Mimicking Metabolic Syndrome Impairs the Hypothalamic-Pituitary-Ovarian Axis in Normal Weight Women

Presentation Number: OR15-3
Date of Presentation: March 6th, 2015

Justin Chosich*1, Andrew P Bradford1, Jane E Reusch2, Irene Elizabeth Schauer1 and Nanette Santoro3
1University of Colorado School of Medicine, Aurora, CO, 2Denver Veterans Administration Medical Center, Denver, CO, 3University of Colorado Anschutz Medical Campus, Aurora, CO


Introduction: Obesity is associated with high circulating free fatty acids and triglycerides, insulin resistance, and relative hypogonadotropic hypogonadism.  We hypothesized that these metabolic changes (elevated lipids and hyperinsulinemia) impact the hypothalamic-pituitary-ovarian axis, inducing the impaired gonadotropin secretion that is characteristically observed in obese women.  To address this, we investigated serum Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) profiles in normal weight women, during a lipid or saline infusion in the presence or absence of a concurrent hyperinsulinemic, euglycemic clamp.

Methods: A follicular phase (cycle day 6-10), 6-hour infusion study was undertaken in 10 regularly cycling, normal weight women (mean BMI 22.8 ± 0.83) of reproductive age (mean 32.5 ± 1.89 years). A crossover design was employed such that patients received each of the following infusions: control (saline), 20% lipid emulsion/heparin (45ml/h), insulin (40 mU/m2/min) under euglycemic clamp conditions, and a combination of lipid plus insulin, over a series of 4 visits. Blood was collected every 2 hours and FSH and LH measured by a direct chemiluminescent assay (Perkin Elmer; Autodelfia). Transverse mean (±SEM) gonadotropin levels were compared between control and treatments for each patient using a paired t test.

Results: Lipid/heparin infusion elevated fatty acid and triglyceride levels to the high physiological levels typically observed in obesity and metabolic syndrome. Mean control FSH levels (4.06 ± 0.20 U/L) were increased by lipid infusion (4.55 ± 0.19 U/L, p<0.01) and a similar trend was observed in response to insulin (4.76 ± 0.35 U/L, p=0.056). In contrast, infusion of lipid plus insulin significantly suppressed FSH (3.47 ± 0.36 U/L), compared to saline (p<0.005), lipid alone (p<0.0001) or insulin alone (p<0.05).  Similarly, control LH levels (4.85 ± 0.38 U/L) were modestly increased by lipid infusion (5.33 ± 0.36 U/L, p=0.06) and not significantly changed in response to insulin (4.13 ± 0.43 U/L, p=0.51). Infusion of lipid plus insulin significantly decreased LH levels (3.63 ± 0.49 U/L) relative to lipid alone (p<0.0001).

Thus, infusion of insulin or lipid alone did not reduce serum levels of FSH or LH. However, the combination of insulin plus lipid significantly decreased levels of both gonadotropins. 

Conclusion: Hyperinsulinemia and elevated circulating lipids, comorbidities characteristic of metabolic syndrome, act to acutely and synergistically suppress endogenous FSH and LH in normal weight women. This combinatorial effect provides a possible mechanism underlying the relative hypogonadotropic hypogonadism of obesity and indicates that the effects of insulin on the hypothalamic-pituitary-ovarian axis may be dependent on the concomitant metabolic environment.


Nothing to Disclose: JC, APB, JER, IES, NS