Practice Issues
What Is New in Endometrial Hyperplasia Treatment or Prevention? Best Articles From the Past Year Susan C. Modesitt,
MD, FACS
T
his month we focus on current research in endometrial hyperplasia. Dr. Modesitt discusses five recent publications, and each is concluded with a “bottom line” that is the take-home message. The complete reference for each can be found in Box 1 on this page, along with direct links to the abstracts. (Obstet Gynecol 2014;124:1029–30) DOI: 10.1097/AOG.0000000000000530
Endometrial hyperplasia has been classified historically as simple without atypia, complex without atypia, simple with atypia, and complex with atypia with a 1-30% risk of malignant progression. Traditionally, the gold standard of treatment was hysterectomy, but times are changing as the obesity epidemic and the aging population both affect medical decisions. For example, younger women often are affected, and fertility-sparing options must be considered. Additionally, some women may have medical contraindications to surgery owing to severe systemic disease or an astronomical body mass index (BMI, calculated as weight (kg)/[height (m)]2; BMIs in the 50–80 range are no longer rare). The focus of this commentary is on etiology, prevention, and Dr. Modesitt is the Division Director, Gynecologic Oncology Division, in the Department of Obstetrics and Gynecology at the University of Virginia Health System, Charlottesville, Virginia; e-mail: [email protected]. Financial Disclosure The author did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
VOL. 124, NO. 5, NOVEMBER 2014
Box 1. Abstracts Discussed in This Commentary 1. Dumesic DA, Logo RA. Cancer risk and PCOS. Steroids 2013;78:782–5. Available at: http://dx.doi. org/10.1016/j.steroids.2013.04.004. 2. Orbo A, Vereide AB, Arnes M, Pettersen I, Straume B. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicenter randomized trial. BJOG 2014;121:477– 86. Available at: http://dx.doi.org/10.1111/14710528.12499. 3. Hubbs JL, Saig RM, Abaid LN, Bae-Jump VL, Gehrig PA. Systemic and local hormone therapy for endometrial hyperplasia and early adenocarcinoma. Obstet Gynecol 2013;121:1172–80. Available at: http://dx.doi.org/10.1097/ AOG.0b013e31828d6186. 4. Shan W, Ning C, Luo X, Zhou Q, Gu C, Zhang Z, Chen X. Hyperinsulinemia is associated with endometrial hyperplasia and disordered proliferative endometrium: a prospective cross-sectional study. Gynecol Oncol 2014;132:606–10. Available at: http://dx.doi.org/10.1016/j.ygyno.2014.01.004. 5. Campagnoli C, Abba C, Ambroggio S, Brucato T, Pasanisi P. Lifestyle and metformin for the prevention of endometrial pathology in postmenopausal women. Gynecol Endocrinol 2013;29:119–24. Available at: http://dx.doi.org/10.3109/09513590.2012.706671.
non–hysterectomy-based treatment, because it is imperative that obstetrician–gynecologists remember their integral role in primary prevention.
Cancer Risk and PCOS These authors elucidate the increased cancer risk in women with polycystic ovary syndrome (PCOS) and confirm the association with endometrial cancer (threefold increased risk and a 9% lifetime risk) for women with PCOS. Mechanisms for the increased risk include unopposed estrogen, down regulation of progesteroneregulated genes, hyperandrogenism, hypersecretion of
OBSTETRICS & GYNECOLOGY
1029
luteinizing hormone, insulin resistance, increased glucose availability, and increased insulin-like growth factor with subsequent stimulation of multiple related pathways that accelerate tumor growth.
Bottom Line: Women with PCOS remain at incredibly high risk for both endometrial cancer and hyperplasia, and the use of oral contraceptives will reduce risk by about 50–70%, with increasing protection with increased duration of use. Levonorgestrel-Impregnated Intrauterine Device as Treatment for Endometrial Hyperplasia: A National Multicenter Randomized Trial This was a randomized, multicenter trial comparing the levonorgestrel-impregnated intrauterine device (IUD), continuous oral medroxyprogesterone (10 mg daily), and cyclic oral medroxyprogesterone (10 mg for 10 days of the cycle). Seventy-five percent of the 153 women in this study were under age 51 years at entry, and 73% had complex hyperplasia without atypia. Response rates at 6 months were excellent in the levonorgestrel-impregnated IUD (100%) and continuous medroxyprogesterone groups (96%), and both were statistically superior to the cyclic medroxyprogesterone group (69%; P5.01). The majority of the women in the study reported side effects, including irregular bleeding (78%), nausea (35%), and pain (52%), but all were grade 1 or grade 2. Bleeding was more significant in the levonorgestrel-impregnated IUD group and pain more significant in the responders, but otherwise there were no significant differences between groups.
