause Study Group Baltimore, Maryland, and Philadelphia, Pennsylvania OBJECTIVE: We evaluated four oral combinations of conjugated estrogens (Premarin) and medroxyprogesterone acetate in preventing endometrial hyperplasia, which can occur with conjugated estrogens alone. STUDY DESIGN: This was a 1-year prospective, double-blind, randomized, multicenter study in 1724 postmenopausal women. All five groups took conjugated estrogens (0.625 mg) daily. The respective medroxyprogesterone acetate dosages were 2.5 and 5.0 mg daily (groups A and 8) and 5.0 and 10.0 mg for 14 days per 28-c1ay cycle (groups C and D). RESULTS: Among the 1385 patients with valid biopsy data, endometrial hyperplasia developed in 20% in the conjugated estrogens-treated group and :5 1% in each of the four conjugated estrogens/medroxyprogesterone acetate-treated groups. The incidence of endometrial hyperplasia did not differ significantly between any of the conjugated estrogens/medroxyprogesterone acetate regimens. However, none of the patients receiving the two higher medroxyprogesterone acetate dosages (groups 8 and D) had endometrial hyperplasia. CONCLUSION: The endometrial hyperplasia incidence was significantly lower in women treated with conjugated estrogens and medroxyprogesterone acetate than in women treated with conjugated estrogens alone. (AM J OesTET GYNECOL 1994;170:1213-23.)

K"l words: Estrogen replacement therapy, hormone replacement therapy, menopause, endometrial hyperplasia, Premarin, medroxyprogesterone acetate, conjugated estrogens, progestin Estrogen replacement therapy has been used effectively in women for decades to treat postmenopausal

From the Departments of Gynecology and Obstetrics and Pathology, The johns Hopkins Hospital, and Wyeth-Ayerst Research. This study was conducted at 99 sites in the United States and Europe. Names, affiliations, and addresses of the investigators in The Menopause Study Group are lzsted at the end of the article. Supported by Wyeth-Ayerst Research, Philadelphia, Pennsylvania. Presented In part at the Seventh International Congress on the Menopause, Stockholm, Sweden, june 20-24, 1993. Receivedfor publication july 21, 1993; revised November 16, 1993; accepted December 8, 1993. Reprint requests:james H. Pickar, MD, Wyeth-Ayerst Research, P.O. Box 8299, Phtladelphia, PA 19101. Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/53550

symptoms and more recently to prevent osteoporosis. In addition, epidemiologic studies have consistently shown that estrogen use reduces the risk of coronary heart disease. 1 However, it has also been well established that estrogen therapy given without a concomitant progestogen is associated with endometrial hyperplasia and an increased risk of endometrial cancer!-5 This finding should not be surprising because elevated endogenous estrogen levels associated with such conditions as obesity, polycystic ovarian syndrome, and estrogen-producing tumors of the ovaries have also been reported to increase the risk of endometrial cancer.6 Adding a progestogen to estrogen replacement therapy (i.e., hormone replacement therapy) significantly reduces the risk of endometrial disease con1213

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May 1994 Am J Obstet Gynecol

Table I. Dosage regimens for conjugated estrogens and medroxyprogesterone acetate Regimen

Cycle days

Conjugated estrogens (mg)

Medroxyprogesterone acetate (mg)

A B C

1-28 1-28 1-14 15-28 1-14 15-28 1-28

0.625 0.625 0.625 0.625 0.625 0.625 0.625

2.5 5.0 Placebo 5.0 Placebo 10.0 Placebo

D E

nected with unopposed estrogen. 2 • 5 Furthermore, adding a progestogen to estrogen replacement therapy does not interfere with efficacy in treating vasomotor symptoms? or preventing osteoporosis. 8 Although progestogens are frequently prescribed as part of hormone replacement therapy, there are few large randomized controlled trials on which to base the selection of the appropriate progestogen dosages.'· 9 The purpose of this study was to evaluate four oral combinations of conjugated estrogens (Premarin) and medroxyprogesterone acetate in comparison with conjugated estrogens alone with a sufficiently large population to establish statistically significant differences in the incidence of endometrial hyperplasia. Methods

