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Endometrial hyperplasia in women on cyclic or continuous estrogen regimens
F'ERTIUTY AND STERILITY Copyright c 1982 The American Fertility Society
Vol. 37, No. 1, January 1982 Printed in U.SA.
Endometrial hyperplasia in women on cyclic or continuous estrogen regimens
Isaac Schiff, M.D.* Hilla Komarov Sela, M.D. Daniel Cramer, M.D. Dan Tulchinsky, M.D. Kenneth J. Ryan, M.D. Merwpausal Unit, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Lying-In Division, and Haroard Medical School, Boston, Massachusetts 02115
Twenty-five symptomatic postmenopausal women with an intact uterus were assigned in random double-blind fashion to receive 0.625 mg of conjugated estrogens on either a cyclic (3 weeks on, 1 week off) or continuous (daily) basis. The incidence of endometrial hyperplasia as demonstrated by screening biopsies at 6 and 12 months of therapy was 4.5 per 100 woman-months in the cyclic group and 3.7 per 100 womanmonths in the continuous group (a difference not statistically significant). Thus, in this study, cyclic therapy was found to offer no advantage over continuous therapy. In our opinion, the rate of hyperplasia development in both groups is unacceptably high, and efforts must be directed at reducing its incidence primarily. Fertil Steril 37:79, 1982
rolled were in good general health, had normal physical examination and no contraindication for estrogen replacement therapy. After informed consent was obtained, the women were assigned in a random double-blind fashion to either the cyclic (3 weeks of 0.625 mg Premarin [Ayerst Laboratories, New York, N. Y.] and 1 week of placebo given repeatedly for 1 year) or the continuous regimen of 0.625 mg Premarin daily for 1 year. The placebo tablets were indistinguishable from the estrogen tablets in taste, smell, and appearance. On their initial examination, all patients underwent biopsy of the endometrium, which was obtained either by Duncan curette or Vabra aspiration. Biopsies were repeated during the 6th and 12th months of therapy, and adequate samples were obtained in all cases. There were no differences in the results between the two techniques of biopsy. Additional biopsies were performed if bleeding occurred. In women who developed hyperplasia of the endometrium, the therapy was discontinued and 10 mg of oral medroxyprogesterone acetate was instituted for 10
When indications exist for replacement therapy in postmenopausal women, estrogens are usually used in cyclic rather than continuous fashion; and such has also been the recommendation of the Food and Drug Administration. 1 However, no clinical trials have supported this notion. Therefore, we undertook a randomized clinical trial to compare the histologic effect of cyclic versus continuous estrogen regimens on endometrium. MATERIALS AND METHODS
Symptomatic postmenopausal women who attended the Boston Hospital for Women Menopausal Clinic and who desired treatment were invited to participate in the study. All those en-
Received July 1, 1981; revised and accepted August 31, 1981. *Reprint requests: Dr. Isaac Schiff, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115.
79
80
January, 1982
SCHIFF ET AL.
Table 1. Characteristics of Subjects Participating in the Study" Estrogen regimen Cyclic Number of subjects Median age at entry Median age at menopause Percentage nulliparous Average weight (kg) Presenting .symptoms Vasomotor flushes Vaginal dryness Insomnia Depression
Continuous
12 55.5 53 17% 61 11 4 4 2
(92%) (33%) (33%) (17%)
13 47 45 23% 64 13 3 3 2
(100%) (23%) (23%) (15%)
aPatients may appear in more than one category.
days, after which a biopsy was performed. Histologic slides were reviewed independently by two pathologists from two institutions.
