Endocrine disturbances in HD and their link with disease severity have not been investigated previously in a large matched case-control study, despite their pathophysiological and clinical relevance 
. We demonstrated impairments of several anterior pituitary axes in HD patients (). Both central (GH) and peripheral (IGF-1) somatotropic hormones were higher in the patients than in the healthy controls and increased with disease severity. Among corticotropic-axis hormones, only cortisol was increased. In contrast, the thyrotropic-axis and, in men, gonadotropic-axis hormones were decreased with disease severity. The prolactin was increased in patients with neuroleptic treatment. Of the five axes, only the somatotropic axis was related to weight loss.
Levels of pituitary and peripheral hormones according to HD stage and comparatively to controls.
Both typical and atypical neuroleptics treatment influence hormonal levels of prolactin and GH by altering their dopaminergic regulation 
. To avoid the biais of neuroleptic treatment, firstly we adjusted on neuroleptics treatment in our multivariate regression models. After, we compared hormonal levels in controls and patients with and without neuroleptics treatment. Using this approach, we found that the prolactin increase in the HD group compared to the matched control group was entirely ascribable to neuroleptic use. On the contrary, neuroleptics blunted partially the high significant difference in GH levels between patients and controls in the overall population. Indeed, this significant difference in GH was higher in non-users group then in group taking neuroleptics.
Basal plasma cortisol was higher in HD patients than in controls, in keeping with earlier studies 
. This increase was independent from ACTH levels and from disease severity. The dissociation of cortisol levels from ACTH levels suggests a role for other factors in the cortisol increase seen in the patients. An earlier study showed a blunted ACTH response to exogenous corticotropin-releasing hormone 
. Presumably, chronic stress may be associated with alteration in the hypothalamo-pituitary axes and particularly contributes to increase the cortisol levels 
in the patients, as seen in other chronic diseases such as schizophrenia 
and depression 
Alterations in sexual behavior have been reported in patients with HD 
. Our hormone level data fail to provide convincing explanations to these alterations, as plasma testosterone levels were not significantly different between HD patients and controls. An earlier study showed lower testosterone levels in males with HD compared to healthy controls 
. However, the patients with stage I or II disease had normal testosterone levels, and testosterone levels showed a negative correlation with disease severity 
. Patients with stage I and II disease contributed 69% of our study population and patients with stage IV or V only 9%. In keeping with the earlier study 
, we found that testosterone levels declined with disease severity. A transgenic mouse model of HD (the R6/2 model) is characterized by atrophy of the testes and infertility 
, which may be related to loss of hypothalamic neurons producing gonadotropin-releasing hormone (GnRH) 
. The reduction in plasma testosterone levels in our patients was not associated with decreases in FSH and LH, indicating a role for loss of the direct neuronal hypothalamic-testicular pathway in patients with advanced disease.
TSH levels in our patients did not differ significantly from those in the controls but declined with disease progression, in keeping with a previous study 
. Since, none of the thyroid hormones in our study differed between patients and controls, the declining TSH levels suggest loss of hypothalamic neurons. However, additional studies are needed to clarify this point.
Plasma GH levels were higher in patients than controls, in accordance with previous reports 
. A few studies conducted in smaller numbers of patients found no increase in GH 
. However, we found increases not only in GH, but also in the GH effector (free IGF-1). Furthermore, this increased somatotropic activity was associated with disease severity. Importantly, weight loss was significantly related to GH elevation and was independent from motor disorders and other endocrine disturbances. GH deficiency is associated with obesity and GH treatment decreases the fat mass by inducing lipolysis within fat tissue 
. Thus, increased GH release may be related to the weight loss often seen in HD patients 
Concerning IGF-1, the present finding extend and reinforce the observations that level of circulating IGF-1 is altered in many type of human neurodegenerative disease. In HD, it may exert a neuroprotective role by activating the enzyme serine/threonine kinase Akt 
, which phosphorylates the mutant huntingtin protein at serine 421. A protective effect of IGF-1 has been suggested in other neurodegenerative diseases 
. As well, this elevation of IGF-1 level reflect a resistant state 
and it is likely due to a loss of sensitivity of target cell to the action of growth hormone.
Therefore, prospective study is necessary to determine whether GH increase is the cause or the result of weight loss and other impairment and to verify if the IGF-1 elevation seen in our patients could reflect an adaptive response to cell death.
In conclusion, our data advocate several neuroendocrine abnormalities in HD. These alterations, although possibly non-specific, may shed light on some of the pathophysiological mechanisms involved in disease progression. Although neuroendocrine dysfunction may contribute to peripheral symptoms such as weight loss, its link to disease progression remains to be confirmed.