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 journalArticle

3 Citations (Scopus)

Abstract

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
Volume454
DOIs
Publication statusPublished - Oct 15 2017

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Eunuchism
Iron Overload
Iron
Nutrition
Diet
Gonadotropin-Releasing Hormone
Hypogonadism
Hypothalamus
Pituitary Hormone-Releasing Hormones
Neurons
Median Eminence
Hemochromatosis
Luteinizing Hormone
Leptin
Weight Gain
Testosterone
Adipose Tissue
Testis

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms. / Macchi, Chiara; Steffani, Liliana; Oleari, Roberto; Lettieri, Antonella; Valenti, Luca; Dongiovanni, Paola; Romero-Ruiz, Antonio; Tena-Sempere, Manuel; Cariboni, Anna; Magni, Paolo; Ruscica, Massimiliano.

In: Molecular and Cellular Endocrinology, Vol. 454, 15.10.2017, p. 135-145.

Research output: Contribution to journalArticle

Macchi, C, Steffani, L, Oleari, R, Lettieri, A, Valenti, L, Dongiovanni, P, Romero-Ruiz, A, Tena-Sempere, M, Cariboni, A, Magni, P & Ruscica, M 2017, 'Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms', Molecular and Cellular Endocrinology, vol. 454, pp. 135-145. https://doi.org/10.1016/j.mce.2017.06.019
Macchi, Chiara ; Steffani, Liliana ; Oleari, Roberto ; Lettieri, Antonella ; Valenti, Luca ; Dongiovanni, Paola ; Romero-Ruiz, Antonio ; Tena-Sempere, Manuel ; Cariboni, Anna ; Magni, Paolo ; Ruscica, Massimiliano. / Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms. In: Molecular and Cellular Endocrinology. 2017 ; Vol. 454. pp. 135-145.
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abstract = "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.",
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AU - Macchi, Chiara

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AU - Oleari, Roberto

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AU - Valenti, Luca

AU - Dongiovanni, Paola

AU - Romero-Ruiz, Antonio

AU - Tena-Sempere, Manuel

AU - Cariboni, Anna

AU - Magni, Paolo

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N2 - 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.

AB - 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.

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