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      Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome

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          Abstract

          Polycystic ovary syndrome (PCOS) has been traditionally perceived as a reproductive disorder due to its most common presentation with menstrual dysfunction and infertility. However, it is now clear that women with PCOS are at increased risk of metabolic dysfunction, from impaired glucose tolerance and type 2 diabetes mellitus to nonalcoholic fatty liver disease and cardiovascular disease. PCOS is characterised by androgen excess, with cross-sectional data showing that hyperandrogenism is directly complicit in the development of metabolic complications. Recent studies have also shown that C11-oxy C19 androgens are emerging to be clinically and biochemically significant in PCOS, thus emphasising the importance of understanding the impact of both classic and C11-oxy C19 androgens on women’s health. Here we discuss androgen metabolism in the context of PCOS, and dissect the role played by androgens in the development of metabolic disease through their effects on metabolic target tissues in women.

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          The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

          Robert Rosenfield, David A Ehrmann (2016)
          Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
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            Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis.

            Lisa J. Moran, Marie L Misso, Robert Wild … (2010)
            BACKGROUND Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women associated with impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM2) and the metabolic syndrome. METHODS A literature search was conducted (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) identifying studies reporting prevalence or incidence of IGT, DM2 or metabolic syndrome in women with and without PCOS. Data were presented as odds ratio (OR) [95% confidence interval (CI)] with fixed- and random-effects meta-analysis by Mantel-Haenszel methods. Quality testing was based on Newcastle-Ottawa Scaling and The Cochrane Collaboration's risk of bias assessment tool. Literature searching, data abstraction and quality appraisal were performed by two investigators. RESULTS A total of 2192 studies were reviewed and 35 were selected for final analysis. Women with PCOS had increased prevalence of IGT (OR 2.48, 95% CI 1.63, 3.77; BMI-matched studies OR 2.54, 95% CI 1.44, 4.47), DM2 (OR 4.43, 95% CI 4.06, 4.82; BMI-matched studies OR 4.00, 95% CI 1.97, 8.10) and metabolic syndrome (OR 2.88, 95% CI 2.40, 3.45; BMI-matched studies OR 2.20, 95% CI 1.36, 3.56). One study assessed IGT/DM2 incidence and reported no significant differences in DM2 incidence (OR 2.07, 95% CI 0.68, 6.30). One study assessed conversion from normal glucose tolerance to IGT/DM2 (OR 2.4, 95% CI 0.7, 8.0). No studies reported metabolic syndrome incidence. CONCLUSIONS Women with PCOS had an elevated prevalence of IGT, DM2 and metabolic syndrome in both BMI and non-BMI-matched studies. Few studies have determined IGT/DM2 or metabolic syndrome incidence in women with and without PCOS and further research is required.
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              Gluteofemoral body fat as a determinant of metabolic health.

              K. N. Manolopoulos, F Karpe, K. Frayn (2010)
              Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality. Here, we review the evidence and possible mechanisms that support a specific protective role of gluteofemoral body fat. Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk. Studies of adipose tissue physiology in vitro and in vivo confirm distinct properties of the gluteofemoral fat depot with regards to lipolysis and fatty acid uptake: in day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage. Further, a beneficial adipokine profile is associated with gluteofemoral fat. Leptin and adiponectin levels are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat, as observed in Cushing's syndrome and lipodystrophy is associated with an increased metabolic and cardiovascular risk. This underlines gluteofemoral fat's role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition.
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                Author and article information

                Contributors
                Punith Kempegowda
                Eka Melson:
                ORCID: https://orcid.org/0000-0003-0685-4819
                Konstantinos N. Manolopoulos
                Wiebke Arlt
                Michael W. O’Reilly
                Journal
                Journal ID (nlm-ta): Ther Adv Endocrinol Metab
                Journal ID (iso-abbrev): Ther Adv Endocrinol Metab
                Journal ID (publisher-id): TAE
                Journal ID (hwp): sptae
                Title: Therapeutic Advances in Endocrinology and Metabolism
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 2042-0188
                ISSN (Electronic): 2042-0196
                Publication date (Electronic): 24 June 2020
                Publication date Collection: 2020
                Volume: 11
                Electronic Location Identifier: 2042018820934319
                Affiliations
                [1-2042018820934319]Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK
                [2-2042018820934319]Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [3-2042018820934319]Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK
                [4-2042018820934319]Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [5-2042018820934319]Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK
                [6-2042018820934319]Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [7-2042018820934319]Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK
                [8-2042018820934319]Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
                [9-2042018820934319]RCSI Medical School, Beaumont Hospital, Dublin, 2, Ireland
                [10-2042018820934319]Department of Endocrinology, Beaumont Hospital, Dublin, D09 YD60 Ireland
                Author notes
                Author information
                https://orcid.org/0000-0003-0685-4819
                Article
                Publisher ID: 10.1177_2042018820934319
                DOI: 10.1177/2042018820934319
                PMC ID: 7315669
                PubMed ID: 32637065
                SO-VID: 930a522a-69ba-4d60-8aec-a0648bc70f97
                Copyright © © The Author(s), 2020
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 9 March 2020
                Date accepted : 24 May 2020
                Categories
                Subject: Review
                Custom metadata
                cover-date January-December 2020
                typesetter ts1

                Keywords: adipose tissue,androgens,c11-oxy c19 androgens,diabetes,metabolic disease,obesity,pcos
                Data availability:
                Keywords: adipose tissue, androgens, c11-oxy c19 androgens, diabetes, metabolic disease, obesity, pcos

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