Amyotrophic lateral sclerosis (ALS) and the endocrine system: Are there any further ties to be explored?

Abstract

Amyotrophic Lateral Sclerosis (ALS) belongs to the family of neurodegenerative disorders and is classified as fronto-temporal dementia (FTD), progressive muscular atrophy, primary lateral sclerosis, and pseudobulbar palsy. Even though endocrine dysfunction independently impacts the ALS-related survival rate, the complex connection between ALS and the endocrine system has not been studied in depth. Here we review earlier and recent findings on how ALS interacts with hormones a) of the hypothalamus and pituitary gland, b) the thyroid gland, c) the pancreas, d) the adipose tissue, e) the parathyroid glands, f) the bones, g) the adrenal glands, and h) the gonads (ovaries and testes). Of note, endocrine issues should always be explored in patients with ALS, especially those with low skeletal muscle and bone mass, vitamin D deficiency, and decreased insulin sensitivity (diabetes mellitus). Because ALS is a progressively deteriorating disease, addressing any potential endocrine co-morbidities in patients with this malady is quite important for decreasing the overall ALS-associated disease burden. Importantly, as this burden is estimated to increase globally in the decades to follow, in part because of an increasingly aging population, it is high time for future multi-center, multi-ethnic studies to assess the link between ALS and the endocrine system in significantly larger patient populations. Last, the psychosocial stress experienced by patients with ALS and its psycho-neuro-endocrinological sequelae, including hypothalamic–pituitaryadrenal dysregulation, should become an area of intensive study in the future.

Introduction

Amyotrophic Lateral Sclerosis (ALS) (also, maladie de Charcot or Lou Gehring’s disease) is clinically characterized by rapid deterioration of muscle spasticity and atrophy, leading to the dysfunction of respiratory muscles, and upper and lower motor neurons in the brain and spinal cord), and ultimately death in ∼3–5 years post diagnosis [111]. Amyotrophic refers to the death of spinal motor neurons, which leads to muscle atrophy through denervation, and lateral sclerosis refers to the scarring of motor neuron axons in the lateral spinal cord [151]. A schematic representation of muscle dysfunction and ALS pathology is depicted in Fig. 1. Initial clinical manifestations of the disease have been heterogeneous among afflicted patients (e.g., spinal or bulbar onset leading to muscle weakness of limbs and difficulty swallowing/speaking) [65]. At the cellular level, ALS appears to be a multi-step process, which involves protein aggregation, formation of prion-like structures, and hallmarked by the presence of Bunina bodies, which are defined as small eosinophilic intraneuronal inclusions in the remaining lower motor neurons [5], [110]. Given the contribution of reactive astrocytes, microglia, and compromised oligodendroglial function, ALS should be considered a non-cellular, autonomous disease [5].

Fig. 1.

Schematic diagram showing the effects of amyotrophic lateral sclerosis (ALS) on nerve and muscle cell morphology. The left panel depicts muscle tissue innervated by a normal nerve cell innervating and the right panel shows the diseased state. ALS is a complex neuron disease leading to progressive neural dysfunction, resulting in stiffness, twitching, weakening and atrophy of voluntary muscles, and ultimately death of the patient.

Despite the initial descriptions of the disease in the nineteenth century, the complete etiology of ALS remains unknown. Its therapy mainly consists of riluzole administration, while it additionally focuses on symptom management and palliative care [38]. Of note, intraventricular administration of cerebrospinal fluid from patients with ALS to mouse models expressing human TDP43WT leads to neuroinflammation and pathology resembling ALS; this suggests an endogenous ALS transmitting factor [98]. Besides the role of environmental factors and cellular stochastic events, the appearance of ALS is explained, in most cases, by varying degrees of genetic contribution, from typical Mendelian patterns (e.g., SOD1 mutation) to epistatic associations of rare variants (for discussion, see [150]). In patients with familial ALS, the penetrance of most implicated genes is not high; thus, the phenotype is not frequently associated with the genotype [6]. Although polygenic risk scores have recently been developed, the implications of genetic classification on diagnosis, treatment, and prognosis of patient outcomes are still unknown [13]. As a result, ALS remains a clinically defined disease, in which imaging and/ or laboratory tests (except electromyography) are not generally included in the diagnostic criteria. Classification of ALS varies according to the diagnostic criteria, such as the El Escorial [20] or Awaji criteria [56]. Notably, the high prevalence of cognitive and behavioral symptoms in patients with ALS, alongside with the discovery of the first major link between hexanucleotide repeat expansions (on the order of hundreds of repeats [77] in the C9orf72 gene/0 and the ALS-FTD continuum [43], [124] have both played a role in re-characterizing ALS as a neurodegenerative rather than a neuromuscular disorder.

