Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Defining the impact of endometriosis on the hormone responsiveness of human endometrial epithelia utilising endometrial epithelial organoids. (128590)

Jenna Douglas 1 2 , Taylah Williams 1 3 , Ralf Schittenhelm 4 , Han Lee 4 , Shanti Gurung 1 2 , Caroline Gargett 1 2 , Beverley Vollenhoven 2 , Harriet Fitzgerald 1 2
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
  3. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
  4. Proteomics and Metabolomics Platform, Monash University, Clayton, Victoria, Australia

The inner lining of the uterus, the endometrium, completely remodels in response to ovarian steroid hormones during the menstrual cycle. Endometriosis is a chronic, debilitating gynaecological disorder that affects more than 10% of women (1), with 30-50% of these women suffering from infertility (2) likely due to disruptions in hormone-driven processes critical for receptivity and embryo implantation. The underlying mechanisms of endometriosis-associated infertility remain largely unknown. Our objective was to utilise human endometrial epithelial organoids (EEO) to investigate the impact of endometriosis on the hormone-responsiveness of endometrial glands and their secreted products.

EEO derived from the eutopic endometrium of patients diagnosed with minimal-mild (stages I-II, n=6), moderate-severe (stages III-IV, n=3) and without endometriosis (control, n=3) were treated with either vehicle control, 17β-estradiol (E2), or E2 and medroxyprogesterone acetate (MPA) to mimic menstrual cycle phases. Gene expression of steroid hormone receptors PGR, ESR1 and ESR2 were examined by RT-qPCR. The basolateral secreted proteome of hormone-treated EEO was analysed by mass spectrometry.

EEO treated with E2+MPA demonstrated progesterone-mediated downregulation of PGR, resembling in vivo cycle phase-dependent expression patterns, in control patients (p<0.05) and stage I-II endometriosis (p<0.05) compared to vehicle treatment, but not in patients with stage III-IV endometriosis. 39 significantly differentially abundant proteins were identified in the basolateral secreted proteome of EEO from patients with endometriosis compared to those without endometriosis and between hormone treatments, including, CRISP3 (FC=20.39, p<0.0001), INHBB (FC=8.17, p<0.001), MGAT1 (FC=4.11, p<0.01) and WNT7A (FC=8.46, p<0.05).

EEO from endometriosis patients demonstrate an impaired response to hormones, leading to an altered steroid hormone receptor expression pattern in patients with moderate-severe endometriosis, and an aberrant secreted proteome in endometriosis. These findings are critical in determining the impact of endometriosis on the hormone-driven processes required for endometrial receptivity and embryo implantation and to develop treatments targeting endometriosis-associated infertility.

  1. Health AIo, Welfare. Endometriosis. Canberra: AIHW; 2023.
  2. Prescott J, Farland LV, Tobias DK, Gaskins AJ, Spiegelman D, Chavarro JE, et al. A prospective cohort study of endometriosis and subsequent risk of infertility. Human Reproduction. 2016;31(7):1475- 82