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Endometrial histology during use of a low-dose estrogen-desogestrel oral contraceptive with a reduced hormone-free interval
Endometrial Histology During Use of a Low-Dose Estrogen-Desogestrel Oral Contraceptive With a Reduced Hormone-Free Interval David F. Archer
The object of the study was to determine the effect of a new low-dose ethinyl estradiol– desogestrel oral contraceptive on endometrial histology. The oral contraceptive regimen contained fixed doses of ethinyl estradiol (20 g) and desogestrel (150 g) for days 1–21, placebo on days 22 and 23, and ethinyl estradiol alone (10 g) on days 24 –28. Endometrial histology was assessed in tissue samples obtained during treatment cycles 13 and 14. All endometrial samples were sent to a central laboratory for processing and evaluation. No endometrial hyperplasia or metaplasia was found in the endometrial biopsy specimens obtained during cycles 13 and 14 in a subset of 12 women participating in a multicenter efficacy and safety study. These results suggest that this oral contraceptive regimen, which includes 5 days of unopposed ethinyl estradiol, is not associated with endometrial hyperplasia or metaplasia. The endometrial histologic findings observed in this study were similar to those observed during the use of 21-day combination oral contraceptive regimens. CONTRACEPTION 1999;60:151–154 © 1999 Elsevier Science Inc. All rights reserved. KEY WORDS: desogestrel, endometrial histology, ethinyl estradiol, oral contraceptive
Introduction
E
strogen-progestin combined oral contraceptives have become the mainstay of fertility control during the last three decades. Since their introduction in 1960, extensive research has been devoted to the optimization of oral contraceptive treatment.
The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia Name and address for correspondence: David F. Archer, M.D., The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507-1627; Tel.: (757) 446-7444; Fax: (757) 446-8996; e-mail: [email protected] Submitted for publication July 27, 1999 Accepted for publication September 9, 1999
© 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
To this end, the research strategy has been twofold: 1) to determine the lowest combined dose of estrogen and progestin that effectively inhibits ovulation and maintains a regular, acceptable bleeding pattern while decreasing the incidence and severity of adverse events and other complications of therapy; and 2) to develop progestins that are associated with a reduction in biochemical or metabolic effects, such as undesirable changes in lipid profiles, while retaining or enhancing the desired pharmacologic activity.1 When compared to older oral contraceptives, the newer regimens that employ the more recently developed progestins and lower doses of ethinyl estradiol appear to be associated with fewer side effects and a reduced risk of long-term complication.2,3 There is a concern that the reduced steroid levels employed in the new regimens may be lower than those required to produce an antigonadotropic effect.4 A partial inhibition of ovarian activity with a resultant secretion of endogenous estrogen could lead to an increase in the development of functional ovarian cysts and a potential reduction in the known protective effects of combined oral contraceptives for endometrial and ovarian cancers and benign breast disease.2,4 The current study was designed to evaluate the effects of a combined oral contraceptive regimen with a reduced hormone free interval (Mircette®) on endometrial histology as an indirect assessment of the estrogenic and progestational activities of this product. During the first 21 days of the 28-day cycle, the regimen employs a low ethinyl estradiol dose (20 g/day) combined with desogestrel (150 g/day). After a 2-day hormone-free interval, ethinyl estradiol (10 g/day) is given alone for 5 days. This new regimen was designed to stimulate endometrial progestin receptors and to suppress follicle-stimulating hormone, as an approach to improving cycle control and suppressing ovarian activity, respectively. ISSN 0010-7824/99/$20.00 PII S0010-7824(99)00076-1
152
Archer