The epidemiology of ALS is characterized by low prevalence rates and high fatality. In Europe, the incidence of ALS is in the range of two to three cases per 100,000 individuals [129]. In contrast to earlier assumptions, ALS incidence varies according to ancestral origin, with European population-related studies showing a coarse incidence of greater than three cases per 100,000 individuals [31], [66]. However, in South and East Asia, the incidence is significantly lower, i.e., at ∼0.8 cases/100,000 individuals and ∼0.7 cases/100,000 individuals, respectively)). Global epidemiology of ALS is biased due to the fact that 80 percent of the studies have been conducted in the United States and Europe, with patient cohorts primarily of Northern European ancestry [65]. Of note, the prevalence of ALS is expected to increase by ∼70% by 2040, most likely due to an aging population; this increase will exacerbate the socio-economic burden of disease [11], which was predicted for each country over a 25-year time span [44]. A recent umbrella systematic review identified several environmental risk factors for ALS, with either strong (i.e., previous exposure to lead) or suggestive evidence in low socio-demographic index (SDI) nations (i.e., farming, exposure to other heavy metals, head injury, and β-carotene intake) [16]. However, the high degree of ALS rates in regions with high SDI, such as North America, Australia, and Western Europe (2018), suggest that a number of unidentified risk factors remain to be identified.

An average of 20 genes are implicated in the majority of familial cases of ALS, which represent ten percent of all patients with the disorder; nonetheless, these genes can only explain 10% of sporadic cases, which make up to 90% of all patients with ALS [29] (for a review on genes implicated in ALS, see [30]. Moreover, several genetic loci have been linked to ALS progression, many among which are implicated in the regulation of transcription and mitochondrial function, suggesting that these two processes have a major role in the pathogenesis of ALS (Table 1). Interestingly, some of these ALS genes encode proteins that can potentially disrupt the ubiquitin–proteasome system or exocytosis-related release of vesicles, for instance, the genes for superoxide dismutase-1 (SOD1), transitional endoplasmic reticulum ATPase or Valosin-containing protein (VCP), ubiquilin-2 (UBQLN2) [64], and Unc-13 homolog A (UNC13A) [45]. Moreover, chaperone protein dysregulation contributes to the progression of ALS that is associated with mutations of TARDBP and SOD1 [17], [28]. FIG4 and alsin mutants were also implicated through their effects on autophagy, although the underlying pathophysiology is yet to be understood [50]. In addition, cytoskeleton proteins, like dynactin and tubulin, have been associated with ALS pathology, as well [84].

Table 1.

Examples of genes associated with the ALS phenotype.

ALS-linked Genes	Pathologic Biomarkers	ALS phenotypes	References
FUS/TLS	TDP-43 Mutation	Inherited ALS	[88]
SOD1	SOD1	Familial ALS	[46]
SQSTM1	P62	Familial and Sporadic	[152]
MAPT, PGRN, VCP, CHMP2B, TDP-43, FUS	Tau	Behavioral variant FTD and ALS	[51]
P56S and T46I	VAPB	Familial ALS	[71]
ANG and TARDBP	FUS	Genetic ALS	[21]
ERBB4	Neuregulin-ErbB4	Familial ALS	[149]
ALS2	ALS2	Juvenile ALS	[139]
E478G	OPTN	Familial ALS	[89]
CHCHD10	CHCHD10	Familial ALS	[116]

