Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Defining the dysregulated endometrial hormone response in endometriosis-associated infertility (#48)

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

Endometriosis, affecting more than 10% of women, is a chronic, debilitating disorder where endometrial-like tissue forms lesions outside of the uterus. 30-50% of women with endometriosis are infertile due to the inability of the endometrium to undergo hormone-induced endometrial remodelling critical in making it receptive to the implanting embryo. However, the underlying mechanisms remain largely unknown. Our aim was to utilise human endometrial epithelial organoids (EEO) to define the hormone response of endometrial glands from women with endometriosis.

 

EEO derived from women with (n=3) and without (n=3) endometriosis were grown for 4 days in expansion medium. EEO were treated for two days with estradiol-17β (E2) and then either with vehicle control, E2 or E2 and medroxyprogesterone acetate in base medium for 6 days. EEO establishment was assessed by organoid formation assays. Expression of steroid hormone receptors ESR1 and PGR was examined by RT-qPCR. The secretome of hormone-treated EEO was analysed by mass spectrometry.

 

EEO generated from single cells from women with and without endometriosis showed similar organoid forming capacity when treated with hormones, although fewer EEO were generated from women with endometriosis. EEO from patients with endometriosis had greater ESR1 expression overall and increased expression of PGR following E2 treatment compared to EEO from women without endometriosis. Abundance of EEO basolaterally secreted proteins was significantly different between patients with and without endometriosis and by hormone treatments, including CRISP3, INHBB, SELENOP, BMP1 and WNT7A.

 

EEO from endometriosis patients have an altered response to menstrual cycle hormones resulting in an impaired endometrial gland secretory response to hormones both in gene expression and secreted proteome. Our results provide a mechanism for the inability of the endometrium to become receptive in endometriosis patients, leading to embryo implantation failure and infertility. These findings provide essential foundations for the development of treatments targeting endometriosis-associated endometrial infertility.