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Endometrial Hyperplasia : Causes

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Prolonged, unopposed estrogenic stimulation of the endometrium that is not counterbalanced by progesterone leads to endometrial hyperplasia (EH). It creates conditions favorable for the subsequent development of adenocarcinoma. It may be caused by anovulatory cycles (due to obesity or polycystic ovary disease), excess estrogen production from endogenous sources, or exogenous estrogen. Some of the causes/conditions associated with EH and endometrial carcinoma are as follows:

Obesity: About 57% of endometrial carcinomas in the US are attributable to obesity. After menopause, adipose tissue is the main site of estrogen synthesis. Increased adiposity increases aromatase activity, leading to enhanced conversion of androgens to estrogen. Obesity-associated proinflammatory cytokines such as leptins, interleukin-6, and TNF-alpha suppress normal insulin signaling leading to hyperinsulinemia, increased IGF1 levels, and hyperglycemia which promote endometrial proliferation.

Type II Diabetes: The role of type II diabetes as a risk factor for endometrial hyperplasia and carcinoma is largely mediated through its association with obesity. There is some evidence that hyperglycemia is a risk factor for endometrial carcinoma independent of obesity.

Polycystic Ovary Syndrome (PCOS): It is an endocrine disorder characterized by multiple follicular cysts or cystic follicles in the ovary along with dense fibrosis of the superficial cortex. Patients often develop amenorrhea, sterility, hyperandrogenism (with virility), and increased risk of endometrial hyperplasia and carcinoma. Dyslipidemia, insulin resistance, and type II diabetes also frequently occur in PCOS.

Estrogen Replacement Therapy: Postmenopausal women receiving supplemental estrogens are at an increased risk of endometrial hyperplasia and carcinoma if a progestin is not used to oppose the proliferative actions of estrogens on endometrium.

Tamoxifen: Tamoxifen is a selective estrogen receptor modulator that is widely used in the treatment of breast cancer and for chemoprophylaxis in high risk women. It increases the risk of developing atypical endometrial hyperplasia and carcinoma. See next slide for details.

Stromal Hyperplasia/Stromal Hyperthecosis: Non-neoplastic proliferation of ovarian stromal cells (stromal hyperplasia) and stromal cell luteinization in ovarian parenchyma away from the follicles (stromal hyperthecosis) may be seen together and are associated with androgenic features (virilization, acne), estrogenic manifestations (disordered proliferative endometrium, endometrial hyperplasia, and carcinoma), obesity, hyperinsulinemia, and hypertension.

Adult Granulosa Cell Tumor of Ovary: It is the most common sex cord-stromal tumor and is associated with estrogenic manifestations (menometrorrhagia, post-menopausal bleeding) in two-thirds of patients and androgenic features in 10% of cases. The risk of concurrent endometrial hyperplasia and carcinoma is 25% and 6% respectively.

Androgen-secreting Tumors of Adrenal Cortex with peripheral conversion of androgens to estrogen is a rare cause of endometrial hyperplasia and endometrial carcinoma.

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