When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?
Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.
The following case represents a common scenario for ObGyns.
CASE Patient with proliferative endometrial changes
A menopausal patient with a body mass index (BMI) > 30 kg/m2 presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.
When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.
However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.22
Endometrial changes and what they suggest
In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.
The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).23
Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.24
For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.
In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.25 These women had a mean BMI of 34 kg/m2. During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.25
Progestin treatment
Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.
We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.26
Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.27 Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.22 In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.28
Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.22
Role of ultrasonography
Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.29 In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.29
Assessing risk
If proliferative endometrium is found, Abraham suggests assessing risk using22:
- age
- comorbidities (including obesity)
- endometrial echo thickness on vaginal ultrasonography.
Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.
Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.30 Accordingly, synthetic progestins represent first-line options in this setting.
In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.22 ●
WHAT THIS EVIDENCE MEANS FOR PRACTICE
ObGyns may choose to adopt Abraham’s approach or to hold off on progestin therapy while performing follow-up endometrial sampling. Either way, the take-home message is that the finding of proliferative endometrial changes on biopsy for postmenopausal bleeding requires proactive management.
ObGyns may choose to adopt Abraham’s approach or to hold off on progestin therapy while performing follow-up endometrial sampling. Either way, the take-home message is that the finding of proliferative endometrial changes on biopsy for postmenopausal bleeding requires proactive management.