Progesterone receptor expression is selectively reduced in adenomyosis among endometriosis-associated lesions: a cross-sectional immunohistochemical study of 118 specimens from 100 women

Progesterone receptor expression is selectively reduced in adenomyosis among endometriosis-associated lesions: a cross-sectional immunohistochemical study of 118 specimens from 100 women | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Progesterone receptor expression is selectively reduced in adenomyosis among endometriosis-associated lesions: a cross-sectional immunohistochemical study of 118 specimens from 100 women Yu Horibe, Tomoko Yamamoto, Kei Koshimizu, Jun Kumakiri, Yoji Nagashima, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-10865216/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 17 You are reading this latest preprint version Abstract Background. Endometriosis and adenomyosis are both oestrogen-dependent and both are treated with progestins, yet response to progestin therapy is not uniform. Progesterone resistance is usually described as a property of endometriosis as a whole. Whether reduced progesterone receptor (PR) expression is shared by all endometriosis-associated lesions, or is concentrated in one lesion type, has not been established in a cohort with the lesion site recorded for every specimen. Methods. We analysed 118 surgical specimens from 100 consecutive women operated on for endometriosis-associated disease at one centre between November 2022 and May 2026. Oestrogen receptor (ER) and PR were quantified immunohistochemically using the modified H-score (0-300). Each specimen was assigned one lesion site: adenomyosis (uterus, n = 49), ovarian endometrioma (n = 60), deep infiltrating endometriosis (DIE, n = 4) or other (n = 5). Because 12 women contributed more than one specimen, the primary analysis was a linear mixed-effects model with patient as a random intercept, adjusted for age, pelvic adhesions and menopausal status. Three further analytical strategies and a within-patient paired comparison were prespecified as sensitivity analyses. Results. PR differed across lesion sites (Kruskal-Wallis p < 0.001), and the difference was confined to adenomyosis: median PR H-score 135.0 (IQR 60.0-185.0) versus 210.0 (150.0-255.0) in endometrioma, 220.0 (183.8-257.5) in DIE and 230.0 (185.0-260.0) in other lesions, the three non-uterine sites being mutually indistinguishable (all Holm-adjusted p = 1.00). Adenomyosis remained associated with lower PR after adjustment (beta = -75.7, 95% CI -102.5 to -48.9, p < 0.001) and under all four strategies. Among nine women contributing both an adenomyotic and a non-uterine specimen, PR was lower in the adenomyotic lesion in 9 of 9 (Wilcoxon p = 0.004). ER showed no comparable site effect (adjusted beta = -24.3, 95% CI -48.9 to 0.3, p = 0.053) and instead tracked age (beta = + 22.9 per SD, p = 0.004). Conclusions. Within endometriosis-associated disease, reduced PR expression is a property of the adenomyotic lesion rather than a generalised feature of the disease, and is dissociated from ER, which is governed by age. Lesion type may be relevant when progestin therapy is selected. Adenomyosis Endometriosis Progesterone receptor Oestrogen receptor Immunohistochemistry Progesterone resistance Progestin therapy Mixed-effects model Figures Figure 1 Figure 2 Figure 3 Background Endometriosis affects approximately one in ten women of reproductive age and imposes a chronic burden of pain, infertility and repeated surgery [ 1 , 2 ]. Adenomyosis, in which endometrial glands and stroma are found within the myometrium, frequently coexists with endometriosis and shares much of its clinical presentation and its presumed origin in retrograde menstruation and endometrial stem-cell dysfunction [ 3 – 6 ]. The two conditions are managed with an overlapping pharmacological repertoire: combined oral contraceptives, gonadotropin-releasing hormone analogues and, increasingly, progestins such as dienogest and the levonorgestrel-releasing intrauterine system [ 7 – 10 ]. Both diseases are oestrogen-dependent [ 11 ], and both have been described as showing progesterone resistance — a reduced capacity of target tissue to respond to progesterone, attributed to loss or silencing of the progesterone receptor (PR), particularly the PR-B isoform [ 12 , 13 ]. This concept has been developed largely from studies of ectopic endometriotic tissue and is commonly applied to endometriosis-associated disease as a single category. Mechanistic work in adenomyosis has separately demonstrated impaired progesterone signalling [ 14 ], and receptor isoform distribution in the adenomyotic uterus differs from that in the unaffected uterus [ 15 ]. What has been much less clear is whether the two lesion types differ from each other. If progesterone resistance were a uniform property of endometriosis-associated disease, PR expression should be comparably low wherever the lesion sits. If instead it were concentrated in one lesion type, that would imply that the pharmacological target is unequally available across lesions within the same patient — a distinction with direct implications for how progestin therapy is selected. Studies comparing steroid receptor expression across anatomical sites of endometriosis exist [ 16 ], but they have generally treated each specimen as an independent observation. Because a woman undergoing surgery for endometriosis-associated disease commonly yields more than one lesion, specimens from the same patient are correlated, and analyses that ignore this correlation overstate precision. The design that most directly addresses the question — comparing lesion types within the same woman — has rarely been reported. We therefore examined oestrogen receptor (ER) and PR expression in a consecutive surgical cohort in which the anatomical site was recorded for every specimen and the patient identifier permitted specimens to be linked. Our aim was to determine whether reduced PR expression is a generalised feature of endometriosis-associated lesions or is specific to the adenomyotic lesion, and to establish whether any such difference is independent of the patient characteristics — age, menopausal status and adhesive disease — that differ systematically between women presenting with uterine and with ovarian disease. Methods Study design and participants This was a cross-sectional analysis of consecutive women who underwent surgery for endometriosis-associated disease at a single tertiary centre between November 2022 and May 2026. Women were eligible if surgery yielded at least one lesion with a histopathological diagnosis of endometriosis or adenomyosis and if archived tissue was adequate for immunohistochemistry. No exclusion was applied on the basis of age, menopausal status or previous medical treatment. One hundred women contributed 118 specimens; 88 women contributed a single specimen, 8 contributed two, 2 contributed three and 2 contributed four. Lesion site assignment Every specimen was assigned to exactly one anatomical site on the basis of the operative record and the corresponding pathology report: adenomyosis (uterine specimen), ovarian endometrioma, deep infiltrating endometriosis (DIE), or other endometriosis-associated lesion. Where a woman had both uterine and ovarian disease, each specimen retained its own site label; the woman was not assigned to a single diagnostic category. This specimen-level assignment is what permits the within-patient comparison described below. Immunohistochemistry and scoring Formalin-fixed, paraffin-embedded sections were stained for ER and PR according to the laboratory's routine diagnostic protocol. Expression was quantified using the modified H-score [ 17 ], calculated as the sum across staining-intensity categories of (intensity grade 0–3) × (percentage of nuclei at that intensity), giving a continuous score from 0 to 300. Scoring was performed by the reporting pathologist as part of routine diagnostic assessment, without reference to the study hypothesis. The PR/ER ratio was computed as a secondary descriptor of the relative balance of the two receptors. Three-micrometre-thick sections were cut from a representative tissue block. Immunohistochemical staining was performed using the Ventana BenchMark ULTRA IHC/ISH System (Roche Diagnostics, Basel, Switzerland) according to the manufacturer’s instructions. Ventana detection kits were used for ER (SP1, rabbit monoclonal, Cat. no. 107925, Roche), PgR (1E2, rabbit monoclonal, Cat. no. 102333, Roche) and HER2 (4B5, rabbit monoclonal, Cat. no. 107918, Roche) staining. 3,3’-Diaminobenzidine tetrahydrochloride was used as the chromogen and haematoxylin as the counterstain. Each specimen was classified by site of origin as ovarian endometrioma, adenomyosis, deep infiltrating endometriosis (DIE) or other. This site classification was assigned at the specimen level and was handled separately from the patient-level clinical diagnosis, which may include the coexistence of multiple lesions. Covariates Age at surgery, menopausal status, presence of pelvic adhesions at operation, gravidity, parity, body mass index, serum CA125, operative time, intraoperative blood loss and length of stay were extracted from the clinical record. Preoperative hormonal treatment was recorded and classified as progestin exposure (dienogest or luteal-phase progestin) or other. Age was standardised (mean-centred and divided by its standard deviation of 9.4 years) so that regression coefficients express the change in H-score per standard deviation of age. Statistical analysis Distributions of ER, PR and the PR/ER ratio departed significantly from normality (Shapiro–Wilk p < 0.001 for all three), so non-parametric methods were used for unadjusted comparisons. Continuous variables are summarised as median [interquartile range] and compared with the Mann–Whitney U test for two groups or the Kruskal–Wallis test across four lesion sites; pairwise comparisons following a significant Kruskal–Wallis test were adjusted by the Holm method. Categorical variables were compared with Fisher's exact test. Effect size for two-group comparisons is reported as the rank-biserial correlation. The prespecified primary analysis addressed the correlation between specimens from the same woman. A linear mixed-effects model was fitted with the receptor H-score as