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

Discussion

In this study, we have shown that PR status is strongly associated with response of endometriosis to progestinbased therapies (including combined OCs). Subjects who did not respond to progestin-based therapies had significantly lower PR levels than subjects who did respond. These data support the notion that PR levels are an important modulator of progesterone resistance in endometriosis.

Our data confirm previous findings that PR levels are altered in endometriotic lesions.[19–21] Attia et al.[12] were the first to report lower expression of PR in ectopic endometrium compared with paired eutopic endometrium. When comparing ectopic endometrium of women with endometriosis to the eutopic endometrium of controls, PR has also been found to be lower in endometriotic lesions.[14,22] Utilizing endometriosis tissue microarray and immunohistochemistry, Colon-Caraballo et al.[23] found that there were differences in PR expression levels in endometriotic lesions across different subjects' samples. Similarly, PR levels in deep infiltrating endometriosis is variable among different subjects' samples.[24] In our subject cohort, we found important intersubject and intrasubject variation in the PR levels of endometriotic lesions. Given the role of PR levels in progesterone resistance, and variation of PR levels in endometriotic lesions, this raises the possibility of using PR levels for individual tailoring of hormonal therapy.

Unlike our study, prior work has not assessed the ability of PR status to predict response to progestin-based therapy. We previously demonstrated that PR levels in the eutopic endometrium of endometriosis subjects differ and predicted that PR status would also be variable in ectopic lesions.[25] We have further built upon our previous work by using ectopic endometrium and comparing PR status in lesions to subjects' response to progestincontaining agents.

A major strength of our study is that, for a subset of subjects (n = 21), we included multiple endometriotic lesions in the development of the classification thresholds. In subjects with multiple lesions, we observed variation in PR levels, with values in the high, medium, and low range. In responders with H-scores > 80, only two had an additional lesion with an H-score < 6, which would have resulted in misclassification of these two subjects had analysis been limited to a single sample. As we had a binary outcome for response/no response, in responders we would expect improvement in symptoms in the presence of some PR-expressing lesions. Because all subjects with at least one lesion in the high PR group responded to progestin-based therapies, we found the H-score threshold of ≥80 to be a very strong positive predictor of response to progestin-based therapy. Thus, we chose to use the highest H-score in our model, to avoid the potential for misclassification. We did find that one subject in the clinical response group was classified as a nonresponder by H-score. As this patient had only one lesion removed at the time of laparoscopy, there may have been an unbiopsied lesion with high PR, explaining her prior response to progestin-based therapy despite an H-score < 6. Given this variability and at times discrepancy in H-score and response, we recommend sampling several lesions per patient, as having multiple lesions available for analysis will help prevent inappropriate categorization of patients. Sampling multiple lesions and utilizing the highest H-score avoids any subject being incorrectly classified.

One novelty of our study lies in the double threshold approach to classify PR levels, allowing identification of subjects very likely to respond (high H-score group) and very unlikely to respond (low H-score group) to progestin based-therapy. As such, in nearly half of subjects, a clear prediction of response (negative or positive) to therapy can be made, and management can be adjusted appropriately. In addition, given an intraclass correlation coefficient of 0.985 between the two blinded investigators, the H-score holds potential as a reliable scoring system for determining PR expression levels. As this scoring system will be used exclusively after surgery, the existing clinical paradigm of trialing patients on OCs preoperatively remains. In patients not responding to progestins, options include undergoing surgical evaluation, or alternative hormonal therapy. Utilizing PR expression of excised lesions allows the provider to determine the reason for failed response to OCs. For example, lesions may be predominantly adhesions/fibrosis, which are unlikely to respond to progestinbased therapy. Conversely, lesions can have some PR expression, suggesting that lack of response may be due to insufficient progestin dose or noncompliance with therapy (i.e., inability to tolerate side effects). Postoperatively, this scoring system may have utility in that it would help identify patients in whom progestin therapy is unlikely to be successful. In patients who are found to be PR resistant (i.e., low H-score), it may be prudent to avoid progestin-containing agents in favor of alternative therapeutic options—GnRH analogs, danazol, or aromatase inhibitors.[5,26] In patients with medium PR expression, and/or multiple lesions with variable PR expression, OCs or high-dose progestins can be trialed, yet with a low threshold to adjust therapy if endometriosis-associated pain recurs.

It is plausible that the presence of varying levels of PR in lesions from the same subject may ultimately lead to selective growth of PR-resistant lesions while on progestin treatment. We will continue to follow these subjects to understand how the heterogeneity of PR expression in endometriotic lesions affects PR resistance. As it can take years for endometriosis to recur following surgery, this will be a long-term endeavor.[27] Future studies will allow us to determine if the presence of PR heterogeneity may result in more PR-resistant disease after progestin treatment. If so, then patients with PR heterogeneity may benefit from treatment options other than long-term progestin-based regiments.

