Endometriomas are heterogeneous for functional FSH receptor expression and steroidogenic function

Abstract

We investigated whether ovarian endometriomas uniformly express functional FSH receptors (FSHR) and respond to FSH by activating transcriptional programs that drive aromatase and steroid hormone production. Endometrioma cyst capsules were obtained from 18 patients undergoing surgery between January 2020 and December 2024. FSHR and steroidogenic pathway components were evaluated using qRT-PCR, quantitative immunoblotting, and immunohistochemistry. To assess FSH responsiveness, explant cultures were exposed to FSH, and the expression of five FSH-responsive CYP19A1 (aromatase) transcript variants (alternative exons I.1, I.2; I.3; I.4, and promoter II) was quantified; estradiol (E2) and progesterone (P4) were measured in spent culture media. Human granulosa cells served as positive controls for steroidogenesis/FSHR, and the eutopic endometrium served as the estrogen receptor profiling control. FSHR transcripts were detected in all endometriomas and were several-fold higher than in granulosa-cell controls; however, FSHR protein abundance was lower and highly variable, and transcript–protein levels were discordant, indicating marked mRNA–protein uncoupling. FSH did not elicit a uniform aromatase response: only selected transcript variants were upregulated in a lesion-dependent manner, and induction of one or more CYP19A1 variants did not consistently translate into increased E2 output. Moreover, E2 production did not correlate with aromatase protein abundance. Protein expression of StAR and downstream steroidogenic enzymes (CYP11A1/SCC, 3β-HSD, and 17β-HSD) also showed substantial inter-patient heterogeneity. Collectively, ovarian endometriomas exhibit pronounced heterogeneity in functional FSHR expression, steroidogenic enzyme profiles, FSH-driven aromatase transcript programs, and hormone output, which may contribute to variable lesion behavior during ovarian stimulation; findings were derived from unilateral endometriomas and may not generalize to multifocal disease or other lesion types