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Management of endometrial hyperplasia

Authors
Susan D Reed, MD, MPH
Renata R Urban, MD
Section Editor
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG

INTRODUCTION

The endometrium (lining of the uterus) may develop endometrial hyperplasia (EH), which includes non-neoplastic entities (disordered proliferative endometrium, benign hyperplasia, simple and complex hyperplasias without atypia) characterized by a proliferation of endometrial glands of irregular size and shape, and precancerous neoplasms (endometrial intraepithelial neoplasms [EIN], and all atypical complex hyperplasia) characterized by neoplastic features but without invasion. EH frequently results from chronic estrogen stimulation unopposed by the counterbalancing effects of progesterone [1].

Obese women and women with chronic ovulatory dysfunction (eg, polycystic ovarian syndrome) are at high risk for EH, as well as women at increased genetic risk of endometrial cancer (Lynch syndrome). The majority of women with EH present with abnormal uterine bleeding.

The management of EH is reviewed here. Related topics can be found separately:

Histopathology, classification, and diagnosis of EH (see "Classification and diagnosis of endometrial hyperplasia")

Other etiologies of abnormal uterine bleeding (see "Approach to abnormal uterine bleeding in nonpregnant reproductive-age women" and "Postmenopausal uterine bleeding")

                                         
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Literature review current through: Nov 2017. | This topic last updated: Nov 29, 2017.
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References
Top
  1. Hedrick Ellenson L, Ronnett BM, Kurman RJ. Precursor Lesions of Endometrial Carcinoma. In: Blaustein's Pathology of the Female Genital Tract, 6th ed, Kurman RJ, Hedrick Ellenson L, Ronnett, BM (Eds), Springer, New York 2010. p.360-361.
  2. Emons G, Beckmann MW, Schmidt D, et al. New WHO Classification of Endometrial Hyperplasias. Geburtshilfe Frauenheilkd 2015; 75:135.
  3. Allison KH, Reed SD, Voigt LF, et al. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol 2008; 32:691.
  4. McCawley GM, Ferriss JS, Geffel D, et al. Cancer in obese women: potential protective impact of bariatric surgery. J Am Coll Surg 2009; 208:1093.
  5. Zhang Q, Qi G, Kanis MJ, et al. Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia. Oncotarget 2017; 8:57642.
  6. Pronin SM, Novikova OV, Andreeva JY, Novikova EG. Fertility-Sparing Treatment of Early Endometrial Cancer and Complex Atypical Hyperplasia in Young Women of Childbearing Potential. Int J Gynecol Cancer 2015; 25:1010.
  7. Pashov AI, Tskhay VB, Ionouchene SV. The combined GnRH-agonist and intrauterine levonorgestrel-releasing system treatment of complicated atypical hyperplasia and endometrial cancer: a pilot study. Gynecol Endocrinol 2012; 28:559.
  8. Agorastos T, Vaitsi V, Pantazis K, et al. Aromatase inhibitor anastrozole for treating endometrial hyperplasia in obese postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2005; 118:239.
  9. Tabatabaie A, Karimi Zarchi M, Dehghani-Tafti M, et al. Comparing letrozole with medroxyprogesterone acetate (MPA) as hormonal therapy for simple endometrial hyperplasia without atypia in adult and middle-aged women. Eur J Gynaecol Oncol 2013; 34:552.
  10. Kistner RW, Lewis JL, Steiner GJ. Effects of clomiphene citrate on endometrial hyperplasia in the premenopausal female. Cancer 1966; 19:115.
  11. Tas M, Kutuk MS, Serin IS, et al. Comparison of antiproliferative effects of metformine and progesterone on estrogen-induced endometrial hyperplasia in rats. Gynecol Endocrinol 2013; 29:311.
  12. Shan W, Wang C, Zhang Z, et al. Conservative therapy with metformin plus megestrol acetate for endometrial atypical hyperplasia. J Gynecol Oncol 2014; 25:214.
  13. Mariani L, Sedati A, Giovinazzi R, et al. Postmenopausal endometrial hyperplasia: role of danazol therapy. Int J Gynaecol Obstet 1994; 44:155.
  14. Sedati A, Mariani L, Giovinazzi R, et al. The effectiveness of danazol therapy in postmenopausal women affected by endometrial hyperplasia. Clin Exp Obstet Gynecol 1992; 19:161.
  15. Grio R, Piacentino R, Marchino GL, et al. Danazol in the treatment of endometrial hyperplasia. Panminerva Med 1993; 35:231.
  16. Cianferoni L, Giannini A, Franchini M. Hysteroscopic resection of endometrial hyperplasia. J Am Assoc Gynecol Laparosc 1999; 6:151.
  17. Eichner E, Abellera M. Endometrial hyperplasia treated by progestins. Obstet Gynecol 1971; 38:739.
  18. Gal D, Edman CD, Vellios F, Forney JP. Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia. Am J Obstet Gynecol 1983; 146:316.
  19. Gambrell RD Jr. Progestogens in estrogen-replacement therapy. Clin Obstet Gynecol 1995; 38:890.
