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Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review
Journal Pre-proof Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review Amy Newhouse, MD, Zeina Chemali, MD PII:
S0033-3182(19)30223-3
DOI:
https://doi.org/10.1016/j.psym.2019.11.002
Reference:
PSYM 1035
To appear in:
Psychosomatics
Received Date: 27 August 2019 Revised Date:
4 November 2019
Accepted Date: 5 November 2019
Please cite this article as: Newhouse A, Chemali Z, Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review, Psychosomatics (2019), doi: https://doi.org/10.1016/j.psym.2019.11.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.
Title: Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review Authors: Amy Newhouse, MD and Zeina Chemali, MD Abstract: Background: Neurodegenerative diseases cause progressive irreversible neuronal loss that have broad downstream effects. The neuroendocrine system regulates homeostasis of circuits that control critical functions such as the stress response, metabolism, reproduction, fluid balance and glucose control. These systems are frequently disrupted in neurodegenerative disorders though often overlooked in clinical practice. Objective: This review aims synthesize the available data regarding these disturbances in Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease and also to demonstrate the volume of literature in these individual arenas. Method: Using the scoping review framework, a literature search was performed in PubMed to identify relevant articles published within the past thirty years (January, 1988 – November, 2018). The search criteria produced a total of 2022 articles, 328 of which were identified as relevant to this review. Discussion: These neuroendocrine disturbances may be a precursor to the illness, a part of the primary pathophysiology, a direct consequence of the disease or independent of it. They have the potential to further understanding of the disease, exacerbate the underlying pathology or provide therapeutic benefit. Conclusion: By synthesizing the data from a systems’ perspective, we aim to broaden how clinicians think about these illnesses and provide care. Introduction: Neurodegenerative diseases cause progressive irreversible loss of specific neuronal populations. The disrupted neural circuitry often involves system disturbances which extend beyond the diseased territory in the brain. The neuroendocrine system is the interface between the central and peripheral endocrine systems and is a principal system affected by neuronal loss, though the relationship is rarely discussed. When functioning properly, this system helps maintain homeostatic balance that is in appropriate response to external signals. When disrupted, there can be broad downstream effects. The endocrine system is comprised of the central endocrine glands, such as the hypothalamus, pineal gland, anterior and posterior pituitary, in addition to the peripheral endocrine glands, including the thyroid and parathyroid glands, adrenal glands, the pancreas, ovaries and testes. The most commonly discussed neuroendocrine axes are the hypothalamicpituitary-adrenal (HPA) axis, hypothalamic-pituitary-thyroid (HPT) axis, hypothalamic-pituitarygonadal (HPG) axis, hypothalamic-pituitary-somatotropic (HPS) axis, and hypothalamic-
neurohypophyseal (HPN) system. Additionally, the role of both peripheral and central insulin signaling is becoming increasingly recognized. The HPA axis is primarily involved in regulating the stress response. The HPT axis is most relevant in regulation of metabolism. The HPG axis governs the reproductive system. The hypothalamic-neurohypophyseal system regulates the release of oxytocin, primarily involved with lactation, and vasopressin, which is an antidiuretic hormone with effects on fluid balance. See figure 1 for a visual depiction of the neuroendocrine axes. The burden of neurodegenerative diseases continues to grow and investigation of their pathophysiology and potential treatment remains an intense focus of the medical community. Certain neuroendocrine disturbances have been associated with neurodegenerative disorders. They may be a part of the primary pathophysiology, a direct result of the disease or independent of it. They have the potential both to aggravate underlying pathology and to be avenues with therapeutic potential. This review aims to synthesize the available data regarding the interactions between the neuroendocrine system and the following neurodegenerative disorders: Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington’s disease (HD). While the identified mechanisms of these diseases are quite distinct, they all involve progressive regional central neuronal loss that has broad systemic downstream effects. In exploring the involvement of the neuroendocrine system across multiple different neurodegenerative diseases, this review aims to broaden the discussion on management of these diseases in a multidisciplinary fashion. Figure 1: Methods: Given the broad scope and heterogenous nature of this undertaking, a scoping review framework was utilized to map the literature and demonstrate the volume published in these individual arenas 1 2. A literature search was performed in PubMed to identify relevant articles published within the past thirty years (January, 1988 – November, 2018). The following search (MeSH) terms were used: ‘Alzheimer’s’, ‘Parkinson’s’, ‘frontotemporal dementia’, ‘amyotrophic lateral sclerosis’, ‘Huntington’s’ and ‘dementia’ paired with ‘neuroendocrinology’ and ‘endocrinology’ individually. In addition, ‘dementia’ was paired with ‘HPA axis’. Articles were excluded if they were in vitro studies, not in the English language, or if they were not primarily focused on neurodegenerative disorders and the endocrine system, including those focused primarily on genetics, nutrition and those that discussed endocrinology in the context of the brain, but not in relation to aging or dementias. All selected articles were further reviewed and relevant data were consolidated in this review. Results: The search criteria produced a total of 2022 articles. Individual disease search terms paired with endocrinology produced 1564 articles. Those paired with neuroendocrinology produced a total of 313 articles. 145 articles were generated with the search terms dementia and HPA axis. Figure 2 demonstrates the search term results and their subsequent filtration. Based on the above criteria, 328 articles were identified as relevant to this review. In an effort