As ALS is a motor neuron-related disorders, the endocrine system is not primarily involved in its pathophysiology. However, endocrine dysfunction could independently impact the ALS-related survival rate, even though the connection of ALS with the endocrine system has not been clearly established. Importantly, specific endocrine dysfunction symptoms have been observed in different groups of ALS patients, with phenotypes varying in different systems and organs. In general, the hormone profile of patients with ALS is substantially different from that of normal controls; for example, these patients exhibited higher levels of testosterone (T), a higher dehydroepiandrosterone sulfate/cortisol ratio, and a lower progesterone/free testosterone ratio, particularly in those patient subgroups with worse prognosis [54]. However, in animal models for ALS, low testosterone levels have been detected in both the adrenal glands and the plasma, alongside with high corticosterone levels [59]. In light of such differences in the literature, we aim here to report on earlier and recent findings and to discuss the dysfunction of endocrine organs during ALS progression, ultimately aiming to highlight medically important findings in this ALS-endocrine system cross-talk.

Amyotrophic lateral sclerosis, the hypothalamus, and the pituitary gland

Among the hormones of the hypothalamus and pituitary gland, growth hormone (GH) is the one most studied in connection with ALS. GH is made up of a single polypeptide chain of 191 amino acids and is mainly responsible for regulating physiological processes, such as growth and metabolism. Somatotroph cells synthesize and secrete GH from the anterior pituitary gland into the systemic circulation. GH secretion is chiefly regulated by the hypothalamus; however, GH can also be partially stimulated by ghrelin, estrogen, exercise, and fasting. GH is inhibited by hyperglycemia, chronic glucocorticoid exposure, and dihydrotestosterone [2]. Of note, GH levels are reduced in around two thirds of patients with ALS, especially those with bulbar-onset disease [101], [134]. Also, modified levels of GH have been noted in the hypothalamus and pituitary gland, alongside with dipeptide repeat proteins-associated features, such as aggregates of TDP-43 in patients with ALS [42].

Moreover, in patients with lesions in the hypothalamus or removal of growth hormone-producing pituitary adenomas resulted in (or at least contributed in part to) the appearance of ALS [99]. At the molecular level, GH exercised positive effects both in terms of neuroprotection and neurogenesis through several signaling pathways, such as the PI3K, MAPK, and JAK pathways [36]. Also, even though GH (and, in turn, insulin-like growth factor) levels were elevated at the onset of ALS (at least in certain mouse models) possibly as a way to reverse muscle innervation, hormone levels decreased as the disease progressed [145], [147]. However, results of both previous and more recent studies administering recombinant GH in patients with ALS have not been promising [134], [145].

Insulin and IGF-1 signaling may be impaired in patients with ALS; in particular, high circulating IGF-1 levels have been associated with higher survival rates in ALS, possibly because insulin signaling appeared to reverse several features of neurodegeneration [12], [138], [105]. Intiguingly, IGF-1 bound to its receptor (IGF-1R), which activated the mammalian target of rapamycin (mTOR) pathway and inhibited autophagy (in particular, macro-autophagy), and led to dysfunction of astrocytes that might have caused motor neuron death. In contrast, the inhibition of the above pathway reversed these cellular processes [62]. The same receptor (i.e., IGF-1R) affected the axonal transport of signaling endosomes (but interestingly, not lysosomes and/or mitochondria) in a dynein family protein-mediated manner, ultimately affecting neuronal survival [49].

Broadly, it is reasonable to mention that the ALS-related degenerative processes could be affected by regional afflictions in lesions of the hypothalamus, notably atrophy of both the anterior and posterior hypothalamus [4], [60]. Likewise, a decreased hypothalamic volume may be associated with disease onset, whereas decreased hypothalamic volume due to weight loss may further influence ALS onset [60], [160], [161]. Of note, the most critical question is how a hypothalamic perturbation relates mechanistically to ALS progression. The well-established connection between neurodegenerative and neuroinflammatory diseases with hypothalamic–pituitaryadrenal (HPA) axis dysregulation, where corticotropin-releasing hormone, ACTH, and glucocorticoids play a pivotal role, has not been adequately studied in ALS and necessitates further investigation [92], [32], [33], [34], [35], [156], [157]. Particularly, one of the hallmarks of a dysregulated HPA axis-related neuroinflammation or, more broadly, inflammation, is interleukin (IL)-6 (IL-6) secretion [7], [154]. Thus, during stress, IL-6 secretion by immune cells is stimulated and, in turn, activates the HPA axis, contributing to a stress system- immune system inter-regulatory loop [91], [170].