the outcome, patient identity as a random intercept, and fixed effects for lesion type (adenomyosis versus all other lesion sites), standardised age, pelvic adhesions and menopausal status. This model was fitted separately for PR and for ER. One specimen lacked adhesion status, so adjusted models include 117 specimens. Four analytical strategies were compared to demonstrate that the findings do not depend on how clustering is handled: (i) ordinary least squares treating all specimens as independent; (ii) ordinary least squares with cluster-robust standard errors grouped by patient; (iii) ordinary least squares restricted to one specimen per patient; and (iv) the mixed-effects model, which was the primary analysis. Two further sensitivity analyses were performed: the primary model with preoperative progestin exposure added as a covariate, and a within-patient paired comparison, restricted to women who contributed both an adenomyotic and a non-uterine specimen, tested with the Wilcoxon signed-rank test. An interaction between lesion type and age on PR was examined as a prespecified exploratory analysis and is reported as hypothesis-generating only. Two-sided p values below 0.05 were considered statistically significant; no adjustment was made for the number of models fitted, and the analysis is accordingly interpreted as estimation rather than confirmatory hypothesis testing. Analyses were performed in Python 3.11 using pandas, SciPy and statsmodels. Results Cohort One hundred women contributed 118 specimens: 49 adenomyotic (uterine), 60 ovarian endometrioma, 4 DIE and 5 other endometriosis-associated lesions. Median age at surgery was 46 years (IQR 41–52). Women whose specimens were adenomyotic were older than those whose specimens were from other sites (median 50 [46–53] versus 43 [36–49] years, p < 0.001), had higher gravidity (1 [0–2] versus 0 [0–1], p = 0.006), less frequently had pelvic adhesions (42.9% versus 82.4%, p < 0.001), had longer operations (207.5 [143.2–264.0] versus 162.0 [116.0–244.0] min, p = 0.043) and longer hospital stays (7 [ 6 – 9 ] versus 6 [ 6 – 8 ] days, p = 0.012). Body mass index, CA125 and intraoperative blood loss did not differ. Preoperative progestin exposure was recorded in 19 of 118 specimens (16.1%) and was not differentially distributed between adenomyotic and other specimens (12.2% versus 18.8%, p = 0.448). Full characteristics are given in Table 1 . Table 1 Characteristics of adenomyotic and other endometriosis-associated specimens. Continuous variables are median [interquartile range] and compared with the Mann-Whitney U test; categorical variables are n (%) and compared with Fisher's exact test. Characteristic Adenomyosis specimens (n = 49) Other lesion specimens (n = 69) p value Age (years) 50.0 [46.0–53.0] 43.0 [36.0–49.0] < 0.001 Body mass index (kg/m2) 23.0 [21.5–25.0] 21.9 [19.7–25.8] 0.359 Gravidity 1.0 [0.0–2.0] 0.0 [0.0–1.0] 0.006 Parity 0.0 [0.0–2.0] 0.0 [0.0–1.0] 0.053 CA125 (U/mL) 58.0 [19.5-176.5] 61.0 [26.0-164.5] 0.591 Operative time (min) 207.5 [143.2–264.0] 162.0 [116.0-244.0] 0.043 Intraoperative blood loss (mL) 18.5 [6.0-55.4] 27.0 [6.0-200.0] 0.309 Length of stay (days) 7.0 [6.0–9.0] 6.0 [6.0–8.0] 0.012 Postmenopausal, n (%) 13 (26.5) 9 (13.0) 0.092 Pelvic adhesions, n (%) 21 (42.9) 56 (82.4) < 0.001 Preoperative progestin, n (%) 6 (12.2) 13 (18.8) 0.448 PR is reduced in adenomyosis and not in other lesion types PR expression differed across the four lesion sites (Kruskal–Wallis H = 24.75, p < 0.001). The difference was accounted for entirely by the adenomyotic lesion. Median PR H-score was 135.0 (IQR 60.0–185.0) in adenomyosis, compared with 210.0 (150.0–255.0) in ovarian endometrioma, 220.0 (183.8–257.5) in DIE and 230.0 (185.0–260.0) in other lesions (Fig. 1 a). In Holm-adjusted pairwise comparisons, adenomyosis differed from endometrioma (p = 0.0001) and from other lesions (p = 0.029), and differed from DIE at a magnitude consistent with the other contrasts but without reaching significance in four specimens (p = 0.064); the three non-uterine sites were mutually indistinguishable (all p = 1.00). Pooling all non-uterine specimens, PR was 135.0 in adenomyosis versus 215.0 elsewhere (p < 0.001, rank-biserial r = − 0.52) (Table 2 ). Table 2 Receptor expression by lesion site. Marker Group n Median [IQR] / test ER Adenomyosis (uterus) 49 220.0 [162.5–260.0] ER Endometrioma (ovary) 60 190.0 [142.2–230.0] ER DIE 4 240.0 [221.2-247.5] ER Other 5 260.0 [245.0-260.0] ER Kruskal-Wallis (4 sites) H = 8.19, p = 0.0422 ER Adenomyosis vs all others p = 0.3571, rank-biserial r = + 0.10 PR Adenomyosis (uterus) 49 135.0 [60.0-185.0] PR Endometrioma (ovary) 60 210.0 [150.0-255.0] PR DIE 4 220.0 [183.8-257.5] PR Other 5 230.0 [185.0-260.0] PR Kruskal-Wallis (4 sites) H = 24.75, p < 0.0001 PR Adenomyosis vs all others p < 0.0001, rank-biserial r=-0.52 PR/ER ratio Adenomyosis (uterus) 49 0.7 [0.3–1.1] PR/ER ratio Endometrioma (ovary) 60 1.1 [0.8–1.4] PR/ER ratio DIE 4 1.0 [0.9-1.0] PR/ER ratio Other 5 0.9 [0.7-1.0] PR/ER ratio Kruskal-Wallis (4 sites) H = 16.01, p = 0.0011 PR/ER ratio Adenomyosis vs all others p = 0.0001, rank-biserial r=-0.42 Table 2 b Holm-adjusted pairwise comparisons of PR H-score between lesion sites. Group A Group B raw p Holm p Adenomyosis Endometrioma 0.0 0.0001 Adenomyosis DIE 0.016 0.0639 Adenomyosis Other 0.0057 0.0287 Endometrioma DIE 0.5507 1.0 Endometrioma Other 0.3557 1.0 DIE Other 1.0 1.0 The same pattern was seen in the PR/ER ratio, which was 0.74 in adenomyosis versus 1.07 in other lesions (p < 0.001, rank-biserial r = − 0.42), indicating that the reduction is specific to PR rather than reflecting a general loss of steroid receptor expression. The association is independent of age, adhesions and menopausal status In the mixed-effects model with patient as a random intercept, adenomyosis remained associated with a substantially lower PR H-score after adjustment for standardised age, pelvic adhesions and menopausal status (β = −75.7, 95% CI − 102.5 to − 48.9, p < 0.001; n = 117). Postmenopausal status was independently associated with lower PR (β = −46.3, 95% CI − 87.4 to − 5.1, p = 0.027), whereas age (β = +11.6, 95% CI − 5.7 to 28.8, p = 0.189) and adhesions (β = −7.1, 95% CI − 38.3 to 24.0, p = 0.652) were not (Table 3 ). Table 3 Linear mixed-effects models with patient as a random intercept (n = 117 specimens from 100 women; one specimen lacked adhesion status). Coefficients are the change in H-score. Outcome Term beta 95% CI p value PR Adenomyosis (vs other lesion sites) -75.7 -102.5 to -48.9 3.2e-08 PR Age (per 1 SD, 9.4 years) + 11.6 -5.7 to 28.8 0.189 PR Pelvic adhesions -7.1 -38.3 to 24.0 0.652 PR Postmenopausal -46.3 -87.4 to -5.1 0.027 ER Adenomyosis (vs other lesion sites) -24.3 -48.9 to 0.3 0.053 ER Age (per 1 SD, 9.4 years) + 22.9 7.4 to 38.4 0.004 ER Pelvic adhesions -30.9 -58.8 to -3.0 0.030 ER Postmenopausal -14.5 -51.3 to 22.3 0.439 The finding does not depend on how patient clustering is handled The adenomyosis coefficient was essentially unchanged across all four analytical strategies: −75.4 (95% CI − 105.2 to − 45.6) treating specimens as independent, − 75.4 (− 104.3 to − 46.5) with cluster-robust standard errors, − 79.1 (− 112.9 to − 45.4) restricting to one specimen per patient, and − 75.7 (− 102.5 to − 48.9) in the mixed-effects model, with p < 0.001 throughout (Fig. 3 a, Table 4 ). Adding preoperative progestin exposure to the primary model left the estimate unchanged (β = −75.8, 95% CI − 102.7 to − 49.0, p < 0.001), and progestin exposure itself was not associated with PR (β = −18.4, p = 0.309). Table 4 Sensitivity analyses for the association between adenomyosis and PR H-score. All regression models adjust for standardised age, pelvic adhesions and menopausal status. Analytical strategy n beta (PR H-score) 95% CI p value Role All specimens (OLS) 117 -75.4 -105.2 to -45.6 2.0e-06 Sensitivity Cluster-robust SE 117 -75.4 -104.3 to -46.5 3.1e-07 Sensitivity One per patient 99 -79.1 -112.9 to -45.4 1.1e-05 Sensitivity Mixed-effects 117 -75.7 -102.5 to -48.9 3.2e-08 Primary Mixed-effects + progestin pre-treatment 117 -75.8 -102.7 to -49.0 3.1e-08 Sensitivity Within-patient paired (n = 9 women with both lesions) 9 Lower in 9/9 - 0.0039 Sensitivity Nine women contributed both an adenomyotic and a non-uterine specimen and therefore served as their own controls. PR was lower in the adenomyotic lesion in every one of the nine (median 160 versus 240; Wilcoxon signed-rank p = 0.004) (Fig. 1 b). Because both specimens in each pair come from the same woman at the same operation, this comparison is unaffected by age, menopausal status, systemic hormonal milieu or prior treatment. ER shows no comparable site specificity and is governed by age ER expression showed only a weak difference across lesion sites (Kruskal–Wallis H = 8.19, p = 0.042), and adenomyosis was not the low group: median ER was 220.0 (162.5–260.0) in adenomyosis, 190.0 (142.2–230.0) in endometrioma, 240.0 (221.2–247.5) in DIE and 260.0 (245.0–260.0) in other lesions (Fig. 2 a). Adenomyosis did not differ from pooled non-uterine specimens (p = 0.357, r = + 0.10), and in the adjusted model the lesion-type coefficient was approximately one third the size of that seen for PR and did not reach significance (β = −24.3, 95% CI − 48.9 to 0.3, p = 0.053); it fell below significance in both clustering-aware models (Fig. 3 b). What did predict ER was patient age. ER rose with age across the whole cohort (Spearman rho = + 0.36, p < 0.001; Fig. 2 b) and age remained the dominant term in the adjusted model (β = +22.9 per SD of 9.4 years, 95% CI 7.4 to 38.4, p = 0.004), with pelvic adhesions additionally associated with lower ER (β = −30.9, 95% CI − 58.8 to − 3.0, p = 0.030). PR, by contrast, was not associated with age (p = 0.189). The two receptors are therefore governed by different variables: PR by lesion type, ER by patient age. Exploratory analysis An interaction between lesion type and age on PR was statistically significant (β = −42.6, 95% CI − 73.1 to − 12.1, p = 0.006): PR fell with age within adenomyotic specimens (rho = − 0.44, p = 0.001) while rising with age within endometrioma specimens (rho = + 0.31, p = 0.016) (Additional file 1: Fig. S1). However, within adenomyotic specimens the age effect did not persist after adjustment for menopausal status (β = −24.0, p = 