The role of the AR in areas relevant to the neurological and psychological symptoms of PFS

Cognitive dysfunction, Anhedonia and Anxiety

Anxiety, loss of motivation, loss of aggression, lack of feelings of wellbeing, severe anhedonia and visuospatial and cognitive impairment are some the most frequent neuropsychological complaints in PFS. These can manifest with a profound severity and entail a devastating impact on quality of life. This is strongly suggestive of impairment in executive, reward and motivational circuitry in the brain. The important role of metabolite neurosteroids ​(Diotel et al., 2018)​, shown to be broadly deregulated in PFS ​(Melcangi et al., 2017)​, may have additional relevance to these symptomatic areas. However, this is beyond the scope of this review, which is focused upon a potential pleiotropic pathomechanism with direct relevance to the full clinical picture and underlying the pathology.

Low serum testosterone is strongly associated with an increase in depression in aging men ​(Ford et al., 2016)​ and men undergoing ADT ​(Lee et al., 2014)​. Androgens have mostly anxiolytic and antidepressant properties in humans and animals ​(Liang et al., 2018; McHenry et al., 2014; Zarrouf et al., 2009)​. Androgens regulate gene expression in key areas of the brain that are fundamental to the etiology of depression and anxiety ​(McHenry et al., 2014)​. AR-deficient mice rapidly develop depressive-like behaviour with exposure to chronic mild stress ​(Hung et al., 2019)​ and significant comparative reductions in AR in the hypothalamic paraventricular nucleus (PVN) has been identified in autopsied depression patients ​(Wang et al., 2008)​. Androgen administration has anti-depressive effects in middle-aged men with low testosterone levels ​(Amanatkar et al., 2014)​. Owens et al. reported significantly increased AR mRNA in the PFC of patients with bipolar disorder as surprising given the association of depression with low androgen levels but noted the association of excessive androgen signaling with psychological illness ​(Owens et al., 2019)​.

Impaired executive functioning and visuospatial abilities are the most frequently reported cognitive consequences of androgen deprivation therapy ​(Nelson et al., 2008)​. Additionally, multiple lines of evidence including in anabolic steroid abuse and polycystic ovary syndrome suggests increased androgen action is markedly associated with psychological illnesses including schizophrenia, psychosis, bipolar disorder, tics, anxiety and depression ​(Cesta et al., 2016; Piacentino et al., 2015; Wood, 2008)​. In an important review of the role of androgens in the mesolimbic system and of evidence that both high and low androgen signaling causes cognitive impairment in both human and animals, Tobiansky et al. suggested that optimally required levels of androgen signaling are required within the mesolimbic system ​(Tobiansky et al., 2018)​. Mesolimbic areas crucial to executive function including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC) express AR ​(Kritzer, 1997; Low et al., 2017; Tobiansky et al., 2018)​, areas which functionally align with the effects of androgens on behaviour ​(Kritzer, 1997)​. As the AR relevant to function in these areas is often not concentrated in neuronal nuclei, this has been traditionally difficult to quantify and easily overlooked. Executive functioning, which includes behavioural prioritisation of goal attainment, attention, inhibitory control and working memory, critically depends on PFC function ​(Tobiansky et al., 2018)​. Importantly, all major prefrontal cortical projections in the VTA are substantially AR enriched. Androgen signaling regulates the essential dopamine innervation of the PFC and regulates glutamate signaling, potentially through these circuits ​(Aubele & Kritzer, 2011)​. The NAc is critically involved in reward behaviour and is an integrative and convergent site for reward systems in the brain ​(Sesack & Grace, 2009)​. Neurons in the NAc respond to both excitatory and inhibitory afferents from the ventral hippocampus (vHPC) ​(Scudder et al., 2018)​. In the rat, AR is colocalised with dopamine neurons in the midbrain that project to the amygdala and nucleus accumbens ​(Creutz & Kritzer, 2004)​. In line with human studies suggesting an increase in testosterone raises striatal dopamine ​(Hermans et al., 2010)​, studies in the male rat have demonstrated AR-driven modulation of molecular measures of dopamine responsivity of the nigrostriatal pathway including regulating mRNA, levels of molecules involved in pre-synaptic dopamine synthesis, dopamine reuptake, packaging, breakdown and reception ​(Purves-Tyson et al., 2014)​. Dopamine is increased in reward regions of the rat brain in under 30 minutes ​(de Souza Silva et al., 2009)​, and the testosterone-induced effect on reward behaviour is abolished by administration of the dopamine receptor antagonist α-flupentixol ​(Packard et al., 1998)​. Coincident with a sharp decline in voluntary physical activity, AR knockout mice show a substantial loss of dopamine and dopamine receptor expression in the striatum, with upregulation of mRNA levels of the metabolic enzymes monoamine oxidase A and B ​(Jardí et al., 2018)​. Alongside a significant reduction in voluntary activity, mice with knockout of hypothalamus-specific AR exhibited a large decrease in D₁ receptor mRNA and an increase in MOAB mRNA ​(Clarke et al., 2019)​. Interestingly, androgen-anabolic steroids significantly decrease D₁ receptor in the NAc ​(Kindlundh et al., 2001)​ and testosterone administration impairs D₁ receptor-dependent set-shifting behaviour in rats ​(Wallin & Wood, 2015)​. DHT treatment inhibits the open-field induced dopamine increase in the PFC ​(Handa et al., 1997)​. This has important implications for cognitive functioning considering the importance of PFC functions. Loss of adequate D₁ receptor function in the PFC of Rhesus macaques causes cognitive deficits close to surgical ablation of the site ​(Brozoski et al., 1979; Tobiansky et al., 2018)​.