Of note, IL-6 has been a promising biomarker for assessing functional status (notably, muscle atrophy and pulmonary inflammation) in patients with ALS, at least in those harboring specific variants of the IL-6 receptor (IL-6 R) gene [121], [167]. Therefore, monoclonal antibodies targeting the IL-6R, such as tocilizumab, may be a promising therapeutic option in patients with ALS [96]. However, there are other equally important pathways through which ALS is linked to neuroinflammation, such as the cellular NF-κB signaling pathway and the potential inflammation-related role of TDP-43 [19], [72], whose description exceeds the scope of this review. In contrast, histamine could exert a potential anti-inflammatory action in ALS, as recently shown through several lines of evidence [9]. To begin with, histamine activated H1 and H4 receptors, which attenuated several inflammatory markers, including NF-κB and NADPH oxidase 2, but increased levels of arginase 1, P2Y12 receptor, and the anti-inflammatory cytokines IL-6, IL-10, CD206, and CD163, only in the microglia of ALS mouse models and not in healthy mice (ref). In addition, a downregulation of H1 and H2 receptors, as well as several enzymes that metabolize histamine, have been observed in neuronal tissue of ALS mouse models [9]. Other modes of histamine function in ALS include the activation of the AKT and ERK1/2 pathways, an increase in mitochondrial function and, in turn, ATP content, a reduction in myelin basic protein, denervation of the neuromuscular junction, and alteration in the expression level of genes implicated in histamine receptor response, histamine transport/secretion, histamine metabolic processes, and intracellular signal transduction [101], [8].

Recent studies have suggested other hypothalamic hormones could be of potential importance in ALS, especially in FTD (further reviewed in [1], [2]). In particular, among the different neuronal subtypes (i.e., those related to oxytocin, vasopressin, cocaine- and amphetamine-regulating transcript, orexin, etc.), ALS-related hypothalamic atrophy appears linked mostly to loss of orexin and oxytocin neurons [52]. Moreover, in specific hypermetabolic mouse models of ALS, the disruption of electric signals of the secondary motor cortex and other brain regions to the hypothalamus was observed [14]. A previous study applied single-cell next-generation sequencing methods to neurons of the primary motor cortex from patients with ALS [119], and this approach could be applied to study secondary motor cortex, as well.

Amyotrophic lateral sclerosis and the thyroid gland

Thyroid dysfunction has been linked to several neurological disorders, which include proximal myopathies and peripheral neuropathies; hence, it remains unknown whether a dysfunctional thyroid could contribute to ALS pathogenesis. In a West Germany-based study, forty-four patients suffering from ALS living in an iodine-deficient area were assessed for thyroid function [78]; all of them had normal thyroid function on the basis of biochemical and clinical criteria, including radioimmunoassay of triiodothyronine (T3), thyroxine (T4), human thyroxine-binding globulin (TBG), and human thyrotropin (Deng et al.). In addition, these patients underwent thyrotropin-releasing hormone (TRH) stimulation tests, which were reportedly normal. Moreover, goiter incidence in that population was not higher than that of an endemic goiter population. Therefore, this study strongly suggests that thyroid dysfunction is not linked to ALS onset and prognosis, an observation corroborated by more recent studies [169]. Nonetheless, we cannot exclude the possibility that a poorly functional thyroid system could influence ALS-related myopathy or muscle disease, exacerbating muscular weakness and cramps [93].

Amyotrophic lateral sclerosis & metabolism

Historically, in the late 1940s and early 1950s, the connection between ALS and dysregulated metabolism (the latter notably through pancreatic endocrine dysfunction) was highlighted in reports linking motor neuron disease and pancreatic islet tumors. Nowadays, some lines of research have linked ALS and carbohydrate intolerance; for instance, it has been suggested that close to half of all patients with ALS suffer from glucose intolerance, indicating potential ties between ALS and diabetes. In these cases, impaired glucose tolerance was characterized by a diabetic-type glucose response curve [10].