RESULTS Thirty-three patients were ·initially enrolled, but 7 dropped out of the study after the initial visit and were thus excluded in the analysis. At the time of the study much adverse publicity occurred concerning estrogens, and these patients therefore chose to discontinue the drug. An 8th patient was removed from the study because her baseline biopsy showed cystic hyperplasia. Of the 25 remaining women who had an initial and repeat biopsy, 12 received cyclic therapy and 13 the continuous regimen. The clinical information about these women is shown in Table 1. All subjects were Caucasian and ranged in age from 37 to 67. By chance, women assigned to the continuous regimen were younger and had an earlier age of menopause than women assigned to the cyclic regimen. The percentage of nulliparous subjects and the average weights were similar in both groups. The predominant symptom and indication for therapy in both groups was vasomotor flushes. Five of the 12 patients on the cyclic regimen and 4 out of 13 patients on the continuous regimen developed endometrial cystic hyperplasia. There were no cases of severe adenomatous hyperplasia. Figure 1 illustrates the development of hyperplasia by life table analysis. By the end of 12 months, the cumulative rate of hyperplasia development was 48% in the cyclic group and 44% in the continuous group. Table 2 shows the incidence of hyperplasia by exact woman-months of exposure to the two drug regimens. All subjects
contributed 218 woman-months of exposure, and 9 developed hyperplasia, for an overall rate of 4.1 per 100 woman-months. The subjects on the cyclic regimen contributed 111 woman-months of exposure, and 5 developed hyperplasia, for a rate of 4.5 per 100 woman-months of exposure. There were no differences by weight, age, or years since menopause of the bleeders versus nonbleeders, those who developed hyperplasia versus those who did not, and those in whom hyperplasia developed earlier versus those in whom it developed later. The subjects on the continuous regimen contributed 107 woman-months of exposure, and 4 developed hyperplasia, to give an incidence of 3.7 per 100 woman-months of exposure. By neither the life table analysis nor the womanmonths of exposure did the rate of hyperplasia development differ significantly between the two groups. During the course of therapy, six patients developed irregular bleeding and required endometrial biopsy at unscheduled times (3 prior to the 6-month biopsy and 3 after the 6-month biopsy). Table 3 illustrates that of the patients who bled, five were on the continuous regimen and only one was on the cyclic regimen (P = 0.10). Additionally, of the women with irregular bleeding, 4 (67%) had hyperplasia, compared with a rate of 5 of 19 (26%) (P = 0.10) for asymptomatic patients (Ta-
.5
-----Continuous --Cyclic
.4
.3 .2
, , ,'
.I
,'
, •"
, ,,
,,
oK-~~~~--~~~-L~~--~~
3
6 MONTHS
9
12
Figure I This figure represents the cumulative rate of hyperplasia in women on cyclic or continuous therapy. The ordinate represents the rate of hyperplasia and the abscissa, the months of use of estrogen. I I I I ·represents the continuous use and - - the cyclic.
Vol. 37, No. 1
81
CYCLIC VERSUS CONTINUOUS ESTROGEN THERAPY
Table 2. Hyperplasia Developing by Woman-Months' Exposure to Cyclic and Continuous Regimensa Estrogen regimen Total Cyclic
No. developed 5 hyperplasia Woman-months 111 of exposure Rate 4.5 per 100 womanmonths
Continuous
4
9
107
218
3.7 per 100 womanmonths
4.1 per 100 womanmonths
~e difference between rates is not significant by normal approximation to the binomial; P - 0.80.