0.122), so the divergence cannot be separated from the menopausal transition in this cohort. This analysis is reported as hypothesis-generating and is not part of the primary claim. Discussion In this consecutive surgical cohort, reduced PR expression was a property of the adenomyotic lesion and not of endometriosis-associated disease in general. Ovarian endometrioma, DIE and other endometriosis-associated lesions had similar PR levels and were statistically indistinguishable from one another, while adenomyosis sat well below all of them. The difference corresponded to roughly 76 points on a 0–300 H-score scale after adjustment, was unchanged across four analytical strategies, was unaffected by preoperative progestin exposure, and was reproduced in every one of the nine women who contributed both an adenomyotic and a non-uterine lesion at the same operation. Relation to existing work Progesterone resistance is a well-established concept in endometriosis, and much of the mechanistic evidence — PR-B promoter hypermethylation, altered PR isoform ratios, impaired downstream signalling — has been generated from ectopic endometriotic tissue and generalised to the disease as a category [ 12 , 13 ]. Our data are not inconsistent with that literature, but they locate the receptor deficit more precisely. When lesion types are compared directly within the same cohort, and in some cases within the same woman, the low-PR phenotype belongs to the adenomyotic lesion. This aligns with the independent adenomyosis literature: impaired progesterone signalling has been demonstrated in adenomyosis in a murine model [ 14 ], receptor isoform distribution in the adenomyotic uterus differs from the unaffected uterus across the cycle [ 15 ], and single-cell and next-generation sequencing work has identified adenomyosis-specific mesenchymal–epithelial signalling that is not simply a copy of endometriotic biology [ 4 , 18 ]. Recent syntheses emphasise shared pathophysiology between the two conditions [ 5 , 6 ]; our findings suggest that the sharing is incomplete at the level of the progesterone receptor, and that the two lesions should not be assumed to be pharmacologically equivalent. Previous cross-site comparisons of steroid receptor expression in endometriosis [ 16 ] have generally analysed specimens as independent observations. In our cohort 12 of 100 women contributed more than one specimen, and treating those 118 specimens as independent would have overstated precision. We therefore made the clustering-aware model the primary analysis and reported the naive analysis only as one of four strategies. That the point estimate barely moved across strategies is reassuring, but the design point stands: with a larger proportion of multi-lesion patients the choice would matter, and the within-patient comparison is the most informative single piece of evidence in this study precisely because it removes the patient entirely from the contrast. The ER–PR dissociation The behaviour of ER makes the PR finding more interpretable. ER was not reduced in adenomyosis, showed at most a weak and non-robust difference across sites, and was instead determined by patient age — rising by roughly 23 H-score points per standard deviation of age. Had both receptors been low in adenomyosis, the most parsimonious explanation would have been generalised tissue differences: fixation, cellularity, or the proportion of stroma to epithelium in myometrial specimens. That ER was preserved, and that the PR/ER ratio was itself reduced in adenomyosis, argues that the finding reflects the progesterone axis specifically rather than a technical property of uterine tissue. This is consistent with experimental work in which oestrogen and progesterone act on endometriotic tissue through separable programmes [ 19 ], and with evidence that ERβ signalling drives lesion progression through pathways that do not depend on PR [ 20 ]. Clinical implications Progestins are first-line medical therapy for both endometriosis and adenomyosis [ 8 – 10 , 21 ], and adenomyosis-specific guidance recommends them while acknowledging variable response [ 7 ]. Dienogest and the levonorgestrel-releasing intrauterine system are effective in many women with adenomyosis but not in all [ 9 ]. If the pharmacological target is quantitatively less available in the adenomyotic lesion than in coexisting endometriotic lesions, then a woman with both may experience differential response at different sites — pelvic pain from endometriotic implants improving while uterine symptoms persist. This is a hypothesis generated by, not demonstrated in, the present data: we measured receptor protein, not treatment response, and no clinical outcome of progestin therapy was analysed. The testable prediction is that baseline lesion PR expression predicts symptomatic response to progestin therapy, and that this relationship differs by lesion site. A prospective study linking pretreatment receptor scores to symptom trajectories would settle it. Strengths and limitations The principal strengths are that lesion site was recorded specimen by specimen rather than assigned per patient, that patient identifiers allowed the correlation between specimens to be modelled rather than ignored, and that the central comparison was reproduced within individual women. The cohort was consecutive, reducing selection at the level of who entered the study. Several limitations qualify the findings. First, the study is cross-sectional and single-centre, and the association between lesion type and PR cannot establish that the receptor deficit precedes or causes anything clinically. Second, DIE and other lesions were represented by four and five specimens respectively; those groups are descriptive only, and the conclusion that the three non-uterine sites are equivalent rests mainly on the endometrioma comparison. Third, the within-patient analysis, though internally the cleanest, involved nine women. Fourth, the H-score was assigned during routine diagnostic reporting; whether scoring was independently duplicated and what inter-observer agreement was achieved must be stated by the authors, and its absence would be a legitimate reviewer concern. Fifth, PR isoforms A and B were not distinguished, although the isoform ratio is central to mechanistic accounts of progesterone resistance [ 13 , 15 ]; total PR by immunohistochemistry is a coarser measure. Sixth, menstrual cycle phase at the time of surgery was not available, and receptor expression varies across the cycle [ 15 , 22 ]; this is a genuine source of unmeasured variability, though it is unlikely to be systematically different between the uterine and ovarian specimens taken from the same woman at the same operation, which is what the paired analysis compares. Finally, no correction was applied for multiple modelling, and the exploratory age-by-site interaction did not survive adjustment for menopausal status and should not be carried forward as a finding. Conclusions Among endometriosis-associated lesions, reduced progesterone receptor expression is specific to adenomyosis rather than being a generalised feature of the disease, and it is dissociated from oestrogen receptor expression, which is governed by patient age. The association survives adjustment for age, adhesions and menopausal status, is stable across four analytical strategies, and is reproduced within individual women who contributed both lesion types at the same operation. These findings support treating adenomyosis as endocrinologically distinct from other endometriosis-associated lesions and motivate prospective work testing whether lesion PR expression predicts response to progestin therapy. Abbreviations CI confidence interval DIE deep infiltrating endometriosis ER oestrogen receptor IQR interquartile range OLS ordinary least squares PR progesterone receptor SD standard deviation. Declarations Ethics approval and consent to participate. This study was conducted with the approval of the Ethics Committee of Tokyo Women’s Medical University (approval number 2025-0098). Informed consent to participate was obtained from all of the participants in the study. This study complies with the Declaration of Helsinki. Consent for publication. Not applicable. Availability of data and materials. All data generated or analyzed during this study are included in the link below or its supplementary information files. https://docs.google.com/spreadsheets/d/1AbL8eDbMVzOWf-DjPRf76QqjmXc40oGe/edit?usp=sharing&ouid=115859921286273484238&rtpof=true&sd=true Competing interests. The authors declare that they have no competing interests. Funding. This research received no specific grant. Authors' contributions. Yu Horibe; Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing, Tomoko Yamamoto; Immunostaining, Resources Kei Koshimizu; Data Curation, Investigation Jun Kumakiri; Supervision Yoji Nagashima; Immunostaining, Resources Tsutomu Tabata; Supervision Acknowledgements. Not applicable. Use of AI-assisted technologies. AI-assisted analytical tool (Claude Science) were used for the statistical analysis and English translation. The authors take full responsibility for the interpretation of the analytical results and for the content of the manuscript. References Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839–52. 10.1016/S0140-6736(21)00389-5. . PMID:33640070. Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379:e070750. 10.1136/bmj-2022-070750. . PMID:36375827. Zhai J, Vannuccini S, Petraglia F, Giudice LC, Adenomyosis. Mechanisms and Pathogenesis. Semin Reprod Med. 2020;38(2–03):129–43. 10.1055/s-0040-1716687. . PMID:33032339. Bulun SE, Yildiz S, Adli M, Wei JJ. Adenomyosis pathogenesis: insights from next-generation sequencing. Hum Reprod Update. 2021;27(6):1086–97. 10.1093/humupd/dmab017. . PMID:34131719. Bulun SE, Yildiz S, Adli M, Chakravarti D, Parker JB, Milad M, et al. Endometriosis and adenomyosis: shared pathophysiology. Fertil Steril. 2023;119(5):746–50. 10.1016/j.fertnstert.2023.03.006. . PMID:36925057. Benagiano G, Brosens I, Habiba M. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. Hum Reprod Update. 2014;20(3):386–402. 10.1093/humupd/dmt052. . PMID:24140719. Dason ES, Maxim M, Sanders A, Papillon-Smith J, Ng D, Chan C, et al. Guideline 437: Diagnosis and Management of Adenomyosis. J Obstet Gynaecol Can. 2023;45(6):417–e4291. 