It is well-established that mitochondria play a major role in the regulation of insulin production and that their dysfunction contributes to diabetes mellitus. In patients with ALS, disease-specific pathophysiological changes are strongly linked to marked and gradual alterations in mitochondrial morphology, calcium, and bioenergetics. Therefore, impaired mitochondrial function seems to have a role in rapid neurodegeneration in ALS [102], [144]. Thus, analyzing mitochondrial involvement in ALS pathogenesis would provide meaningful answers to questions on the potential pathophysiologic ties between ALS and diabetes.

Potential metabolic biomarkers for ALS include defects in respiratory complex I and IV activity, downregulation of mitochondrial protein expression in muscle, and upregulation of mitochondrial uncoupling protein in muscle [115], [148]. A body of evidence from studies in both animal models and patients with ALS suggested strong links between ALS progression and mitochondrial dysfunction [118]; for instance, defects in mitochondrial transport was responsible for accumulating pathological mitochondria in motor neuron axons [83], [68]. Based on in vitro studies in transgenic animal models, perturbation of the mitochondrial oxidative capacity further impacted mitochondrial respiration through impaired the electron transport chain (ETC) activity and ATP production [159]. Low ATP levels could be attributed to the weakening of motor neurons, thus, creating a vicious cycle further worsening ALS disease manifestations [148]. In addition, mitochondria from patients with ALS have impaired homeostasis of Ca²⁺; the latter is both an important second messenger required by the pancreatic β-cells and neurons [76], as well as a potential biomarker predicting the progression of ALS during its initial stages. Nevertheless, perturbation in Ca²⁺ levels could also be linked to increased production of reactive oxygen species (ROS) that may lead to oxidative-related damage, which, in turn, induces changes in protein carbonylation and tyrosine nitration [27], [58].

Of note, future clinical studies could assess whether defects in mitochondria corroborate functional aspects of ALS disease progression. A schematic diagram showing ALS mitochondrial dysfunction is shown in Fig. 2. An additional focus is how sensitive are patients with ALS to insulin levels’ fluctuation. In a previous study [61], plasma glucose and insulin levels were measured after oral administration of 50 g of glucose during a glucose tolerance test in patients with ALS. These patients exhibited significantly different levels of both glucose and insulin from those in the control group. These results indicate that patients with ALS may have impaired insulin secretion and/or action.

Fig. 2.

Pathophysiology of amyotrophic lateral sclerosis (ALS). Several pathophysiologic mechanisms underlie ALS-related neurodegeneration, with scientific evidence in favor of a complex interaction between intracellular biochemical pathways and mitochondrial dysfunction. The latter results in the perturbation of the mitochondrial electron transport chain that leads to generating free oxygen radicals, which contribute to neurodegeneration. Mitochondrial dysfunction results in reduced ATP levels and increased mitochondrial Ca²⁺, which leads to increased mitochondrial membrane depolarization and release of cytochrome c. The latter, combined with activation of caspases 9 and 3 (not depicted), culminates in death by apoptosis. Of further relevance is the formation of intracellular aggregates affecting cellular processed related to neurofilaments and axonal transport. Associated activation of microglia leads to secretion of proinflammatory cytokines, e.g., interleukin-1 (IL-1), tumor necrosis factor-a (TNF-α) and interferon-g (IFN-γ)), which further damage the nearby nerves. IL-1: interleukin-1b; TNF-α: tumor necrosis factor-a; IFN-γ: interferon-γ.

Various factors could play a role in the glucose intolerance that is observed in patients with ALS. It has been shown that auto-antibodies in people with ALS target and destroy the insulin-secreting β-cells in the pancreas, leading to the progression of type 2 diabetes mellitus (T2DM) [140]. More than half of patients with ALS and T2DM comorbidity have elevations in cytosolic free Ca²⁺ concentration ([Ca2+]_i) that are induced by potassium. Ca²⁺ homeostasis plays a key role in glucose-dependent insulin secretion, which is mediated by K⁺_ATP channels, membrane depolarization, and Ca²⁺ entry. The above phenotype was primarily attributed to pathogenic IgG auto-antibodies in the serum of patients with ALS-T2DM. The causal IgGs stimulated the voltage-dependent Ca²⁺ channel subunit CaVα2δ1 in the plasma membrane, leading to CaV1 channel-mediated Ca²⁺ influx and [Ca²⁺]_I elevation, which, in turn, resulted in attenuated mitochondrial function [100]. Collectively, impaired [Ca2+]_i dynamics, mitochondrial dysfunction, and perturbed insulin secretion led to pancreatic β-cell toxicity in patients with ALS [122]. Moreover, these reports suggest that ALS-T2DM patients possess a cytotoxic IgG autoantibody that may be the causal link between ALS and T2DM. However, extensive research is required to better understand the ALS-T2DM axis, considering that other epidemiological reports suggest T2DM (in contrast to T1DM) is a protective factor regarding ALS [79].

