Endometrial hyperplasia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]

Overview

Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio. The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue. Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium. Unopposed oestrogen stimulation may be either from an endogenous or exogenous source.

Pathophysiology

Pathogenesis

• Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio.
• The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.
• Normal endometrial changes during menstrual cycle:
  • The proliferative phase is the second phase in normal mentrual cycle when estrogen causes the lining of the uterus to proliferate. As the ovarian follicles mature, they begin to secrete increasing amounts of estradiol and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium.
  • After ovulation, the remains of the dominant follicle in the ovary become a corpus luteum which produces large amounts of progesterone.
  • Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium.
• Unopposed estrogen stimulation may be either from an endogenous or exogenous source.
  • Excessive endogenous estrogen in pre or perimenopausal women may result from chronic anovulation caused by obesity, polycystic ovary disease, and estrogen producing tumors (e.g. granulosa cell tumor).
  • Excessive exogenous estrogen may result from hormone replacement therapy or non-prescription herbal medications.
• Tamoxifen therapy in breast cancer patients results in an endometrial lesion within 6-36 months of therapy.
  • Tamoxifen is a non-steroidal anti-estrogen that binds to the estrogen receptor and is used primarily for adjuvant therapy in breast cancer
  • Tamoxifen may also act as an estrogen agonist in a low estradiol environment
  • Any patient who develops bleeding while on tamoxifen needs evaluation
• Endometrial hyperplasia may rarely result from the peripheral conversion of androgens to estrogens in androgen-secreting tumors of the adrenal cortex.

Pathways

The normal menstrual cycle is characterized by increasing expression of the oncogene bcl-2 throughout the proliferative phase of the cycle. bcl-2 is an oncogene located on chromosome 18 that was first recognized in follicular lymphoma (9–11) but has since been reported in many other human neoplasms (12–17). Cellular apoptosis is partially inhibited by the expression of bcl-2 leading to prolonged cell survival (18). Expression of bcl-2 appears to be partly regulated through hormonal control, and its expression is markedly decreased at the onset of the secretory phase of the menstrual cycle (19, 20). The declining expression of bcl-2 correlates with the appearance of apoptotic cells within the endometrium noted on electron microscopy during the secretory phase of the menstrual cycle (21).

The identification of bcl-2 expression in normal proliferative endometrium prompted investigators to study the potential role of bcl-2 in endometrial hyperplasia. bcl-2 expression has been demonstrated to be increased in endometrial hyperplasia (19,22). However, this increase in bcl-2 expression seems to be limited to complex hyperplasia. Surprisingly, its expression is decreased in atypical hyperplasia and endometrial carcinoma relative to proliferative endometrium (22).

The role of the Fas/FasL gene also has been investigated recently in the development of endometrial hyperplasia (27). Fas is a member of the tumor necrosis factor/nerve growth factor family that binds to FasL (Fas ligand) and initiates apoptosis. Fas and FasL expression are increased in endometrial samples after progestational treatment (27). An interaction between Fas and bcl-2 expression could contribute to the development of endometrial hyperplasia. bcl-2 expression has been demonstrated to decrease in the presence of intrauterine progesterone, whereas Fas expression was noted to increase (28).

The aforementioned studies have begun to give us some insight into the molecular changes that lead to the clinical development of endometrial hyperplasia and carcinoma. However, our understanding is incomplete and further studies are necessary to better clarify the influence of bcl-2 and Fas/FasL on the molecular pathogenesis of endometrial hyperplasia and endometrial carcinoma.

Mtor

In young mice, mTOR signaling is required for estrogen-mediated growth of endometrial cells, and dysregulated mTOR signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions [35–39]. Rapamycin treatment of young rats (5mg/kg i.p. on alternate days for 10wks) increases the ovarian follicular reserve [40], suggesting that treatment with this drug might prolong the reproductive lifespan, delay menopause, and improve reproductive fitness. However, all the rapamycin-rats displayed irregular estrous cycle and were unable to get pregnant [40]. It is now clear that several of the side effects of long-term treatment of rapamycin are due to disruption of mTORC2 signaling [13]. Because mTORC2 signaling is essential for follicular survival and endometrial development [41], it is likely that some of the reproductive functional defects observed after rapamycin treatment are due, at least in part, to altered mTORC2 signaling. Recently, two independent studies have shown that intermittent dosing of rapamycin delivers many of the benefits of rapamycin treatment on lifespan and healthspan with minimum negative effects on glucose homeostasis and immune system [42, 43]. It will be an interest of our future studies to examine if these new treatment regimens will have similar beneficial effects on reproductive functions of mice. In this study, we have shown that hyperactive mTOR signaling is present in the hyperplastic endometrium of aged women and mice, and inhibition of this pathway leads to suppression of endometrial lesions in mice.

Gross pathology

Gross features

Endometrial hyperplasia typically translates as a thickened endometrial stripe on transvaginal ultrasound and increased volume of endometrial tissue on hysteroscopy or curettage, although it may not be associated with any gross abnormalities. Although hyperplasia may be associated with abundant endometrial tissue, the amount is typically no more impressive than that observed in normal secretory-phase endometrium with the appearance being that of diffuse, somewhat polypoid, tan, velvety tissue. In some instances, localized hyperplasia may mimic a polyp, arise in a background of a polyp, or involve adenomyosis, including deep foci (the outer half of the myometrium).

Microscopic Pathology

• Prolonged estrogenic stimulation results in larger, more complex, and proliferating endometrial glands.
• On microscopic histopathological analysis, the proliferating endometrium is characterized by the following:

Character	Simple hyperplasia	Complex hyperplasia
Gland to stroma ratio	Normal or slightly increased	Increased
Endometrium	Irregularly dilated cystic glands Out‐pouching, infoldings, and budding of the glands may be present	Glandular crowding Luminal outpouching of glands
Mitoses	May or may not be present	Typically present
Location	Generalized	Focal
Nuclear atypia	Not seen	Not seen

Gallery

• 
  Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle
• 
  Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands