BACKGROUND AND AIMS
Endometrial tissue produces steroids locally that can be relevant in endometriosis;1 oestrogens control lesion establishment, progestogens oppose oestrogen action, androgens are oestrogen precursors, and corticosteroids suppress inflammation. To elucidate to what extent steroid metabolism is implicated in endometriosis, and what inter- and intra-patient variability exists, the authors profiled major steroids in blood and tissue (normal endometrium and endometriosis) of patients, and also determined the expression levels of major enzymes involved in local steroid metabolism.
MATERIALS AND METHODS
This was a retrospective study using biobanked frozen patient material. Eutopic endometrium, multiple endometriotic lesions from each patient, and peripheral blood of 14 women (seven in the luteal and seven in the follicular phase) with histologically confirmed endometriosis were analysed. Endometriotic lesions originated from the uterosacral ligament/Pouch of Douglas, bladder, ovarian fossa, and rectum/rectosigmoid. Patients had Stage I (n=1), II (n=9), III (n=3), or IV (n=1) endometriosis (American Society for Reproductive Medicine [ASRM] classification). Patients with endometriosis were not under hormonal medication for six months prior to the biopsy. Plasma, eutopic endometrium samples (n=14), and endometriotic lesions (n=39) were obtained and stored following the Endometriosis Phenome and Biobanking Harmonisation Project (EPHect)/World Endometriosis Research Foundation (WERF) guidelines.2RNA expression was determined by whole RNA sequencing. Levels of major steroids were measured by liquid chromatography-mass spectrometry (LC-MS).3 HSD17B1 activity was measured in cell-free extracts by high-performance liquid chromatography (HPLC).4,5
Oestrogens (oestrone, oestradiol) were non-statistically significantly higher in eutopic and endometriotic tissues compared with blood (oestradiol: 1.0 pmol/g eutopic; 3.2 pmol/g endometriotic; 0.4 pmol/mL blood; and oestrone: 0.3 pmol/g eutopic; 1.1 pmol/g endometriotic; 0.3 pmol/mL blood). Of note, oestradiol:oestrone ratios, approximately 1 in blood, are approximately 3 in tissue, indicating active local synthesis. 17-hydroxy-progestogens and androstenedione were over four-fold higher in endometriotic lesions than eutopic tissue (p<0.05). The activity of HSD17B1 was comparable between eutopic and endometriotic tissues.
Regarding corticosteroids, active cortisol was four-fold higher in endometriosis than in the eutopic tissue (p<0.001), whereas inactive cortisone was 2.5-fold lower in endometriosis (p<0.001). HSD11B1 (activation to cortisol) and HSD11B2 (deactivation to cortisone) mRNA levels were in line with the corticosteroid levels; HSD11B1 mRNA was higher in endometriosis, and the opposite was observed for HSD11B2 compared with the eutopic endometrium (p<0.001 for both enzymes). The levels of compounds acting as precursors for corticosteroid synthesis (i.e., 11-deoxycortisol, 11-deoxycorticosterone) were higher in endometriosis compared with the eutopic tissue (p<0.05), and a number of enzymes involved in the generation of active compounds from these precursors were expressed in both eutopic endometrium and endometriotic tissue.
Although this was a retrospective study and included patients with all stages of disease and with manifestation of different symptoms in a pooled analysis, these data show that steroid levels differ between normal and endometriotic tissue. Irrespective of the location, endometriosis shows active synthesis of oestrogens and sustained corticosteroid levels.