One of the limitations of our study is that the sample size of the response group is substantially lower than the no response group, with an overall response rate to medical therapy of 27%. This can be explained by our selection process. Only subjects with histologic confirmation of endometriosis and biopsies to assess were included. Hence the cohort was composed of women undergoing surgery for endometriosis. Subjects not responding to medical therapy are more likely to undergo surgery. As use of hormonal therapy could be a confounder, we performed a subgroup analysis for this using a Mann-Whitney U test. In both the response and no response group, there was no significant difference in H-scores between subjects using or not using hormonal medication.

Subjects who respond well to current medical treatment are less likely to undergo surgery. However, we did have a subset of subjects not on hormonal therapy at the time of surgery classified as responders. These subjects had responded to progestin-based therapy in the past, but stopped medication to conceive. Given recurrence of pain while off therapy, they underwent surgery. The majority of these subjects had H-scores placing them in the high or medium PR group. Although the study did not include subjects currently using and responding to progestinbased therapy, it would be interesting to study this population in the future.

We did have 17 subjects with eutopic endometrium collected at time of surgery, which was used to assess the correlation between H-scores in ectopic and eutopic endometrium. There was poor correlation between matched eutopic and ectopic lesions in responders or nonresponders. Thus H-scores in eutopic endometrium cannot be used to predict response to progestin-based therapy. Given the lack of correlation, ectopic lesions will be needed for prediction of response to progestin-based therapy.

Although hormonal therapy is aimed at reducing disease burden, it is important to recognize that endometriosis is a systemic disorder with effects on the brain and metabolic and inflammatory processes.[28–30] Women with endometriosis have altered pain sensitization and an increased incidence of anxiety and depression.[28] Endometriosis modulates gene expression in regions of the brain controlling pain response, as well as emotional and behavioral changes.[28] Similarly, women with endometriosis have a lower body mass index (BMI), which may be explained by the effects of endometriosis on gene expression in the liver.[29] In a murine model of endometriosis, a lower BMI was recapitulated, and it was demonstrated that the lower BMI was due to changes in hepatic gene expression in metabolic pathways.[29] Endometriosis is also considered a proinflammatory state.[31] Although inflammation in endometriosis has been well established, the mechanism by which endometriosis results in increased systemic inflammation is not clear. We have previously demonstrated that differential expression of miRNAs 125b-5p and let7b-5p can influence cytokine expression of macrophages, contributing to increased inflammation.[30] As miRNAs are stable circulating markers in the blood stream, this provides further support of endometriosis having systemic effects distant from ectopic endometrium in the pelvis. Although surgical therapy may treat local disease in the pelvis, it is also important to identify appropriate treatments that will also affect the systemic aspects of this disease.

Taken together, we have shown that PR status can be used to predict response to progestin-based therapy. Although endometriosis is not a malignant condition, it is a chronic, debilitating disorder with adverse effects on quality of life, including substantial cost burden.[3,32] Delays not only in diagnosis, but also finding the most effective treatment, further contribute to reduced quality of life.[1] The goal of hormonal therapy is to induce atrophy of endometriotic lesions. Yet the ability to predict which medication each individual patient will respond to has not been established. Similarly, as existing medical therapies allow for suppression (as opposed to regression) of endometriotic lesions, patients require long-term treatment.[33] Hormonal therapy and surgery are the two cornerstones of endometriosis management. Recurrence rates are high even following surgery. Yet it is not known if surgery itself was incomplete (i.e., microscopic disease) or if other factors, such as aberrant PR expression, influence recurrence. Although this is a retrospective study, we were able to propose a scoring system/clinical algorithm that can be used in practice to help guide hormonal therapy choice following surgical management of endometriosis. Our proposed algorithm can be used postoperatively to provide insight into the reason for lack of response to preoperative hormonal therapy and determine the ideal postsurgical hormonal therapy. Following surgery, it is routine to place patients on hormonal therapy in an effort to reduce risk of recurrence, and including our model may further reduce this risk by choosing therapy based on PR expression/Hscores. PR status in endometriosis could be used in a manner analogous to the use of estrogen receptor/PR status in breast cancer for tailoring hormonal-based regimens after obtaining tissue. In summary, although our scoring system/clinical algorithm requires validation in prospective clinical trials, we anticipate that utilization of patients' PR status will allow for a novel, targeted approach to treating endometriosis.

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