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.
Highlights
What Do We Mean by ‘Intracrinology’?The term ‘intracrine’ emerged in the 1980s as a new concept in endocrinology based on the ability of cells within non-gonadal tissues to both produce (synthesise) a hormone (peptide, protein or steroid) and to respond to that same factor [1,2]
Peripheral tissue metabolism of steroids is 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
We will provide a brief overview of the structure of the endometrium, its regulation by ovarian-derived steroids and expression of steroid receptors as the prelude for a review of the evidence supporting a role for local tissue activation/biosynthesis of bioactive oestrogens and androgens in the normal endometrium and in some disorders associated with endometrial malfunction
Summary
The term ‘intracrine’ emerged in the 1980s as a new concept in endocrinology based on the ability of cells within non-gonadal tissues to both produce (synthesise) a hormone (peptide, protein or steroid) and to respond to that same factor [1,2]. In more recent studies and reviews, ‘intracrinology’ is usually discussed on the basis that it is tissue-specific, local production (and inactivation) of sex steroids without significant release of active sex steroids into the peripheral circulation [1,5,6], with less attention being paid to the source and site of action being in the same cell and a greater emphasis on the tissue micro-environment In this regard, a strong case has been made that the ‘inactive’ adrenal steroid dehydroepiandrosterone (DHEA) is the most important precursor of bioactive androgens in women [7]. We will briefly review the evidence that supplementation with inactive steroids or administration of drugs targeting intracrine steroid biosynthesis may offer a new therapeutic opportunity to treat a range of disorders, including infertility
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