Endometriosis is an estrogen-dependent inflammatory disorder frequently associated with infertility and characterized by progesterone resistance and impaired endometrial receptivity. While ectopic lesions define the disease, accumulating evidence indicates that molecular abnormalities within the eutopic endometrium substantially contribute to infertility. In this study, we performed transcriptomic analysis of proliferative-phase eutopic endometrium from women with and without endometriosis and identified 44 dysregulated genes, including 13 upregulated and 31 downregulated genes, in women with endometriosis compared with controls. Among the significantly altered genes, YWHAZ (14-3-3 zeta) emerged as a prominently downregulated gene. Reduced YWHAZ expression was further validated at the protein level in both epithelial and stromal compartments of the endometrium from women with endometriosis. To investigate its physiological regulation, we examined YWHAZ expression during early pregnancy in mice and observed a dynamic, stage-specific pattern during the peri-implantation period, with strong expression at gestational days 3.5 and 4.5 and robust expression at the primary decidual zone at gestational day 5.5. Notably, YWHAZ expression was nearly abolished in uteri from progesterone receptor knockout and uterine signal transducer and activator of transcription 3 conditional knockout (Pgrcre/+Stat3f/f) mice, indicating that YWHAZ is dependent on intact progesterone receptor and STAT3 signaling. Together, these findings identify YWHAZ as a hormonally and transcriptionally regulated endometrial factor that is disrupted in endometriosis and tightly linked to implantation and decidual progression. This study highlights YWHAZ as a potential molecular node connecting progesterone resistance and STAT3 dysregulation to defective endometrial function and infertility in endometriosis.
PMID 41885596 41885596 DOI 10.1093/reprod/xaag038 10.1093/reprod/xaag038 Santos da Silva et al. 2026, Santos da Silva 2026
Cite this article
Santos da Silva, A., Rahman, M. S., Jeong, E. M., Nahar, S., Young, S. L., Lessey, B. A., Jeong, J. W., & Kim, T. H. (2026). YWHAZ loss is associated with endometrial dysfunction in proliferative-phase endometriosis.. Reproduction (Cambridge, England), 171(4). https://doi.org/10.1093/reprod/xaag038
Santos da Silva A, Rahman MS, Jeong EM, Nahar S, Young SL, Lessey BA, Jeong JW, Kim TH. YWHAZ loss is associated with endometrial dysfunction in proliferative-phase endometriosis.. Reproduction (Cambridge, England). 2026;171(4). doi:10.1093/reprod/xaag038
Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.
Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.
Aghajanova L et al., 2010·Seminars in reproductive medicine
Progesterone plays an important role in regulating multiple events in the uterus. It controls endometrial proliferation and differentiation, which are important for uterine function. Dysregulation of progesterone signaling leads to impaired physiological functions. Indeed, aberrant expression of progesterone-regulated genes in the endometrium has been implicated in several gynecologic disorders, including endometriosis, polycystic ovarian syndrome (PCOS), and endometrial hyperplasia. Although several investigators have analyzed eutopic endometrial expression of progesterone-target genes, the genesis and consequences of progesterone resistance remain unclear. We review evidence for progesterone resistance in endometrium of women with endometriosis, PCOS, and endometrial hyperplasia, and we identify possible mechanisms associated with reduced progesterone activity in endometrium of (some) women with these gynecologic disorders that have a significant impact on women's health and well-being.
Progesterone supplementation reverses 83% of transcript changes in the secretory endometrium induced by postovulatory mifepristone, potentially mitigating its antiprogestogenic effects. Mifepristone (RU486) antagonizes progesterone signaling in human endometrium interfering in the secretory phenotype after estradiol priming. The objective of the present study was to determine effect in the endometrial transcript profile of progesterone supplementation after the administration of 200 mg of the antiprogestin mifepristone 48 h after the LH peak (LH+2, LH+0 = LH peak). Endometrial samples were obtained on LH+7 after vaginal administration of micronized progesterone 200 mg/day for 3 days in nine women of proven fertility, each one contributing with one cycle treated with progesterone and another with a placebo. In addition, endometrial samples were obtained in LH+7 from a subgroup of four women with no administration of mifepristone, with each one contributing with one cycle treated with vaginal progesterone supplementation or placebo as a reference. RNA-seq was used to identify transcripts significantly regulated under the administration of progesterone vs placebo with or without postovulatory mifepristone. We observed that 713 transcripts changed significantly in the endometrium under mifepristone after progesterone supplementation in group A. Of these, progesterone reversed approximately 83% of the transcripts affected by mifepristone in the secretory endometrium. Bioinformatic analyses revealed that these transcripts were enriched in genes associated with mitochondrial function, particularly oxidative phosphorylation. In addition, NR2C2 and DLX1 were identified as potential transcription factors that may mediate the effects of progesterone in the endometrium. We conclude that progesterone supplementation after postovulatory mifepristone administration can reverse the antiprogestogenic effects for most of the affected endometrial transcripts.