Intracrine androgen biosynthesis, metabolism and action revisited

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Abstract

Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone. However, the intracellular or intracrine activation of C19 androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates. In this review we provide an overview of human C19 steroid biosynthesis including the production of 11-oxygenated androgens, their transport in circulation and uptake into peripheral tissues. We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen metabolites and conjugates to assess intracrine androgen production is discussed.

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Sources of estrogen and their importance.

E.R Simpson (2003)

In premenopausal women, the ovaries are the principle source of estradiol, which functions as a circulating hormone to act on distal target tissues. However, in postmenopausal women when the ovaries cease to produce estrogen, and in men, this is no longer the case, because estradiol is no longer solely an endocrine factor. Instead, it is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. These sites include the mesenchymal cells of adipose tissue including that of the breast, osteoblasts and chondrocytes of bone, the vascular endothelium and aortic smooth muscle cells, and numerous sites in the brain. Thus, circulating levels of estrogens in postmenopausal women and in men are not the drivers of estrogen action, they are reactive rather than proactive. This is because in these cases circulating estrogen originates in the extragonadal sites where it acts locally, and if it escapes local metabolism then it enters the circulation. Therefore, circulating levels reflect rather than direct estrogen action in postmenopausal women and in men. Tissue-specific regulation of CYP19 expression is achieved through the use of distinct promoters, each of which is regulated by different hormonal factors and second messenger signaling pathways. Thus, in the ovary, CYP19 expression is regulated by FSH which acts through cyclic AMP via the proximal promoter II, whereas in placenta the distal promoter I.1 regulates CYP19 expression in response to retinoids. In adipose tissue and bone by contrast, another distal promoter--promoter I.4--drives CYP19 expression under the control of glucocorticoids, class 1 cytokines and TNFalpha. The importance of this unique aspect of the tissue-specific regulation of aromatase expression lies in the fact that the low circulating levels of estrogens which are observed in postmenopausal women have little bearing on the concentrations of estrogen in, for example, a breast tumor, which can reach levels at least one order of magnitude greater than those present in the circulation, due to local synthesis within the breast. Thus, the estrogen which is responsible for breast cancer development, for the maintenance of bone mineralization and for the maintenance of cognitive function is not circulating estrogen but rather that which is produced locally at these specific sites within the breast, bone and brain. In breast adipose of breast cancer patients, aromatase activity and CYP19 expression are elevated. This occurs in response to tumor-derived factors such as prostaglandin E2 produced by breast tumor fibroblasts and epithelium as well as infiltrating macrophages. This increased CYP19 expression is associated with a switch in promoter usage from the normal adipose-specific promoter I.4 to the cyclic AMP responsive promoter, promoter II. Since these two promoters are regulated by different cohorts of transcription factors and coactivators, it follows that the differential regulation of CYP19 expression via alternative promoters in disease-free and cancerous breast adipose tissue may permit the development of selective aromatase modulators (SAMs) that target the aberrant overexpression of aromatase in cancerous breast, whilst sparing estrogen synthesis in other sites such as normal adipose tissue, bone and brain.

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The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

Gerard Conway, Didier Dewailly, Evanthia Diamanti-Kandarakis … (2014)

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

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The Regulation of Steroid Action by Sulfation and Desulfation

Jonathan Mueller, Lorna Gilligan, Jan Idkowiak … (2015)

Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.