Local Steroid Metabolism in Eutopic Endometrium and Corresponding Endometriotic Lesions: Intra-Patient Variability - European Medical Journal

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Local Steroid Metabolism in Eutopic Endometrium and Corresponding Endometriotic Lesions: Intra-Patient Variability

1 Mins
Reproductive Health
Authors:
Sofia Xanthoulea,1 Bert Delvoux,1 Pasi Koskimies,2 Merja R Häkkinen,3 Johanna Koskivuori,3 Seppo Auriola,3 Arne Vanhie,4 Carla Tomassetti,4 *Andrea Romano1

1. GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht,
The Netherlands
2. Forendo Pharma Ltd., Turku, Finland
3. School of Pharmacy, University of Eastern Finland, Kuopio, Finland
4. KU Leuven, Leuven, Belgium
*Correspondence to [email protected]

Disclosure:

Dr Koskimies reports personal fees from Forendo Pharma Ltd., during the conduct of the study; and personal fees as an employee of Forendo Pharma Ltd., outside the submitted work. Dr Tomassetti reports unrestricted research grants to their institution (LUFC – UZ Leuven) from Ferring Pharmaceuticals and Merck SA, during the conduct of the study; a grant for clinical research fellowship under their supervision at LUFC from Merck SA; sponsoring to attend scientific meetings from Ferring Pharmaceuticals, Merck SA, Lumenis, and Gedeon Richter; speaker fees paid to their institution from Merck SA; an advisory board position with payments to institution but no private revenue from Lumenis, Nordic Pharma, and Gedeon Richter; and non-financial support from MSD, outside the submitted work. The other authors have declared no conflicts of interest.

Acknowledgements:

The authors would like to thank the Stichting Fertility Foundation for the financial support.

Citation:
Repro Health. ;6[1]:35-36. Abstract Review No: AR7.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

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

RESULTS

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.

CONCLUSION

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.

References
Konings G et al. Intracrine regulation of estrogen and other sex steroid levels in endometrium and non-gynecological tissues; pathology, physiology, and drug discovery. Front Pharmacol. 2018;9:940. World Endometriosis Research Foundation. WERF Endometriosis Phenome and Biobanking Harmonisation Project (EPHect). 2019. Available at: https://endometriosisfoundation.org/ephect/. Last accessed: June 2020. Tangen I et al; ENITEC. Blood steroids are associated with prognosis and fat distribution in endometrial cancer. Gynecol Oncol. 2019;152(1):46-52 Delvoux B et al. Inhibition of type 1 17beta-hydroxysteroid dehydrogenase impairs the synthesis of 17beta-estradiol in endometriosis lesions. J Clin Endocrinol Metab. 2014;99(1):276-84 Delvoux B et al. Increased production of 17beta-estradiol in endometriosis lesions is the result of impaired metabolism. J Clin Endocrinol Metab. 2009;94(3):876-83.

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