Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms

Chiara Macchi, Liliana Steffani, Roberto Oleari, Antonella Lettieri, Luca Valenti, Paola Dongiovanni, Antonio Romero-Ruiz, Manuel Tena-Sempere, Anna Cariboni, Paolo Magni, Massimiliano Ruscica

Research output: Contribution to journalArticlepeer-review


Introduction Iron 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. Aim To 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. Results Mice 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. Conclusions IED-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.

Original languageEnglish
Pages (from-to)135-145
Number of pages11
JournalMolecular and Cellular Endocrinology
Publication statusPublished - Oct 15 2017


  • GnRH
  • Hypogonadism
  • Iron overload
  • Median eminence
  • Testes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology


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