In late adolescent rats, finasteride remarkably decreases the activity of the dopaminergic system, exploratory and motor behaviours through decreasing DHT production and consequently androgen receptor activation on dopamine neurons in the Substantia nigra and VTA. Interestingly, this effect was not seen in older or younger rats ​(Li et al., 2017)​. The reported reduction in brain DHT of late adolescent rats had not been observed in younger rats in a previous study ​(Giatti et al., 2015)​, suggesting significant interruption in brain dopaminergic activity occurs when AR activation is inhibited during the time testosterone levels are at their natural peak ​(Li et al., 2017)​. This spatiotemporal observation of age-related difference is of potential relevance to the prevalence of PFS in young adult men of fertile age.

Androgens have been demonstrated to modulate the HPA stress response and modulate anxiety behaviours ​(Mhaouty-Kodja, 2018)​. While all metabolites of testosterone, including DHT, influence anxiety-like behaviours in animal models, aged male rats are more anxious than female counterparts. This difference is abolished by prepubertal orchiectomy, demonstrating this difference is androgen dependent ​(Domonkos et al., 2017)​. Evidence suggests the anxiolytic effect of T is mediated at least in part through the AR. Men treated with flutamide experience increased anxiety ​(Almeida et al., 2004)​. Intrahippocampal flutamide increases anxiety behaviour of intact and DHT-replaced male rats, but not when independently administered to gonadectomised rats ​(Edinger & Frye, 2006)​. Corticotropin-releasing hormone is an important regulator of the HPA axis and response. AR mediates regulation of corticotropin-releasing hormone mRNA in the PVN, possibly via AR-colocalising projecting neurons in the bed nucleus of the stria terminalis ​(Heck & Handa, 2019)​.