10.1016/j.jogc.2023.04.008. . PMID:37244746. Vannuccini S, Clemenza S, Rossi M, Petraglia F. Hormonal treatments for endometriosis: The endocrine background. Rev Endocr Metab Disord. 2022;23(3):333–55. 10.1007/s11154-021-09666-w. . PMID:34405378. Kobayashi H, Efficacy. Adverse Events, and Challenges of Dienogest in the Management of Symptomatic Adenomyosis: A Comparison with Different Hormonal Treatments. Gynecol Obstet Invest. 2023;88(2):71–80. 10.1159/000529185. . PMID:36682346. Rafique S, Decherney AH. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485–96. 10.1097/GRF.0000000000000292. . PMID:28590310. Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. Endometriosis: the pathophysiology as an estrogen-dependent disease. J Steroid Biochem Mol Biol. 2002;83(1–5):149–55. 10.1016/s0960-0760(02)00260-1. . PMID:12650711. Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. Int J Mol Sci. 2023;24(8). 10.3390/ijms24086992. . PMID:37108154. Wu Y, Strawn E, Basir Z, Halverson G, Guo SW. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics. 2006;1(2):106–11. PMID:17965625. Squatrito M, Vervier J, Bindels J, Bernet L, Blacher S, Nisolle M, et al. Impaired fertility in adenomyosis: a murine model reveals endometrial receptivity and progesterone resistance imbalances. Reproduction. 2024;167(5). 10.1530/REP-24-0019. . PMID:38451875. Mehasseb MK, Panchal R, Taylor AH, Brown L, Bell SC, Habiba M. Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis. Fertil Steril. 2011;95(7):2228–35. 2235.e1. PMID:21444077. Massarotti C, Mirabelli Badenier I, Paudice M, Scaglione G, Remorgida V, Vellone VG. Steroids receptors immunohistochemical expression in different sites of endometriosis. J Gynecol Obstet Hum Reprod. 2021;50(3):101861. 10.1016/j.jogoh.2020.101861 . PMID:32652301. McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985;109(8):716–21. PMID:3893381. Yildiz S, Kinali M, Wei JJ, Milad M, Yin P, Adli M, et al. Adenomyosis: single-cell transcriptomic analysis reveals a paracrine mesenchymal-epithelial interaction involving the WNT/SFRP pathway. Fertil Steril. 2023;119(5):869–82. 10.1016/j.fertnstert.2023.01.041. . PMID:36736810. Zhang R, Yang Y, Li R, Ma Y, Ma S, Chen X, et al. Construction organoid model of ovarian endometriosis and the function of estrogen and progesterone in the model. Sci Rep. 2025;15(1):6636. 10.1038/s41598-025-90329-0. . PMID:39994247. Hu L, Zhang J, Lu Y, Fu B, Hu W. Estrogen receptor beta promotes endometriosis progression by upregulating CD47 expression in ectopic endometrial stromal cells. J Reprod Immunol. 2022;151:103513. 10.1016/j.jri.2022.103513 . PMID:35305523. Clemenza S, Capezzuoli T, Eren E, Garcia Garcia JM, Vannuccini S, Petraglia F. Progesterone receptor ligands for the treatment of endometriosis. Minerva Obstet Gynecol. 2023;75(3):288–97. 10.23736/S2724-606X.22.05157-0. . PMID:36255163. Chodankar RR, Murray A, Nicol M, Whitaker LHR, Williams ARW, Critchley HOD. The endometrial response to modulation of ligand-progesterone receptor pathways is reversible. Fertil Steril. 2021;116(3):882–95. 10.1016/j.fertnstert.2021.02.008. . PMID:33865567. Additional Declarations No competing interests reported. Supplementary Files floatimage4.png Additional file 1: Fig. S1 Exploratory analysis of the age-by-lesion-site interaction on PR. PR falls with age within adenomyotic specimens and rises with age within endometrioma specimens. The interaction term is significant in the adjusted model, but the age effect within adenomyotic specimens does not persist after adjustment for menopausal status; this analysis is hypothesis-generating only. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 05 Oct, 2026 Reviewers agreed at journal 04 Oct, 2026 Reviews received at journal 03 Oct, 2026 Reviews received at journal 02 Oct, 2026 Reviewers agreed at journal 02 Oct, 2026 Reviewers agreed at journal 02 Oct, 2026 Reviews received at journal 01 Oct, 2026 Reviewers agreed at journal 01 Oct, 2026 Reviewers agreed at journal 01 Oct, 2026 Reviews received at journal 01 Oct, 2026 Reviewers agreed at journal 01 Oct, 2026 Reviewers agreed at journal 01 Oct, 2026 Reviewers invited by journal 01 Oct, 2026 Editor invited by journal 22 Sep, 2026 Editor assigned by journal 01 Sep, 2026 Submission checks completed at journal 01 Sep, 2026 First submitted to journal 31 Aug, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-10865216","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":729594646,"identity":"1e276a2c-25ca-44d2-af04-8240ca92f3eb","order_by":0,"name":"Yu Horibe","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYDCCA3CCh4HhA5BiYydFC+MMkBZmUrQw84BoQlr4jvcYPuY5c0fO4HbvMWmbX9vk+ZgZGD98zMGtRfLMGWNjnhvPjA3unEuTzu27bdjGzMAsOXMbbi0GN3LMpHk+HE7cBmLk9txmBGphY+YlWotlz217IrXcgGph+HE7kaAWyTPHig3nnDlsbH/njLFlb8Pt5DZmxma8fuE73rzxwZtjh+UkZ/cY3vjx57bt/Pbmgx8+4tHCwMBhAKElGFgkGNtALMYGfOqBgP0BTAvzB4Y/BBSPglEwCkbBiAQAohBYPfZXwqgAAAAASUVORK5CYII=","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Horibe","suffix":""},{"id":729594647,"identity":"24cb7af0-b310-4ccb-8049-ec6535870623","order_by":1,"name":"Tomoko Yamamoto","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Yamamoto","suffix":""},{"id":729594648,"identity":"473d0024-2c59-4d5b-802d-c1724423029a","order_by":2,"name":"Kei Koshimizu","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Koshimizu","suffix":""},{"id":729594649,"identity":"db6f13fb-826f-44c4-ba70-8197565b7f91","order_by":3,"name":"Jun Kumakiri","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Kumakiri","suffix":""},{"id":729594650,"identity":"169844e7-d339-488c-9453-13e7cc68a1a1","order_by":4,"name":"Yoji Nagashima","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoji","middleName":"","lastName":"Nagashima","suffix":""},{"id":729594651,"identity":"c3cf062a-a3c9-491f-8163-c1e55bc3eeac","order_by":5,"name":"Tsutomu Tabata","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tsutomu","middleName":"","lastName":"Tabata","suffix":""}],"badges":[],"createdAt":"2026-08-30 02:08:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-10865216/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-10865216/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":122908766,"identity":"bf5a5427-f242-4233-9e65-3a4606b90445","added_by":"auto","created_at":"2026-10-14 13:45:43","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":324590,"visible":true,"origin":"","legend":"\u003cp\u003eProgesterone receptor expression is reduced in adenomyosis alone. a PR H-score by lesion site; boxes show median and interquartile range with individual specimens overlaid, n per group indicated below each box. Brackets show the overall Kruskal-Wallis test and the Holm-adjusted adenomyosis-versus-endometrioma contrast. b Within-patient comparison restricted to the nine women who contributed both an ovarian endometrioma and an adenomyotic specimen at the same operation; each line joins one woman's two specimens.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-10865216/v1/8cc676fb10e560ecf18ac21d.jpeg"},{"id":122974597,"identity":"6b50e264-cf96-41a7-844a-0189a386763e","added_by":"auto","created_at":"2026-10-15 06:37:08","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":351844,"visible":true,"origin":"","legend":"\u003cp\u003eOestrogen receptor shows no comparable site specificity. a ER H-score by lesion site; the difference across sites is weak and adenomyosis is not the low group, and the site effect does not persist after adjustment for age. b ER plotted against age at surgery for all 118 specimens, with adenomyotic specimens highlighted; the fitted line is the ordinary least-squares fit across the whole cohort.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-10865216/v1/f276043c695b3d22e272b0ab.jpeg"},{"id":122974879,"identity":"5d8c7d96-5a5f-45b3-b17c-6f0150e0af44","added_by":"auto","created_at":"2026-10-15 06:39:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":160069,"visible":true,"origin":"","legend":"\u003cp\u003eThe adenomyosis-PR association is stable across analytical strategies. Adjusted difference in receptor H-score for adenomyosis versus all other lesion sites, estimated under four strategies for handling repeated specimens from the same woman. Points are point estimates, horizontal bars 95 % confidence intervals, dashed line the null. a PR. b ER. All models adjust for standardised age, pelvic adhesions and menopausal status.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-10865216/v1/7f271e6f7892c67ca2a40f31.png"},{"id":122977015,"identity":"11c6fc64-f443-4a74-a464-bb70b2106d71","added_by":"auto","created_at":"2026-10-15 06:45:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1062368,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-10865216/v1/16e8d5fb-38d6-4d07-97a9-126b7bb20b68.pdf"},{"id":122908772,"identity":"74f76483-9e77-4342-a89a-5dd3cbda36f5","added_by":"auto","created_at":"2026-10-14 13:45:44","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":213526,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 1: Fig. S1 Exploratory analysis of the age-by-lesion-site interaction on PR. PR falls with age within adenomyotic specimens and rises with age within endometrioma specimens. The interaction term is significant in the adjusted model, but the age effect within adenomyotic specimens does not persist after adjustment for menopausal status; this analysis is hypothesis-generating only.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-10865216/v1/0da9835f839d6ee48feb1981.