Amyotrophic lateral sclerosis and adipose tissue

Nutritional abnormalities, including cachexia, may lead to ALS progression [22], [131]. Importantly, reduction in BMI is one of the strongest predictors of mortality in patients with ALS [40]. In contrast, high body mass index (BMI), onset of diabetes, and hyperlipidemia have been associated with increased survival in patients with ALS. In an EPIC cohort study focused on nutrition and ALS, increased body fat was significantly linked to decreased risk of ALS [53]. In another study, data from a large (n = 6098) meta-analysis corroborated the effects of BMI (measured before the disease diagnosis or progression) on the survival rates of patients with ALS. Importantly, increased BMI was considered a protective factor in terms of overall survival in patients with ALS, whereas underweight individuals were at increased risk of developing ALS and death from the disease’s progression [40]. Conversely, hypercaloric diets may lead to increased survival rates in animal models, but the results have been less encouraging in humans [165].

Several factors are implicated in linking adipose tissue with ALS. To begin with, ghrelin regulates appetite and food intake, as well as secretion of growth hormone. These processes help avert excessive loss of body weight and catabolic processes observed in ALS [107]. Moreover, patients with ALS were found to have lower levels of serum retinol-binding protein 4 (RBP4), which serves both as a transport protein for vitamin A and an adipokine involved in insulin resistance [146], compared to controls, but higher levels of neuropeptide Y (NPY), a neuropeptide mostly expressed in interneurons and linked to neurogenesis, and leptin levels. Of note, leptin and adiponectin levels were respectively negatively and positively correlated with survival rates in patients with ALS [130], [107], [3], [104]. However, one study reported no statistically significant differences between these biomarkers, at least in cerebrospinal fluid, in ALS [90].

Amyotrophic lateral sclerosis, parathyroid glands, and calcitonin

Studies have both supported and refuted the association between primary hyperparathyroidism (PHP) and ALS [57], [143]. In one study, patients with PHP and ALS improved their muscular endurance after having undergone parathyroid adenoma resection [26], [114]. However, other studies reported no significant pathogenic associations between thyroid or/and parathyroid dysfunction and ALS progression [128]. In support of the latter findings, Jackson et al. [67] showed that in five patients with ALS and PHP, in whom parathyroid adenoma resection was performed, all of them maintained normal serum calcium and PTH levels; however, later, during the course of the diseases, all patients presented progressive muscle weakness, which eventually led to death within three years. Of note, some similarities were observed in the pattern of PHP and ALS progression, such as proximal weakness, muscular atrophy, and/or dysarthria; however, most studies did not support any definite association between ALS and hyperparathyroidism, while only a few case reports have described ALS and hyperparathyroidism comorbidities [67], [97], [127].

Equally noteworthy are the studies assessing how ALS pathophysiology is affected by the calcitonin gene-related peptide (CGRP), an alternatively spliced isoform of calcitonin [133], which is physiologically expressed in the spinal cords alongside with its receptor and associated molecules [153], [120]. Particularly, CGRP has long been known to be accumulated in both the anterior and posterior spinal horns of patients with familial ALS [74], potentially being entraped during axonal transport (at least as suggested in [75]). More recently, CGRP high expression levels were associated with higher levels of motor neuron degeneration [126], especially with regards to astrogliosis and less with vacuolization [125]. Collectively, more elaborate studies (fundamental, preclinical, and clinical) would be needed to support any association between the two complex disorders.