ble 3). The two women who bled and did not have hyperplasia were able to complete the study without further incident. The last obtained biopsy on each patient was read by a second reference pathologist. Overall, there was concordance of the diagnosis in 21 of the 25 cases (84%). Although our pathologist was more likely to call the biopsy abnormal, this difference was not statistically significant (P = 0.62 by McNemar's test). However, there was agreement on all the cases of hyperplasia. The patients in whom hyperplasia developed were given 10 mg ofmedroxyprogesterone acetate for 10 days. A repeat biopsy was performed, and none showed evidence of hyperplasia. DISCUSSION
It is generally believed that replacement therapy for menopausal symptoms administered cyclically better approximates premenopausal estrogen secretion patterns and results in less endometrial stimulation than estrogen given on a continuous basis. But there is little evidence to support this notion; and studies in primates suggest that estrogens given on a continuous (daily) basis result in less endometrial stimulation than those given cyclically, as indexed by the number of mitoses in the tissue. 2 Moreover, in one case/ control study of endometrial cancer, women on the continuous estrogen regimen were at a slightly, although not significantly, lower risk for developing endometrial cancer than women on cyclic regimens. 3 This prospective study of a small group of women on low-dose estrogen showed that, compared with the cyclic estrogen regimen, the continuous (daily) regimen was not associated with a higher risk for endometrial hyperplasia. It is important to emphasize that whereas only 1 of 33 women had endometrial hyperplasia before the treatment, the rate of hyperplasia devel-
opment in both groups after treatment was high. Within 1 year of the initiation of estrogen therapy, 9 of 25 patients developed· hyperplasia; ·an incidence rate of 4.1 per 100 woman-months of exposure. Ninety-five percent lower incidence limits of the rate suggest that the incidence of endometrial hyperplasia in women receiving this dose of estrogen is likely to be at least 1.9 per 100 woman-months of exposure. We could find no similar studies in the literature. There have been several studies of endometrial pathology in women receiving estrogens, but pretreatment biopsies were generally not taken, nor was the duration of therapy considered. Therefore, the true incidence of hyperplasia in women receiving estrogen could not be determined. Buchman et al. found a prevalence of endometrial hyperplasia of 30% (35 of 11 7) in women receiving 1.25 mg or less of conjugated estrogens in cyclic fashion. 4 Rosenwaks et al. found a prevalence of hyperplasia of 15% (7 of 46) in hypogonadal women receiving various dosages of estrogen and progestins. 5 He noted that the development of hyperplasia was related to the length of use and the dosage of estrogens. Whitehead et al. found a prevalence of 18% (6 of 33) in patients receiving low-dose cyclic therapy with conjugated estrogens. 6 In our study, the risk of Table 3. Aspects of Hyperplasia Development Among Symptomatic (Bleeding) and Asymptomatic Patients on the Cyclic Regimen or the Continuous Regimen Estrogen regimen Cyclic
Total patients
Continuous
A. Occurrence of bleeding among women on cyclic or continuous regimen (P = 0.10 by the Fisher Exact Test) Bleeding 1 5 6 No bleeding 11 8 19 13. 25 Total 12 Bleeding
No bleeding
Total patients
B. Occurrence of hyperplasia among bleeders and nonbleeders (P = 0.10 by the Fisher Exact Test) Developed hyper4a 5 9 plasia No hyperplasia 2 14 16 Total 6 19 25 Cyclic
Continuous
Total patients
C. Occurrence of hyperplasia among asymptomatic patients on the two regimens (P = 0.27 by the Fisher Exact Test) Developed hyper4 1 5 plasia No hyperplasia 7 7 14 Total 11 8 19 aofthese, one was on cyclic therapy and three on continuous therapy.
82
January, 1982
SCHIFF ET AL.
developing hyperplasia during a year of therapy on either cyclic or continuous estrogen was between 40% and 50%, based on life table analysis, which is much higher than the studies previously reported. Differences in the reported rates of hyperplasia could reflect differences in pathologic criteria. However, we found agreement of 84% between two pathologists in the Boston area. It should be emphasized that the lesions in both groups were mild to moderate cystic hyperplasia. No severe hyperplasias or endometrial cancers were noted during 1 year of therapy, but longer periods of exposure to estrogens were not tested. Therefore, efforts must be directed toward lowering the incidence of hyperplasia by prevention; and there is accumulating evidence that the addition of a progestin to the estrogen regimen will accomplish this, 7• 8 as it did in all our patients in whom it developed. This suggests as well that the hyperplasia that developed in our subjects may not have been significant because it was treated rather easily with the short course of a progestin. A drawback to this study was that we did not employ a control group to determine what would happen to the endometrium of untreated patients. Finally, it is important that one note that abnormal uterine bleeding was often indicative of the development of hyperplasia. In addition, we could not establish that the incidence of endometrial hyperplasia differed in patients on cyclic versus continuous estrogen therapy. The unacceptably high rate of hyperplasia in both groups caused us to discontinue the study rather than to attempt to enlarge the study group. The addition
of progestin to any estrogen regimen therapy should be considered in light of these findings and others. 7 • 8 Acknowledgments. The authors wish to thank Ayerst Lab· oratories and Mr. Harold Lafort for supplying the Premarin, and to Denise Lung for typing the manuscript. We are appreciative of Dr. Shirley Driscoll and Dr. Stanley Robboy, who read the slides.