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Progesterone receptor expression is selectively reduced in adenomyosis among endometriosis-associated lesions: a cross-sectional immunohistochemical study of 118 specimens from 100 women","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometriosis affects approximately one in ten women of reproductive age and imposes a chronic burden of pain, infertility and repeated surgery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Adenomyosis, in which endometrial glands and stroma are found within the myometrium, frequently coexists with endometriosis and shares much of its clinical presentation and its presumed origin in retrograde menstruation and endometrial stem-cell dysfunction [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The two conditions are managed with an overlapping pharmacological repertoire: combined oral contraceptives, gonadotropin-releasing hormone analogues and, increasingly, progestins such as dienogest and the levonorgestrel-releasing intrauterine system [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBoth diseases are oestrogen-dependent [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and both have been described as showing progesterone resistance \u0026mdash; a reduced capacity of target tissue to respond to progesterone, attributed to loss or silencing of the progesterone receptor (PR), particularly the PR-B isoform [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This concept has been developed largely from studies of ectopic endometriotic tissue and is commonly applied to endometriosis-associated disease as a single category. Mechanistic work in adenomyosis has separately demonstrated impaired progesterone signalling [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and receptor isoform distribution in the adenomyotic uterus differs from that in the unaffected uterus [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. What has been much less clear is whether the two lesion types differ from each other. If progesterone resistance were a uniform property of endometriosis-associated disease, PR expression should be comparably low wherever the lesion sits. If instead it were concentrated in one lesion type, that would imply that the pharmacological target is unequally available across lesions within the same patient \u0026mdash; a distinction with direct implications for how progestin therapy is selected.\u003c/p\u003e \u003cp\u003eStudies comparing steroid receptor expression across anatomical sites of endometriosis exist [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], but they have generally treated each specimen as an independent observation. Because a woman undergoing surgery for endometriosis-associated disease commonly yields more than one lesion, specimens from the same patient are correlated, and analyses that ignore this correlation overstate precision. The design that most directly addresses the question \u0026mdash; comparing lesion types within the same woman \u0026mdash; has rarely been reported.\u003c/p\u003e \u003cp\u003eWe therefore examined oestrogen receptor (ER) and PR expression in a consecutive surgical cohort in which the anatomical site was recorded for every specimen and the patient identifier permitted specimens to be linked. Our aim was to determine whether reduced PR expression is a generalised feature of endometriosis-associated lesions or is specific to the adenomyotic lesion, and to establish whether any such difference is independent of the patient characteristics \u0026mdash; age, menopausal status and adhesive disease \u0026mdash; that differ systematically between women presenting with uterine and with ovarian disease.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eStudy design and participants\u003c/p\u003e \u003cp\u003eThis was a cross-sectional analysis of consecutive women who underwent surgery for endometriosis-associated disease at a single tertiary centre between November 2022 and May 2026. Women were eligible if surgery yielded at least one lesion with a histopathological diagnosis of endometriosis or adenomyosis and if archived tissue was adequate for immunohistochemistry. No exclusion was applied on the basis of age, menopausal status or previous medical treatment. One hundred women contributed 118 specimens; 88 women contributed a single specimen, 8 contributed two, 2 contributed three and 2 contributed four.\u003c/p\u003e \u003cp\u003eLesion site assignment\u003c/p\u003e \u003cp\u003eEvery specimen was assigned to exactly one anatomical site on the basis of the operative record and the corresponding pathology report: adenomyosis (uterine specimen), ovarian endometrioma, deep infiltrating endometriosis (DIE), or other endometriosis-associated lesion. Where a woman had both uterine and ovarian disease, each specimen retained its own site label; the woman was not assigned to a single diagnostic category. This specimen-level assignment is what permits the within-patient comparison described below.\u003c/p\u003e \u003cp\u003eImmunohistochemistry and scoring\u003c/p\u003e \u003cp\u003eFormalin-fixed, paraffin-embedded sections were stained for ER and PR according to the laboratory's routine diagnostic protocol. Expression was quantified using the modified H-score [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], calculated as the sum across staining-intensity categories of (intensity grade 0\u0026ndash;3) \u0026times; (percentage of nuclei at that intensity), giving a continuous score from 0 to 300. Scoring was performed by the reporting pathologist as part of routine diagnostic assessment, without reference to the study hypothesis. The PR/ER ratio was computed as a secondary descriptor of the relative balance of the two receptors.\u003c/p\u003e \u003cp\u003eThree-micrometre-thick sections were cut from a representative tissue block. Immunohistochemical staining was performed using the Ventana BenchMark ULTRA IHC/ISH System (Roche Diagnostics, Basel, Switzerland) according to the manufacturer\u0026rsquo;s instructions. Ventana detection kits were used for ER (SP1, rabbit monoclonal, Cat. no. 107925, Roche), PgR (1E2, rabbit monoclonal, Cat. no. 102333, Roche) and HER2 (4B5, rabbit monoclonal, Cat. no. 107918, Roche) staining. 3,3\u0026rsquo;-Diaminobenzidine tetrahydrochloride was used as the chromogen and haematoxylin as the counterstain.\u003c/p\u003e \u003cp\u003eEach specimen was classified by site of origin as ovarian endometrioma, adenomyosis, deep infiltrating endometriosis (DIE) or other. This site classification was assigned at the specimen level and was handled separately from the patient-level clinical diagnosis, which may include the coexistence of multiple lesions.\u003c/p\u003e \u003cp\u003eCovariates\u003c/p\u003e \u003cp\u003eAge at surgery, menopausal status, presence of pelvic adhesions at operation, gravidity, parity, body mass index, serum CA125, operative time, intraoperative blood loss and length of stay were extracted from the clinical record. Preoperative hormonal treatment was recorded and classified as progestin exposure (dienogest or luteal-phase progestin) or other. Age was standardised (mean-centred and divided by its standard deviation of 9.4 years) so that regression coefficients express the change in H-score per standard deviation of age.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDistributions of ER, PR and the PR/ER ratio departed significantly from normality (Shapiro\u0026ndash;Wilk p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all three), so non-parametric methods were used for unadjusted comparisons. Continuous variables are summarised as median [interquartile range] and compared with the Mann\u0026ndash;Whitney U test for two groups or the Kruskal\u0026ndash;Wallis test across four lesion sites; pairwise comparisons following a significant Kruskal\u0026ndash;Wallis test were adjusted by the Holm method. Categorical variables were compared with Fisher's exact test. Effect size for two-group comparisons is reported as the rank-biserial correlation.\u003c/p\u003e \u003cp\u003eThe prespecified primary analysis addressed the correlation between specimens from the same woman. A linear mixed-effects model was fitted with the receptor H-score as the outcome, patient identity as a random intercept, and fixed effects for lesion type (adenomyosis versus all other lesion sites), standardised age, pelvic adhesions and menopausal status. This model was fitted separately for PR and for ER. One specimen lacked adhesion status, so adjusted models include 117 specimens.\u003c/p\u003e \u003cp\u003eFour analytical strategies were compared to demonstrate that the findings do not depend on how clustering is handled: (i) ordinary least squares treating all specimens as independent; (ii) ordinary least squares with cluster-robust standard errors grouped by patient; (iii) ordinary least squares restricted to one specimen per patient; and (iv) the mixed-effects model, which was the primary analysis. Two further sensitivity analyses were performed: the primary model with preoperative progestin exposure added as a covariate, and a within-patient paired comparison, restricted to women who contributed both an adenomyotic and a non-uterine specimen, tested with the Wilcoxon signed-rank test.\u003c/p\u003e \u003cp\u003eAn interaction between lesion type and age on PR was examined as a prespecified exploratory analysis and is reported as hypothesis-generating only.\u003c/p\u003e \u003cp\u003e Two-sided p values below 0.05 were considered statistically significant; no adjustment was made for the number of models fitted, and the analysis is accordingly interpreted as estimation rather than confirmatory hypothesis testing. Analyses were performed in Python 3.11 using pandas, SciPy and statsmodels.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eCohort\u003c/p\u003e \u003cp\u003eOne hundred women contributed 118 specimens: 49 adenomyotic (uterine), 60 ovarian endometrioma, 4 DIE and 5 other endometriosis-associated lesions. Median age at surgery was 46 years (IQR 41\u0026ndash;52). Women whose specimens were adenomyotic were older than those whose specimens were from other sites (median 50 [46\u0026ndash;53] versus 43 [36\u0026ndash;49] years, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), had higher gravidity (1 [0\u0026ndash;2] versus 0 [0\u0026ndash;1], p\u0026thinsp;=\u0026thinsp;0.006), less frequently had pelvic adhesions (42.9% versus 82.4%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), had longer operations (207.5 [143.2\u0026ndash;264.0] versus 162.0 [116.0\u0026ndash;244.0] min, p\u0026thinsp;=\u0026thinsp;0.043) and longer hospital stays (7 [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] versus 6 [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] days, p\u0026thinsp;=\u0026thinsp;0.012). Body mass index, CA125 and intraoperative blood loss did not differ. Preoperative progestin exposure was recorded in 19 of 118 specimens (16.1%) and was not differentially distributed between adenomyotic and other specimens (12.2% versus 18.8%, p\u0026thinsp;=\u0026thinsp;0.448). Full characteristics are given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of adenomyotic and other endometriosis-associated specimens. Continuous variables are median [interquartile range] and compared with the Mann-Whitney U test; categorical variables are n (%) and compared with Fisher's exact test.