Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

Abstract

Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilize inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women’s health disorders such as endometriosis and endometrial cancer has prompted renewed interest in development of drugs targeting these pathways opening up new opportunities for targeted therapies and precision medicine.   

Relationship between postpartum uterine involution and biomarkers of inflammation and oxidative stress in clinically healthy mares (Equus caballus)

“…To the best of our knowledge, no studies about endometrial DHEA conversion in androgens/estrogens are present in the literature. However, circulating DHEA and DHEA-S can be utilized as androgen/estrogen precursors by the human endometrium, and this conversion can be differently regulated in both normal and pathologic endometrium (Gibson et al, 2018).…”

Uterine bleeding: how understanding endometrial physiology underpins menstrual health

“…Sex steroid hormone biosynthesis. The availability of biologically active sex steroids within the endometrium is dependent on the action of local endometrial sex steroid-metabolizing enzymes 59 (fIg. 3).…”

“…62 ). Endometrial steroid hormone metabolism studies, which extend over nearly 50 years, initially demonstrated steroid sulfatase activity, and these were followed by studies concerning oxidative and reductive 17β-hydroxysteroid dehydrogenase (17β-HSD) activities 59 . These steroid-metabolizing enzymes are involved in endometrial steroid hormone (ligand) availability and thus are involved with modulation of the local endometrial hormone environment.…”

“…Pregnenolone undergoes two enzymatic conversions mediated via CYP17A1, first to 17α-hydroxypregnenolone (17α-hydroxylase activity) and then, following 17,20 lyase action, to dehydroepiandrosterone (DHEA). Expression of steroidogenic acute regulatory protein, CYP11A1 and CYP17A1 has been reported in the endometrium 59,63 . However, no study has identified definitive de novo steroidogenesis from normal endometrial tissue.…”

An approach to classifying occupational exposures to endocrine disrupting chemicals by sex hormone function using an expert judgment process

“…There is growing evidence that EDCs may affect fertility (8)(9)(10)(11) and the progression of some diseases like obesity, endometriosis and some cancers (8,12,13). The disruption of sex hormone homeostasis (14) has been associated with the risk of sex-specific cancers, including: breast and prostate cancers (15,16), and possibly endometrial and ovarian cancers (17,18). The incidence of colorectal cancer differs by sex (19), and accumulating epidemiologic evidence shows that exposure to certain female sex hormones is associated with a lower risk of colorectal cancer (20)(21)(22)(23).…”