to be both comprehensive and concise, the most pertinent data was consolidated for this manuscript. Only the articles specifically cited in the manuscript are listed in the references. Table 1 summarizes the neuroendocrine systems and hormones that have been associated with neurodegenerative disorders. Figure 2: Discussion: Alzheimer’s Disease Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the most common presenting symptom being memory deficits followed by problems with executive functioning, language, and mood lability 3. The pathophysiology is not entirely known however it does include deposition of amyloid plaques and neurofibrillary tangles 4, in addition to acetylcholine deficiency 5 and regional subcortical and cortical volume loss, primarily of the temporal and parietal lobes followed by the frontal cortex and cingulate gyrus 6. HPA Axis: The HPA axis has many functions, though it is felt primarily to modulate the stress response in the body. The hypothalamus secretes corticotropin releasing hormone (CRH) which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). This then signals the adrenal glands to release cortisol, which has many downstream metabolic effects. Many studies suggest heightened HPA axis activity in AD. Elevated cortisol levels have been found in the CSF, urine, and serum (both before and after a dexamethasone suppression test) 7 8 . Elevated CSF cortisol and mineralocorticoid receptors have been associated with ApoE4 genotype 7. Hippocampal volume and general brain volume have been shown to be reduced with hypercortisolism 9. Cognitive status is negatively associated with both plasma 10 and CSF cortisol 7. In fact, higher levels of dementia with agitation have been found in those with a lack of dexamethasone suppression 11 12. In animal studies, stress and glucocorticoid administration increase amyloid beta formation in the cortex 13 and tau hyperphosphorylation in the hippocampus and prefrontal cortex 14. Interestingly, treatment with mifepristone, a glucocorticoid receptor antagonist, reduces cerebral amyloid beta, tau deposition and cognitive impairment in mouse models 15. HPA axis activation may serve as a marker of disease, contribute to underlying pathology and also may serve as a target for therapeutic intervention. HPG Axis: The HPG axis regulates the reproductive system in both men and women. The hypothalamus releases gonadotropin releasing hormone (GnRH) which signals the anterior pituitary to release luteinizing hormone (LH) and follicular stimulating hormone (FSH). In turn, FSH and LH signal the ovaries to release estrogen and progesterone or the testes to release testosterone. In the past, estrogen received a lot of attention for its relevance in AD but other reproductive hormones may be relevant as well 16. Elevated levels of FSH and LH have been demonstrated in AD 17. Low levels of estrogen confer increased risk of AD 16. There is conflicting evidence regarding the effect of estrogen replacement therapy (ERT). In brief, there
may be a “critical period” effect where women who receive ERT while entering menopause have reduced risk of AD 18 but in those who are 10 years past menopause, ERT is associated with an increased risk of dementia 19. Moreover, low peripheral and central levels of testosterone have been associated with AD in men 17. Dihydrotestosterone, the active form of testosterone, has been shown to reduce brain amyloid burden and behavioral impairment in mice 20 21. HPT Axis: The hypothalamus secretes thyrotropin releasing hormone (TRH) which signals the anterior pituitary to release thyroid stimulating hormone (TSH). In response to this, the thyroid secretes thyroxine (T4) and triiodothyronine (T3) which regulate metabolism throughout the body. Results regarding thyrotropin releasing hormone and AD have been conflicting however there have been more data to suggest low levels in AD 22. Additionally, TRH is decreased in the hippocampi of those with AD 23. Finally, low T3, but not TSH or T4, has been associated with AD 24 . HPS Axis: The hypothalamic-pituitary-somatotropic axis is also referred to as the hypothalamicpituitary-growth axis. The hypothalamus releases growth hormone releasing hormone (GHRH) and somatostatin which have stimulating and inhibiting effects on the anterior pituitary, respectively. When activated, the anterior pituitary releases growth hormone (GH) which primarily exerts effect on the liver. In response, the liver releases insulin-like growth factor-1 (IGF-1), which has broad downstream effects, such as bone growth, muscle development, cardiovascular function and on the brain. Lower levels of serum IGF-1 have been associated with increased risk of AD 25. In mouse models, IGF-1 receptor blockade in the choroid plexus induced changes similar to those found in AD such as amyloidosis, tau deposition and cognitive impairment 26. Restoring receptor function lead to improvement in these symptoms 26. IGF-1 and vitamin D have a complex relationship that involves the kidneys, parathyroid glands, bones and sun exposure. Finally, it has been shown that over 70% of those with AD have vitamin D deficiency 27. Parkinson’s Disease Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is caused primarily by neuronal death of the dopamine secreting cells of the substantia nigra in the basal ganglia in addition to Lewy body deposition 28. This leads to progressive motor symptoms including tremors, rigidity, bradyphrenia and shuffling gait in addition to cognitive decline and mood disturbances 29. HPA Axis: There is less information for the relationship of the HPA axis in PD. Of that available, there is conflicting evidence regarding HPA axis activity; both hyperactivity and hypoactivity have been found 30. Heightened activity has been demonstrated by elevated plasma levels of ACTH and cortisol 30. Additionally, interleukin-2 (IL-2), a cytokine relevant in the immune response, has been found to be elevated in the plasma of those with untreated PD. Treatment
with levodopa reduces IL-2 levels suggesting that the heightened immunoreactivity is related to altered dopaminergic signaling 30. Circadian rhythm disturbances are common in PD and it has been theorized that this drives the cortisol abnormalities as cortisol release is highly correlated with circadian rhythm 31. HPG Axis: There is a higher incidence of PD in men than women and in women with early menopause or hysterectomy compared to those without 32. Estrogen is thought to be protective against PD 33. In rodent models, 17 beta-estradiol has been demonstrated to be neuroprotective to dopaminergic neurons 33. Progesterone has also been found to be neuroprotective in animal models 32. Finally, in a study of 36 patients with PD, men with lower testosterone had faster progression of disease 34. HPS Axis: The gait and cognitive disturbances that occur in PD confer added fall risk. However, those with PD are also more likely to have decreased bone mineral density 35 thought to be due to low levels of vitamin D and secondary hyperparathyroidism 36. Having PD is associated with an elevated risk of fracture and treatment with levodopa has been show to actually confer added risk 36. Huntington’s Disease: Huntington’s Disease (HD) is characterized by progressive loss of coordination followed by chorea in addition to progressive cognitive and mood disturbance 37. It is caused by expansion of CAG triplets in the Huntingtin gene which results in production of abnormal Huntingtin protein 37 38. This protein damages the striatum initially and then spreads more broadly 38. HPA Axis: HPA axis disturbances have been demonstrated in humans with HD and also in animal models. Most studies have demonstrated HPA axis hyperactivity that may manifest early in the disease process; one study demonstrated both elevated total cortisol secretion rate and amplitude of diurnal release 39. It is thought that this might be due to impaired negative feedback as a result of mutant huntingtin protein deposition in the hypothalamus 40. Rodent models parallel the finding of elevated baseline cortisol and in addition demonstrate that the levels correlate with HD symptom progression 41. HPT Axis: Overall, the HPT axis has been found to be overly activated in HD in both patients and animal models. This is also thought to have potential influence on the metabolic hyperactivity and subsequent weight loss seen in HD. In one study of 9 patients with early stage HD, TSH was was not significantly elevated however total T3 and T4 levels were significantly higher than controls 42. In the same study, the higher degree of T3 correlation was associated with worse motor impairment while elevated T4 levels correlated with higher number of mutant cytosineadenine-guanine (CAG) repeat size 42. These findings may be related to central and peripheral
