A randomized clinical trial demonstrating cell type specific effects of hyperlipidemia and hyperinsulinemia on pituitary function

Abstract

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.

A high-fat eucaloric diet induces reprometabolic syndrome of obesity in normal weight women

“…Circulating markers of endoplasmic reticulum stress, such as CCAAT-enhancer-binding protein (C/EBP) homologous protein transcription factor (CHOP) and glucose-regulated protein (GRP 78), and the metabolic regulator fibroblast growth factor (FGF) 21 was similarly unchanged by lipid plus insulin infusion. In the same women, we examined a number of nonreproductive pituitary hormones in response to acute hyperlipidemia and hyperinsulinemia and observed no significant differences in levels of thyroid-stimulating hormone (TSH), prolactin, growth hormone, insulin-like growth factor (IGF)-1, or creatinine, although a small but statistically significant increase in leptin was noted ( 22 ). Taken together, the data favor a direct and selective effect of high-fat exposure on gonadotropes.…”

“…In follow-up experiments, we performed frequent blood sampling in a sample of 15 normal-weight women in the early follicular phase of the menstrual cycle with and without an infusion of insulin and lipid, and demonstrated a partial induction of reprometabolic syndrome, with significantly reduced follicle-stimulating hormone (FSH) secretion and LH response to gonadotropin-releasing hormone (GnRH) ( 20 ). These effects were not accompanied by any clinically meaningful change in inflammatory markers ( 21 ) or other pituitary hormones ( 22 ).…”

Obesity-Related Hypogonadism in Women

“…In addition, peak gonadotropin levels were blunted following GnRH stimulation, indicating reduced pituitary sensitivity (peak LH and peak FSH were ∼12 IU/L and 22 IU/L in the lipid/infusion group vs 16 IU/L and 14 IU/L in saline groups) ( 113 ). The same protocol did not alter proinflammatory cytokine levels ( 114 ) or other pituitary hormone levels such as TSH, prolactin, and or cortisol ( 115 ), suggesting an effect specific to gonadotropins.…”

Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases

“…The chang-es in GH levels as described in the previous chapter indicate that GH-producing somatotrophs could be affected, but the exact cellular adaptations have not been clearly investigated. One study indicates decrease of specific trophic hormones in response to lipid/ insulin infusion, suggesting that there could be cell type specific effects on the HPA axis in response to diet and metabolism [43]. In an older study, the number of corticotrophs in the anterior lobe was found to be increased in obese rats, correlating with increased ACTH levels and hyperactivity of the HPA axis [49].…”

“…Interestingly, leptin has been shown to stimulate GnRH secretion by acting on neuropeptides, stimulating LH and FSH secretion by the pituitary gland [42]. Also, in a study of women with normal weight, infusion with lipid/insulin mainly led to a decrease in gonadotropins but did not affect trophic hormones [43].…”