Material and Methods Study Overview Participants in the endometrial histology study were a subset of patients from a larger, open-label, noncomparative study designed to evaluate the efficacy, vaginal bleeding patterns, acceptability, and safety of Mircette. The substudy subjects were enrolled in the study at the Clinical Research Center at Eastern Virginia Medical Center (Norfolk, VA); the study was approved by the local ethics committee and was conducted in compliance with the principles of the Declaration of Helsinki. The overall study design and procedures have been described in detail previously.5 Participants received up to 18 consecutive cycles of contraceptive treatment with Mircette. Substudy Subjects The subjects in the substudy had not taken oral contraceptives during the 2-month period preceding the start of the study, and had consented in writing to the required endometrial biopsy procedures. Endometrial biopsies were performed during the pretreatment screening period, approximately 7 days before the expected onset of menses, and again during cycles 13 (between days 11 and 21) and 14 (between days 2 and 5) of active treatment. All biopsies were performed after the receipt of negative urine pregnancy test results; during active treatment, biopsies were performed while the patients were not menstruating. Study Medication The study medication was supplied in 28-day blister strips containing 28 oral tablets. Each strip included 21 white tablets containing 20 mg ethinyl estradiol/ 150 g desogestrel, which were taken on days 1–21 of a cycle. Two green tablets containing inactive ingredients were taken on days 22 and 23; five yellow tablets, each containing 10 g ethinyl estradiol, were taken on days 24 through 28. Subjects were instructed to begin using the study medication on the Sunday after their first menstrual period after they were admitted to the study. Endometrial Biopsies Biopsy specimens were collected with a Pipelle (Cooper Surgical, Shelton, CT). The endometrial tissue obtained was placed directly into formalin fixative and refrigerated. Endometrial tissue samples were sent to Kyto-Meridian Diagnostics LLC (New York, NY) for hematoxylin and eosin staining and examination by light microscopy.
Contraception 1999;60:151–154
Table 1. Endometrial histology during cycles 13 and 14 in women using an oral contraceptive regimen of desogestrel/ ethinyl estradiol, 2 days placebo, and 10 days ethinyl estradiol Biopsy Day
Late Proliferative Secretory Inactive menstrual Total
Cycle 13 11 18 19 20 21 Total Cycle 14 2 3 4 5 Total
1 1
0 3 3 1 1 8
4
1
6
1
1 1
1 0
0
1
1 1 0 5 1 8 3 3 2 1 9
Results Twelve subjects with a mean age of 29 years (range 23–35 years) and a mean body mass index of 25.6 kg/m2 (range 20.8 –32.6 kg/m2) were enrolled in the substudy. All underwent the baseline endometrial biopsy; 11 had follow-up biopsies. Eight participants had a biopsy between days 11 and 21 of cycle 13; one had a cycle 13 biopsy performed inadvertently on day 10; nine had a biopsy between days 2 and 5 of cycle 14. Secretory changes in the endometrium were present in six of eight biopsy specimens obtained on days 11–21 of cycle 13; one specimen, obtained on day 20, was classified as inactive; one obtained on day 21 was classified as late menstrual (Table 1). One subject whose biopsy was inadvertently performed on day 10 had a secretory endometrium (not shown in Table 1). The lumens of the glands contained secretory material compatible with a progestational effect (Figure 1). As shown in the inset, nuclei were present in the basal portion of the glandular cells. Vacuolization was observed in the apical portion of the cells. No cases of endometrial hyperplasia or metaplasia were observed in any of these endometrial specimens. Of the nine endometrial specimens obtained from subjects whose biopsies were performed on days 2–5 of treatment cycle 14, eight were classified as proliferative and one as late menstrual (Table 1). The proliferative specimens were classical in appearance, showing short, straight narrow glands (Figure 2) with evident epithelial mitoses (inset). The glands then became more undulant and convoluted with moderately dense growing stroma.
Contraception 1999;60:151–154
Low-Dose Estrogen-Desogestrel OC With Reduced Hormone-Free Interval
Figure 1. Progestationally altered endometrium. During the progestogenic phase of the contraceptive cycle, the glands are small and tortuous, the secretions are exhausted, and there is no mitotic activity. The epithelial cells are cuboidal with basally located nuclei. Often the cells contain apically located vacuoles (inset).