disturbances. Dopamine is related to TSH secretion and loss of D2 receptors in the hypothalamus and anterior pituitary have been demonstrated in early-stage HD patients 43 41. The fact that only elevated T4 levels were related to mutant CAG repeat size suggested that this effect was mediated peripherally 42. HPG Axis: The same study that demonstrated the disrupted HPT axis in HD also found that prolactin secretion is slightly elevated and more irregular in HD. The authors theorized that the hypothalamic dopamine disruption accounted for this 42. HPS Axis: There is limited and conflicting evidence regarding the HPS axis in HD 44. Some studies have demonstrated elevated basal growth hormone levels 45 while others have not 46. In one older study that evaluated the effect of dopamine agonists on growth hormone levels, a heighted response of growth hormone was seen in response to bromocriptine, apomorphine and levodopa when compared to controls 47. This was theorized to be related to heightened sensitivity of dopamine receptors in a damaged central dopaminergic system 47. However, a similar study did not find an increase in growth hormone after bromocriptine administration 46. Amyotrophic Lateral Sclerosis: Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle stiffness, fasciculations and weakness 48. Cognitive and behavioral disturbances can follow as well 49. The pathophysiology is not fully understood however involves cell death of upper and lower motor neurons 49. HPT Axis: Thyrotropin releasing hormone (TRH) has been shown to have trophic effect on motor neurons in animal models 50. In motor neuron disease, such as ALS, TRH content in the anterior horn region is decreased 51. Trials looking at the potential benefit of TRH administration in humans have had conflicting results, though this may serve as a target for potential adjunctive treatment in the future 52. HPN Axis: Plasma levels of arginine vasopressin (AVP) have been shown to be decreased in patients with ALS and in mouse models 52 53. HPS Axis: Baseline growth hormone levels have been shown to be reduced in patients with ALS as has the GH response to growth hormone releasing hormone plus arginine 54. Some studies have shown reduced IGF-1 levels in ALS patients 55 and IGF-1 is thought to be involved in GH secretion 54. Taken together, this suggests HPS axis disruption and has led to treatment trials with GH and IGF-1 analogues 54. Thus far, GH and IGF-1 have been shown to induce neuroprotection in ALS mouse models however clinical trials in ALS patients have failed to show benefit 56.
Frontotemporal Dementia: This diagnosis encompasses several different clinical syndromes all of which derive from degeneration primarily of the frontal or temporal lobes 57. This can cause a variety of behavioral, cognitive, motor and language deficits 58. The pathology is not fully understood though is often thought to involve abnormal tau protein deposition 58. Notably these syndromes are being increasingly recognized as components of ALS suggesting the potential of shared pathophysiology 59 60. There is notably little written about the interplay between the neuroendocrine system and FTD. One article does summarize the various physiological disturbances seen in FTD, in addition to ALS and AD, such as eating, metabolism, sleep and autonomic functioning 61. The authors hypothesize that most of these effects are mediated by disrupted circuitry involving the hypothalamus and it’s projections 61. For example, the hyperphagia and hypermetabolism seen in behavioral variant FTD is thought to be related disrupted homeostasis of hunger and satiety combined with dysregulated reward pathways 62. Another group has hypothesized a “bottom up” model for the FTD syndrome seen in ALS that may be partially mediated by estrogen levels as their study suggested estrogen was neuroprotective based on measures of cognition 63.
Insulin and Neurodegenerative Disorders Many studies have shown that diabetes mellitus (DM) is a risk factor for dementia overall. One meta-analysis found a 73% increased risk of all types of dementia, a 56% increase in risk of AD, and a 127% increase in vascular dementia in those with DM 64. DM occurs when there is either peripheral insulin resistance or decreased insulin production. Insulin is a hormone that is released by the pancreas and its primary function is to regulate glucose homeostasis. DM certainly is a cardiovascular risk factor and it follows that diabetic patients are at increased risk of vascular disease in the brain, such as strokes and vascular dementia. Moreover, there is growing evidence that insulin may have additional impact on the central nervous system, both directly and indirectly. While insulin in the brain is not commonly considered in the clinical setting, there are a large number of insulin receptors throughout the cerebral cortex and hippocampus, which is thought to have a key role in memory 65. The data regarding these relationships remains predominantly in the research realm at this time but they certainly have the potential for significant clinical relevance. For example, in those with the apolipoprotein E4 allele, elevated blood glucose is associated with more severe AD pathology post-mortem 66. Low levels of insulin in the CSF are found in AD 67. Insulin signals release of beta amyloid peptide to the external surface of the cell and induces expression of insulin degrading enzyme. Insulin degrading enzyme is also involved in the breakdown of amyloid beta 68. Central insulin regulation is also thought to be relevant in tau phosphorylation. Insulin resistance has been shown to exacerbate tau lesions. There is evidence that normal tau functions to regulate central insulin and when tau hyperphosphorylation occurs, there is subsequent loss of normal central insulin homeostasis 69. The brains of patients with AD are considered to be insulin resistant, a syndrome with a suggested name of “type 3 diabetes” 70. Treatment for DM has been and continues to be explored for potential benefit in AD. Thus far, there is conflicting evidence regarding the impact of metformin and sulfonylureas 71.
