Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms

Publication date: Available online 23 June 2017
Source:Molecular and Cellular Endocrinology
Author(s): Chiara Macchi, Liliana Steffani, Roberto Oleari, Antonella Lettieri, Luca Valenti, Paola Dongiovanni, Antonio Romero-Ruiz, Manuel Tena-Sempere, Anna Cariboni, Paolo Magni, Massimiliano Ruscica
IntroductionIron overload leads to multiple organ damage including endocrine organ dysfunctions. Hypogonadism is the most common non-diabetic endocrinopathy in primary and secondary iron overload syndromes.AimTo explore the molecular determinants of iron overload-induced hypogonadism with specific focus on hypothalamic derangements. A dysmetabolic male murine model fed iron-enriched diet (IED) and cell-based models of gonadotropin-releasing hormone (GnRH) neurons were used.ResultsMice fed IED showed severe hypogonadism with a significant reduction of serum levels of testosterone (−83%) and of luteinizing hormone (−86%), as well as reduced body weight gain, body fat and plasma leptin. IED mice had a significant increment in iron concentration in testes and in the pituitary. Even if iron challenge of in vitro neuronal models (GN-11 and GT1-7 GnRH cells) resulted in 10- and 5-fold iron content increments, respectively, no iron content changes were found in vivo in hypothalamus of IED mice. Conversely, mice placed on IED showed a significant increment in hypothalamic GnRH gene expression (+34%) and in the intensity of GnRH-neuron innervation of the median eminence (+1.5-fold); similar changes were found in the murine model HFE^−/-, resembling human hemochromatosis.ConclusionsIED-fed adult male mice show severe impairment of hypothalamus-pituitary-gonadal axis without a relevant contribution of the hypothalamic compartment, which thus appears sufficiently protected from systemic iron overload.



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