Study design. This was a prospective, double-blind, parallel, controlled study conducted with healthy postmenopausal women at 99 sites in the United States and Europe. Because the expected incidence of endometrial hyperplasia is low, use of pooled data from many sites was considered more meaningful than analysis of data from anyone site alone. With a hypothesized incidence of endometrial hyperplasia of 7.5% in the conjugated estrogens alone group and 2% in the conjugated estrogens/medroxyprogesterone acetate groups, a sample size of 215 patients per treatment group would have provided 80% power to detect at least one statistically significant difference at the 0.0125 level (Bonferroni adjustment for four multiple comparisons). To allow for a 20% discontinuation rate, an enrollment of about 270 patients per group was planned. The patients were randomly assigned to one of five treatment groups for 13 cycles (1 year). The effects of four conjugated estrogens/medroxyprogesterone acetate combinations and of conjugated estrogens alone on the incidence of endometrial hyperplasia were evaluated. Other parameters evaluated in this study included bleeding profiles lo and metabolic safety (data on file). Approval from the institutional review boards was obtained and the patients gave informed consent before enrollment in the study. Patient selection. Generally healthy women who were 45 to 65 years old with an intact uterus were

eligible for the study if their last natural menstrual cycle had been at least 12 months before the baseline screening. The serum follicle-stimulating hormone concentrations had to be higher than the lower limit for postmenopausal women for the given laboratory (most were between 25 and 35 mIU/ml). Patients could not have used any estrogen- or progestogen-containing medication for at least 2 weeks before the pre study screening. Dosages. The dosage regimens are shown in Table I. The conjugated estrogens dosage selected, 0.625 mg daily, is the minimum effective dosage to prevent bone loss. II. 12 Conjugated estrogens and either medroxyprogesterone acetate or a matching medroxyprogesterone acetate placebo were taken orally once daily at approximately the same time each day. (The study medications were from Wyeth-Ayerst Laboratories, Philadelphia.) Regimens A and B were continuous combined (i.e., conjugated estrogens [0.625 mg] and medroxyprogesterone acetate [2.5 mg in regimen A and 5.0 mg in regimen B] were both given daily). Regimens C and D were sequential with cornugated estrogens (0.625 mg) given daily and medroxyprogesterone acetate (5.0 mg in regimen C and 10.0 mg in regimen D) given for the last 14 days of each 28-day cycle. During the course of each cycle, patients in groups A and C received a total of 70 mg of medroxyprogesterone acetate and those in groups Band D received a total of 140 mg of medroxyprogesterone acetate. The patients in group E took conjugated estrogens and a placebo. Each patient was given diary cards for daily recording of tablets taken or omitted. Concomitant medication. Throughout the study the knowledge or permission of the investigator was generally required for the use of concomitant medications, with the exception of oral calcium. Patients were prohibited from taking any estrogen or progestogen other than the trial medication during the study. They were also prohibited from taking any other steroids for > 10 days during the study. Evaluation for endometrial hyperplasia. Scheduled endometrial biopsies were performed before treatment began (baseline) and during days 22 to 28 of cycles 6 and 13. Additionally, an endometrial biopsy could be done at any time if medically indicated. If an endome-