  20. Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol 1989; 160:126.
  21. Affinito P, Di Carlo C, Di Mauro P, et al. Endometrial hyperplasia: efficacy of a new treatment with a vaginal cream containing natural micronized progesterone. Maturitas 1994; 20:191.
  22. Perino A, Quartararo P, Catinella E, et al. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil 1987; 18:137.
  23. Wildemeersch D, Dhont M. Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Am J Obstet Gynecol 2003; 188:1297.
  24. Vereide AB, Arnes M, Straume B, et al. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol 2003; 91:526.
  25. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997; 90:434.
  26. Dhar KK, NeedhiRajan T, Koslowski M, Woolas RP. Is levonorgestrel intrauterine system effective for treatment of early endometrial cancer? Report of four cases and review of the literature. Gynecol Oncol 2005; 97:924.
  27. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002; 186:651.
  28. Lindahl B, Willén R. Endometrial hyperplasia. Clinico-pathological considerations of a prospective randomised study after abrasio only or high-dose gestagen treatment. Results of 2 years follow-up of 292 patients. Anticancer Res 1991; 11:403.
  29. Reed SD, Voigt LF, Newton KM, et al. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol 2009; 113:655.
  30. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol 2012; 125:477.
  31. Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012; 207:266.e1.
  32. Casper RF. Regulation of estrogen/progestogen receptors in the endometrium. Int J Fertil Menopausal Stud 1996; 41:16.
  33. Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol 2015; 213:469.
  34. Simpson AN, Feigenberg T, Clarke BA, et al. Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin. Gynecol Oncol 2014; 133:229.
  35. Cholakian D, Hacker K, Fader AN, et al. Effect of oral versus intrauterine progestins on weight in women undergoing fertility preserving therapy for complex atypical hyperplasia or endometrial cancer. Gynecol Oncol 2016; 140:234.
  36. Orbo A, Vereide A, Arnes M, et al. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. BJOG 2014; 121:477.
  37. Horn LC, Schnurrbusch U, Bilek K, et al. Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment. Int J Gynecol Cancer 2004; 14:348.
  38. Gallos ID, Alazzam M, Clark TJ, et al. Management of Endometrial Hyperplasia. Green-top Guideline No. 67. https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_67_endometrial_hyperplasia.pdf (Accessed on July 30, 2015).
  39. Nooh AM, Abdeldayem HM, Girbash EF, et al. Depo-Provera Versus Norethisterone Acetate in Management of Endometrial Hyperplasia Without Atypia. Reprod Sci 2016; 23:448.
  40. Marra C, Penati C, Ferrari L, et al. Treatment of simple and complex endometrial non-atypical hyperplasia with natural progesterone: response rate to different doses. Gynecol Endocrinol 2014; 30:899.
  41. Gibbons WE, Toner JP, Hamacher P, Kolm P. Experience with a novel vaginal progesterone preparation in a donor oocyte program. Fertil Steril 1998; 69:96.
  42. Dolapcioglu K, Boz A, Baloglu A. The efficacy of intrauterine versus oral progestin for the treatment of endometrial hyperplasia. A prospective randomized comparative study. Clin Exp Obstet Gynecol 2013; 40:122.
  43. Gupta JK, Daniels JP, Middleton LJ, et al. A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia: the ECLIPSE trial. Health Technol Assess 2015; 19:i.
  44. Irani J, Salomon L, Oba R, et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol 2010; 11:147.
  45. Loprinzi CL, Barton DL, Sloan JA, et al. Mayo Clinic and North Central Cancer Treatment Group hot flash studies: a 20-year experience. Menopause 2008; 15:655.
  46. Barton D, Loprinzi C, Quella S, et al. Depomedroxyprogesterone acetate for hot flashes. J Pain Symptom Manage 2002; 24:603.
  47. Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms--a placebo-controlled randomized trial in healthy postmenopausal women. Menopause 2012; 19:886.
  48. Jetley S, Rana S, Jairajpuri ZS. Morphological spectrum of endometrial pathology in middle-aged women with atypical uterine bleeding: A study of 219 cases. J Midlife Health 2013; 4:216.
  49. Damle RP, Dravid NV, Suryawanshi KH, et al. Clinicopathological Spectrum of Endometrial Changes in Peri-menopausal and Post-menopausal Abnormal Uterine Bleeding: A 2 Years Study. J Clin Diagn Res 2013; 7:2774.
  50. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985; 56:403.
  51. Lacey JV Jr, Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol 2010; 28:788.
  52. Kurman RJ, Félix JC, Archer DF, et al. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol 2000; 96:373.
  53. ESHRE Capri Workshop Group. Ovarian and endometrial function during hormonal contraception. Hum Reprod 2001; 16:1527.
