Date of Award

January 2022

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Clare Flannery


With the rising prevalence of endometrial cancer and its precursor atypical hyperplasia (AH) in reproductive-age women amid the obesity epidemic, understanding the pathogenesis of this disease process is crucial to improving medical management. We sought to identify factors that may contribute to progestin-resistant AH via analysis of clinical data as well as investigation of hormonal regulation of endometrial gene and protein expression. We conducted a retrospective review of women with AH (n=63) compared to those with benign hyperplasia (BH) (n=73), which has a significantly lower risk of progression to malignant disease. Subsequently, we analyzed a sub-cohort of women with progestin-responsive (n=10) and resistant AH (n=6), and we quantified progesterone receptor (PR) and estrogen receptor (ER) expression in archived endometrial tissues via immunohistochemistry. Finally, we analyzed in vitro insulin- and progesterone-regulated alterations in primary endometrial epithelial cell gene expression using RNA sequencing. We found that women with AH were significantly more likely to have type 2 diabetes and infertility, compared to those with BH (p<0.01 and p<0.05, respectively). Our investigation did not identify any clinical risk factors for progestin resistance among women with AH nor significant differences in PR or ERα expression, although the assessment was limited by small sample size. Analysis of the epithelial transcriptome yielded 414 unique differentially expressed genes as well as three hallmark gene sets that appear to be regulated by the combined action of insulin and progesterone, which represent promising targets for further investigation of progestin resistance in AH.


This thesis is restricted to Yale network users only. It will be made publicly available on 06/16/2024