Woodruff and Pickar

Volume 170, Number 5, Part 1 Am ] Obstet Gynecol

trial biopsy performed during the study indicated endometrial hyperplasia, the patient was withdrawn from the study and given appropriate therapy. Medically accepted procedures for obtaining an endometrial tissue specimen suitable for histologic evaluation were used. Approximately 75% of the biopsies were performed by means of either the Pipelle endometrial suction curette (Prodimed, France), the Novak curette, or the Vabra aspirator (Berkeley Medevices, Inc., Berkeley, Calif.). The remaining 25% were obtained with 14 other uterine endocervical curettes. To ensure uniformity in interpretation, all endometrial biopsy specimens were evaluated by one of us (I.D.W.) at The Johns Hopkins Hospital, Baltimore. The terminology used to report endometrial hyperplasia in this publication (cystic or adenomatous hyperplasia without atypia; cystic or adenomatous hyperplasia with atypia) corresponds to the alternative classifications of simple hyperplasia, complex hyperplasia; simple atypical or complex atypical hyperplasia, respectively. The criteria and terminology used have been appropriately described in the literature. 13. 14 Briefly, cystic or simple hyperplasia is characterized by a proliferative epithelium with the usual number of typical mitoses. There is no abnormal crowding of the glands and the glands vary in size and shape. In adenomatous or complex hyperplasia the glands are more closely packed with little intervening stroma. Cytologic atypias are identified by an atypical proliferation of the epithelium with "stromal invasion." It must be emphasized that this is a cytologic change. The epithelium is so proliferative that the glands cannot accommodate the increased number of cells leading to infolding of the epithelium. Such crowding of the glands virtually eliminates the intervening stroma and increases the nuclear/cytoplasmic ratio. The nuclei are enlarged or irregular with coarse chromatin clumping and prominent nucleoli. Mitotic activity is not of mqior importance for the diagnosis of atypicality because it is found in all proliferative endometria. Atypical mitosis is an ambiguous designation and is not used in this manuscript. Patients were considered to be eligible for the 12month efficacy evaluation if they had a pretreatment endometrial biopsy, had taken at least one dose of study medication, and either underwent an endometrial biopsy during cycles 12 to 14 or had endometrial hyperplasia in an earlier cycle. Data for these patients were included in the 12-month analysis. The 12-month analysis included the results from the 6-month evaluation. The incidence of endometrial hyperplasia at the 12-month evaluation was calculated with the formula I = NB. In this formula I = incidence at the 12-month evaluation, A = all patients with biopsy specimens showing endometrial hyperplasia, and B = all patients

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undergoing biopsies during cycles 12 through 14 plus all patients with biopsy specimens showing endometrial hyperplasia before cycle 12. A similar approach was used to calculate the incidence of endometrial hyperplasia with the 6-month data. Cycles 5 to 7 served as the basis for determining the status of endometrial hyperplasia at month 6. In no case was any patient counted more than once. Statistical analysis. Fisher's exact test was used to compare the incidence of endometrial hyperplasia between the co~ugated estrogens alone group and each conjugated estrogens/medroxyprogesterone acetate group. The incidence of endometrial hyperplasia was compared at 6 and at 12 months. All pairwise comparisons were made by use of two-sided tests. A Bonferroni adjustment for the four multiple comparisons was made in the significance levels. Detection of one or more differences significant at the 0.0125 level controlled the experiment-wise type I error rate at the 0.05 level. Results

A total of 1724 postmenopausal women were enrolled. The population that completed this I-year study with endometrial biopsy data valid for analysis was composed of 1385 patients. Although the protocol specified that patients be 45 to 65 years old, one patient in group A and three patients in group C were 44 years old. The data for these patients were included in the analysis even though their enrollment constituted a protocol violation. Prestudy characteristics of the population that completed the study are summarized in Table II. The prestudy characteristics of this population were similar to those of the study population as a whole. There were no statistically significant (p < 0.05) differences among treatment groups in any demographic characteristics. Among women taking the continuous combined regimens (groups A and B), approximately 20% of the biopsy specimens had either no tissue or no endometrial tissue identified. This may be an indication of atrophy of the endometrium. Those who took the sequential regimens (groups C and D) had either no tissue or no endometrial tissue in only 10% of biopsy specimens, and those in the conjugated estrogens alone group (group E) had either no tissue or no endometrial tissue in approximately 15% of biopsy specimens. Endometrial hyperplasia developed in 23 (2%) of 1469 patients included in the evaluation of the 6-month data. The incidence of hyperplasia by treatment group and the results of the statistical analysis are provided in Table III. The incidence with each of the conjugated estrogens/medroxyprogesterone acetate regimens was significantly lower than that with conjugated estrogens alone. There were no statistically significant differences

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Woodruff and Pickar

May 1994 Am J Obstet Gynecol

Table II. Demographic and baseline data for population that completed study with valid data on endometrial hyperplasia Treatment group* Attribute Age (yr) Mean ± SD Range Age at menopause (yr)t Mean ± SD Range Time since menopause (yr)t Mean ± SD Range Race (no. of patients) White Black Other Weight (kg) Mean ± SD Range