Pioglitazone has shown benefit in mild to moderate AD 72. Glucagon-like peptide receptor agonists also have shown benefit. Finally, intranasal insulin has been shown to enhance both memory and mood in AD patients 73. There has been conflicting evidence regarding whether tighter glycemic control slows the rate of progression of cognitive decline 74. That being said, it should be noted that management of concurrent DM and dementia is a complex scenario as it requires balancing the optimal therapy with the cognitive capabilities of the patient and their environmental context; both hyper and hypoglycemia can have significant detrimental consequences in this population 75. Table 1:
Therapeutic Considerations: Broadly speaking, thinking about these various illnesses with a neuroendocrine lens may lead to innovative therapeutic approaches. The data consolidated in this article have implications for risk assessment, diagnosis, and treatment. For example, there might be an element of subclinical Cushing’s syndrome in those with rapidly progressive AD; if so, this could be screened for and potentially treated 76. Behaviors such as exercise might have protective benefit due to their stress reduction and anti-inflammatory effects. Perhaps we should be taking a more thorough history of symptoms of hypogonadism and menopause when assessing for AD. If TRH confers neuroprotection in AD, the pathway could be mimicked. Perhaps further studies of IGF-1 agents will demonstrate more robust therapeutic benefit in AD 26. Bone health could become a component of PD management. In those with subjective memory complaints, we might more aggressively recommend better glucose control. Targeting the HPA axis hyperactivity in HD might slow progression of disease as it has been theorized that the metabolic consequence of elevated cortisol levels may contribute to weight loss and death 77. Perhaps evaluating neuroendocrine status should be a larger part of determining risk of developing neurodegenerative diseases. This information could be combined with other data to generate a risk prediction model similar to those commonly utilized in assessing cardiovascular disease risk. These models typically combine data such as age, sex, blood pressure, lipid values, smoking habits and comorbidities to generate an individual’s risk score. Perhaps a similar approach could be used with dementias. For example, an algorithm combining cortisol, A1C, estrogen, and exercise level might be able to generate a risk score for AD. With better risk assessment, there may be more avenues to modify outcomes preemptively. Finally, given the growing impact of these diseases and the increasing knowledge that their impact extends beyond the brain, there may be a role for a broader, multi-domain approach to treatment of neurodegenerative disorders, similar to those used in management of other chronic diseases. As a comparison, good diabetes care involves not only management of glucose levels, but also includes screening for kidney disease, checking for peripheral neuropathy, prescribing ace inhibitors for blood pressure and statins for cardiovascular risk. If neurodegenerative disorders were approached in a similar way, perhaps a visit to the clinic would not be limited to a neurological exam and bedside cognitive testing, but would include addressing bone health, diabetes and HPA axis imbalance.
As we await additional research with definitive answers to the queries posed above, we recommend considering how the evidence available can be incorporated into current practice. Checking vitamin D levels and hemoglobin A1C are relatively simple ways to start. Asking about menopause can initiate dialogue about estrogen replacement therapy and its relevance in AD. Finally, familiarizing oneself with the different diabetes medications and their neurologic relevance will likely prove useful as more research is done in this arena. Limitations: This review aimed to demonstrate the utility in thinking about neurodegenerative disorders through a neuroendocrine lens. Many examples were included but a review of this length cannot be exhaustive. In addition to the limitations imposed by language restrictions and the search engine utilized, the selection process was likely informed by the authors’ educational and training background. Certain diseases have had much more written about them than others which influenced the amount of material from which to select data. Finally, the quality of the data was not verified for the purpose of this review so we acknowledge that the caliber of study designs written about was likely mixed. Conclusions: Neurodegenerative disorders lead to progressive regional neuronal cell death. Despite their distinct entities, they share the common pattern of a brain pathology that has broad downstream effects. The neuroendocrine system regulates homeostasis throughout the body and the highest levels of control are located in the brain. There is evidence that neuroendocrine disturbances often predate diagnosis and may confer risk. These disturbances may also occur in parallel with these various disorders or be direct results of them. These findings translate into many different potential avenues for intervention in terms of risk reduction and treatment. More data are needed to understand the risks and benefits of pertinent interventions. However, we propose that further research be done with a neuroendocrine approach to provide a broader, multi-disciplinary approach to caring for neurodegenerative diseases. Disclosures: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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42. Aziz NA, Pijl H, Frolich M, Roelfsema F, Roos RAC. Altered thyrotropic and lactotropic axes regulation in Huntington’s disease. Clin Endocrinol (Oxf). 2010;73(4):540-545. doi:10.1111/j.1365-2265.2010.03836.x 43. Politis M, Pavese N, Tai YF, Tabrizi SJ, Barker RA, Piccini P. Hypothalamic involvement in Huntington’s disease: an in vivo PET study. Brain J Neurol. 2008;131(Pt 11):2860-2869. doi:10.1093/brain/awn244 44. Saleh N, Moutereau S, Durr A, et al. Neuroendocrine Disturbances in Huntington’s Disease. PLOS ONE. 2009;4(3):e4962. doi:10.1371/journal.pone.0004962 45. Phillipson OT, Bird ED. Plasma growth hormone concentrations in Huntington’s chorea. Clin Sci Mol Med. 1976;50(6):551-554. doi:10.1042/cs0500551 46. Chalmers RJ, Johnson RH, Keogh HJ, Nanda RN. Growth hormone and prolactin response to bromocriptine in patients with Huntington’s chorea. J Neurol Neurosurg Psychiatry. 1978;41(2):135-139. 47. Muller EE, Parati EA, Panerai AE, Cocchi D, Caraceni T. Growth hormone hyperresponsiveness to dopaminergic stimulation in Huntington’s chorea. Neuroendocrinology. 1979;28(5):313-319. doi:10.1159/000122878 48. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet | National Institute of Neurological Disorders and Stroke. https://web.archive.org/web/20170105002627/http://www.ninds.nih.gov/Disorders/PatientCaregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet. Published January 5, 2017. Accessed July 18, 2019. 49. van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet Lond Engl. 2017;390(10107):2084-2098. doi:10.1016/S0140-6736(17)31287-4 50. Fone KC, Dix P, Tomlinson DR, Bennett GW, Marsden CA. Spinal effects of chronic intrathecal administration of the thyrotrophin-releasing hormone analogue (CG 3509) in rats. Brain Res. 1988;455(1):157-161. 51. Mitsuma T, Adachi K, Mukoyama M, Ando K. Concentrations of thyrotropin-releasing hormone in the brain of patients with amyotrophic lateral sclerosis. J Neurol Sci. 1986;76(23):277-281. 52. Gonzalez De Aguilar J-L, Rene F, Dupuis L, Loeffler J-P. Neuroendocrinology of neurodegenerative diseases. Insights from transgenic mouse models. Neuroendocrinology. 2003;78(5):244-252. doi:10.1159/000074445 53. González de Aguilar JL, Gordon JW, René F, Lutz-Bucher B, Kienlen-Campard P, Loeffler JP. A mouse model of familial amyotrophic lateral sclerosis expressing a mutant superoxide dismutase 1 shows evidence of disordered transport in the vasopressin hypothalamoneurohypophysial axis. Eur J Neurosci. 1999;11(12):4179-4187.