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis specimens (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther lesion specimens (n\u0026thinsp;=\u0026thinsp;69)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.0 [46.0\u0026ndash;53.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43.0 [36.0\u0026ndash;49.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.0 [21.5\u0026ndash;25.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21.9 [19.7\u0026ndash;25.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGravidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.0 [0.0\u0026ndash;2.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0 [0.0\u0026ndash;1.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0 [0.0\u0026ndash;2.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0 [0.0\u0026ndash;1.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125 (U/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58.0 [19.5-176.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61.0 [26.0-164.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.591\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOperative time (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e207.5 [143.2\u0026ndash;264.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e162.0 [116.0-244.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraoperative blood loss (mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.5 [6.0-55.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27.0 [6.0-200.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.309\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.0 [6.0\u0026ndash;9.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.0 [6.0\u0026ndash;8.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmenopausal, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePelvic adhesions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56 (82.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative progestin, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.448\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePR is reduced in adenomyosis and not in other lesion types\u003c/p\u003e \u003cp\u003ePR expression differed across the four lesion sites (Kruskal\u0026ndash;Wallis H\u0026thinsp;=\u0026thinsp;24.75, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The difference was accounted for entirely by the adenomyotic lesion. Median PR H-score was 135.0 (IQR 60.0\u0026ndash;185.0) in adenomyosis, compared with 210.0 (150.0\u0026ndash;255.0) in ovarian endometrioma, 220.0 (183.8\u0026ndash;257.5) in DIE and 230.0 (185.0\u0026ndash;260.0) in other lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). In Holm-adjusted pairwise comparisons, adenomyosis differed from endometrioma (p\u0026thinsp;=\u0026thinsp;0.0001) and from other lesions (p\u0026thinsp;=\u0026thinsp;0.029), and differed from DIE at a magnitude consistent with the other contrasts but without reaching significance in four specimens (p\u0026thinsp;=\u0026thinsp;0.064); the three non-uterine sites were mutually indistinguishable (all p\u0026thinsp;=\u0026thinsp;1.00). Pooling all non-uterine specimens, PR was 135.0 in adenomyosis versus 215.0 elsewhere (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, rank-biserial r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.52) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eReceptor expression by lesion site.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarker\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian [IQR] / test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis (uterus)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e220.0 [162.5\u0026ndash;260.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioma (ovary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e190.0 [142.2\u0026ndash;230.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e240.0 [221.2-247.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e260.0 [245.0-260.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKruskal-Wallis (4 sites)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u0026thinsp;=\u0026thinsp;8.19, p\u0026thinsp;=\u0026thinsp;0.0422\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis vs all others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.3571, rank-biserial r\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis (uterus)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e135.0 [60.0-185.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioma (ovary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e210.0 [150.0-255.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e220.0 [183.8-257.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e230.0 [185.0-260.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKruskal-Wallis (4 sites)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u0026thinsp;=\u0026thinsp;24.75, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis vs all others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, rank-biserial r=-0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR/ER ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis (uterus)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7 [0.3\u0026ndash;1.1]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR/ER ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioma (ovary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.1 [0.8\u0026ndash;1.4]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR/ER ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0 [0.9-1.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR/ER ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.9 [0.7-1.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR/ER ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKruskal-Wallis (4 sites)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u0026thinsp;=\u0026thinsp;16.01, p\u0026thinsp;=\u0026thinsp;0.0011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR/ER ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis vs all others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0001, rank-biserial r=-0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eb Holm-adjusted pairwise comparisons of PR H-score between lesion sites.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eraw p\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHolm p\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenomyosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenomyosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0639\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenomyosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.5507\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrioma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.3557\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe same pattern was seen in the PR/ER ratio, which was 0.74 in adenomyosis versus 1.07 in other lesions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, rank-biserial r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.42), indicating that the reduction is specific to PR rather than reflecting a general loss of steroid receptor expression.\u003c/p\u003e \u003cp\u003eThe association is independent of age, adhesions and menopausal status\u003c/p\u003e \u003cp\u003eIn the mixed-effects model with patient as a random intercept, adenomyosis remained associated with a substantially lower PR H-score after adjustment for standardised age, pelvic adhesions and menopausal status (β = \u0026minus;75.7, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;102.5 to \u0026minus;\u0026thinsp;48.9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; n\u0026thinsp;=\u0026thinsp;117). Postmenopausal status was independently associated with lower PR (β = \u0026minus;46.3, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;87.4 to \u0026minus;\u0026thinsp;5.1, p\u0026thinsp;=\u0026thinsp;0.027), whereas age (β = +11.6, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;5.7 to 28.8, p\u0026thinsp;=\u0026thinsp;0.189) and adhesions (β = \u0026minus;7.1, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;38.3 to 24.0, p\u0026thinsp;=\u0026thinsp;0.652) were not (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLinear mixed-effects models with patient as a random intercept (n\u0026thinsp;=\u0026thinsp;117 specimens from 100 women; one specimen lacked adhesion status). Coefficients are the change in H-score.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTerm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ebeta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis (vs other lesion sites)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-75.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-102.5 to -48.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2e-08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (per 1 SD, 9.4 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-5.7 to 28.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.189\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePelvic adhesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-38.3 to 24.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.652\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-46.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-87.4 to -5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenomyosis (vs other lesion sites)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-24.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-48.9 to 0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (per 1 SD, 9.4 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;22.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.4 to 38.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePelvic adhesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-30.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-58.8 to -3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-51.3 to 22.