REFERENCES 1. Physicians' Desk Reference, 34th Edition. Oradell, N.J., Medical Economics Company, 1980, p 623 2. Hisaw FL, Hisaw FL Jr: Action of estrogen and progesterone on the reproductive tract of lower primates. In Sex and Internal Secretion. Vol 2. Third edition. Edited by WC Young. Baltimore, Williams & Wilkins, 1961, p 556 3. Antunes CMF, Stolley PD, Rosenshein NB, Davies JL, Tonascia JA, Brown C, Burnett L, Tutledge A, Pokempner M, Garcia R: Endometrial cancer and estrogen use. N Engl J Med 300:9, 1979 4. Buchman Ml, Kramer E, Feldman GB: Aspiration curettage for asymptomatic patients receiving estrogen. Obstet Gynecol 51:339, 1978 5. Rosenwaks Z, Wentz AC, Jones GS, Urban MD, Lee PA, Migeon CJ, Parmley TH, Woodruff JD: Endometrial pathology and estrogens. Obstet Gynecol 53:403, 1979 6. Whitehead MI, McQueen J, King RJB, Campbell S: En. dometrial histology and biochemistry in climacteric women during oestrogen and oestrogen/progestogen therapy. J Roy Soc Med 72:322, 1979 7. Sturdee DW, Wade-Evans T, Paterson MEL, Thorn M, Studd JWW: Relations between bleeding pattern, endometrial histology, and oestrogen treatment in menopausal women. Br Med J 1:1575, 1978 8. King RJB, Whitehead Ml, Campbell S, Minardi J: Effect of estrogen and progestin treatments on endometria from postmenopausal women. Cancer Res 39:1094, 1979
Vol. 37, No. 1, January 1982 Printed in U.SA.
Endometrial hyperplasia in women on cyclic or continuous estrogen regimens
Isaac Schiff, M.D.* Hilla Komarov Sela, M.D. Daniel Cramer, M.D. Dan Tulchinsky, M.D. Kenneth J. Ryan, M.D. Merwpausal Unit, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Lying-In Division, and Haroard Medical School, Boston, Massachusetts 02115
Twenty-five symptomatic postmenopausal women with an intact uterus were assigned in random double-blind fashion to receive 0.625 mg of conjugated estrogens on either a cyclic (3 weeks on, 1 week off) or continuous (daily) basis. The incidence of endometrial hyperplasia as demonstrated by screening biopsies at 6 and 12 months of therapy was 4.5 per 100 woman-months in the cyclic group and 3.7 per 100 womanmonths in the continuous group (a difference not statistically significant). Thus, in this study, cyclic therapy was found to offer no advantage over continuous therapy. In our opinion, the rate of hyperplasia development in both groups is unacceptably high, and efforts must be directed at reducing its incidence primarily. Fertil Steril 37:79, 1982
rolled were in good general health, had normal physical examination and no contraindication for estrogen replacement therapy. After informed consent was obtained, the women were assigned in a random double-blind fashion to either the cyclic (3 weeks of 0.625 mg Premarin [Ayerst Laboratories, New York, N. Y.] and 1 week of placebo given repeatedly for 1 year) or the continuous regimen of 0.625 mg Premarin daily for 1 year. The placebo tablets were indistinguishable from the estrogen tablets in taste, smell, and appearance. On their initial examination, all patients underwent biopsy of the endometrium, which was obtained either by Duncan curette or Vabra aspiration. Biopsies were repeated during the 6th and 12th months of therapy, and adequate samples were obtained in all cases. There were no differences in the results between the two techniques of biopsy. Additional biopsies were performed if bleeding occurred. In women who developed hyperplasia of the endometrium, the therapy was discontinued and 10 mg of oral medroxyprogesterone acetate was instituted for 10
When indications exist for replacement therapy in postmenopausal women, estrogens are usually used in cyclic rather than continuous fashion; and such has also been the recommendation of the Food and Drug Administration. 1 However, no clinical trials have supported this notion. Therefore, we undertook a randomized clinical trial to compare the histologic effect of cyclic versus continuous estrogen regimens on endometrium. MATERIALS AND METHODS
Symptomatic postmenopausal women who attended the Boston Hospital for Women Menopausal Clinic and who desired treatment were invited to participate in the study. All those en-
Received July 1, 1981; revised and accepted August 31, 1981. *Reprint requests: Dr. Isaac Schiff, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115.
