Catch it before it kills: progesterone, obesity, and the prevention of endometrial cancer

Abstract

The lifetime risk for developing endometrial cancer, the fourth most common malignancy in women, is approximately 3%. Endometrial cancer is a hormone-driven cancer, with approximately 80% of endometrial cancers arising attributable to either an excess of estrogen or a lack of progesterone. In the normal endometrium, the proliferative effects of estrogen are normally countered by progesterone, but the absence of progesterone allows estrogen to induce oncogenesis, an effect that is amplified in situations of excess estrogen. One of the major emerging causes of the estrogen/progesterone imbalance is obesity. Obesity is associated with several hormonal derangements as well as dysregulation of insulin/insulin-like growth factor activity, which collectively contribute to hyperplasia and carcinogenesis in the endometrium. In this article, we provide an in-depth description of how obesity mechanistically promotes this hormone and growth factor imbalance. Given that endometrial cancer is clearly associated with obesity, we put forth the hypothesis that a large portion of these cancers might be prevented by treatment with progesterone.

Figure 1

Progesterone receptor levels in an early-grade endometrioid adenocarcinoma. Note the well-differentiated nature of the tumor, with obvious glands and stroma.

Figure 2

Proposed model in which an imbalance in hormones and growth factors induces endometrial cancer. Obesity also promotes many of these same imbalances. We propose that endometrial cancer can be prevented in the obese population by treatment with progesterone, which counters the effects of excess estrogen. Additional preventative measures to decrease BMI may serve to further reduce the incidence of endometrial cancer in the obese population.

Figure 3

Schematic of estrogen production in postmenopausal women. (A) In premenopausal women, estradiol (E2) is produced primarily by the ovary during the secretory and proliferative phases. Progesterone (P4) is also produced by the ovary during the secretory phase. After menopause, a majority of estradiol is produced by adipocytes, which contain aromatase that converts androgen (A) to estrone (E1). (B) Estrone (E1) is converted to estradiol (E2) by 17-β hydroxysteroid dehydrogenase type I in the endometrium, thereby increasing local E2 levels, activating estrogen receptor (ER) transcriptional activity, and promoting cell proliferation.