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

Results

We identified 57 subjects who fulfilled the inclusion criteria of our study (histological confirmation of endometriosis, minimum one lesion available for immunohistochemistry, previous use of medical treatment of endometriosis). The electronic medical record of subjects was analyzed for information on the response tomedical therapy. Five subjects were excluded because of missing or insufficient data. Out of 52 subjects included for analysis, 14 had responded to a progestin-based medical therapy, most commonly an OC, in the past, and 38 had inadequate or no response to therapy. No subject had used dienogest, as this study was conducted entirely in the United States, where dienogest is not available. Of the 52 included subjects, 21 had more than one lesion collected at the time of surgery, and 17 had eutopic endometrium collected at the time of laparoscopy. Demographic and clinical data of the 52 subjects included for analysis are shown in Table 1. The demographics, medical history, and characteristics of endometriosis were similar for the response and no response group except for current use of medication (Table 1).

Representative images of immunohistochemical staining for PR expression, as calculated by H-score, are shown in Figure 1. For all H-scores, the intraclass correlation coefficient score between the two blinded investigators was 0.985 (P < 0.0001; 95% CI: 0.978 < intraclass correlation coefficient < 0.99).

Figure 1.

PR immunohistochemistry. A to C, Representative images of PR expression in endometriotic lesions. PR expression quantified using H-score: A, high PR staining; B, medium PR staining; C, low PR staining. Arrows denote glandular epithelium (magnification ×20).

The H-score was significantly higher in responders compared with nonresponders (P < 0.0001, Figure 2). The ROC curve for prediction of response based on H-score showed an area under the curve of 84% (95%CI: 71% to 96%; P = 0.002).

Figure 2.

H-scores in the response and no response subjects. Comparison of H-scores in responders and nonresponders. Data are shown as box plots (median and interquartile range 25th to 75th percentiles) and whisker plots (minimum to maximum). H-scores were higher in the response group (*P < 0.0001).

Based on ROC curve analysis with a two-threshold strategy, 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 (Figure 1). The threshold of H-score > 5 was selected because of its high sensitivity (93%, 95% CI: 69% to 100%) and negative predictive value (94%, 95% CI: 73% to 100%). The threshold of H-score ≥ 80 was selected because of its high specificity (100%, 95% CI: 91% to 100%) and positive predictive value (100%, 95% CI: 65% to 100%).

Contingency table analysis showed that PR status was significantly associated with response to progestin therapy (P < 0.0001; Table 2). All subjects with high PR responded to progestin therapy (100%). Ninety-four percent of subjects in the low PR group did not respond to progestin therapy. The medium PR group had a response rate of 21%, in line with the overall response rate of 27%.

In subjects with more than one lesion collected at the time of surgery, the number of additional lesions ranged from 1 to 6, with a mean of 2.8 lesions per subject. There was intrasubject variation between lesions, however with only two subjects in the responder group having a lesion with both a high and low H-score value.

Of the 17 subjects with eutopic endometrium collected at time of laparoscopy, 5 subjects were responders, while 12 were nonresponders. The eutopic endometrium in all 5 responders had H- scores > 80. In 5 of 12 nonresponders, the H-scores in the eutopic endometrium were also >80, compared with H-scores < 80 in the ectopic lesions (P = 0.17, r = 0.4). High PR expression in eutopic endometrium does not assure high PR in the ectopic lesion or response to therapy.

The proportion of subjects on hormonal medication at the time of surgery was different in the response vs the no response group (Table 1). In the no response group, more subjects were using hormonal medication at the time of surgery, while in the response group, more subjects were not using medication at the time of surgery. Therefore, we performed a subgroup analysis for this possible confounder 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 (respective P values: 0.84 and 0.45; Figure 3).

Figure 3.

H-scores in responders and nonresponders by medication use. Subgroup analysis of current medication use at time of surgery, represented as a scatter plot. Error bars represent the group mean ± SD. There was no significant difference in H-scores in the response and no response group with respect to medication use at time of surgery. NR-M, no response on medication; NR-NM, no response not on medication; R-M, response on medication; R-NM, response not on medication.

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