Bottom Line: The levonorgestrel-impregnated IUD and continuous medroxyprogesterone were statistically superior to cyclic medroxyprogesterone for the treatment of endometrial hyperplasia. Side effects, especially irregular bleeding, were common in the first 6 months. Systemic and Local Hormone Therapy for Endometrial Hyperplasia and Early Adenocarcinoma The authors retrospectively reviewed the women at their institution treated with hormonal therapy for endometrial hyperplasia and early adenocarcinoma; mean age was 49.6 years, and the most common reason for hormonal therapy initiation was medical comorbidities (46%) and fertility preservation (21%). This was a very obese group, with mean BMIs ranging from a low of 36 to 50.8; the highest BMIs were found in the cancer groups. Complete response (defined as con-
1030
Modesitt
firmed regression without later recurrence) was highest in the hyperplasia groups at 66–70% compared with the cancer groups at 6–13%; there were no significant differences based on the route of hormonal administration (systemic compared with IUD).
Bottom Line: Hormonal treatment works well in hyperplasia patients, less so in cancer patients, and all need close monitoring for recurrence or progression. Hyperinsulinemia Is Associated With Endometrial Hyperplasia and Disordered Proliferative Endometrium: A Prospective Cross-Sectional Study The authors enrolled 314 women in China with disordered proliferative endometrium (18%), hyperplasia (62%), and type I endometrial cancer (8%) and compared them with 39 controls with regard to glucose, insulin responsiveness, and lipid levels. The groups were all surprisingly lean, with mean BMIs ranging from 23 to 25. The authors confirmed on multivariate analysis that insulin resistance, hyperinsulinemia, and metabolic disarray (but not hyperlipidemia) were associated not only with endometrial cancer but also with hyperplasia and disordered proliferative endometrium.
Bottom Line: It is no longer all about unopposed estrogen. Glucose and insulin homeostasis also have important roles in the pathogenesis of endometrial hyperplasia and cancer. Lifestyle and Metformin for the Prevention of Endometrial Pathology in Postmenopausal Women The authors explore the well-known associations with lifestyle factors and endometrial hyperplasia and cancer, including obesity, diabetes, and sedentary behavior, and focus on their respective mechanisms of action of increased endogenous hormones, increased insulin, and inflammatory responses. They show data demonstrating the positive effect of lifestyle modifications such as weight loss, bariatric surgery, increased physical activity, and decreased sedentary behavior. Lastly, they review metformin’s emerging role as an anticancer agent owing to its antiproliferative effects that may be additive to the effect on the other risk factors for endometrial cancer (eg, weight and diabetes).
Bottom Line: Metformin has many roles in obstetrics and gynecology and includes treatment for diabetes, PCOS, and obesity and has the added bonus of endometrial cancer prevention and treatment.
What’s New in Endometrial Hyperplasia Treatment
OBSTETRICS & GYNECOLOGY
What Is New in Endometrial Hyperplasia Treatment or Prevention? Best Articles From the Past Year Susan C. Modesitt,
MD, FACS
T
his month we focus on current research in endometrial hyperplasia. Dr. Modesitt discusses five recent publications, and each is concluded with a “bottom line” that is the take-home message. The complete reference for each can be found in Box 1 on this page, along with direct links to the abstracts. (Obstet Gynecol 2014;124:1029–30) DOI: 10.1097/AOG.0000000000000530
Endometrial hyperplasia has been classified historically as simple without atypia, complex without atypia, simple with atypia, and complex with atypia with a 1-30% risk of malignant progression. Traditionally, the gold standard of treatment was hysterectomy, but times are changing as the obesity epidemic and the aging population both affect medical decisions. For example, younger women often are affected, and fertility-sparing options must be considered. Additionally, some women may have medical contraindications to surgery owing to severe systemic disease or an astronomical body mass index (BMI, calculated as weight (kg)/[height (m)]2; BMIs in the 50–80 range are no longer rare). The focus of this commentary is on etiology, prevention, and Dr. Modesitt is the Division Director, Gynecologic Oncology Division, in the Department of Obstetrics and Gynecology at the University of Virginia Health System, Charlottesville, Virginia; e-mail: [email protected]. Financial Disclosure The author did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
VOL. 124, NO. 5, NOVEMBER 2014
Box 1. Abstracts Discussed in This Commentary 1. Dumesic DA, Logo RA. Cancer risk and PCOS. Steroids 2013;78:782–5. Available at: http://dx.doi. org/10.1016/j.steroids.2013.04.004. 2. Orbo A, Vereide AB, Arnes M, Pettersen I, Straume B. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicenter randomized trial. BJOG 2014;121:477– 86. Available at: http://dx.doi.org/10.1111/14710528.12499. 3. Hubbs JL, Saig RM, Abaid LN, Bae-Jump VL, Gehrig PA. Systemic and local hormone therapy for endometrial hyperplasia and early adenocarcinoma. Obstet Gynecol 2013;121:1172–80. Available at: http://dx.doi.org/10.1097/ AOG.0b013e31828d6186. 4. Shan W, Ning C, Luo X, Zhou Q, Gu C, Zhang Z, Chen X. Hyperinsulinemia is associated with endometrial hyperplasia and disordered proliferative endometrium: a prospective cross-sectional study. Gynecol Oncol 2014;132:606–10. Available at: http://dx.doi.org/10.1016/j.ygyno.2014.01.004. 5. Campagnoli C, Abba C, Ambroggio S, Brucato T, Pasanisi P. Lifestyle and metformin for the prevention of endometrial pathology in postmenopausal women. Gynecol Endocrinol 2013;29:119–24. Available at: http://dx.doi.org/10.3109/09513590.2012.706671.
non–hysterectomy-based treatment, because it is imperative that obstetrician–gynecologists remember their integral role in primary prevention.