  54. Wildemeersch D, Janssens D, Pylyser K, et al. Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up. Maturitas 2007; 57:210.
  55. Gallos ID, Shehmar M, Thangaratinam S, et al. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2010; 203:547.e1.
  56. Terakawa N, Kigawa J, Taketani Y, et al. The behavior of endometrial hyperplasia: a prospective study. Endometrial Hyperplasia Study Group. J Obstet Gynaecol Res 1997; 23:223.
  57. Reed SD, Newton KM, Garcia RL, et al. Complex hyperplasia with and without atypia: clinical outcomes and implications of progestin therapy. Obstet Gynecol 2010; 116:365.
  58. Trimble CL, Method M, Leitao M, et al. Management of endometrial precancers. Obstet Gynecol 2012; 120:1160.
  59. Ørbo A, Arnes M, Hancke C, et al. Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol 2008; 111:68.
  60. Gallos ID, Krishan P, Shehmar M, et al. Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up. Hum Reprod 2013; 28:1231.
  61. Rakha E, Wong SC, Soomro I, et al. Clinical outcome of atypical endometrial hyperplasia diagnosed on an endometrial biopsy: institutional experience and review of literature. Am J Surg Pathol 2012; 36:1683.
  62. Lacey JV Jr, Ioffe OB, Ronnett BM, et al. Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan. Br J Cancer 2008; 98:45.
  63. Attard Montalto S, Coutts M, Devaja O, et al. Accuracy of frozen section diagnosis at surgery in pre- malignant and malignant lesions of the endometrium. Eur J Gynaecol Oncol 2008; 29:435.
  64. Salman MC, Usubutun A, Dogan NU, Yuce K. The accuracy of frozen section analysis at hysterectomy in patients with atypical endometrial hyperplasia. Clin Exp Obstet Gynecol 2009; 36:31.
  65. Morotti M, Menada MV, Moioli M, et al. Frozen section pathology at time of hysterectomy accurately predicts endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia. Gynecol Oncol 2012; 125:536.
  66. Indermaur MD, Shoup B, Tebes S, Lancaster JM. The accuracy of frozen pathology at time of hysterectomy in patients with complex atypical hyperplasia on preoperative biopsy. Am J Obstet Gynecol 2007; 196:e40.
  67. Takeshima N, Hirai Y, Yano K, et al. Ovarian metastasis in endometrial carcinoma. Gynecol Oncol 1998; 70:183.
  68. Boronow RC, Morrow CP, Creasman WT, et al. Surgical staging in endometrial cancer: clinical-pathologic findings of a prospective study. Obstet Gynecol 1984; 63:825.
  69. Lee TS, Kim JW, Kim TJ, et al. Ovarian preservation during the surgical treatment of early stage endometrial cancer: a nation-wide study conducted by the Korean Gynecologic Oncology Group. Gynecol Oncol 2009; 115:26.
  70. Matsuo K, Cahoon SS, Yoshihara K, et al. Association of Low-Dose Aspirin and Survival of Women With Endometrial Cancer. Obstet Gynecol 2016; 128:127.
  71. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987; 60:2035.
  72. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006; 106:812.
  73. Baker J, Obermair A, Gebski V, Janda M. Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature. Gynecol Oncol 2012; 125:263.
  74. Gallos ID, Krishan P, Shehmar M, et al. LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Hum Reprod 2013; 28:2966.
  75. Luo L, Luo B, Zheng Y, et al. Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia. Cochrane Database Syst Rev 2013; :CD009458.
  76. Wheeler DT, Bristow RE, Kurman RJ. Histologic alterations in endometrial hyperplasia and well-differentiated carcinoma treated with progestins. Am J Surg Pathol 2007; 31:988.
  77. Lindahl B, Willén R. Steroid receptor concentrations as a prognostic factor in atypical endometrial hyperplasia. Anticancer Res 1998; 18:3793.
  78. Gunderson CC, Dutta S, Fader AN, et al. Pathologic features associated with resolution of complex atypical hyperplasia and grade 1 endometrial adenocarcinoma after progestin therapy. Gynecol Oncol 2014; 132:33.
  79. Gallos ID, Devey J, Ganesan R, Gupta JK. Predictive ability of estrogen receptor (ER), progesterone receptor (PR), COX-2, Mlh1, and Bcl-2 expressions for regression and relapse of endometrial hyperplasia treated with LNG-IUS: a prospective cohort study. Gynecol Oncol 2013; 130:58.
  80. Ørbo A, Arnes M, Vereide AB, Straume B. Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens. BJOG 2016; 123:1512.
  81. Gull B, Karlsson B, Milsom I, Granberg S. Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 2003; 188:401.
  82. Park JY, Lee SH, Seong SJ, et al. Progestin re-treatment in patients with recurrent endometrial adenocarcinoma after successful fertility-sparing management using progestin. Gynecol Oncol 2013; 129:7.
  83. Sletten ET, Arnes M, Lysa LM, et al. Prediction of Relapse After Therapy Withdrawal in Women with Endometrial Hyperplasia: A Long-term Follow-up Study. Anticancer Res 2017; 37:2529.
  84. Koskas M, Uzan J, Luton D, et al. Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis. Fertil Steril 2014; 101:785.