Amyotrophic lateral sclerosis and bone metabolism

In general, the quality of bone is quite low in all subgroups of patients with ALS, thus explaining (at least partially) the high number of skeletal fractures in these patients; nonetheless, the mechanisms behind how alterations in bone marrow could impact ALS is poorly understood, even though they implicate TSH- and vitamin D-related pathways [24]. Of note, ALS is characterized by progressive bone decalcification, even though this association has not been fully confirmed, as studies report conflicted findings [70], [86]. Using bone density and serum biochemical techniques, Sato et al. [135] identified vitamin D deficiency in two out of eleven patients with ALS vs. a control group. Thus, could vitamin D supplementation be beneficial to patients with ALS and other neuromuscular diseases? Even though vitamin D supplementation is inefficient in treating ALS symptoms, it could still be used to manage symptoms of vitamin D deficiency in these patients [85], [155]. There is increasing evidence that the loss of bone formation in ALS may affect muscular atrophy, not only the reverse, as previously considered [171]. Further studies exploring the prevalence of metabolic bone disorder in patients with ALS are necessary to ultimately determine the best treatment strategies.

On a tissue level, the features of bone loss have been described as decreased trabecular bone mass, thinner trabeculae, and decreased cortical bone thickness, and cortical area in comparison to control mice [82]. Moreover, the molecular underpinnings of ALS-related muscular atrophy leading to attenuated bone formation seem to involve sclerostin, a protein that inhibits osteoblasts [87], RANKL, a protein that activates osteoclasts and their β-catenin [142], and bone morphogenetic protein 4, which plays a critical role in creating endochondral bone [166], [141], [172]. However, other bone metabolism-related molecules that are associated with higher and lower survival in ALS refer to C-terminal telopeptides of type I collagen and N-terminal peptides of procollagen type I, respectively [47]. Last, variants in genes such as sequestosome 1 (SQSTM1), VCP/p47 complex-interacting protein 1 (VCP), and optineurin (OPTN), which are associated with bone metabolic diseases (i.e., Paget’s disease of the bone) have also been linked to ALS and FTD [132].

Amyotrophic lateral sclerosis and the adrenal glands

Patients with ALS demonstrate elevated glucocorticoid levels, enlarged adrenal glands, and an attenuated response in glucocorticoid regulation. Elevated levels of adrenal glucocorticoids may also inhibit their response to exogenous steroids [41], [113], [123]. Moreover, stable levels of cortisol after a mild stress test and loss of circadian control of cortisol secretion (i.e., elevated levels of cortisol in the evening), as observed in aging subjects and in posttraumatic stress, is observed in patients with ALS as well; as such, it presents a major biomarker of adrenal dysregulation [55], [113], [117]. Therefore, it would be interesting to explore how chronic stress, and as a corollary, enhanced glucocorticoid signaling, could mechanistically contribute to ALS progression. Several studies have shown significant differences in salivary biomarkers (as proxy for blood) of patients with ALS vs. healthy subjects [48], [136], [162]. Dysfunction in the adrenal glands may not directly reflect progression of ALS; however, it may exacerbate progression of ALS in the context of chronic stress. For example, glucocorticoids have been shown to exacerbate oxygen rich free radicals–mediated neurotoxicity [94], a process potentially implicated in ALS-related neurodegeneration. Reportedly, adrenal dysregulation in patients with ALS may not be related to the clinical symptoms or the progression of the disease [80], indicating that further studies are necessary in this field. In this context, the hypothalamic–pituitaryadrenal axis dysregulation, associated with psychosocial stress and other potential psycho-neuro-endocrinological sequelae in patients with ALS, should become an area of intensive study in the future, similarly to other disorders of the nervous (e.g., multiple sclerosis [95], and other systems [92], [32], [33], [34], [35], [156], [157]).

On the pathology level, several observations have been made: a) the adrenal glands of patients with ALS are enlarged, although not as enlarged as those observed in Multiple Sclerosis [123]; b) the adrenal medulla harbors accumulations of TDP-43 in the cytoplasm [109], and c) major statistical differences were observed in the levels of tyrosine hydroxylase (which is implicated in the biosynthesis of catecholamines [103], but not choline acetyltransferase (as assessed by immunohistochemistry) in the adrenal glands of the SOD1 vs. non-mutant mice. As tyrosine hydroxylase is linked to adrenal gland function, the above results suggest a major role of the adrenal glands in the sympathetic function of patients with ALS [73].