Williams et al. demonstrated sex differences in the resilience to stress-induced anhedonia in mice and revealed an androgen-mediated mechanism underlying lower vHPC-NAc excitability and correlated increase in subchronic stress resistance in male mice. Reduced sucrose preference following subchronic variable stress (SVS) was demonstrated to be female specific. Orchidectomy rendered male mice vulnerable to SVS-induced anhedonia. Testosterone to female mice was protective of SVS-induced anhedonia and decreased vHPC-NAc excitability in females. Ovariectomy, by contrast, did not affect female vHPC-NAc neuron excitability, suggesting direct mediation by the AR. It was determined that vHPC-NAc projection neurons, and many surrounding vHPC CA1 pyramidal cells highly express AR, and that bath application of the antiandrogen flutamide increased the excitability of cells ​(Williams et al., 2020)​, further suggesting interruption of androgen signalling conferred this susceptibility. The identification of this specific androgen-driven circuitry and its causal link to anhedonia suggests that a tissue-specific deregulation of the AR, as we propose in PFS, would have significant implications for dopaminergic signalling in the NAc and consequently anhedonia symptoms.

Providing a vital addition to the understanding of both the rapid effect of nonclassical androgen signaling on human social behaviour and the AR-dependency of testosterone’s influence on aggression, Geniole et al. demonstrated that a single administration of testosterone to men with high-risk personality profiles increased aggression. This effect was negatively correlated with AR CAG repeat length, with shorter CAG repeat subjects exhibiting an enhanced effect. These effects were associated with increase reward feelings associated with aggression as opposed to anger associated with aggression, suggesting a rapid AR-mediated modulation of dopamine pathways in line with existing evidence ​(Geniole et al., 2019)​.

Conclusively, significant evidence indicates the curvilinear tissue response of androgen action is relevant to anxiety and mood ​(Owens et al., 2019)​ as well as cognitive function ​(Tobiansky et al., 2018)​.

Memory and spatial processing

Severe memory impairment is a common and problem reported by PFS patients, with many extremely serious implications for the patient’s life. The hippocampus is critical to a broad range of learning, memory, visual, spatial, and navigatory functions in mammals ​(Eichenbaum, 2017; Rolls & Wirth, 2018)​. In humans, CA1 neurons are crucial to memory formation and retrieval, as well as self-continuity, autonoetic consciousness and detailed memory revisitation ​(Bartsch et al., 2011)​. The AR is highly expressed in the hippocampus, particularly in CA1 pyramidal neurons. In addition to nuclear and cytoplasmic presence, AR is localised in spines, and synaptic AR rapidly responds to androgen, directly modulating spine density by kinase network activation ​(Hatanaka et al., 2015; Soma et al., 2018)​. Pyramidal CA1 neurons require NMDA receptors for spatial and temporal memory ​(Huerta et al., 2000)​. Neural AR deletion in mice impaired NMDAR activation and prevented temporal differentiation between objects seen, revealing hippocampal CA1 AR is critical for processing of visual temporal information, possibly through an observed modulation of glutamatergic transmission ​(Picot et al., 2016)​.

AR overexpression is demonstrated to strongly alter memory-related genes in the CA1 region ​(Ramzan et al., 2018)​. Finasteride has been demonstrated to significantly decrease brain DHT levels and reversibly reduce neurogenesis in the hippocampus of mice, affecting neuronal plasticity on a structural level ​(Römer et al., 2010)​. Hippocampal AR in humans is highly expressed in both sexes. Remarkably, this is of the same order of magnitude as AR expression in the prostate of BPH patients ​(Beyenburg et al., 2000)​. Multiple studies suggest androgens as important organisational modulators of hippocampal physiology that maintain active hippocampal functions throughout life ​(Hamson et al., 2016; Kerr et al., 1995)​. Perceived male sex-related advantages in spatio-visual and navigatory abilities have been attributed to androgens rather than evolutionary adaptation ​(Clint et al., 2012)​. Reports on the effects of androgens on spatial ability have provided contradictory results, suggestive of complex regulation ​(Shahrzad & Nasser, 2015)​. Men with Alzheimer’s disease have lower brain testosterone, and findings suggest that low androgens may predispose to Alzheimer’s ​(Rosario et al., 2011)​. In Alzheimer’s models, testosterone has been demonstrated to exert a protective effect via an AR-mediated increase hippocampal neurons, synaptic plasticity and dendritic spine density ​(Jia et al., 2019)​. However, prelimbic testosterone injection causes impairment in spatial learning and memory in male Wistar rats ​(Gholaminejad et al., 2019)​. Clearly, crucial sites involved in learning, memory and spatial processing are markedly sensitive to alteration in androgen signaling.

