Negative Effects of High Glucose Exposure in Human Gonadotropin-Releasing Hormone Neurons

Abstract

Metabolic disorders are often associated with male hypogonadotropic hypogonadism, suggesting that hypothalamic defects involving GnRH neurons may impair the reproductive function. Among metabolic factors hyperglycemia has been implicated in the control of the reproductive axis at central level, both in humans and in animal models. To date, little is known about the direct effects of pathological high glucose concentrations on human GnRH neurons. In this study, we investigated the high glucose effects in the human GnRH-secreting FNC-B4 cells. Gene expression profiling by qRT-PCR, confirmed that FNC-B4 cells express GnRH and several genes relevant for GnRH neuron function (KISS1R, KISS1, sex steroid and leptin receptors, FGFR1, neuropilin 2, and semaphorins), along with glucose transporters (GLUT1, GLUT3, and GLUT4). High glucose exposure (22 mM; 40 mM) significantly reduced gene and protein expression of GnRH, KISS1R, KISS1, and leptin receptor, as compared to normal glucose (5 mM). Consistent with previous studies, leptin treatment significantly induced GnRH mRNA expression at 5 mM glucose, but not in the presence of high glucose concentrations. In conclusion, our findings demonstrate a deleterious direct contribution of high glucose on human GnRH neurons, thus providing new insights into pathogenic mechanisms linking metabolic disorders to reproductive dysfunctions.

Age, Insulin Requirements, Waist Circumference, and Triglycerides Predict Hypogonadotropic Hypogonadism in Patients with Type 1 Diabetes

“…The idea that adipose tissue promotes cyclization of androgens to estrogens, thereby reducing androgen levels and inhibiting the hypothalamic–pituitary axis [1], has been confronted by recent studies that do not find a relationship between low testosterone and increased estrogen levels [23]. On the other hand, the excess of visceral fat leads to increased production of proinflammatory cytokines and free fatty acids that produce hypertriglyceridemia and insulin resistance, leading to a decreased expression of GnRH and gonadotropin secretion [24]. Moreover, a negative correlation between glucose and the number of LH pulses has been recently reported, supporting the hypothesis of a negative effect of hyperglycemia on the hypothalamic GnRH secretion or production [25].…”

Obesity and late-onset hypogonadism

“…TNFα), and gastrointestinal hormones (e.g. ghrelin, peptide YY), along with an increased estrogen production by the expanded fat deposits, have been advocated as causing the gonadotropin failure (Fernandez-Fernandez et al, 2006, Morelli et al, 2013a, Morelli et al, 2014a. However, leptin has a permissive role on GnRH neuron activity (Morelli et al, 2009) and its levels are increased, and not decreased, in obesity.…”

“…Interestingly, a similar increase in T levels was reported by transdermal supplementation with patch or gel in a recent meta-analysis of 20 randomized controlled trials (RCT,Borst et al, 2014). Hence, consistent weight loss is as efficient as treatment with transdermal T, the most popular form of TS worldwide(Buvat et al, 2013, Corona et al, 2012b, 2013a. Bariatric surgery also induced an average reduction of E2 level of 23 pmol/L(Figure 2, panel F).…”

Perspective: Regulatory Agencies' Changes to Testosterone Product Labeling

“…Accordingly, in our population almost three-fourth of cases of the unknown causes of HG can be attributed to the aforementioned conditions (71.8% for primary HG and 70.7% for sHG). We recently reported in a rabbit model of MetS, characterized by sHG, the presence of hypothalamus inflammation and a decrease of several genes involved in the formation and release of GnRH [8]. In translational medicine, this indicates that metabolic disturbances are associated with discrete abnormalities in the arcuate nucleus of the hypothalamus, such as the other "organic" problems mentioned by the FDA.…”