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Physiology, Pituitary Gland Copyright © 2019, StatPearls Publishing LLC. https://creativecommons.org/licenses/by/4.0/
Figure 1: Visual depiction of the neuroendocrine hormones and their target organs
Figure 2: Flowchart demonstrating the search terms, the numbers of articles identified, and those selected for review in this study
System HPA
HPT
HPG
GH / IGF-1
Posterior Pituitary
Hormones CRH ACTH Cortisol TRH Thyrotropin TSH T4 T3 GnRH LH FSH Prolactin Estrogen Progesterone Testosterone GH IGF-1 Somatostatin Ghrelin Vasopressin Oxytocin Insulin
Glucose Metabolism Sleep Cycle Melatonin
AD • • • •
PD
Huntington’s ALS
• •
•
FTD
• • • •
• • • • •
• • • •
• •
•
•
• •
•
•
• •
•
•
•
•
•
•
Table 1: Summary table of hormones associated with neurodegenerative disorders
S0033-3182(19)30223-3
DOI:
https://doi.org/10.1016/j.psym.2019.11.002
Reference:
PSYM 1035
To appear in:
Psychosomatics
Received Date: 27 August 2019 Revised Date:
4 November 2019
Accepted Date: 5 November 2019
Please cite this article as: Newhouse A, Chemali Z, Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review, Psychosomatics (2019), doi: https://doi.org/10.1016/j.psym.2019.11.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.
Title: Neuroendocrine Disturbances in Neurodegenerative Disorders: A Scoping Review Authors: Amy Newhouse, MD and Zeina Chemali, MD Abstract: Background: Neurodegenerative diseases cause progressive irreversible neuronal loss that have broad downstream effects. The neuroendocrine system regulates homeostasis of circuits that control critical functions such as the stress response, metabolism, reproduction, fluid balance and glucose control. These systems are frequently disrupted in neurodegenerative disorders though often overlooked in clinical practice. Objective: This review aims synthesize the available data regarding these disturbances in Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease and also to demonstrate the volume of literature in these individual arenas. Method: Using the scoping review framework, a literature search was performed in PubMed to identify relevant articles published within the past thirty years (January, 1988 – November, 2018). The search criteria produced a total of 2022 articles, 328 of which were identified as relevant to this review. Discussion: These neuroendocrine disturbances may be a precursor to the illness, a part of the primary pathophysiology, a direct consequence of the disease or independent of it. They have the potential to further understanding of the disease, exacerbate the underlying pathology or provide therapeutic benefit. Conclusion: By synthesizing the data from a systems’ perspective, we aim to broaden how clinicians think about these illnesses and provide care. Introduction: Neurodegenerative diseases cause progressive irreversible loss of specific neuronal populations. The disrupted neural circuitry often involves system disturbances which extend beyond the diseased territory in the brain. The neuroendocrine system is the interface between the central and peripheral endocrine systems and is a principal system affected by neuronal loss, though the relationship is rarely discussed. When functioning properly, this system helps maintain homeostatic balance that is in appropriate response to external signals. When disrupted, there can be broad downstream effects. The endocrine system is comprised of the central endocrine glands, such as the hypothalamus, pineal gland, anterior and posterior pituitary, in addition to the peripheral endocrine glands, including the thyroid and parathyroid glands, adrenal glands, the pancreas, ovaries and testes. The most commonly discussed neuroendocrine axes are the hypothalamicpituitary-adrenal (HPA) axis, hypothalamic-pituitary-thyroid (HPT) axis, hypothalamic-pituitarygonadal (HPG) axis, hypothalamic-pituitary-somatotropic (HPS) axis, and hypothalamic-
neurohypophyseal (HPN) system. Additionally, the role of both peripheral and central insulin signaling is becoming increasingly recognized. The HPA axis is primarily involved in regulating the stress response. The HPT axis is most relevant in regulation of metabolism. The HPG axis governs the reproductive system. The hypothalamic-neurohypophyseal system regulates the release of oxytocin, primarily involved with lactation, and vasopressin, which is an antidiuretic hormone with effects on fluid balance. See figure 1 for a visual depiction of the neuroendocrine axes. The burden of neurodegenerative diseases continues to grow and investigation of their pathophysiology and potential treatment remains an intense focus of the medical community. Certain neuroendocrine disturbances have been associated with neurodegenerative disorders. They may be a part of the primary pathophysiology, a direct result of the disease or independent of it. They have the potential both to aggravate underlying pathology and to be avenues with therapeutic potential. This review aims to synthesize the available data regarding the interactions between the neuroendocrine system and the following neurodegenerative disorders: Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington’s disease (HD). While the identified mechanisms of these diseases are quite distinct, they all involve progressive regional central neuronal loss that has broad systemic downstream effects. In exploring the involvement of the neuroendocrine system across multiple different neurodegenerative diseases, this review aims to broaden the discussion on management of these diseases in a multidisciplinary fashion. Figure 1: Methods: Given the broad scope and heterogenous nature of this undertaking, a scoping review framework was utilized to map the literature and demonstrate the volume published in these individual arenas 1 2. A literature search was performed in PubMed to identify relevant articles published within the past thirty years (January, 1988 – November, 2018). The following search (MeSH) terms were used: ‘Alzheimer’s’, ‘Parkinson’s’, ‘frontotemporal dementia’, ‘amyotrophic lateral sclerosis’, ‘Huntington’s’ and ‘dementia’ paired with ‘neuroendocrinology’ and ‘endocrinology’ individually. In addition, ‘dementia’ was paired with ‘HPA axis’. Articles were excluded if they were in vitro studies, not in the English language, or if they were not primarily focused on neurodegenerative disorders and the endocrine system, including those focused primarily on genetics, nutrition and those that discussed endocrinology in the context of the brain, but not in relation to aging or dementias. All selected articles were further reviewed and relevant data were consolidated in this review. Results: The search criteria produced a total of 2022 articles. Individual disease search terms paired with endocrinology produced 1564 articles. Those paired with neuroendocrinology produced a total of 313 articles. 145 articles were generated with the search terms dementia and HPA axis. Figure 2 demonstrates the search term results and their subsequent filtration. Based on the above criteria, 328 articles were identified as relevant to this review. In an effort