A (n = 279)

B (n = 274)

C (n

54.2 ± 4.6 44-65

54.1 ± 4.6 45-65

49.0 ± 3.8 30-58

= 277)

D (n = 272)

E (n = 283)

53.9 ± 4.8 44-65

54.0 ± 4.7 45-65

54.0 ± 4.4 45-65

48.8 ± 4.2 31-60

48.6 ± 4.0 34-57

48.8 ± 3.9 32-58

48.8 ± 4.2 31-61

5.2 ± 4.1 0-28

5.3 ± 4.2 1-33

5.3 ± 4.3 1-27

5.2 ± 4.5 0-25

5.3 ± 4.3 0-31

273 (98%) 2 (1%) 4 (1%)

264 (96%) 5 (2%) 5 (2%)

269 (97%) 5 (2%) 3 (1%)

263 (97%) 5 (2%) 4 (1%)

277 (98%) 4 (1%) 2 (1%)

64.4 ± 8.5 46-87

63.7 ± 8.2 42-89

64.3 ± 8.5 45-88

65.6 ± 8.5 43-91

64.3 ± 8.7 43-91

*All groups received conjugated estrogens 0.625 mg every day of a 28-day cycle. The following medroxyprogesterone acetate dosages were taken: group A, 2.5 mg, days I to 28; group B, 5.0 mg, days 1 to 28; group C, 5.0 mg, days 15 to 28; group D, 10.0 mg, days 15 to 28; group E. no medroxyprogesterone acetate (placebo). tn = 278 for group A; n = 273 for group B; n = 276 for group C.

Table III. Incidence of endometrial hyperplasia at 6 and 12 months Patients wzth positive biopsy speczmens Treatment group*

I

Comparison with conjugated estrogens alond

No.

No.

D E

295 291 293 292 298

1 0 1 0 21

<1 0 <1 0 7

P< P< P< P<

0.001 0.001 0.001 0.001

D E

279 274 277 272 283

2 0 3 0 57

<1 0 1 0 20

P< P< P< P<

0.001 0.001 0.001 0.001

6mo A B C 12 mo A B C

%

*All groups received conjugated estrogens 0.625 mg every day of a 28-day cycle. The following medroxyprogesterone acetate dosages were taken: group A, 2.5 mg, days 1 to 28; group B, 5.0 mg, days 1 to 28; group C, 5.0 mg, days 15 to 28; group D, 10.0 mg, days 15 to 28; group E, no medroxyprogesterone acetate (placebo). tBased on Fisher's exact test.

between the lower-dose and higher-dose medroxyprogesterone acetate regimens or between the continuous combined regimens and the sequential regimens. The evaluation of the 12-month data (including 6-month data) showed that endometrial hyperplasia had developed in 62 (4%) of the 1385 patients included in the analysis. The incidence of hyperplasia and the results of the statistical comparison by treatment group for the 12-month data are also presented in Table III. As with the evaluation of the 6-month data, the incidence of endometrial hyperplasia was significantly

lower with each of the conjugated estrogens/medroxyprogesterone acetate regimens than with conjugated estrogens alone. Additionally, there were no statistically significant differences in the incidence of endometrial hyperplasia between any of the four conjugated estrogens/medroxyprogesterone acetate treatment groups or between the continuous combined regimens and the sequential regimens. However, there were a total of five cases of endometrial hyperplasia in the two lower-dose medroxyprogesterone acetate groups (A and C) and no

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Table IV. Incidence of endometrial hyperplasia over total treatment period, excluding patients with focal cystic hyperplasia Patients wIth positwe biopsy speCImens

I

Treatment group*

No.

No.

