A Randomized Clinical Trial Demonstrating Cell Type Specific Effects of Hyperlipidemia and Hyperinsulinemia on Pituitary Function

Introduction: Obesity is characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism, reducing fertility and increasing risk of pregnancy complications and birth defects. We termed this phenotype 'Reprometabolic Syndrome' and showed that it can be recapitulated by acute infusions of lipid/insulin into healthy, normal weight, eumenorrheic women. Herein, we examined the broader impact of hyperlipidemia and euglycemic hyperinsulinemia on anterior pituitary trophic hormones and their targets.

Methods: Serum FSH, LH, TSH, growth hormone (GH), prolactin (PRL), thyroid hormones (free T4, total T3), cortisol, IGF-1, adiponectin, leptin and creatinine were measured in a secondary analysis of an interventional crossover study of 12 normal weight cycling women who underwent saline and heparin (control) infusion, or a euglycemic insulin infusion with heparin and Intralipid® (lipid/insulin), between days 2-5 in sequential menstrual cycles.

Results: In contrast to the decrease in gonadotropins, FSH and LH, infusion of lipid/insulin had no significant effects on other trophic hormones; TSH, PRL or GH. Thyroid hormones (fT4 and total T3), cortisol, IGF-1, adiponectin and creatinine also did not differ between saline or lipid/insulin infusion conditions. Leptin increased in response to lipid/insulin (p<0.02).

Conclusion: Acute hyperlipidemia and hyperinsulinemia exerted differential, cell type specific effects on the hypothalamic-pituitary-gonadal, adrenal and thyroid axes. Elucidation of mechanisms underlying the selective modulation of pituitary trophic hormones, in response to changes in diet and metabolism, may facilitate therapeutic intervention in obesity-related neuroendocrine and reproductive dysfunction.