to be both comprehensive and concise, the most pertinent data was consolidated for this manuscript. Only the articles specifically cited in the manuscript are listed in the references. Table 1 summarizes the neuroendocrine systems and hormones that have been associated with neurodegenerative disorders. Figure 2: Discussion: Alzheimer’s Disease Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the most common presenting symptom being memory deficits followed by problems with executive functioning, language, and mood lability 3. The pathophysiology is not entirely known however it does include deposition of amyloid plaques and neurofibrillary tangles 4, in addition to acetylcholine deficiency 5 and regional subcortical and cortical volume loss, primarily of the temporal and parietal lobes followed by the frontal cortex and cingulate gyrus 6. HPA Axis: The HPA axis has many functions, though it is felt primarily to modulate the stress response in the body. The hypothalamus secretes corticotropin releasing hormone (CRH) which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). This then signals the adrenal glands to release cortisol, which has many downstream metabolic effects. Many studies suggest heightened HPA axis activity in AD. Elevated cortisol levels have been found in the CSF, urine, and serum (both before and after a dexamethasone suppression test) 7 8 . Elevated CSF cortisol and mineralocorticoid receptors have been associated with ApoE4 genotype 7. Hippocampal volume and general brain volume have been shown to be reduced with hypercortisolism 9. Cognitive status is negatively associated with both plasma 10 and CSF cortisol 7. In fact, higher levels of dementia with agitation have been found in those with a lack of dexamethasone suppression 11 12. In animal studies, stress and glucocorticoid administration increase amyloid beta formation in the cortex 13 and tau hyperphosphorylation in the hippocampus and prefrontal cortex 14. Interestingly, treatment with mifepristone, a glucocorticoid receptor antagonist, reduces cerebral amyloid beta, tau deposition and cognitive impairment in mouse models 15. HPA axis activation may serve as a marker of disease, contribute to underlying pathology and also may serve as a target for therapeutic intervention. HPG Axis: The HPG axis regulates the reproductive system in both men and women. The hypothalamus releases gonadotropin releasing hormone (GnRH) which signals the anterior pituitary to release luteinizing hormone (LH) and follicular stimulating hormone (FSH). In turn, FSH and LH signal the ovaries to release estrogen and progesterone or the testes to release testosterone. In the past, estrogen received a lot of attention for its relevance in AD but other reproductive hormones may be relevant as well 16. Elevated levels of FSH and LH have been demonstrated in AD 17. Low levels of estrogen confer increased risk of AD 16. There is conflicting evidence regarding the effect of estrogen replacement therapy (ERT). In brief, there
may be a “critical period” effect where women who receive ERT while entering menopause have reduced risk of AD 18 but in those who are 10 years past menopause, ERT is associated with an increased risk of dementia 19. Moreover, low peripheral and central levels of testosterone have been associated with AD in men 17. Dihydrotestosterone, the active form of testosterone, has been shown to reduce brain amyloid burden and behavioral impairment in mice 20 21. HPT Axis: The hypothalamus secretes thyrotropin releasing hormone (TRH) which signals the anterior pituitary to release thyroid stimulating hormone (TSH). In response to this, the thyroid secretes thyroxine (T4) and triiodothyronine (T3) which regulate metabolism throughout the body. Results regarding thyrotropin releasing hormone and AD have been conflicting however there have been more data to suggest low levels in AD 22. Additionally, TRH is decreased in the hippocampi of those with AD 23. Finally, low T3, but not TSH or T4, has been associated with AD 24 . HPS Axis: The hypothalamic-pituitary-somatotropic axis is also referred to as the hypothalamicpituitary-growth axis. The hypothalamus releases growth hormone releasing hormone (GHRH) and somatostatin which have stimulating and inhibiting effects on the anterior pituitary, respectively. When activated, the anterior pituitary releases growth hormone (GH) which primarily exerts effect on the liver. In response, the liver releases insulin-like growth factor-1 (IGF-1), which has broad downstream effects, such as bone growth, muscle development, cardiovascular function and on the brain. Lower levels of serum IGF-1 have been associated with increased risk of AD 25. In mouse models, IGF-1 receptor blockade in the choroid plexus induced changes similar to those found in AD such as amyloidosis, tau deposition and cognitive impairment 26. Restoring receptor function lead to improvement in these symptoms 26. IGF-1 and vitamin D have a complex relationship that involves the kidneys, parathyroid glands, bones and sun exposure. Finally, it has been shown that over 70% of those with AD have vitamin D deficiency 27. Parkinson’s Disease Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is caused primarily by neuronal death of the dopamine secreting cells of the substantia nigra in the basal ganglia in addition to Lewy body deposition 28. This leads to progressive motor symptoms including tremors, rigidity, bradyphrenia and shuffling gait in addition to cognitive decline and mood disturbances 29. HPA Axis: There is less information for the relationship of the HPA axis in PD. Of that available, there is conflicting evidence regarding HPA axis activity; both hyperactivity and hypoactivity have been found 30. Heightened activity has been demonstrated by elevated plasma levels of ACTH and cortisol 30. Additionally, interleukin-2 (IL-2), a cytokine relevant in the immune response, has been found to be elevated in the plasma of those with untreated PD. Treatment
