Molecular Biology of Endometriosis: From Aromatase to Genomic Abnormalities

Abstract

Endometriosis has been initially described as the presence of ectopic endometrial tissue on pelvic organs or in extrapelvic sites; and this has been used as its key pathologic feature ever since. Endometriosis responds to fluctuations in estrogen and progesterone by growth and inflammation, leading to pain aggravated by menses. It was proposed that pelvic endometriosis primarily originate from retrograde menstruation of a critical number of eutopic endometrial cells with stem characteristics. This postulate is supported by the molecular defects found in ectopic endometriotic tissue. Genome-wide differences in CpG methylation between eutopic endometrial and endometriotic stromal cells are present. Defective CpG methylation affecting several genes that encode key transcription factors such as GATA6, steroidogenic factor-1, and estrogen receptor-β in endometriosis gives rise to overproduction of local estrogen and prostaglandins and suppression of progesterone receptor. Progesterone receptor deficiency leads to progesterone resistance, resulting in decreased retinol uptake and retinoic acid production and altered retinoic acid action. These molecular defects collectively give rise to poor cellular differentiation, enhanced survival, and increased inflammation, which are the biological hallmarks of endometriotic tissue.

Endometriosis: where are we and where are we going?

“…While we understand that several other factors are involved in the pathogenesis and progression of this disease, including genetics and epigenetics, and significant advances in these components have been made, covering them in depth is beyond the scope of this review. For researchers interested in these topics, an elegant and comprehensive review by Bulun et al (2015) recently addresses the molecular biology, genetics, and epigenetics of endometriosis and covers 25 years of research (1990-2015).…”

Aromatase/Seladin-1 Interactions in Human Neuronal Cell Culture, the Hippocampus of Healthy Rats and Transgenic Alzheimer’s Disease Mice

“…Furthermore, several mechanisms underlying the effect of E 2 on aromatase expression have also been shown in other studies. These mechanisms include the following: (a) the binding of E 2 to ERα and the activation of the transcription factor AP-1 in mouse brain [43]; (b) the stimulation of FSH or LH in rat granulosa cells [44]; and (c) the binding of E 2 to ERβ and the induction of the expression of several genes encoding signaling proteins such as kinases and GTPases that affect aromatase expression or interact with other transcription factors, such as specific protein-1 or COX2 [45], or by increasing tyrosine phosphorylation activated by c-Src kinase in breast cancer cells [46]. Therefore, the aromatase level might also be decreased by these mechanisms mentioned above as a result of a decreased E 2 level in the seladin-1 inhibited group.…”

Physiological and pathological implications of retinoid action in the endometrium

“…Approximately 10% of all women and up to 30%-50% of symptomatic premenopausal women are affected and commonly suffer pelvic pain and/or infertility (Nnoaham et al 2011, Stilley et al 2012. Classical and neoclassical concepts of endometriosis etiology were reviewed comprehensively elsewhere (Bulun 2009, Taylor 2010, Burney & Giudice 2012, Bulun et al 2015, Taylor et al 2015 and will not be reiterated thoroughly in this review. Although the theories of endometriosis histogenesis remain controversial, recent findings suggest that defective epigenetic landscape possibly associated with deficient differentiation of endometrial tissue stem cells is a central mechanism responsible for the cellular origins of endometriosis (Bulun et al 2015).…”

“…Classical and neoclassical concepts of endometriosis etiology were reviewed comprehensively elsewhere (Bulun 2009, Taylor 2010, Burney & Giudice 2012, Bulun et al 2015, Taylor et al 2015 and will not be reiterated thoroughly in this review. Although the theories of endometriosis histogenesis remain controversial, recent findings suggest that defective epigenetic landscape possibly associated with deficient differentiation of endometrial tissue stem cells is a central mechanism responsible for the cellular origins of endometriosis (Bulun et al 2015). Meanwhile, retinoid pathway is fundamentally flawed in endometriotic tissues and even systemically in women with endometriosis (Pavone et al 2010, Pierzchalski et al 2014, Taylor et al 2015.…”

“…These studies suggested that flaws in RA production and degradation might play a role in the pathogenesis of endometriosis. Pavone et al (2011Pavone et al ( , 2017 Estrogen plays a critical role in the establishment and maintenance of endometriosis (Osteen et al 2005, Bulun 2009, Bulun et al 2015. 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) catalyzes the conversion of estradiol to estrone, a much less biologically potent estrogen, and plays a crucial role in local estradiol inactivation in the endometrium (Cheng et al 2007).…”