79
80
January, 1982
SCHIFF ET AL.
Table 1. Characteristics of Subjects Participating in the Study" Estrogen regimen Cyclic Number of subjects Median age at entry Median age at menopause Percentage nulliparous Average weight (kg) Presenting .symptoms Vasomotor flushes Vaginal dryness Insomnia Depression
Continuous
12 55.5 53 17% 61 11 4 4 2
(92%) (33%) (33%) (17%)
13 47 45 23% 64 13 3 3 2
(100%) (23%) (23%) (15%)
aPatients may appear in more than one category.
days, after which a biopsy was performed. Histologic slides were reviewed independently by two pathologists from two institutions.
RESULTS Thirty-three patients were ·initially enrolled, but 7 dropped out of the study after the initial visit and were thus excluded in the analysis. At the time of the study much adverse publicity occurred concerning estrogens, and these patients therefore chose to discontinue the drug. An 8th patient was removed from the study because her baseline biopsy showed cystic hyperplasia. Of the 25 remaining women who had an initial and repeat biopsy, 12 received cyclic therapy and 13 the continuous regimen. The clinical information about these women is shown in Table 1. All subjects were Caucasian and ranged in age from 37 to 67. By chance, women assigned to the continuous regimen were younger and had an earlier age of menopause than women assigned to the cyclic regimen. The percentage of nulliparous subjects and the average weights were similar in both groups. The predominant symptom and indication for therapy in both groups was vasomotor flushes. Five of the 12 patients on the cyclic regimen and 4 out of 13 patients on the continuous regimen developed endometrial cystic hyperplasia. There were no cases of severe adenomatous hyperplasia. Figure 1 illustrates the development of hyperplasia by life table analysis. By the end of 12 months, the cumulative rate of hyperplasia development was 48% in the cyclic group and 44% in the continuous group. Table 2 shows the incidence of hyperplasia by exact woman-months of exposure to the two drug regimens. All subjects
contributed 218 woman-months of exposure, and 9 developed hyperplasia, for an overall rate of 4.1 per 100 woman-months. The subjects on the cyclic regimen contributed 111 woman-months of exposure, and 5 developed hyperplasia, for a rate of 4.5 per 100 woman-months of exposure. There were no differences by weight, age, or years since menopause of the bleeders versus nonbleeders, those who developed hyperplasia versus those who did not, and those in whom hyperplasia developed earlier versus those in whom it developed later. The subjects on the continuous regimen contributed 107 woman-months of exposure, and 4 developed hyperplasia, to give an incidence of 3.7 per 100 woman-months of exposure. By neither the life table analysis nor the womanmonths of exposure did the rate of hyperplasia development differ significantly between the two groups. During the course of therapy, six patients developed irregular bleeding and required endometrial biopsy at unscheduled times (3 prior to the 6-month biopsy and 3 after the 6-month biopsy). Table 3 illustrates that of the patients who bled, five were on the continuous regimen and only one was on the cyclic regimen (P = 0.10). Additionally, of the women with irregular bleeding, 4 (67%) had hyperplasia, compared with a rate of 5 of 19 (26%) (P = 0.10) for asymptomatic patients (Ta-
.5
-----Continuous --Cyclic
.4
.3 .2
, , ,'
.I
,'
, •"
, ,,
,,
oK-~~~~--~~~-L~~--~~
3
6 MONTHS
9
12
Figure I This figure represents the cumulative rate of hyperplasia in women on cyclic or continuous therapy. The ordinate represents the rate of hyperplasia and the abscissa, the months of use of estrogen. I I I I ·represents the continuous use and - - the cyclic.