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.439\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe finding does not depend on how patient clustering is handled\u003c/p\u003e \u003cp\u003eThe adenomyosis coefficient was essentially unchanged across all four analytical strategies: \u0026minus;75.4 (95% CI\u0026thinsp;\u0026minus;\u0026thinsp;105.2 to \u0026minus;\u0026thinsp;45.6) treating specimens as independent, \u0026minus;\u0026thinsp;75.4 (\u0026minus;\u0026thinsp;104.3 to \u0026minus;\u0026thinsp;46.5) with cluster-robust standard errors, \u0026minus;\u0026thinsp;79.1 (\u0026minus;\u0026thinsp;112.9 to \u0026minus;\u0026thinsp;45.4) restricting to one specimen per patient, and \u0026minus;\u0026thinsp;75.7 (\u0026minus;\u0026thinsp;102.5 to \u0026minus;\u0026thinsp;48.9) in the mixed-effects model, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 throughout (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Adding preoperative progestin exposure to the primary model left the estimate unchanged (β = \u0026minus;75.8, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;102.7 to \u0026minus;\u0026thinsp;49.0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and progestin exposure itself was not associated with PR (β = \u0026minus;18.4, p\u0026thinsp;=\u0026thinsp;0.309).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analyses for the association between adenomyosis and PR H-score. All regression models adjust for standardised age, pelvic adhesions and menopausal status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnalytical strategy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ebeta (PR H-score)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRole\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll specimens (OLS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-75.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-105.2 to -45.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.0e-06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCluster-robust SE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-75.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-104.3 to -46.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.1e-07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne per patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-79.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-112.9 to -45.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.1e-05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-75.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-102.5 to -48.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.2e-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed-effects\u0026thinsp;+\u0026thinsp;progestin pre-treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-75.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-102.7 to -49.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.1e-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithin-patient paired (n\u0026thinsp;=\u0026thinsp;9 women with both lesions)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLower in 9/9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNine women contributed both an adenomyotic and a non-uterine specimen and therefore served as their own controls. PR was lower in the adenomyotic lesion in every one of the nine (median 160 versus 240; Wilcoxon signed-rank p\u0026thinsp;=\u0026thinsp;0.004) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Because both specimens in each pair come from the same woman at the same operation, this comparison is unaffected by age, menopausal status, systemic hormonal milieu or prior treatment.\u003c/p\u003e \u003cp\u003eER shows no comparable site specificity and is governed by age\u003c/p\u003e \u003cp\u003eER expression showed only a weak difference across lesion sites (Kruskal\u0026ndash;Wallis H\u0026thinsp;=\u0026thinsp;8.19, p\u0026thinsp;=\u0026thinsp;0.042), and adenomyosis was not the low group: median ER was 220.0 (162.5\u0026ndash;260.0) in adenomyosis, 190.0 (142.2\u0026ndash;230.0) in endometrioma, 240.0 (221.2\u0026ndash;247.5) in DIE and 260.0 (245.0\u0026ndash;260.0) in other lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Adenomyosis did not differ from pooled non-uterine specimens (p\u0026thinsp;=\u0026thinsp;0.357, r\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.10), and in the adjusted model the lesion-type coefficient was approximately one third the size of that seen for PR and did not reach significance (β = \u0026minus;24.3, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;48.9 to 0.3, p\u0026thinsp;=\u0026thinsp;0.053); it fell below significance in both clustering-aware models (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhat did predict ER was patient age. ER rose with age across the whole cohort (Spearman rho\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.36, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb) and age remained the dominant term in the adjusted model (β = +22.9 per SD of 9.4 years, 95% CI 7.4 to 38.4, p\u0026thinsp;=\u0026thinsp;0.004), with pelvic adhesions additionally associated with lower ER (β = \u0026minus;30.9, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;58.8 to \u0026minus;\u0026thinsp;3.0, p\u0026thinsp;=\u0026thinsp;0.030). PR, by contrast, was not associated with age (p\u0026thinsp;=\u0026thinsp;0.189). The two receptors are therefore governed by different variables: PR by lesion type, ER by patient age.\u003c/p\u003e \u003cp\u003eExploratory analysis\u003c/p\u003e \u003cp\u003eAn interaction between lesion type and age on PR was statistically significant (β = \u0026minus;42.6, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;73.1 to \u0026minus;\u0026thinsp;12.1, p\u0026thinsp;=\u0026thinsp;0.006): PR fell with age within adenomyotic specimens (rho\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.44, p\u0026thinsp;=\u0026thinsp;0.001) while rising with age within endometrioma specimens (rho\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.31, p\u0026thinsp;=\u0026thinsp;0.016) (Additional file 1: Fig. S1). However, within adenomyotic specimens the age effect did not persist after adjustment for menopausal status (β = \u0026minus;24.0, p\u0026thinsp;=\u0026thinsp;0.122), so the divergence cannot be separated from the menopausal transition in this cohort. This analysis is reported as hypothesis-generating and is not part of the primary claim.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this consecutive surgical cohort, reduced PR expression was a property of the adenomyotic lesion and not of endometriosis-associated disease in general. Ovarian endometrioma, DIE and other endometriosis-associated lesions had similar PR levels and were statistically indistinguishable from one another, while adenomyosis sat well below all of them. The difference corresponded to roughly 76 points on a 0\u0026ndash;300 H-score scale after adjustment, was unchanged across four analytical strategies, was unaffected by preoperative progestin exposure, and was reproduced in every one of the nine women who contributed both an adenomyotic and a non-uterine lesion at the same operation.\u003c/p\u003e \u003cp\u003eRelation to existing work\u003c/p\u003e \u003cp\u003eProgesterone resistance is a well-established concept in endometriosis, and much of the mechanistic evidence \u0026mdash; PR-B promoter hypermethylation, altered PR isoform ratios, impaired downstream signalling \u0026mdash; has been generated from ectopic endometriotic tissue and generalised to the disease as a category [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Our data are not inconsistent with that literature, but they locate the receptor deficit more precisely. When lesion types are compared directly within the same cohort, and in some cases within the same woman, the low-PR phenotype belongs to the adenomyotic lesion. This aligns with the independent adenomyosis literature: impaired progesterone signalling has been demonstrated in adenomyosis in a murine model [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], receptor isoform distribution in the adenomyotic uterus differs from the unaffected uterus across the cycle [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and single-cell and next-generation sequencing work has identified adenomyosis-specific mesenchymal\u0026ndash;epithelial signalling that is not simply a copy of endometriotic biology [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Recent syntheses emphasise shared pathophysiology between the two conditions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; our findings suggest that the sharing is incomplete at the level of the progesterone receptor, and that the two lesions should not be assumed to be pharmacologically equivalent.\u003c/p\u003e \u003cp\u003ePrevious cross-site comparisons of steroid receptor expression in endometriosis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] have generally analysed specimens as independent observations. In our cohort 12 of 100 women contributed more than one specimen, and treating those 118 specimens as independent would have overstated precision. We therefore made the clustering-aware model the primary analysis and reported the naive analysis only as one of four strategies. That the point estimate barely moved across strategies is reassuring, but the design point stands: with a larger proportion of multi-lesion patients the choice would matter, and the within-patient comparison is the most informative single piece of evidence in this study precisely because it removes the patient entirely from the contrast.