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Female Reproductive System

Endometrial hyperplasia (EH)

Endometrial hyperplasia (EH) is a pre-cancerous, non-physiological, non-invasive proliferation of the endometrium that results in increased volume of endometrial tissue with alterations of glandular architecture (shape and size) and endometrial gland to stroma ratio of greater than 1:1.

Endometrial hyperplasia (EH) is a pre-cancerous, non-physiological, non-invasive proliferation of the endometrium that results in increased volume of endometrial tissue with alterations of glandular architecture (shape and size) and endometrial gland to stroma ratio of greater than 1:1.


Classification

Endometrial Hyperplasia classification
Endometrial Hyperplasia classification systems | Patel, B. M. (2019). Endometrial Hyperplasia: Diagnosis and Management BT – Preventive Oncology for the Gynecologist. In S. Mehta & A. Singla (Eds.) (pp. 25–43). Singapore: Springer Singapore. https://doi.org/10.1007/978-981-13-3438-2_3

Etiology

↑ Oestrogen exposure:

Factors contributing to ‘unopposed’ oestrogen stimulation of the endometrium
Factors contributing to ‘unopposed’ oestrogen stimulation of the endometrium. SHBG = sex hormone binding globulin, FSH = follicle stimulating hormone, FSH:LH = follicle stimulating hormone to luteinizing hormone ratio, HRT = hormone replacement therapy, PCOS = polycystic ovarian syndrome. | Sanderson, P. A., Critchley, H. O. D., Williams, A. R. W., Arends, M. J., & Saunders, P. T. K. (2017). New concepts for an old problem: the diagnosis of endometrial hyperplasia. Human Reproduction Update, 23(2), 232–254. https://doi.org/10.1093/humupd/dmw042

Presentation

Abnormal uterine bleeding (M/C):

Endometrial hyperplasia (EH) is one of the most frequent causes of abnormal uterine bleeding (AUB)
  • Premenopausal:
    • Menorrhagia (heavy/prolonged menstrual bleeding)
    • Metrorrhagia (bleeding between menstrual cycles)
    • Menometrorrhagia (menorrhagia + metrorrhagia)
  • Postmenopausal: Any bleeding

Amenorrhoea (missed menstrual cycles)


Complications

↑ risk of endometrial cancer:
  • Endometrial intraepithelial neoplasia: Premalignant lesion, characterised by increased volume of glandular crowding (greater than the stromal volume), the presence of cytological alterations, size of lesion larger than 1 mm, and exclusion of mimics or carcinoma.
Mechanism for monoclonal development of EIN.
Mechanism for monoclonal development of EIN. Oestrogen (E2), acting as a promotor, drives proliferation of the endometrial glands. This process can be reversible, e.g. with progestin (P) therapy acting as a suppressor. In ‘at risk’ individuals, a mutant clone may develop in this environment. The mutant clone occurs within phenotypically normal appearing endometrial glands. The mutant clone is selected for and progresses, aided by the influence of unopposed oestrogens. Over time, with the accrual of further genetic damage, not yet fully elucidated (bottom arrow shows suggestions), the mutant clone proliferates and an EIN lesion can be diagnosed during routine light microscopic examination of an H&E stained section. Endocrine modifiers can alter the balance of EIN progression versus involution. The patient may present with symptoms of abnormal uterine bleeding (AUB) and a thickened endometrium on ultrasound imaging. With the continued accumulation of further genetic damage, not yet fully elucidated (bottom arrow shows suggestions), the EIN lesion undergoes malignant transformation to EC. | Sanderson, P. A., Critchley, H. O. D., Williams, A. R. W., Arends, M. J., & Saunders, P. T. K. (2017). New concepts for an old problem: the diagnosis of endometrial hyperplasia. Human Reproduction Update, 23(2), 232–254. https://doi.org/10.1093/humupd/dmw042

Management

Investigations and management schemes for endometrial hyperplasia.
Investigations and management schemes for endometrial hyperplasia. CCHRT, continuous-combined hormone replacement therapy. | Chandra, V., Kim, J. J., Benbrook, D. M., Dwivedi, A., & Rai, R. (2016). Therapeutic options for management of endometrial hyperplasia. Journal of Gynecologic Oncology, 27(1), e8–e8. https://doi.org/10.3802/jgo.2016.27.e8

Main therapies:

  1. Cyclic progestin therapy
  2. GnRH therapy
  3. Hysterectomy

Cyclic progestin therapy:

  • Medroxyprogesterone acetate (MDPA) or Megestrol (DRUG OF CHOICE)
    • MPA prevents overgrowth in the uterine lining in postmenopausal women receiving estrogen hormone and decreases the risk of EH progression.
    • Cyclic MPA has been shown to be a safer and more acceptable therapy than continuous MPA
    • Use: Absent/irregular menstrual periods, or AUB
  • Megestrol acetate (MA)
  • Levonorgestrel (LNG)
    • LNG-impregnated intrauterine device (LNG-IUD) is currently a very common treatment option for EH. This device releases a constant amount of LNG inside the uterus and effectively opposes the estrogenic effect
  • Norethisterone (or norethindrone)
    • Orally active steroidal progestin with antiandrogen and antiestrogen effects
    • Use: Oral contraceptive pills (OCP) and to treat premenstrual syndrome, irregular intense bleeding, irregular and painful periods, menopausal syndrome in combination with estrogen, or to postpone a period

Other drugs:

  • Danazol
  • Genistein
  • Metformin

GnRH agonists:

  • Histrelin
  • Nafarelin

Surgical management:

  • Hysterectomy + bilateral salpingo-oophorectomy

Summary

Overview of endometrial hyperplasia
Overview of endometrial hyperplasia, risk factors, classification and treatment options. (A) The cross-sectional view of uterus showing endometrium. (B) H&E staining of endometrium at proliferative and secretory phase of endometrium. (Adapted from Horne et al., Oxford University Press.) (C) Risk factors associated with endometrial hyperplasia. (D) The cross-sectional view of uterus showing proliferative endometrium and the H&E staining of endometrium hyperplasia showing abnormal increase of endometrial glands. (E) H&E stained section of endometrial: (a) proliferative endometrium; (b) simple hyperplasia; (c) complex hyperplasia; and (d) complex atypical hyperplasia. (Adapted from Palmer et al., John Wiley and Sons.) (F) Different therapeutic options of endometrial hyperplasia. MPA, medroxy-progesterone acetate. | Chandra, V., Kim, J. J., Benbrook, D. M., Dwivedi, A., & Rai, R. (2016). Therapeutic options for management of endometrial hyperplasia. Journal of Gynecologic Oncology, 27(1), e8–e8. https://doi.org/10.3802/jgo.2016.27.e8

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