Progesterone Receptor Status Predicts Response to Progestin Therapy in Endometriosis

Valerie A. Flores; Arne Vanhie; Tran Dang; Hugh S. Taylor

Disclosures

J Clin Endocrinol Metab. 2018;103(12):4561-4568. 

In This Article

Abstract and Introduction

Abstract

Context: Progestin-based therapy is the first-line treatment for managing endometriosis-associated pain. However, response to progestins is currently variable and unpredictable. Predictive markers for response to progestin-based therapy would allow for a personalized approach to endometriosis treatment.

Objective: We hypothesize that progesterone receptor (PR) levels in endometriotic lesions determine response to progestin-based therapy.

Design: Retrospective cohort study.

Setting: Academic center.

Patients: Fifty-two subjects with histologically confirmed endometriosis and a previous documented response to hormonal therapy were included.

Interventions: Immunohistochemistry was performed on sections of endometriotic lesions using a rabbit polyclonal IgG for detection of PR-A/B.

Main Outcome Measures: The Histo (H)-score was used for quantifying PR status. Response to progestin-based therapies was determined from review of the electronic medical record.

Results: H-score was higher in responders compared with nonresponders. Subjects were categorized into three groups: high (H-score > 80, n = 7), medium (H-score 6 to 80, n = 28), and low (H-score ≤ 5, n = 17) PR status. The threshold of PR > 80 was associated with a 100% positive predictive value. The threshold of PR < 5 was associated with a 94% negative predictive value.

Conclusion: PR status is strongly associated with response to progestin-based therapy. Receptor status in endometriosis could be used to tailor hormonal-based regimens after surgery, and negate trialing progestin-based therapy to determine resistance. Ascertainment of PR status may allow for a novel, targeted, precision-based approach to treating endometriosis.

Introduction

Endometriosis is a chronic gynecologic disease affecting approximately one in 10 reproductive-aged women and up to 50% to 60% of women with pelvic pain or unexplained infertility.[1] It is characterized by endometrial-like tissue outside of the uterus, most frequently on the pelvic viscera and peritoneum.[1] Endometriosis varies in appearance, from few minimal lesions on otherwise intact pelvic organs to large ovarian endometriotic cysts and deep infiltrating nodules.[2] Women with endometriosis suffer from pelvic pain, dysmenorrhea, dyspareunia, and infertility.[1] Endometriotic lesions undergo cycles of growth and bleeding in tandem with the menstrual cycle, explaining the typical cyclic exacerbation of symptoms. These debilitating symptoms severely impact the quality of life of women with endometriosis.[3]

Although the etiology of endometriosis remains largely unknown, estrogen's role in promoting the growth and progression of the disease is well characterized and demonstrated by several clinical observations.[4] Endometriosis predominantly affects women during the reproductive phase of life and regresses after menopause, and the administration of estrogen-containing replacement therapy may cause relapse of the disease.[2] In premenopausal women, the suppression of estradiol levels causes regression of endometriotic lesions and improvement of pain symptoms.[5,6] The recovery of estradiol levels after discontinuation of therapy is associated with relapse of the disease, underscoring the estrogendependent nature of endometriosis.[5,7]

Progesterone acts by regulating endometrial decidualization and inhibition of estrogen-driven endometrial proliferation.[8,9] Although serum levels of progesterone in women with endometriosis are similar to those of women without the disease, endometriotic lesions (ectopic endometrium) do not respond appropriately to progesterone.[10,11] The inappropriate response to progesterone (i.e., progesterone resistance) in endometriotic lesions explains the impaired efficacy of progestin-based therapies for endometriosis management.[8,12] Endometriotic lesions have altered expression of the progesterone receptor (PR).[12,13] Specifically, it has been postulated that progesterone resistance is mediated by lower levels of PR.[8,14] Low PR may explain why progestin-containing agents [including combined oral contraceptives (OCs)] are associated with treatment failure in some patients.[8,14]

Developing an individualized approach to not only treat endometriosis, but also predict response, is needed. As such, the aim of our study was to first characterize PR status in endometriotic lesions. Secondly, we aimed to develop a scoring system based on PR levels for prediction of response to progestin-based therapy. We hypothesized that expression levels of PR in endometriotic lesions can be used to predict response to progestin-based agents. The development of a scoring system based on PR levels for prediction of response to progestin-based therapy could allow for an individualized, precisionbased approach to the treatment of endometriosis.

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