Vol. 37, No. 1
81
CYCLIC VERSUS CONTINUOUS ESTROGEN THERAPY
Table 2. Hyperplasia Developing by Woman-Months' Exposure to Cyclic and Continuous Regimensa Estrogen regimen Total Cyclic
No. developed 5 hyperplasia Woman-months 111 of exposure Rate 4.5 per 100 womanmonths
Continuous
4
9
107
218
3.7 per 100 womanmonths
4.1 per 100 womanmonths
~e difference between rates is not significant by normal approximation to the binomial; P - 0.80.
ble 3). The two women who bled and did not have hyperplasia were able to complete the study without further incident. The last obtained biopsy on each patient was read by a second reference pathologist. Overall, there was concordance of the diagnosis in 21 of the 25 cases (84%). Although our pathologist was more likely to call the biopsy abnormal, this difference was not statistically significant (P = 0.62 by McNemar's test). However, there was agreement on all the cases of hyperplasia. The patients in whom hyperplasia developed were given 10 mg ofmedroxyprogesterone acetate for 10 days. A repeat biopsy was performed, and none showed evidence of hyperplasia. DISCUSSION
It is generally believed that replacement therapy for menopausal symptoms administered cyclically better approximates premenopausal estrogen secretion patterns and results in less endometrial stimulation than estrogen given on a continuous basis. But there is little evidence to support this notion; and studies in primates suggest that estrogens given on a continuous (daily) basis result in less endometrial stimulation than those given cyclically, as indexed by the number of mitoses in the tissue. 2 Moreover, in one case/ control study of endometrial cancer, women on the continuous estrogen regimen were at a slightly, although not significantly, lower risk for developing endometrial cancer than women on cyclic regimens. 3 This prospective study of a small group of women on low-dose estrogen showed that, compared with the cyclic estrogen regimen, the continuous (daily) regimen was not associated with a higher risk for endometrial hyperplasia. It is important to emphasize that whereas only 1 of 33 women had endometrial hyperplasia before the treatment, the rate of hyperplasia devel-
opment in both groups after treatment was high. Within 1 year of the initiation of estrogen therapy, 9 of 25 patients developed· hyperplasia; ·an incidence rate of 4.1 per 100 woman-months of exposure. Ninety-five percent lower incidence limits of the rate suggest that the incidence of endometrial hyperplasia in women receiving this dose of estrogen is likely to be at least 1.9 per 100 woman-months of exposure. We could find no similar studies in the literature. There have been several studies of endometrial pathology in women receiving estrogens, but pretreatment biopsies were generally not taken, nor was the duration of therapy considered. Therefore, the true incidence of hyperplasia in women receiving estrogen could not be determined. Buchman et al. found a prevalence of endometrial hyperplasia of 30% (35 of 11 7) in women receiving 1.25 mg or less of conjugated estrogens in cyclic fashion. 4 Rosenwaks et al. found a prevalence of hyperplasia of 15% (7 of 46) in hypogonadal women receiving various dosages of estrogen and progestins. 5 He noted that the development of hyperplasia was related to the length of use and the dosage of estrogens. Whitehead et al. found a prevalence of 18% (6 of 33) in patients receiving low-dose cyclic therapy with conjugated estrogens. 6 In our study, the risk of Table 3. Aspects of Hyperplasia Development Among Symptomatic (Bleeding) and Asymptomatic Patients on the Cyclic Regimen or the Continuous Regimen Estrogen regimen Cyclic
Total patients
Continuous
A. Occurrence of bleeding among women on cyclic or continuous regimen (P = 0.10 by the Fisher Exact Test) Bleeding 1 5 6 No bleeding 11 8 19 13. 25 Total 12 Bleeding
No bleeding
Total patients
B. Occurrence of hyperplasia among bleeders and nonbleeders (P = 0.10 by the Fisher Exact Test) Developed hyper4a 5 9 plasia No hyperplasia 2 14 16 Total 6 19 25 Cyclic
Continuous
Total patients
C. Occurrence of hyperplasia among asymptomatic patients on the two regimens (P = 0.27 by the Fisher Exact Test) Developed hyper4 1 5 plasia No hyperplasia 7 7 14 Total 11 8 19 aofthese, one was on cyclic therapy and three on continuous therapy.