Discussion Low-dose combination oral contraceptives are knwon to inhibit the normal proliferative changes in the endometrium.6 In the past, use of a sequential oral contraceptive with estrogen for 21 days and an added progestin for 7 days was found to be associated with endometrial adenocarcinoma.7–9 There were few cases, and most were associated with the use of mestranol (100 g/day).8 The use of a continuous estrogen/progestin combination has been found to reduce the incidence of endometrial carcinoma.9 –11 Epidemiologic studies have reported a lower incidence of endometrial cancer in women who have used combination oral contraceptives for as short a period as 1 year.2,10 Indeed, a protective effect of approximately 50% has been found for the development of endometrial cancer in women who had used oral contraceptives compared with those who had never
Figure 2. Proliferative endometrium. The glands are relatively straight. The pseudostratified epithelial cells are mitotically active (inset).
153
used them. The reduced risk seems to persist for up to 15 years after the cessation of treatment.9,10,12 There is substantial evidence for this reduction in risk from both case-control and cohort studies.13–15 The biological mechanism by which oral contraceptive use is associated with a reduced incidence of endometrial cancer remains elusive. An attractive hypothesis is that the progestin inhibits the effect of estrogen on the endometrium. Support for this hypothesis can be found in the results of the World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives,11 which suggested that the reduction of risk was greater among women who used combination oral contraceptives containing what was described as a low dose of estrogen and a high dose of progestin. In view of these findings, a similar protective effect also might be expected for oral contraceptives that contain a relatively highpotency progestin combined with a low dose of estrogen. Alternatively, extending the duration of progestin dosing, as is done in monophasic oral contraceptive formulations, might also be considered protective.6,10,11,16 The presence of proliferative endometrium on days 2–5 of treatment cycle 14 after 5 days of monotherapy with ethinyl estradiol (5 g) and to 5 days of the combination regimen is consistent with the known effects of ethinyl estradiol on the endometrium.7 Combined oral contraceptives are designed to be progestin-dominant. In this study, 2–5 days of desogestrel plus ethinyl estradiol did not alter the effect of the estrogen on the endometrium. A full progestational effect was evident in all biopsies performed in cycle 13 of treatment after 11–21 days of exposure to combined treatment with ethinyl estradiol (20 g) and desogestrel (150 g). The presence of a secretory endometrium in one biopsy specimen obtained on day 11 of cycle 13 demonstrated that the secretory transformation of the endometrium occurred early with the use of this oral contraceptive. The endometrial histology of all biopsy specimens examined in this study was benign. The histology of the specimens reflected the interval within cycles 13 and 14 during which the final biopsy was conducted. There was no evidence of hyperplasia or neoplasia in any of the endometrial tissue specimens obtained from the treated women. These data are in accordance with those described in other published reports of treatment with low-dose monophasic and triphasic oral contraceptive.6,16 The observed reduction in the occurrence of endometrial carcinoma for up to 15 years after the cessation of oral contraceptive treatment is presumed to be secondary to progestational effects on the endometrium.11 Our findings of a progestational change in the
154
Archer
endometrial histology suggest that this lower-dose oral contraceptive regimen, like similar monophasic formulations, would provide adequate endometrial protection. The potential protective effect of this new regimen against endometrial neoplasia remains to be established at this time.
Acknowledgments This study was supported by Organon, Inc., West Orange, New Jersey. The author appreciates the assistance of N.J. Alexander, Ph.D., J. Krasnow, M.D., R. Richart, M.D., and E. Warga in the development and preparation of this manuscript.
