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 language | English |
|---|---|
| Pages (from-to) | 135-145 |
| Number of pages | 11 |
| Journal | Molecular and Cellular Endocrinology |
| Volume | 454 |
| DOIs | |
| Publication status | Published - Oct 15 2017 |
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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 journal › Article
}
TY - JOUR
T1 - Iron overload induces hypogonadism in male mice via extrahypothalamic mechanisms
AU - Macchi, Chiara
AU - Steffani, Liliana
AU - Oleari, Roberto
AU - Lettieri, Antonella
AU - Valenti, Luca
AU - Dongiovanni, Paola
AU - Romero-Ruiz, Antonio
AU - Tena-Sempere, Manuel
AU - Cariboni, Anna
AU - Magni, Paolo
AU - Ruscica, Massimiliano
PY - 2017/10/15
Y1 - 2017/10/15
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.
KW - GnRH
KW - Hypogonadism
KW - Iron overload
KW - Median eminence
KW - Testes
UR - http://www.scopus.com/inward/record.url?scp=85021450873&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021450873&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2017.06.019
DO - 10.1016/j.mce.2017.06.019
M3 - Article
AN - SCOPUS:85021450873
VL - 454
SP - 135
EP - 145
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
ER -