with levodopa reduces IL-2 levels suggesting that the heightened immunoreactivity is related to altered dopaminergic signaling 30. Circadian rhythm disturbances are common in PD and it has been theorized that this drives the cortisol abnormalities as cortisol release is highly correlated with circadian rhythm 31. HPG Axis: There is a higher incidence of PD in men than women and in women with early menopause or hysterectomy compared to those without 32. Estrogen is thought to be protective against PD 33. In rodent models, 17 beta-estradiol has been demonstrated to be neuroprotective to dopaminergic neurons 33. Progesterone has also been found to be neuroprotective in animal models 32. Finally, in a study of 36 patients with PD, men with lower testosterone had faster progression of disease 34. HPS Axis: The gait and cognitive disturbances that occur in PD confer added fall risk. However, those with PD are also more likely to have decreased bone mineral density 35 thought to be due to low levels of vitamin D and secondary hyperparathyroidism 36. Having PD is associated with an elevated risk of fracture and treatment with levodopa has been show to actually confer added risk 36. Huntington’s Disease: Huntington’s Disease (HD) is characterized by progressive loss of coordination followed by chorea in addition to progressive cognitive and mood disturbance 37. It is caused by expansion of CAG triplets in the Huntingtin gene which results in production of abnormal Huntingtin protein 37 38. This protein damages the striatum initially and then spreads more broadly 38. HPA Axis: HPA axis disturbances have been demonstrated in humans with HD and also in animal models. Most studies have demonstrated HPA axis hyperactivity that may manifest early in the disease process; one study demonstrated both elevated total cortisol secretion rate and amplitude of diurnal release 39. It is thought that this might be due to impaired negative feedback as a result of mutant huntingtin protein deposition in the hypothalamus 40. Rodent models parallel the finding of elevated baseline cortisol and in addition demonstrate that the levels correlate with HD symptom progression 41. HPT Axis: Overall, the HPT axis has been found to be overly activated in HD in both patients and animal models. This is also thought to have potential influence on the metabolic hyperactivity and subsequent weight loss seen in HD. In one study of 9 patients with early stage HD, TSH was was not significantly elevated however total T3 and T4 levels were significantly higher than controls 42. In the same study, the higher degree of T3 correlation was associated with worse motor impairment while elevated T4 levels correlated with higher number of mutant cytosineadenine-guanine (CAG) repeat size 42. These findings may be related to central and peripheral
disturbances. Dopamine is related to TSH secretion and loss of D2 receptors in the hypothalamus and anterior pituitary have been demonstrated in early-stage HD patients 43 41. The fact that only elevated T4 levels were related to mutant CAG repeat size suggested that this effect was mediated peripherally 42. HPG Axis: The same study that demonstrated the disrupted HPT axis in HD also found that prolactin secretion is slightly elevated and more irregular in HD. The authors theorized that the hypothalamic dopamine disruption accounted for this 42. HPS Axis: There is limited and conflicting evidence regarding the HPS axis in HD 44. Some studies have demonstrated elevated basal growth hormone levels 45 while others have not 46. In one older study that evaluated the effect of dopamine agonists on growth hormone levels, a heighted response of growth hormone was seen in response to bromocriptine, apomorphine and levodopa when compared to controls 47. This was theorized to be related to heightened sensitivity of dopamine receptors in a damaged central dopaminergic system 47. However, a similar study did not find an increase in growth hormone after bromocriptine administration 46. Amyotrophic Lateral Sclerosis: Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle stiffness, fasciculations and weakness 48. Cognitive and behavioral disturbances can follow as well 49. The pathophysiology is not fully understood however involves cell death of upper and lower motor neurons 49. HPT Axis: Thyrotropin releasing hormone (TRH) has been shown to have trophic effect on motor neurons in animal models 50. In motor neuron disease, such as ALS, TRH content in the anterior horn region is decreased 51. Trials looking at the potential benefit of TRH administration in humans have had conflicting results, though this may serve as a target for potential adjunctive treatment in the future 52. HPN Axis: Plasma levels of arginine vasopressin (AVP) have been shown to be decreased in patients with ALS and in mouse models 52 53. HPS Axis: Baseline growth hormone levels have been shown to be reduced in patients with ALS as has the GH response to growth hormone releasing hormone plus arginine 54. Some studies have shown reduced IGF-1 levels in ALS patients 55 and IGF-1 is thought to be involved in GH secretion 54. Taken together, this suggests HPS axis disruption and has led to treatment trials with GH and IGF-1 analogues 54. Thus far, GH and IGF-1 have been shown to induce neuroprotection in ALS mouse models however clinical trials in ALS patients have failed to show benefit 56.
Frontotemporal Dementia: This diagnosis encompasses several different clinical syndromes all of which derive from degeneration primarily of the frontal or temporal lobes 57. This can cause a variety of behavioral, cognitive, motor and language deficits 58. The pathology is not fully understood though is often thought to involve abnormal tau protein deposition 58. Notably these syndromes are being increasingly recognized as components of ALS suggesting the potential of shared pathophysiology 59 60. There is notably little written about the interplay between the neuroendocrine system and FTD. One article does summarize the various physiological disturbances seen in FTD, in addition to ALS and AD, such as eating, metabolism, sleep and autonomic functioning 61. The authors hypothesize that most of these effects are mediated by disrupted circuitry involving the hypothalamus and it’s projections 61. For example, the hyperphagia and hypermetabolism seen in behavioral variant FTD is thought to be related disrupted homeostasis of hunger and satiety combined with dysregulated reward pathways 62. Another group has hypothesized a “bottom up” model for the FTD syndrome seen in ALS that may be partially mediated by estrogen levels as their study suggested estrogen was neuroprotective based on measures of cognition 63.