References 1. Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception 1994;49:1–32. 2. Drife J. Benefits and risks of oral contraceptives. Adv Contracept 1990;6(Suppl):15–25. 3. Fotherby K, Caldwell ADS. Review: the new low dose oral contraceptives. J Obstet Gynaecol 1994;14:327–32. 4. Denis C. Contraception estroprogestative inconve´nients de la diminution des estrogenes. Contracept Fertil Sex 1993;21:481– 8. 5. The MIRCETTE™ Study Group. An open label multicenter non-comparative safety and efficacy study of the desogestrel containing oral contraceptive, MIRCETTE™. Am J Obstet Gynecol 1998;179:S2– 8. 6. Coenen CM, Hollanders JM, Rolland R, Spielmann D, Bulten J. The effects of a low-dose gestodene-containing oral contraceptive on endometrial histology in healthy women. Eur J Contracept Reprod Health Care 1996;1: 325–9.
Contraception 1999;60:151–154
7. Ober WB, Decker A, Clyman MJ, Roland M. Endometrial morphology after sequential medication with mestranol and chlormadinone. Obstet Gynecol 1996; 28:247–53. 8. Huggins GR, Giuntoli RL. Oral contraceptives and neoplasia. Fertil Steril 1979;32:1–23. 9. Hulka BS, Chambless LE, Kaufman DG, Fowler WC, Jr., Greenberg, BG. Protection against endometrial carcinoma by combination-product oral contraceptives. JAMA 1982;247:475–7. 10. Kaufman DW, Shapiro S, Slone D, et al. Decreased risk of endometrial cancer among oral-contraceptive users. N Engl J Med 1980;303:1045–7. 11. Rosenblatt KA, Thomas DB. Hormonal content of combined oral contraceptives in relation to the reduced risk of endometrial carcinoma. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:870 – 4. 12. La Vecchia C, Franceschi S, Bruzzi P, Parazzini F, Boyle P. The relationship between oral contraceptive use, cancer and vascular disease. Drug Safety 1990;5:436 – 46. 13. La Vecchia C, Tavani A, Franceschi S, Parazzini F. Oral contraceptives and cancer. A review of the evidence. Drug Safety 1996;14:260 –72. 14. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1987;49: 285– 401. 15. Schlesselman JJ. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793– 801. 16. Rabe T, Nitsche DC, Runnebaum B. The effects of monophasic and triphasic oral contraceptives on ovarian function and endometrial thickness. Eur J Contracept Reprod Health Care 1997;2:39 –51.
The object of the study was to determine the effect of a new low-dose ethinyl estradiol– desogestrel oral contraceptive on endometrial histology. The oral contraceptive regimen contained fixed doses of ethinyl estradiol (20 g) and desogestrel (150 g) for days 1–21, placebo on days 22 and 23, and ethinyl estradiol alone (10 g) on days 24 –28. Endometrial histology was assessed in tissue samples obtained during treatment cycles 13 and 14. All endometrial samples were sent to a central laboratory for processing and evaluation. No endometrial hyperplasia or metaplasia was found in the endometrial biopsy specimens obtained during cycles 13 and 14 in a subset of 12 women participating in a multicenter efficacy and safety study. These results suggest that this oral contraceptive regimen, which includes 5 days of unopposed ethinyl estradiol, is not associated with endometrial hyperplasia or metaplasia. The endometrial histologic findings observed in this study were similar to those observed during the use of 21-day combination oral contraceptive regimens. CONTRACEPTION 1999;60:151–154 © 1999 Elsevier Science Inc. All rights reserved. KEY WORDS: desogestrel, endometrial histology, ethinyl estradiol, oral contraceptive
Introduction
E
strogen-progestin combined oral contraceptives have become the mainstay of fertility control during the last three decades. Since their introduction in 1960, extensive research has been devoted to the optimization of oral contraceptive treatment.
