Plasma testosterone in male patients with Huntington's disease: Relations to severity of illness and dementia

Markianos, Manolis; Πάνας, Μάριος; Kalfakis, Nikolaos; Vassilopoulos, Dimitrios

doi:10.1002/ana.20428

Cited by 99 publications

(76 citation statements)

References 38 publications

(32 reference statements)

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“…An analysis of complete neuroendocrine status in HD patients showed no significant difference in the plasma levels of LH, FSH and testosterone between all male HD patients and controls [38]. However, Markianos et al [39] observed significantly lower testosterone and LH levels in HD patients compared with healthy controls. These conflicting results suggested a detailed hormonal analysis of our porcine model.…”

Section: Discussionmentioning

confidence: 99%

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Macakova

Bohuslavová²,

Vochozková³

et al. 2016

Neurodegener Dis

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Background: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. Objective: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. Methods: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. Results: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. Conclusions: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt.

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Section: Discussionmentioning

confidence: 99%

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Macakova

Bohuslavová²,

Vochozková³

et al. 2016

Neurodegener Dis

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“…Similar findings of low testosterone in men with AD have been reported in several (Almeida et al, 2004;Moffat et al, 2004;Paoletti et al, 2004;Rasmuson et al, 2002;Watanabe et al, 2004) but not all (Pennanen et al, 2004) studies. Interestingly, low testosterone has also been linked to several other neurodegenerative diseases, including Parkinson's disease (Okun et al, 2004), vascular dementia (Watanabe et al, 2004), amyotropic lateral sclerosis (Militello et al, 2002), and Huntington's disease (Markianos et al, 2005).…”

Section: Age-related Androgen Depletion and Alzheimer's Diseasementioning

confidence: 99%

Androgen cell signaling pathways involved in neuroprotective actions

Pike

Nguyen

Ramsden

et al. 2008

Hormones and Behavior

110

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As a normal consequence of aging in men, testosterone levels significantly decline in both serum and brain. Age-related testosterone depletion results in increased risk of dysfunction and disease in androgen-responsive tissues, including brain. Recent evidence indicates that one deleterious effect of age-related testosterone loss in men is increased risk for Alzheimer's disease (AD). We discuss recent findings from our laboratory and others that identify androgen actions implicated in protecting the brain against neurodegenerative diseases and begin to define androgen cell signaling pathways that underlie these protective effects. Specifically, we focus on the roles of androgens as (1) endogenous negative regulators of β-amyloid accumulation, a key event in AD pathogenesis, and (2) neuroprotective factors that utilize rapid non-genomic signaling to inhibit neuronal apoptosis. Continued elucidation of cell signaling pathways that contribute to protective actions of androgens should facilitate the development of targeted therapeutic strategies to combat AD and other agerelated neurodegenerative diseases.

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“…It is not known whether the GnRH-producing population in the human HD hypothalamus is affected. Both R6/2 and YAC128 mice display the testicular atrophy which has been found in HD patients, but only the R6/2 mouse recapitulates the clinically reduced testosterone levels in male HD patients [106][107][108] . A recent study investigated peripheral sex hormones in a rat model for HD expressing 51 CAG repeats in the first 22% of the huntingtin gene (tgHD rat) [78,79] .…”

Section: Alterations In the Hypothalamic-pituitary-gonad Axismentioning

confidence: 96%

Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models

Petersén¹,

Hult²,

Kirik³

2009

Neurodegener Dis

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Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although it is characterized by progressive motor impairments, cognitive changes and psychiatric disturbances are major components of the disease. In addition, recent studies have shown that other non-motor symptoms such as alterations in sleep pattern, disruption of the circadian rhythm and increased energy metabolism are common and occur early. Emerging evidence suggests that the latter symptoms are likely results of disturbed functions of the hypothalamus and neuroendocrine circuits, which are known to be central in the regulation of emotion, sleep and metabolism. Whereas clinical data are essential to define key pathological features of HD, animal models that can recapitulate the neurobiological and behavioral features of the disorder are critical tools to elucidate the underlying pathogenic mechanisms. Recent studies employing different HD rodent models have been instrumental in identifying a number of neuroendocrine alterations as well as in highlighting novel potential disease pathways. This review summarizes the current state of knowledge derived from neuroendocrine studies in rodent models of HD in light of clinical relevance and points to future implications for this emerging field.

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Plasma testosterone in male patients with Huntington's disease: Relations to severity of illness and dementia

Cited by 99 publications

References 38 publications

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Androgen cell signaling pathways involved in neuroprotective actions

Huntington’s Disease – New Perspectives Based on Neuroendocrine Changes in Rodent Models

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