Browsing by Subject "Hyperandrogenism"

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    Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion
    (The Endocrine Society, 2014-05) González, Frank; Sia, Chang Ling; Bearson, Dawn M.; Blair, Hilary E.; Department of Obstetrics and Gynecology, IU School of Medicine
    CONTEXT: Hyperandrogenism and inflammation are related in polycystic ovary syndrome (PCOS). Hyperandrogenemia can induce inflammation in reproductive-age women, but the mechanism for this phenomenon is unclear. OBJECTIVE: We examined the in vivo and in vitro effects of hyperandrogenism on mononuclear cell (MNC)-derived androgen receptor (AR) status and TNFα release. DESIGN: This study combined a randomized, controlled, double-blind protocol with laboratory-based cell culture experiments. SETTING: This work was performed in an academic medical center. PARTICIPANTS: Lean, healthy, reproductive-age women were treated with 130 mg of dehydroepiandrosterone (DHEA) or placebo (n = 8 subjects each) for 5 days and also provided untreated fasting blood samples (n = 12 subjects) for cell culture experiments. MAIN OUTCOME MEASURES: AR mRNA content and TNFα release were measured before and after DHEA administration in the fasting state and 2 hours after glucose ingestion. TNFα release in the fasting state was also measured in cultured MNCs exposed to androgens with or without flutamide preincubation. RESULTS: At baseline, subjects receiving DHEA or placebo exhibited no significant difference in androgens and TNFα release from MNCs before and after glucose ingestion. Compared with placebo, DHEA administration raised levels of T, androstenedione, and DHEA sulfate, and increased MNC-derived AR mRNA content and TNFα release in the fasting state and in response to glucose ingestion. Compared with MNC exposure to baseline concentrations of DHEA (175 ng/dL) or T (50 ng/dL), the absolute change in TNFα release increased after exposure to T concentrations of 125 and 250 ng/dL and a DHEA concentration of 1750 ng/dL. Preincubation with flutamide reduced the TNFα response by ≥ 60% across all T concentrations. CONCLUSION: Androgen excess in vivo and in vitro comparable to what is present in PCOS increases TNFα release from MNCs of lean healthy reproductive-age women in a receptor-dependent fashion. Hyperandrogenemia activates and sensitizes MNCs to glucose in this population.
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    Inflammation Triggered by Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome
    (Endocrine Society, 2020-06-01) González, Frank; Considine, Robert V.; Abdelhadi, Ola A.; Acton, Anthony J.; Medicine, School of Medicine
    Context: Inflammation and insulin resistance are often present in polycystic ovary syndrome (PCOS). Objective: We determined the effect of saturated fat ingestion on mononuclear cell (MNC) nuclear factor-κB (NFκB) activation; NFκB, inhibitory-κBα (IκBα), and tumor necrosis factor-α (TNFα) gene expression; and circulating C-reactive protein (CRP) in women with PCOS. Design: Cross-sectional study. Setting: Academic medical center. Patients: Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity). Main outcome measures: Activated NFκB, NFκB heterodimer subunits, IκBα and TNFα messenger ribonucleic acid content and NFκB p65 and IκBα protein content were quantified in mononuclear cells (MNC), and CRP was measured in plasma from blood drawn fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from oral glucose tolerance testing (ISOGTT). Androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. Results: In response to saturated fat ingestion, women with PCOS regardless of weight class exhibited lipid-induced increases in activated NFκB, NFκB, and TNFα gene expression and plasma CRP and decreases in IκBα protein compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. Lipid-stimulated NFκB activation was negatively correlated with ISOGTT, and positively correlated with HCG-stimulated androgen secretion. Conclusion: In PCOS, increases in NFκB activation and circulating CRP and decreases in IκBα protein following saturated fat ingestion are independent of obesity. Circulating MNC and excess adipose tissue are separate and distinct contributors to inflammation in this disorder.
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    Oxidative Stress in Response to Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome
    (Oxford, 2019-07-12) González, Frank; Considine, Robert V; Abdelhadi, Ola A; Acton, Anthony J; Medicine, School of Medicine
    Context Oxidative stress and insulin resistance are often present in polycystic ovary syndrome (PCOS). Objective We determined the effect of saturated fat ingestion on leukocytic reactive oxygen species (ROS) generation, p47phox expression, and circulating thiobarbituric acid–reactive substances (TBARS) in women with PCOS. Design Cross-sectional study. Setting Academic medical center. Patients Twenty women of reproductive age with PCOS (10 lean, 10 with obesity) and 19 ovulatory control subjects (10 lean, 9 with obesity). Main Outcome Measures ROS generation and p47phox mRNA and protein content were quantified in leukocytes, and TBARS was measured in plasma from blood drawn while the subjects were fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while the subjects were fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Results Regardless of weight class, women with PCOS exhibited lipid-induced increases in leukocytic ROS generation and p47phox mRNA and protein content as well as plasma TBARS compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The ROS generation, p47phox, and TBARS responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. Conclusion In PCOS, increases in ROS generation, p47phox gene expression, and circulating TBARS in response to saturated fat ingestion are independent of obesity. Circulating mononuclear cells and excess adi
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    Saturated fat ingestion stimulates proatherogenic inflammation in polycystic ovary syndrome
    (American Physiological Society, 2021) González, Frank; Considine, Robert V.; Abdelhadi, Ola A.; Xue, Jiaping; Acton, Anthony J.; Medicine, School of Medicine
    Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with ISOGTT and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation. NEW & NOTEWORTHY: This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.