The chronic administration of cabergoline normalizes androgen secretion and improves menstrual cyclicity in women with polycystic ovary syndrome

Abstract 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 adipose tissue are separate and distinct contributors to oxidative stress in this disorder.

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Reassessment of adrenal androgen secretion in women with polycystic ovary syndrome

Obstetrics and Gynecology ◽

10.1016/0029-7844(95)00065-y ◽

1995 ◽

Vol 85 (6) ◽

pp. 971-976 ◽

Cited By ~ 33

Author(s):

E CARMINA ◽

F GONZALEZ ◽

L CHANG ◽

R LOBO

Keyword(s):

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Adrenal Androgen ◽

Ovary Syndrome ◽

Androgen Secretion

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Inhibiting Kiss1 Neurons with Kappa Opioid Receptor Agonists to Treat Polycystic Ovary Syndrome and Vasomotor Symptoms

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab602 ◽

2021 ◽

Author(s):

Elizabeth A McCarthy ◽

Daniel Dischino ◽

Caroline Maguire ◽

Silvia Leon ◽

Rajae Talbi ◽

...

Keyword(s):

Body Temperature ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Chronic Administration ◽

Vasomotor Symptoms ◽

Reproductive State ◽

Ovary Syndrome ◽

Receptor Agonists ◽

Kappa Receptor ◽

Kndy Neurons

Abstract Context Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons). Objective We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally-restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood brain barrier) and impedes their down-stream effects. Design Case/control. Setting Academic medical center. Participants Mice. Interventions Administration of peripherally-restricted kappa receptor agonists and frequent blood sampling to determine hormone release, and body temperature. Main Outcome Measures LH pulse parameters and body temperature. Results First, chronic administration of a PRKA to OVX mice with experimentally-induced hyperactivity of KNDy neurons reduces the animals’ elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity. Conclusion The inhibition of Kiss1 neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

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Inflammation Triggered by Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa108 ◽

2020 ◽

Vol 105 (6) ◽

pp. e2152-e2167 ◽

Cited By ~ 6

Author(s):

Frank González ◽

Robert V Considine ◽

Ola A Abdelhadi ◽

Anthony J Acton

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Saturated Fat ◽

Oral Glucose ◽

Weight Class ◽

Ovary Syndrome ◽

Control Subjects ◽

Androgen Secretion

Abstract 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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Saturated fat ingestion stimulates proatherogenic inflammation in polycystic ovary syndrome

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00213.2021 ◽

2021 ◽

Author(s):

Frank Gonzalez ◽

Robert V Considine ◽

Ola A. Abdelhadi ◽

Jiaping Xue ◽

Anthony J. Acton

Keyword(s):

Gene Expression ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Saturated Fat ◽

Oral Glucose ◽

Abdominal Adiposity ◽

Hsp 70 ◽

Ovary Syndrome ◽

Tlr2 Gene ◽

Androgen Secretion

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 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 fasting and 24, 48 and 72 hours after 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. 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.

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Saturated Fat Ingestion Promotes Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01143 ◽

2018 ◽

Vol 104 (3) ◽

pp. 934-946 ◽

Cited By ~ 12

Author(s):

Frank González ◽

Robert V Considine ◽

Ola A Abdelhadi ◽

Anthony J Acton

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Protein Content ◽

Polycystic Ovary ◽

Saturated Fat ◽

Cytokine Signaling ◽

Oral Glucose ◽

Ovary Syndrome ◽

Control Subjects ◽

Androgen Secretion

Abstract Context Inflammation and insulin resistance (IR) are often present in polycystic ovary syndrome (PCOS). Objective We determined the effect of saturated fat ingestion on circulating lipopolysaccharide (LPS) and mononuclear cell (MNC) toll-like receptor-4 (TLR-4) and suppressor of cytokine signaling-3 (SOCS-3) in women with PCOS. Design Cross-sectional study. Setting Academic medical center. Patients Nineteen reproductive-age women with PCOS (10 lean, 9 obese) and 19 ovulatory control subjects (10 lean, 9 obese). Main Outcome Measures LPS and TNFα levels were measured in plasma. TLR-4 and SOCS-3 mRNA and protein content were quantified in MNC from blood collected after 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 collected after fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Results Regardless of PCOS status, subjects who were obese had lipid-induced increases in circulating LPS and TLR-4 protein content compared with subjects who were lean. Lean and obese women with PCOS had lipid-induced increases in plasma TNFα and SOCS-3 mRNA and protein content compared with lean control subjects. Both PCOS groups had lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The LPS and SOCS-3 responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. Conclusion In PCOS, lipid-induced LPS-mediated inflammation through TLR-4 is associated with obesity and worsened by PCOS, whereas lipid-induced increases in SOCS-3 may represent an obesity-independent, TNFα-mediated mechanism of IR.

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