82
January, 1982
SCHIFF ET AL.
developing hyperplasia during a year of therapy on either cyclic or continuous estrogen was between 40% and 50%, based on life table analysis, which is much higher than the studies previously reported. Differences in the reported rates of hyperplasia could reflect differences in pathologic criteria. However, we found agreement of 84% between two pathologists in the Boston area. It should be emphasized that the lesions in both groups were mild to moderate cystic hyperplasia. No severe hyperplasias or endometrial cancers were noted during 1 year of therapy, but longer periods of exposure to estrogens were not tested. Therefore, efforts must be directed toward lowering the incidence of hyperplasia by prevention; and there is accumulating evidence that the addition of a progestin to the estrogen regimen will accomplish this, 7• 8 as it did in all our patients in whom it developed. This suggests as well that the hyperplasia that developed in our subjects may not have been significant because it was treated rather easily with the short course of a progestin. A drawback to this study was that we did not employ a control group to determine what would happen to the endometrium of untreated patients. Finally, it is important that one note that abnormal uterine bleeding was often indicative of the development of hyperplasia. In addition, we could not establish that the incidence of endometrial hyperplasia differed in patients on cyclic versus continuous estrogen therapy. The unacceptably high rate of hyperplasia in both groups caused us to discontinue the study rather than to attempt to enlarge the study group. The addition
of progestin to any estrogen regimen therapy should be considered in light of these findings and others. 7 • 8 Acknowledgments. The authors wish to thank Ayerst Lab· oratories and Mr. Harold Lafort for supplying the Premarin, and to Denise Lung for typing the manuscript. We are appreciative of Dr. Shirley Driscoll and Dr. Stanley Robboy, who read the slides.
REFERENCES 1. Physicians' Desk Reference, 34th Edition. Oradell, N.J., Medical Economics Company, 1980, p 623 2. Hisaw FL, Hisaw FL Jr: Action of estrogen and progesterone on the reproductive tract of lower primates. In Sex and Internal Secretion. Vol 2. Third edition. Edited by WC Young. Baltimore, Williams & Wilkins, 1961, p 556 3. Antunes CMF, Stolley PD, Rosenshein NB, Davies JL, Tonascia JA, Brown C, Burnett L, Tutledge A, Pokempner M, Garcia R: Endometrial cancer and estrogen use. N Engl J Med 300:9, 1979 4. Buchman Ml, Kramer E, Feldman GB: Aspiration curettage for asymptomatic patients receiving estrogen. Obstet Gynecol 51:339, 1978 5. Rosenwaks Z, Wentz AC, Jones GS, Urban MD, Lee PA, Migeon CJ, Parmley TH, Woodruff JD: Endometrial pathology and estrogens. Obstet Gynecol 53:403, 1979 6. Whitehead MI, McQueen J, King RJB, Campbell S: En. dometrial histology and biochemistry in climacteric women during oestrogen and oestrogen/progestogen therapy. J Roy Soc Med 72:322, 1979 7. Sturdee DW, Wade-Evans T, Paterson MEL, Thorn M, Studd JWW: Relations between bleeding pattern, endometrial histology, and oestrogen treatment in menopausal women. Br Med J 1:1575, 1978 8. King RJB, Whitehead Ml, Campbell S, Minardi J: Effect of estrogen and progestin treatments on endometria from postmenopausal women. Cancer Res 39:1094, 1979