A B C D E

279 274 277

2

<1

1

<1

25

8

272 283

o

o

%

o

o

Comparison with conjugated estrogens ala net

p< P< P<

0.001 0.001 0.001 P < 0.001

*All groups received conjugated estrogens 0.625 mg every day of a 28-day cycle. The following medroxyprogesterone acetate dosages were taken: group A, 2.5 mg, days 1 to 28; group B, 5.0 mg, days 1 to 28; group C, 5.0 mg, days 15 to 28; group D, 10.0 mg, days 15 to 28; group E, no medroxyprogesterone acetate (placebo). tBased on Fisher's exact test.

cases of endometrial hyperplasia in the two higher-dose groups (B and D). This difference approached statistical significance (p = 0.06). Most of the 62 women in whom endometrial hyperplasia developed during the study were treated hormonally and had follow-up biopsy specimens without endometrial hyperplasia. Seven women stopped taking the trial medication and were not treated hormonally. Six of these seven women had follow-up biopsy specimens that were negative for endometrial hyperplasia. A biopsy was attempted on the seventh patient, but it was unsuccessful because of cervical stenosis. Three patients did not undergo follow-up endometrial biopsies because the investigators did not think they were necessary in view of the clinical course of these patients. One patient was evaluated by ultrasonography, which revealed no evidence of hyperplasia. One woman underwent a hysterectomy; the pathology report revealed nonsecretory endometrium with focal adenomatous hyperplasia. In addition, one patient was lost to follow-up. There were no reported cases of endometrial cancer in follow-up biopsies of the women who had endometrial hyperplasia. During the course of this study of 1724 postmenopausal women, in addition to the 62 patients with endometrial hyperplasia, two cases of endometrial cancer were reported during the thirteenth cycle after routine examination. One of these women was in treatment group D (0.625 mg of conjugated estrogens and lO mg of medroxyprogesterone acetate) and one was in group E (0.625 mg of conjugated estrogens alone). Both patients underwent hysterectomy. The pathology report on the hysterectomy specimen from the patient in group D specified adenocarcinoma, endometrioid type, grade 2. No myometrial invasion or endometrial hyperplasia was identified. The nonneoplastic endometrium had an inactive pattern. This finding is consistent with a process that may not be hormonally sensitive. The endometrial biopsy and the

hysterectomy specimen from the patient in group E indicated adenocarcinoma of the endometrium, grade I, arising in complex endometrial hyperplasia with cytologic atypia. No myometrial invasion was identified. Both patients should have a good prognosis. Biopsy specimens with focal cystic hyperplasia were categorized under cystic endometrial hyperplasia in this study. A statistical analysis excluding patients with focal cystic hyperplasia (34 of the 62 patients) showed that the incidence of endometrial hyperplasia was still significantly lower with each of the conjugated estrogens/medroxyprogesterone acetate regimens than with conjugated estrogens alone (Table IV). The types of endometrial hyperplasia seen in all treatment groups over the total study period are provided in Table V. None of the 62 patients with endometrial hyperplasia had atypical hyperplasia. Comment

This report provides the results of the largest prospective study done to date comparing four regimens of hormone replacement therapy with conjugated estrogens alone. The results confirm the findings of previous studies showing that unopposed estrogen therapy increases the incidence of endometrial hyperplasia and that the addition of a progestogen to estrogen replacement therapy significantly reduces this risk. 2 . 5 , 14. 15 Endometrial hyperplasia is clinically important in part because it is associated with an increased risk of endometrial cancer.'5 The risk of endometrial cancer increases with higher estrogen doses and increased duration of treatment." 5 The rate of progression of hyperplasia to cancer varies with the type of hyperplasia. It has been estimated that the risk of endometrial cancer is < 5% for women with cystic hyperplasia. '5 As many as 25% of women diagnosed with adenomatous hyperplasia without atypia and as many as 50% of patients diagnosed with atypical hyperplasia have progression to carcinoma. 14, 15

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May 1994 Am J Obstet Gynecol

Table V. Classifications of endometrial hyperplasia: Total treatment period* Treatment groupt Classification

A (n

= 279)

B (n

= 274)

C (n

= 277)

D (n

= 272)

E (n

= 283)

Cystic hyperplasia Adenomatous hyperplasia without atypia

2 0

0 0

3 0

0 0

55 2

TOTAL

2

0

3

0

57

*N1fmbers in table are number of patients.

t All groups received conjugated estrogens 0.625 mg every day of a 28-day cycle. The following medroxyprogesterone acetate

dosages were taken: group A, 2.5 mg, days 1 to 28; group B, 5.0 mg, days 1 to 28; group C, 5.0 mg, days 15 to 28; group D, 10.0 mg, days 15 to 28; group E, no medroxyprogesterone acetate (placebo).

