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Abstract
Endometriosis is a chronic, multifactorial, estrogen-dependent disease. The abnormal endocrine microenvironment of endometriosis lesions is considered a main feature and multiple enzymatic pathways leading to local increased synthesis of estrogens have been identified. However, the relevance of intracrinology in clinical practice is still lacking. Medline, Embase, Scopus database were systematically searched for studies reporting on local estrogens metabolism of endometriotic lesions. The main enzymatic pathways involved in the intracrinology of endometriosis such as aromatase (CYP19A1), 17β-hydroxysteroid dehydrogenase (HSD17B) type 1, type 2 and type 5, steroid sulfatase (STS), estrogen sulfotransferase (SULT1E1) were assessed with a critical perspective on their role in disease endocrine phenotyping, drug resistance and as therapeutic targets. Overall, studies heterogeneity and missing clinical data affect the interpretation of the clinical role of these enzymes. Although the use of some drugs such as aromatase inhibitors has been proposed in clinical practice for two decades, their potential clinical value is still under investigation as well as their modality of administration. A closer look at new, more realistic drug targets is provided and discussed. Altered expression of these key enzymes in the lesions have far reaching implication in the development of new drugs aimed at decreasing local estrogenic activity with a minimal effect on gonadal function; however, given the complexity of the evaluation of the expression of the enzymes, multiple aspects still remains to be clarified.
PMID 36204107 36204107 DOI 10.3389/fendo.2022.950866 10.3389/fendo.2022.950866 Mercorio et al. 2022, Mercorio 2022
Cite this article
Mercorio, A., Giampaolino, P., Romano, A., Dällenbach, P., & Pluchino, N. (2022). Is intracrinology of endometriosis relevant in clinical practice? A systematic review on estrogen metabolism. Frontiers in Endocrinology, 13, 950866. https://doi.org/10.3389/fendo.2022.950866
Mercorio A, Giampaolino P, Romano A, Dällenbach P, Pluchino N. Is intracrinology of endometriosis relevant in clinical practice? A systematic review on estrogen metabolism. Front Endocrinol (Lausanne). 2022;13:950866. doi:10.3389/fendo.2022.950866
Mercorio, A., et al. "Is intracrinology of endometriosis relevant in clinical practice? A systematic review on estrogen metabolism." Frontiers in Endocrinology, vol. 13, 2022, pp. 950866.
Bulun SE et al., 2002·Annals of the New York Academy of Sciences·
Aromatase activity is absent in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis, which gives rise to strikingly high levels of aromatase activity in this tissue. Both aromatase expression and activity are stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, that is, deficient 17beta-HSD type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor.
Endometriosis is an estrogen-dependent, chronic inflammatory disorder characterized by the presence of endometrium-like tissue outside the uterus, affecting approximately 10% of individuals of reproductive age. It contributes to chronic pelvic pain, dysmenorrhea, and subfertility, resulting in substantial societal economic burdens. Genetic and environmental risk factors have been identified, and recent research suggests that endometriosis functions as a systemic disease affecting nonreproductive systems and increasing susceptibility to other health conditions. Various phenotypes-superficial peritoneal endometriosis, ovarian endometriomas, and deep endometriosis-may develop under different mechanisms, yet the relationship between these presentations remains unclear. Diagnosis relies on clinical evaluation, imaging, and surgical staging, and the advent of advanced ultrasonography and magnetic resonance imaging has helped to enhance accuracy. Although medical management focuses on hormonal modulation to alleviate symptoms, surgical intervention remains a critical tool for refractory symptoms. Postoperative care and patient education are essential to manage recurrence and to improve quality of life. Current research emphasizes the need for comprehensive, interdisciplinary approaches to endometriosis management, incorporating novel diagnostic tools, diverse therapeutic avenues, and patient-centered care models. Addressing disparities in treatment access is essential to improving outcomes. To achieve this, recruiting and analyzing data from racially, socioeconomically, and geographically diverse cohorts will reveal how disease presentation and treatment efficacy vary across populations. Continued efforts in research and health care policy are necessary to develop effective and personalized strategies in managing endometriosis.
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, a benign gynecologic disorder, occurs in about 10% of women of reproductive age and in up to 50% of women with infertility. Endometriosis is defined as the presence of endometrial glandular and stromal cells outside their normal location in the uterus. Commonly affected areas in the abdominopelvic cavity include the ovaries, the cul-desac and other kinds of pelvic peritoneum, bowel and diaphragm. Rarely is it found in extraabdominal sites, including the pleura and pericardium. While it is not a malignant disorder, endometriosis exhibits cellular proliferation, cellular invasion and neoangiogenesis. The steroid hormone dependence of endometriosis is underscored by its appearance during the reproductive years. Furthermore, the progress of this enigmatic disease can be tempered by administration of antiestrogens, inhibitors of endogenous estradiol production, and hormonal and surgical castration. It is a disorder that markedly affects well-being and physical and emotional health in women. Research on the pathogenesis of endometriosis currently interfaces with four areas of basic research, including the fields of genetics, environmental science, cancer biology and immunology. Here we focus on current research in the latter two disciplines and their relevance to endometriosis research.