The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia Name and address for correspondence: David F. Archer, M.D., The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507-1627; Tel.: (757) 446-7444; Fax: (757) 446-8996; e-mail: [email protected] Submitted for publication July 27, 1999 Accepted for publication September 9, 1999
© 1999 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
To this end, the research strategy has been twofold: 1) to determine the lowest combined dose of estrogen and progestin that effectively inhibits ovulation and maintains a regular, acceptable bleeding pattern while decreasing the incidence and severity of adverse events and other complications of therapy; and 2) to develop progestins that are associated with a reduction in biochemical or metabolic effects, such as undesirable changes in lipid profiles, while retaining or enhancing the desired pharmacologic activity.1 When compared to older oral contraceptives, the newer regimens that employ the more recently developed progestins and lower doses of ethinyl estradiol appear to be associated with fewer side effects and a reduced risk of long-term complication.2,3 There is a concern that the reduced steroid levels employed in the new regimens may be lower than those required to produce an antigonadotropic effect.4 A partial inhibition of ovarian activity with a resultant secretion of endogenous estrogen could lead to an increase in the development of functional ovarian cysts and a potential reduction in the known protective effects of combined oral contraceptives for endometrial and ovarian cancers and benign breast disease.2,4 The current study was designed to evaluate the effects of a combined oral contraceptive regimen with a reduced hormone free interval (Mircette®) on endometrial histology as an indirect assessment of the estrogenic and progestational activities of this product. During the first 21 days of the 28-day cycle, the regimen employs a low ethinyl estradiol dose (20 g/day) combined with desogestrel (150 g/day). After a 2-day hormone-free interval, ethinyl estradiol (10 g/day) is given alone for 5 days. This new regimen was designed to stimulate endometrial progestin receptors and to suppress follicle-stimulating hormone, as an approach to improving cycle control and suppressing ovarian activity, respectively. ISSN 0010-7824/99/$20.00 PII S0010-7824(99)00076-1
152
Archer
Material and Methods Study Overview Participants in the endometrial histology study were a subset of patients from a larger, open-label, noncomparative study designed to evaluate the efficacy, vaginal bleeding patterns, acceptability, and safety of Mircette. The substudy subjects were enrolled in the study at the Clinical Research Center at Eastern Virginia Medical Center (Norfolk, VA); the study was approved by the local ethics committee and was conducted in compliance with the principles of the Declaration of Helsinki. The overall study design and procedures have been described in detail previously.5 Participants received up to 18 consecutive cycles of contraceptive treatment with Mircette. Substudy Subjects The subjects in the substudy had not taken oral contraceptives during the 2-month period preceding the start of the study, and had consented in writing to the required endometrial biopsy procedures. Endometrial biopsies were performed during the pretreatment screening period, approximately 7 days before the expected onset of menses, and again during cycles 13 (between days 11 and 21) and 14 (between days 2 and 5) of active treatment. All biopsies were performed after the receipt of negative urine pregnancy test results; during active treatment, biopsies were performed while the patients were not menstruating. Study Medication The study medication was supplied in 28-day blister strips containing 28 oral tablets. Each strip included 21 white tablets containing 20 mg ethinyl estradiol/ 150 g desogestrel, which were taken on days 1–21 of a cycle. Two green tablets containing inactive ingredients were taken on days 22 and 23; five yellow tablets, each containing 10 g ethinyl estradiol, were taken on days 24 through 28. Subjects were instructed to begin using the study medication on the Sunday after their first menstrual period after they were admitted to the study. Endometrial Biopsies Biopsy specimens were collected with a Pipelle (Cooper Surgical, Shelton, CT). The endometrial tissue obtained was placed directly into formalin fixative and refrigerated. Endometrial tissue samples were sent to Kyto-Meridian Diagnostics LLC (New York, NY) for hematoxylin and eosin staining and examination by light microscopy.