Endometrial hyperplasia that develops in perimenopausal or postmenopausal women receiving exogenous estrogen usually regresses with the addition of a progestogen to the estrogen therapy.'4 A reduction in the incidence of endometrial hyperplasia should also reduce the risk of endometrial cancer. In the current study the group treated with conjugated estrogens alone had an incidence of endometrial hyperplasia of7% at 6 months and 20% after 12 months of treatment. The latter rate is similar to that reported by Whitehead et al. 16; Hyperplasia developed in 18% of patients taking low-dose estrogens (e.g., 0.625 mg of conjugated estrogens) for an average of about 15 months. The addition of medroxyprogesterone acetate to conjugated estrogens therapy effectively reduced the incidence of endometrial hyperplasia. Endometrial hyperplasia developed in only s; 1% of patients in the four conjugated estrogens/medroxyprogesterone acetate treatment groups during treatment. Although none of the differences between the conjugated estrogens/medroxyprogesterone acetate groups were significant, endometrial hyperplasia developed during treatment only in patients in the groups receiving the lower dosages of medroxyprogesterone acetate. This finding suggests that the lower dosages of medroxyprogesterone acetate (2.5 mg continuously or 5.0 mg given for 14 days per cycle) are the minimum required to counteract the endometrial effects of continuous therapy with 0.625 mg of conjugated estrogens. The type of regimen, continuous combined versus sequential, did not appear to be as important as the dosage. The low rates of endometrial hyperplasia with conjugated estrogens/medroxyprogesterone acetate are similar to the findings of other smaller studies that used this combination. For example, 25 women in a study by Gelfand and F erenczy5 received a cyclic regimen of 0.625 mg of conjugated estrogens for 25 days per cycle concomitantly with 5.0 mg of medroxyprogesterone acetate for 11 days per 30-day cycle. After 6 months, endometrial hyperplasia developed in only 1 (4%) of these patients and there were no cases of hyperplasia at 12 months.

In a 9-month study, Prough et al. 17 evaluated endometrial histologic findings in two groups treated with conjugated estrogens and medroxyprogesterone acetate. Sixteen women took a continuous combined regimen of 0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate. A second group of 10 women took 0.625 mg of conjugated estrogens daily (days 1 to 25) and added 10 mg of medroxyprogesterone acetate daily during cycle days 16 to 25. There were no cases of endometrial hyperplasia in either group. In conclusion, all four medroxyprogesterone acetate regimens used with conjugated estrogens in this study effectively reduced the incidence of endometrial hyperplasia associated with the use of estrogens taken alone. We thank Dr. Robert Doyle for his assistance in coding the endometrial biopsy reports so that computer analysis of the biopsy results was possible. We also thank Dr. J.-P. Sauvanet for his contributions to the study. The Menopause Study Group

United States Eli Y. Adashi, MD Division of Reproductive Endocrinology University of Maryland School of Medicine and Hospital 655 W. Baltimore St. Baltimore, MD 21201 Sezer Aksel, MD University of South Alabama Division of Reproductive Endocrinology CCCB Building, Room 326 Mobile, AL 36688 Rudi Ansbacher, MD Medical Professional Bldg. Room D 2206 University of Michigan Medical Center Ann Arbor, MI 48109-0718 David F. Archer, MD Jones Institute for Reproductive Medicine Eastern Virginia Medical School 601 Colley Ave. Norfolk, VA 23507