Cancer Risk and PCOS These authors elucidate the increased cancer risk in women with polycystic ovary syndrome (PCOS) and confirm the association with endometrial cancer (threefold increased risk and a 9% lifetime risk) for women with PCOS. Mechanisms for the increased risk include unopposed estrogen, down regulation of progesteroneregulated genes, hyperandrogenism, hypersecretion of
OBSTETRICS & GYNECOLOGY
1029
luteinizing hormone, insulin resistance, increased glucose availability, and increased insulin-like growth factor with subsequent stimulation of multiple related pathways that accelerate tumor growth.
Bottom Line: Women with PCOS remain at incredibly high risk for both endometrial cancer and hyperplasia, and the use of oral contraceptives will reduce risk by about 50–70%, with increasing protection with increased duration of use. Levonorgestrel-Impregnated Intrauterine Device as Treatment for Endometrial Hyperplasia: A National Multicenter Randomized Trial This was a randomized, multicenter trial comparing the levonorgestrel-impregnated intrauterine device (IUD), continuous oral medroxyprogesterone (10 mg daily), and cyclic oral medroxyprogesterone (10 mg for 10 days of the cycle). Seventy-five percent of the 153 women in this study were under age 51 years at entry, and 73% had complex hyperplasia without atypia. Response rates at 6 months were excellent in the levonorgestrel-impregnated IUD (100%) and continuous medroxyprogesterone groups (96%), and both were statistically superior to the cyclic medroxyprogesterone group (69%; P5.01). The majority of the women in the study reported side effects, including irregular bleeding (78%), nausea (35%), and pain (52%), but all were grade 1 or grade 2. Bleeding was more significant in the levonorgestrel-impregnated IUD group and pain more significant in the responders, but otherwise there were no significant differences between groups.
Bottom Line: The levonorgestrel-impregnated IUD and continuous medroxyprogesterone were statistically superior to cyclic medroxyprogesterone for the treatment of endometrial hyperplasia. Side effects, especially irregular bleeding, were common in the first 6 months. Systemic and Local Hormone Therapy for Endometrial Hyperplasia and Early Adenocarcinoma The authors retrospectively reviewed the women at their institution treated with hormonal therapy for endometrial hyperplasia and early adenocarcinoma; mean age was 49.6 years, and the most common reason for hormonal therapy initiation was medical comorbidities (46%) and fertility preservation (21%). This was a very obese group, with mean BMIs ranging from a low of 36 to 50.8; the highest BMIs were found in the cancer groups. Complete response (defined as con-
1030
Modesitt
firmed regression without later recurrence) was highest in the hyperplasia groups at 66–70% compared with the cancer groups at 6–13%; there were no significant differences based on the route of hormonal administration (systemic compared with IUD).
Bottom Line: Hormonal treatment works well in hyperplasia patients, less so in cancer patients, and all need close monitoring for recurrence or progression. Hyperinsulinemia Is Associated With Endometrial Hyperplasia and Disordered Proliferative Endometrium: A Prospective Cross-Sectional Study The authors enrolled 314 women in China with disordered proliferative endometrium (18%), hyperplasia (62%), and type I endometrial cancer (8%) and compared them with 39 controls with regard to glucose, insulin responsiveness, and lipid levels. The groups were all surprisingly lean, with mean BMIs ranging from 23 to 25. The authors confirmed on multivariate analysis that insulin resistance, hyperinsulinemia, and metabolic disarray (but not hyperlipidemia) were associated not only with endometrial cancer but also with hyperplasia and disordered proliferative endometrium.
Bottom Line: It is no longer all about unopposed estrogen. Glucose and insulin homeostasis also have important roles in the pathogenesis of endometrial hyperplasia and cancer. Lifestyle and Metformin for the Prevention of Endometrial Pathology in Postmenopausal Women The authors explore the well-known associations with lifestyle factors and endometrial hyperplasia and cancer, including obesity, diabetes, and sedentary behavior, and focus on their respective mechanisms of action of increased endogenous hormones, increased insulin, and inflammatory responses. They show data demonstrating the positive effect of lifestyle modifications such as weight loss, bariatric surgery, increased physical activity, and decreased sedentary behavior. Lastly, they review metformin’s emerging role as an anticancer agent owing to its antiproliferative effects that may be additive to the effect on the other risk factors for endometrial cancer (eg, weight and diabetes).
Bottom Line: Metformin has many roles in obstetrics and gynecology and includes treatment for diabetes, PCOS, and obesity and has the added bonus of endometrial cancer prevention and treatment.
What’s New in Endometrial Hyperplasia Treatment
OBSTETRICS & GYNECOLOGY