Amyotrophic lateral sclerosis and the ovaries and testes

Weiner et al. postulated that ALS may result, at least in part, from defects in motor neuron androgen receptors, with possible involvement of gonadal steroids [163]. Loss of androgen receptors observed in motor neurons may partially explain the progression of ALS [15], by decreasing the nerves’ trophic stimulation, which, in turn, results in degeneration of the axons and muscular atrophy. Similarly, motor neurons in patients with ALS demonstrated decreased concentrations of androgen receptors compared to those of healthy individuals [81]. Such observations are associated with the male sex, the age of ALS onset, and with how the androgen receptors are distributed in motor neurons. To study the effects of treating androgen defects in male patients with ALS, male patients were treated with testosterone cyproterone acetate, an anti-androgen-receptor drug. Even though the levels of basal testosterone were similar between patients with ALS and control subjects, the response of gonadotropin to the luteinising hormone in patients with ALS was decreased compared to that of the healthy controls. This study showed that no direct evidence existed between gonadal defects in male patients and ALS progression per se [69].

With regards to female patients with ALS, studies explored whether ovarian function was linked to the pathogenesis of the disorder. Some studies suggested that basal estradiol levels in patients with ALS were similar to those in the age-matched control group [23], [101]. Also, the gonadotropin responses to gonadotropin-releasing hormone were found within normal levels. However, other studies support a clear protective role of estrogen in ALS, as shown by: a) the effects of ovariectomy in downregulating estrogen’s protective role in spinal cord motor neurons [63], [168], b) the effects of estrogen and progesterone on serotonergic neurons, whose dysfunction is linked to ALS-related clinical manifestations, such as depression [18]; and, c) the ovarian tissue in SOD1-deficient mice exhibited several follicles, which gave rise to oocytes, bur rare corpora lutea, which produced progesterone [39]. Besides, the neuroprotective action of estrogen has long been shown and includes several cellular mechanisms, e.g., from Ca²⁺-related signaling to mitochondrial metabolism [137]. As a result, because of the limited number of studies, it has been difficult to establish whether any association exists between pre- or post-menopausal ALS onset; thus, more studies with a larger number of patients would be needed.

Summary and future directions

In conclusion, our understanding of the underlying causes of ALS pathophysiology has clearly increased [106], [158]. Recent studies suggested that ALS is caused by alterations of various cellular processes, with many interacting molecular pathways [37], [100], [108]. Some therapies examined in clinical trials for ALS include drugs targeting specific factors and SOD1 inhibitors, gene therapies, monoclonal antibodies, and cell-based therapies [25], [112], [164]. In addition, processes involved in ALS pathogenesis, like glutamate signaling, mitochondrial function, Ca²⁺ regulation, oxidative stress, and axonal transport, could be investigated to develop ALS therapeutics. Clinical studies have provided some hope to many patients and opened new horizons for better characterization of the disease pathophysiology. Scientific advancements, including stem cell and genetics-based strategies, have provided researchers with new ways to better understand, diagnose, treat, and prevent the disease. However, because of the multifaceted nature of ALS pathophysiology, combination therapies, such as stem cell, genomic, or antibody strategies coupled with SOD1 or glutamate antagonists, may pave the way for an effective option to tackle ALS.

In the same context, any associations to be unraveled between ALS and the endocrine system (e.g., adrenal glands and stress and/or pancreas and glucose intolerance) could potentially lead to meaningful therapeutic approaches. For instance, such therapeutic approaches could be taken in patients with ALS and potential co-morbid endocrine disorders (e.g., hypothyroidism), and could help alleviate the already high burden of ALS-related morbidity. Of note, by focusing solely on ALS treatment, patients with ALS may neglect and/or worry less about other (e.g., endocrine system) comorbidities which are treatable. Metabolic studies, especially those on sarcopenia and osteopenia, and the associated hormones, such as ghrelin, will help inform on treatment plans for ALS. For example, studies have shown that lower BMI is linked to higher mortality rates in ALS patients and such information would be useful in devising a suitable dietary plan. Assessing whether certain non-metabolically linked yet endocrine system-related therapies, such as vitamin D intake, can assist patients with ALS in averting negative alterations in their musculoskeletal system.