\u003c/p\u003e \u003cp\u003eThe ER\u0026ndash;PR dissociation\u003c/p\u003e \u003cp\u003eThe behaviour of ER makes the PR finding more interpretable. ER was not reduced in adenomyosis, showed at most a weak and non-robust difference across sites, and was instead determined by patient age \u0026mdash; rising by roughly 23 H-score points per standard deviation of age. Had both receptors been low in adenomyosis, the most parsimonious explanation would have been generalised tissue differences: fixation, cellularity, or the proportion of stroma to epithelium in myometrial specimens. That ER was preserved, and that the PR/ER ratio was itself reduced in adenomyosis, argues that the finding reflects the progesterone axis specifically rather than a technical property of uterine tissue. This is consistent with experimental work in which oestrogen and progesterone act on endometriotic tissue through separable programmes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and with evidence that ERβ signalling drives lesion progression through pathways that do not depend on PR [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical implications\u003c/p\u003e \u003cp\u003eProgestins are first-line medical therapy for both endometriosis and adenomyosis [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], and adenomyosis-specific guidance recommends them while acknowledging variable response [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Dienogest and the levonorgestrel-releasing intrauterine system are effective in many women with adenomyosis but not in all [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. If the pharmacological target is quantitatively less available in the adenomyotic lesion than in coexisting endometriotic lesions, then a woman with both may experience differential response at different sites \u0026mdash; pelvic pain from endometriotic implants improving while uterine symptoms persist. This is a hypothesis generated by, not demonstrated in, the present data: we measured receptor protein, not treatment response, and no clinical outcome of progestin therapy was analysed. The testable prediction is that baseline lesion PR expression predicts symptomatic response to progestin therapy, and that this relationship differs by lesion site. A prospective study linking pretreatment receptor scores to symptom trajectories would settle it.\u003c/p\u003e \u003cp\u003eStrengths and limitations\u003c/p\u003e \u003cp\u003eThe principal strengths are that lesion site was recorded specimen by specimen rather than assigned per patient, that patient identifiers allowed the correlation between specimens to be modelled rather than ignored, and that the central comparison was reproduced within individual women. The cohort was consecutive, reducing selection at the level of who entered the study.\u003c/p\u003e \u003cp\u003eSeveral limitations qualify the findings. First, the study is cross-sectional and single-centre, and the association between lesion type and PR cannot establish that the receptor deficit precedes or causes anything clinically. Second, DIE and other lesions were represented by four and five specimens respectively; those groups are descriptive only, and the conclusion that the three non-uterine sites are equivalent rests mainly on the endometrioma comparison. Third, the within-patient analysis, though internally the cleanest, involved nine women. Fourth, the H-score was assigned during routine diagnostic reporting; whether scoring was independently duplicated and what inter-observer agreement was achieved must be stated by the authors, and its absence would be a legitimate reviewer concern. Fifth, PR isoforms A and B were not distinguished, although the isoform ratio is central to mechanistic accounts of progesterone resistance [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; total PR by immunohistochemistry is a coarser measure. Sixth, menstrual cycle phase at the time of surgery was not available, and receptor expression varies across the cycle [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; this is a genuine source of unmeasured variability, though it is unlikely to be systematically different between the uterine and ovarian specimens taken from the same woman at the same operation, which is what the paired analysis compares. Finally, no correction was applied for multiple modelling, and the exploratory age-by-site interaction did not survive adjustment for menopausal status and should not be carried forward as a finding.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAmong endometriosis-associated lesions, reduced progesterone receptor expression is specific to adenomyosis rather than being a generalised feature of the disease, and it is dissociated from oestrogen receptor expression, which is governed by patient age. The association survives adjustment for age, adhesions and menopausal status, is stable across four analytical strategies, and is reproduced within individual women who contributed both lesion types at the same operation. These findings support treating adenomyosis as endocrinologically distinct from other endometriosis-associated lesions and motivate prospective work testing whether lesion PR expression predicts response to progestin therapy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDIE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edeep infiltrating endometriosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eER\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoestrogen receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOLS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eordinary least squares\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogesterone receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was conducted with the approval of the Ethics Committee of Tokyo Women\u0026rsquo;s Medical University (approval number 2025-0098).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent to participate was obtained from all of the participants in the study.\u003c/p\u003e\n\u003cp\u003eThis study complies with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eConsent for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in the link below or its supplementary information files.\u003c/p\u003e\n\u003cp\u003ehttps://docs.google.com/spreadsheets/d/1AbL8eDbMVzOWf-DjPRf76QqjmXc40oGe/edit?usp=sharing\u0026amp;ouid=115859921286273484238\u0026amp;rtpof=true\u0026amp;sd=true\u003c/p\u003e\n\u003cp\u003eCompeting interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYu Horibe; Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTomoko Yamamoto; Immunostaining, Resources\u003c/p\u003e\n\u003cp\u003eKei Koshimizu; Data Curation, Investigation\u003c/p\u003e\n\u003cp\u003eJun Kumakiri; Supervision\u003c/p\u003e\n\u003cp\u003eYoji Nagashima; Immunostaining, Resources\u003c/p\u003e\n\u003cp\u003eTsutomu Tabata; Supervision\u003c/p\u003e\n\u003cp\u003eAcknowledgements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eUse of AI-assisted technologies.\u003c/p\u003e\n\u003cp\u003eAI-assisted analytical tool (Claude Science) were used for the statistical analysis and English translation. The authors take full responsibility for the interpretation of the analytical results and for the content of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTaylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839\u0026ndash;52. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(21)00389-5.\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(21)00389-5.\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e . PMID:33640070.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. 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PMID:33865567.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Adenomyosis, Endometriosis, Progesterone receptor, Oestrogen receptor, Immunohistochemistry, Progesterone resistance, Progestin therapy, Mixed-effects model","lastPublishedDoi":"10.21203/rs.3.rs-10865216/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-10865216/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground. Endometriosis and adenomyosis are both oestrogen-dependent and both are treated with progestins, yet response to progestin therapy is not uniform. Progesterone resistance is usually described as a property of endometriosis as a whole. Whether reduced progesterone receptor (PR) expression is shared by all endometriosis-associated lesions, or is concentrated in one lesion type, has not been established in a cohort with the lesion site recorded for every specimen.\u003c/p\u003e \u003cp\u003eMethods. We analysed 118 surgical specimens from 100 consecutive women operated on for endometriosis-associated disease at one centre between November 2022 and May 2026. Oestrogen receptor (ER) and PR were quantified immunohistochemically using the modified H-score (0-300). Each specimen was assigned one lesion site: adenomyosis (uterus, n\u0026thinsp;=\u0026thinsp;49), ovarian endometrioma (n\u0026thinsp;=\u0026thinsp;60), deep infiltrating endometriosis (DIE, n\u0026thinsp;=\u0026thinsp;4) or other (n\u0026thinsp;=\u0026thinsp;5). Because 12 women contributed more than one specimen, the primary analysis was a linear mixed-effects model with patient as a random intercept, adjusted for age, pelvic adhesions and menopausal status. Three further analytical strategies and a within-patient paired comparison were prespecified as sensitivity analyses.\u003c/p\u003e \u003cp\u003eResults. PR differed across lesion sites (Kruskal-Wallis p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the difference was confined to adenomyosis: median PR H-score 135.0 (IQR 60.0-185.0) versus 210.0 (150.0-255.0) in endometrioma, 220.0 (183.8-257.5) in DIE and 230.0 (185.0-260.0) in other lesions, the three non-uterine sites being mutually indistinguishable (all Holm-adjusted p\u0026thinsp;=\u0026thinsp;1.00). Adenomyosis remained associated with lower PR after adjustment (beta = -75.7, 95% CI -102.5 to -48.9, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and under all four strategies. Among nine women contributing both an adenomyotic and a non-uterine specimen, PR was lower in the adenomyotic lesion in 9 of 9 (Wilcoxon p\u0026thinsp;=\u0026thinsp;0.004). ER showed no comparable site effect (adjusted beta = -24.3, 95% CI -48.9 to 0.3, p\u0026thinsp;=\u0026thinsp;0.053) and instead tracked age (beta\u0026thinsp;=\u0026thinsp;+\u0026thinsp;22.9 per SD, p\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e \u003cp\u003eConclusions. Within endometriosis-associated disease, reduced PR expression is a property of the adenomyotic lesion rather than a generalised feature of the disease, and is dissociated from ER, which is governed by age. Lesion type may be relevant when progestin therapy is selected.\u003c/p\u003e","manuscriptTitle":"Progesterone receptor expression is selectively reduced in adenomyosis among endometriosis-associated lesions: a cross-sectional immunohistochemical study of 118 specimens from 100 women","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-10-14 13:45:25","doi":"10.21203/rs.3.rs-10865216/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision 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