Insulin and Neurodegenerative Disorders Many studies have shown that diabetes mellitus (DM) is a risk factor for dementia overall. One meta-analysis found a 73% increased risk of all types of dementia, a 56% increase in risk of AD, and a 127% increase in vascular dementia in those with DM 64. DM occurs when there is either peripheral insulin resistance or decreased insulin production. Insulin is a hormone that is released by the pancreas and its primary function is to regulate glucose homeostasis. DM certainly is a cardiovascular risk factor and it follows that diabetic patients are at increased risk of vascular disease in the brain, such as strokes and vascular dementia. Moreover, there is growing evidence that insulin may have additional impact on the central nervous system, both directly and indirectly. While insulin in the brain is not commonly considered in the clinical setting, there are a large number of insulin receptors throughout the cerebral cortex and hippocampus, which is thought to have a key role in memory 65. The data regarding these relationships remains predominantly in the research realm at this time but they certainly have the potential for significant clinical relevance. For example, in those with the apolipoprotein E4 allele, elevated blood glucose is associated with more severe AD pathology post-mortem 66. Low levels of insulin in the CSF are found in AD 67. Insulin signals release of beta amyloid peptide to the external surface of the cell and induces expression of insulin degrading enzyme. Insulin degrading enzyme is also involved in the breakdown of amyloid beta 68. Central insulin regulation is also thought to be relevant in tau phosphorylation. Insulin resistance has been shown to exacerbate tau lesions. There is evidence that normal tau functions to regulate central insulin and when tau hyperphosphorylation occurs, there is subsequent loss of normal central insulin homeostasis 69. The brains of patients with AD are considered to be insulin resistant, a syndrome with a suggested name of “type 3 diabetes” 70. Treatment for DM has been and continues to be explored for potential benefit in AD. Thus far, there is conflicting evidence regarding the impact of metformin and sulfonylureas 71.
Pioglitazone has shown benefit in mild to moderate AD 72. Glucagon-like peptide receptor agonists also have shown benefit. Finally, intranasal insulin has been shown to enhance both memory and mood in AD patients 73. There has been conflicting evidence regarding whether tighter glycemic control slows the rate of progression of cognitive decline 74. That being said, it should be noted that management of concurrent DM and dementia is a complex scenario as it requires balancing the optimal therapy with the cognitive capabilities of the patient and their environmental context; both hyper and hypoglycemia can have significant detrimental consequences in this population 75. Table 1:
Therapeutic Considerations: Broadly speaking, thinking about these various illnesses with a neuroendocrine lens may lead to innovative therapeutic approaches. The data consolidated in this article have implications for risk assessment, diagnosis, and treatment. For example, there might be an element of subclinical Cushing’s syndrome in those with rapidly progressive AD; if so, this could be screened for and potentially treated 76. Behaviors such as exercise might have protective benefit due to their stress reduction and anti-inflammatory effects. Perhaps we should be taking a more thorough history of symptoms of hypogonadism and menopause when assessing for AD. If TRH confers neuroprotection in AD, the pathway could be mimicked. Perhaps further studies of IGF-1 agents will demonstrate more robust therapeutic benefit in AD 26. Bone health could become a component of PD management. In those with subjective memory complaints, we might more aggressively recommend better glucose control. Targeting the HPA axis hyperactivity in HD might slow progression of disease as it has been theorized that the metabolic consequence of elevated cortisol levels may contribute to weight loss and death 77. Perhaps evaluating neuroendocrine status should be a larger part of determining risk of developing neurodegenerative diseases. This information could be combined with other data to generate a risk prediction model similar to those commonly utilized in assessing cardiovascular disease risk. These models typically combine data such as age, sex, blood pressure, lipid values, smoking habits and comorbidities to generate an individual’s risk score. Perhaps a similar approach could be used with dementias. For example, an algorithm combining cortisol, A1C, estrogen, and exercise level might be able to generate a risk score for AD. With better risk assessment, there may be more avenues to modify outcomes preemptively. Finally, given the growing impact of these diseases and the increasing knowledge that their impact extends beyond the brain, there may be a role for a broader, multi-domain approach to treatment of neurodegenerative disorders, similar to those used in management of other chronic diseases. As a comparison, good diabetes care involves not only management of glucose levels, but also includes screening for kidney disease, checking for peripheral neuropathy, prescribing ace inhibitors for blood pressure and statins for cardiovascular risk. If neurodegenerative disorders were approached in a similar way, perhaps a visit to the clinic would not be limited to a neurological exam and bedside cognitive testing, but would include addressing bone health, diabetes and HPA axis imbalance.
As we await additional research with definitive answers to the queries posed above, we recommend considering how the evidence available can be incorporated into current practice. Checking vitamin D levels and hemoglobin A1C are relatively simple ways to start. Asking about menopause can initiate dialogue about estrogen replacement therapy and its relevance in AD. Finally, familiarizing oneself with the different diabetes medications and their neurologic relevance will likely prove useful as more research is done in this arena. Limitations: This review aimed to demonstrate the utility in thinking about neurodegenerative disorders through a neuroendocrine lens. Many examples were included but a review of this length cannot be exhaustive. In addition to the limitations imposed by language restrictions and the search engine utilized, the selection process was likely informed by the authors’ educational and training background. Certain diseases have had much more written about them than others which influenced the amount of material from which to select data. Finally, the quality of the data was not verified for the purpose of this review so we acknowledge that the caliber of study designs written about was likely mixed. Conclusions: Neurodegenerative disorders lead to progressive regional neuronal cell death. Despite their distinct entities, they share the common pattern of a brain pathology that has broad downstream effects. The neuroendocrine system regulates homeostasis throughout the body and the highest levels of control are located in the brain. There is evidence that neuroendocrine disturbances often predate diagnosis and may confer risk. These disturbances may also occur in parallel with these various disorders or be direct results of them. These findings translate into many different potential avenues for intervention in terms of risk reduction and treatment. More data are needed to understand the risks and benefits of pertinent interventions. However, we propose that further research be done with a neuroendocrine approach to provide a broader, multi-disciplinary approach to caring for neurodegenerative diseases. Disclosures: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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Physiology, Pituitary Gland Copyright © 2019, StatPearls Publishing LLC. https://creativecommons.org/licenses/by/4.0/
Figure 1: Visual depiction of the neuroendocrine hormones and their target organs
Figure 2: Flowchart demonstrating the search terms, the numbers of articles identified, and those selected for review in this study
System HPA
HPT
HPG
GH / IGF-1
Posterior Pituitary
Hormones CRH ACTH Cortisol TRH Thyrotropin TSH T4 T3 GnRH LH FSH Prolactin Estrogen Progesterone Testosterone GH IGF-1 Somatostatin Ghrelin Vasopressin Oxytocin Insulin
Glucose Metabolism Sleep Cycle Melatonin
AD • • • •
PD
Huntington’s ALS
• •
•
FTD
• • • •
• • • • •
• • • •
• •
•
•
• •
•
•
• •
•
•
•
•
•
•
Table 1: Summary table of hormones associated with neurodegenerative disorders