Contraception 1999;60:151–154
Table 1. Endometrial histology during cycles 13 and 14 in women using an oral contraceptive regimen of desogestrel/ ethinyl estradiol, 2 days placebo, and 10 days ethinyl estradiol Biopsy Day
Late Proliferative Secretory Inactive menstrual Total
Cycle 13 11 18 19 20 21 Total Cycle 14 2 3 4 5 Total
1 1
0 3 3 1 1 8
4
1
6
1
1 1
1 0
0
1
1 1 0 5 1 8 3 3 2 1 9
Results Twelve subjects with a mean age of 29 years (range 23–35 years) and a mean body mass index of 25.6 kg/m2 (range 20.8 –32.6 kg/m2) were enrolled in the substudy. All underwent the baseline endometrial biopsy; 11 had follow-up biopsies. Eight participants had a biopsy between days 11 and 21 of cycle 13; one had a cycle 13 biopsy performed inadvertently on day 10; nine had a biopsy between days 2 and 5 of cycle 14. Secretory changes in the endometrium were present in six of eight biopsy specimens obtained on days 11–21 of cycle 13; one specimen, obtained on day 20, was classified as inactive; one obtained on day 21 was classified as late menstrual (Table 1). One subject whose biopsy was inadvertently performed on day 10 had a secretory endometrium (not shown in Table 1). The lumens of the glands contained secretory material compatible with a progestational effect (Figure 1). As shown in the inset, nuclei were present in the basal portion of the glandular cells. Vacuolization was observed in the apical portion of the cells. No cases of endometrial hyperplasia or metaplasia were observed in any of these endometrial specimens. Of the nine endometrial specimens obtained from subjects whose biopsies were performed on days 2–5 of treatment cycle 14, eight were classified as proliferative and one as late menstrual (Table 1). The proliferative specimens were classical in appearance, showing short, straight narrow glands (Figure 2) with evident epithelial mitoses (inset). The glands then became more undulant and convoluted with moderately dense growing stroma.
Contraception 1999;60:151–154
Low-Dose Estrogen-Desogestrel OC With Reduced Hormone-Free Interval
Figure 1. Progestationally altered endometrium. During the progestogenic phase of the contraceptive cycle, the glands are small and tortuous, the secretions are exhausted, and there is no mitotic activity. The epithelial cells are cuboidal with basally located nuclei. Often the cells contain apically located vacuoles (inset).
Discussion Low-dose combination oral contraceptives are knwon to inhibit the normal proliferative changes in the endometrium.6 In the past, use of a sequential oral contraceptive with estrogen for 21 days and an added progestin for 7 days was found to be associated with endometrial adenocarcinoma.7–9 There were few cases, and most were associated with the use of mestranol (100 g/day).8 The use of a continuous estrogen/progestin combination has been found to reduce the incidence of endometrial carcinoma.9 –11 Epidemiologic studies have reported a lower incidence of endometrial cancer in women who have used combination oral contraceptives for as short a period as 1 year.2,10 Indeed, a protective effect of approximately 50% has been found for the development of endometrial cancer in women who had used oral contraceptives compared with those who had never
Figure 2. Proliferative endometrium. The glands are relatively straight. The pseudostratified epithelial cells are mitotically active (inset).
153
used them. The reduced risk seems to persist for up to 15 years after the cessation of treatment.9,10,12 There is substantial evidence for this reduction in risk from both case-control and cohort studies.13–15 The biological mechanism by which oral contraceptive use is associated with a reduced incidence of endometrial cancer remains elusive. An attractive hypothesis is that the progestin inhibits the effect of estrogen on the endometrium. Support for this hypothesis can be found in the results of the World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives,11 which suggested that the reduction of risk was greater among women who used combination oral contraceptives containing what was described as a low dose of estrogen and a high dose of progestin. In view of these findings, a similar protective effect also might be expected for oral contraceptives that contain a relatively highpotency progestin combined with a low dose of estrogen. Alternatively, extending the duration of progestin dosing, as is done in monophasic oral contraceptive formulations, might also be considered protective.6,10,11,16 The presence of proliferative endometrium on days 2–5 of treatment cycle 14 after 5 days of monotherapy with ethinyl estradiol (5 g) and to 5 days of the combination regimen is consistent with the known effects of ethinyl estradiol on the endometrium.7 Combined oral contraceptives are designed to be progestin-dominant. In this study, 2–5 days of desogestrel plus ethinyl estradiol did not alter the effect of the estrogen on the endometrium. A full progestational effect was evident in all biopsies performed in cycle 13 of treatment after 11–21 days of exposure to combined treatment with ethinyl estradiol (20 g) and desogestrel (150 g). The presence of a secretory endometrium in one biopsy specimen obtained on day 11 of cycle 13 demonstrated that the secretory transformation of the endometrium occurred early with the use of this oral contraceptive. The endometrial histology of all biopsy specimens examined in this study was benign. The histology of the specimens reflected the interval within cycles 13 and 14 during which the final biopsy was conducted. There was no evidence of hyperplasia or neoplasia in any of the endometrial tissue specimens obtained from the treated women. These data are in accordance with those described in other published reports of treatment with low-dose monophasic and triphasic oral contraceptive.6,16 The observed reduction in the occurrence of endometrial carcinoma for up to 15 years after the cessation of oral contraceptive treatment is presumed to be secondary to progestational effects on the endometrium.11 Our findings of a progestational change in the
154
Archer
endometrial histology suggest that this lower-dose oral contraceptive regimen, like similar monophasic formulations, would provide adequate endometrial protection. The potential protective effect of this new regimen against endometrial neoplasia remains to be established at this time.
