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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 utilise 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 the 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 the development of drugs targeting these pathways, opening up new opportunities for targeted therapies and precision medicine.

SUBMITTER: Gibson DA

PROVIDER: S-EPMC6214123 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders.

Gibson Douglas A DA Simitsidellis Ioannis I Collins Frances F Saunders Philippa T K PTK

International journal of molecular sciences 20181022 10

Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilise 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 the activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormon ...[more]

PMID: 30360364

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Project description:BackgroundMetabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells.MethodsA retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage.ResultsWe found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression.ConclusionsOur data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Dataset Information

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders.

Publications

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders.

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