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Matthias Backer, MD Department of Obstetrics and Gynecology, 4th Floor University Hospital 3635 Vista Ave. at Grand Blvd. St. Louis, MO 63110-0250 john A. Board, MD Department of Obstetrics and Gynecology Medical College of Virginia Virginia Commonwealth University Marshall and 11th St., Box 34 Richmond, VA 23298-0034 Regula E. Burki, MD Gynecology and Obstetrics Highland Plaza, Suite 302 3450 Highland Dr. Salt Lake City, UT 84106 Kenneth A. Burry, MD Oregon Health Sciences University Department of Obstetrics and Gynecology 3181 S.W. Sam Jackson Park Road Portland, OR 97201 Bruce R. Carr, MD Department of Obstetrics and Gynecology j 6114 5323 Harry Hines Blvd. University of Texas Southwestern Medical Center Dallas, TX 75235 Linda Carson, MD Box 395, Mayo Memorial Bldg. 420 Delaware St., S.E. Minneapolis, MN 55455 C. Brandon Chenault, MD 600 Oak Hills Medical Building 7711 Louis Pasteur Dr. San Antonio, TX 78229 Christine L. Cook, MD Department of Obstetrics and Gynecology University of Louisville School of Medicine Louisville, KY 40292 Carolyn B. Coulam, MD Center for Reproduction and Transplantation Immunology 1701 N. Senate Blvd. Indianapolis, IN 46202 Bryan D. Cowan, MD Department of Obstetrics and Gynecology University of Mississippi Medical Center 2500 W. State St. jackson, MS 39216 William T. Creasman, MD Department of Obstetrics and Gynecology Medical University of South Carolina 171 Ashley Ave. Charleston, SC 29245

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Prof. Piero Fioretti Clinica Ostetrica e Ginecologica Universita degli Studi di Pisa Via Roma, 67 56100 Pisa PI, Italy Dr. Eduard Florek Weite Gasse 14 CH -5400 Baden, Switzerland Prof. Romano Forleo Ospedale Fatebenefratelli Centro per la Menopausa Piazza Fatebenefratelli Isola Tiberina 00153 Roma RM, Italy Dr. Koen Geerinckx St Niklaaskliniek Houtmarkt 33 8500 Kortrijk, Belgium Dr. R.W. de Haan Nij Smellinghe Compagonsplein 1 9702 NN Drachten, The Netherlands Dr. Jacobus C. Hage St. Franciscus Gasthuis Department of Gynaecology Kleiweg 500 3045 PM Rotterdam, The Netherlands Dr. Jorma E. Heikkinen Isokatu 47B3 90100 Oulu, Finland Dr. Erkki Hirvonen Kalevankadun Laakariasema Kalevankatu 23 SF-00 100 Helsinki, Finland

Prof. V. Danesino Clinic a Ostetrica e Ginecologica Universita degli Studi di Pavia Policlinico S. Matteo Piazzale Golgi, 25 27100 Pavia PV (Milano), Italy

Prof. Rene von Hugo Universitats-Frauenklinik Bugerstr. 80 8600 Bamberg, Germany

Dr. J.L.P. Bosch van Drakenstein Delfzicht Ziekenhuis Jachtlaan 50 9934 JD Delfzijl, The Netherlands

Prof. P. Ide Universitair Ziekenhuis Gasthuisberg Herestraat 49 3000 Leuven, Belgium

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Dr. R.J. Iding Elizabeth Ziekenhuis Merseloseweg 59 5801 CE Venray, The Netherlands Dr. Ulrich Kohoutek Diakonissenstr. 1 7500 Karlsruhe 51 Riippur, Germany Prof. Marc L' Hermite Hopital Brugmann Place A. Van Gehuchten 1020 Bruxelles, Belgium Dr. Enrique Lehmann-Willenbrock U niversitats-Frauenklinik Michaelisstr. 16 2300 Kiel, Germany Dr. Toni Locher Schwyzerstrasse 12 5430 Wettingen, Switzerland Dr. Oswald J.A. Matheussens Sint Elisabeth Ziekenhuis S. Smitweg 1 2353 GA Leiderdorp, The Netherlands Prof. U go Montemagno Istituto di Ostetrica, Ginecologica e Fisiopatologia dell Reproduzione Universita degli Studi di Napoli II Polidinico Via Pansini, 5 80100 Napoli NA, Italy Dr. Umberto Omodei Clinica Ostetrica e Ginecologica Spedali Civili Piazzale Spedali Civili, 2 25100 Brescia (BS), Italy Dr. Hugo Orye F. de Geerlachestraat 2 3500 Hasselt, Belgium Prof. Clemente Pulle Istituto di Ginecologica Universita degli Studi Policlinico G. Martino Via Consolare Valeria 98100 Messina ME (Catania). Italy Prof. Rune Rolland St. Radboud Ziekenhuis Geert Grooteplein Zuid 14 6525 GA Nijmegen, The Netherlands Prof. Rainer Schrage Univ. Frauenklinik Schleichstr. 4 7400 Tubingen (Stuttgart), Germany Prof. Jean Schwers H6pital Erasme Route de Lennick 808 1070 Bruxelles, Belgium