Acknowledgments This study was supported by Organon, Inc., West Orange, New Jersey. The author appreciates the assistance of N.J. Alexander, Ph.D., J. Krasnow, M.D., R. Richart, M.D., and E. Warga in the development and preparation of this manuscript.
References 1. Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception 1994;49:1–32. 2. Drife J. Benefits and risks of oral contraceptives. Adv Contracept 1990;6(Suppl):15–25. 3. Fotherby K, Caldwell ADS. Review: the new low dose oral contraceptives. J Obstet Gynaecol 1994;14:327–32. 4. Denis C. Contraception estroprogestative inconve´nients de la diminution des estrogenes. Contracept Fertil Sex 1993;21:481– 8. 5. The MIRCETTE™ Study Group. An open label multicenter non-comparative safety and efficacy study of the desogestrel containing oral contraceptive, MIRCETTE™. Am J Obstet Gynecol 1998;179:S2– 8. 6. Coenen CM, Hollanders JM, Rolland R, Spielmann D, Bulten J. The effects of a low-dose gestodene-containing oral contraceptive on endometrial histology in healthy women. Eur J Contracept Reprod Health Care 1996;1: 325–9.
Contraception 1999;60:151–154
7. Ober WB, Decker A, Clyman MJ, Roland M. Endometrial morphology after sequential medication with mestranol and chlormadinone. Obstet Gynecol 1996; 28:247–53. 8. Huggins GR, Giuntoli RL. Oral contraceptives and neoplasia. Fertil Steril 1979;32:1–23. 9. Hulka BS, Chambless LE, Kaufman DG, Fowler WC, Jr., Greenberg, BG. Protection against endometrial carcinoma by combination-product oral contraceptives. JAMA 1982;247:475–7. 10. Kaufman DW, Shapiro S, Slone D, et al. Decreased risk of endometrial cancer among oral-contraceptive users. N Engl J Med 1980;303:1045–7. 11. Rosenblatt KA, Thomas DB. Hormonal content of combined oral contraceptives in relation to the reduced risk of endometrial carcinoma. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1991;49:870 – 4. 12. La Vecchia C, Franceschi S, Bruzzi P, Parazzini F, Boyle P. The relationship between oral contraceptive use, cancer and vascular disease. Drug Safety 1990;5:436 – 46. 13. La Vecchia C, Tavani A, Franceschi S, Parazzini F. Oral contraceptives and cancer. A review of the evidence. Drug Safety 1996;14:260 –72. 14. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1987;49: 285– 401. 15. Schlesselman JJ. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793– 801. 16. Rabe T, Nitsche DC, Runnebaum B. The effects of monophasic and triphasic oral contraceptives on ovarian function and endometrial thickness. Eur J Contracept Reprod Health Care 1997;2:39 –51.