May 1994 Am J Obstet Gynecol

Dr. Anna-Liisa Simpanen Tulliportinkatu 26B 70100 Kuopio. Finland Dr. Evert Slager Ijsselland Ziekenhuis Department of Gynaecology Pr. Constantijnweg 2 2906 2C Cappelle AD Ijssel, The Netherlands Prof. Karl Thomas V.C.L. Avenue Hippocrate 10 1200 Bruxelles, Belgium Dr. Risto J. Tuimala Sortvitie 1 SF 33700 Tampere, Finland Dr. Timo Virtavuo Turum Gynekologikeskus Aurakaru 14B 20100 Turku (Helsinki), Finland Prof. J.M. Wenderlein U niversitats-Frauenklinik Prittwitzstr. 43 7900 Ulm, Germany Dr. Tjipke D. Ypma Scheper Ziekenhuis Boermarkeweg 60 7824 AA Emmen, The Netherlands Dr. Jan A. Zandvoort De Wever Ziekenhuis H Dunantstraat 5 6419 PC Heerlen, The Netherlands Dr. Anton F. Zurcher Westfries Gasthuis Fr. Maelsonstraat 3 1642 NP Hoorn, The Netherlands REFERENCES 1. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37. 2. Cust MP, Gangar KF, Hillard TC, Whitehead MI. A riskbenefit assessment of estrogen therapy in postmenopausal women. Drug Saf 1990;5:345-58. 3. Henderson BE. The cancer question: an overview of recent epidemiologic and retrospective data. AM ] OBSTET GyNECOL 1989;161: 1859-64. 4. Hadap S. The benefits and risks of hormone replacement therapy: an epidemiologic overview. AM] OBSTET GYNECOL 1992; 166: 1986-92. 5. Gelfand MM, Ferenczy A. A prospective I-year study of estrogen and progestin in postmenopausal women: effects on the endometrium. Obstet Gynecol 1989;74:398-402. 6. Mishell DR, ed. Menopause: physiology and pharmacology. Chicago: Year Book, 1987:275-98. 7. Cullberg G, Knutsson F, Mattsson L-A. A new combination of conjugated equine oestrogens and medroxyprogesterone for treatment of climacteric complaints. Maturitas 1984;6:55-63. 8. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy. I. A lO-year prospec-

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tive study in the relationship to osteoporosis. Obstet Gynecol 1979;53:277-81. Adami H-O. Long-term consequences of estrogen and estrogen-progestin replacement. Cancer Causes Control 1992;3:83-90. Archer DF, Pickar JH, Bottiglioni F, for The Menopause Study Group. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol [In press]. Genant HK, Cann CE, Ettinger B, Gordan GS. Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med 1982;97:699-705. Lindsay R, Hart DM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 1984;63:759-63.

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13. Novak ER, WoodruffJD. Novak's gynecologic and obstetric pathology with clinical and endocrine relations. 8th ed. Philadelphia: WB Saunders, 1979:171-237. 14. Kurman Rj, ed. Blaustein's pathology of the female genItal tract. 3rd ed. New York: Springer-Verlag, 1987:257372. 15. Morrow CP, Townsend DE, eds. SynopsIs of gynecologic oncology. 2nd ed. New York: John Wiley, 1981:13344. 16. Whitehead MI, King RJB, McQueen J, Campbell S. Endometrial histology and biochemistry III c1imactenc women during oestrogen and oestrogen/progestogen therapy. J R Soc Med 1979;72:322-7. 17. Prough SG, Aksel S, Wiebe RH, Shepherd J. Continuom. estrogen/progestin therapy in menopause. AM J OBSTET GYNECOL 1987;157:1449-53.

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