Insomnia and sleep disordered breathing

PFS has driven patients to suicide through the rapid and persistent destruction of their ability to sleep. In severely affected patients, this can be total. A patient who had resumed finasteride for a very short time with a stated aim of maintaining his hair for upcoming wedding photographs committed suicide after describing the rapid onset of extreme health complaints including debilitating anxiety and insomnia that prevented any sleep for a month. Severely affected patients often describe poor-quality, brief and interrupted sleep many years after brief use of the drug. This is an important and disabling symptom, the severity of which does not appear to be appreciated in literature. Additionally, patients have reported onset or worsening of sleep apnoea. Irwig found that insomnia was a common complaint in the medical records of 6 patients who committed suicide following use of Finasteride and development of persistent symptoms, and this was amongst their most debilitating symptoms ​(Irwig, 2020)​. Evidence suggests that, as well as low testosterone being associated with a decrease in sleep quality ​(Barrett-Connor et al., 2008)​, increased androgen signaling may be associated with sleep disruption and disordered breathing. Higher testosterone levels are associate with lower sleep intensity and higher ventilatory instability in men ​(Morselli et al., 2018)​, and whole genome methylation analysis has shown elevated AR protein is associated with obstructive sleep apnoea (OSA) via ventilatory instability ​(Chen et al., 2016)​. High dose exogenous testosterone can cause significant disruption of sleep to the extent of clinically relevant harm, as well as inducing and exacerbating OSA ​(Kim & Cho, 2019; Liu et al., 2003)​. Exogenous T has induced sleep apnoea in a female patient ​(Johnson et al., 1984)​. In the hyperandrogenic condition PCOS, meta-analysis of research has indicated a significant association of OSA with the syndrome ​(Helvaci et al., 2017)​. As previously mentioned, a high occurrence of sleep disorders has been reported in SBMA patients ​(Romigi et al., 2014)​. Androgens act locally in the suprachiasmatic nucleus, the hypothalamic structure controlling behavioural and physiological circadian rhythms, to influence plastic structural reorganisation and alter circadian period ​(Model et al., 2015)​. Androgen receptors are present in the suprachiasmatic nucleus, are regulated locally by androgens, and thus are an obvious site of action for a direct effect of androgen steroids ​(Karatsoreos & Silver, 2007)​. Significant clinical differences in the response of healthy men and women to a single dose of Olanzapine ​(Giménez et al., 2011)​ suggest sex differences in the mechanisms regulating sleep (Mong & Cusmano, 2016). The exact influence of sex steroids over sleep remains an important knowledge gap ​(Mong & Cusmano, 2016)​.

Head pressure

A central and potentially causative role of androgen signaling was recently demonstrated in idiopathic intracranial hypertension (IIH), which entails an increase of CSF pressure. O’Reilly et al. identified a pattern of androgen excess in female IIH patients. Like human choroid plexus, rat cells expressed AR along with androgen-metabolising enzymes. It was demonstrated that testosterone drove CSF output in rodent choroid plexus cells ​(O’Reilly et al., 2019)​. O’Reilly et al. noted that while a determinant role for androgens in IIH may seem biologically implausible considering IIH occurs less frequently in men, androgens are now known to exert sexually dimorphic effects on metabolism. The metabolic phenotype of hypogonadal men resembles that of women with androgen excess, including an increased risk of type 2 diabetes, non-alcoholic fatty liver disease and cardiovascular mortality ​(Ding et al., 2006; Kautzky-Willer et al., 2016)​. O’Reilly et al. suggest epigenetic modifications to local androgen action or differences in AR signaling in both sexes as a plausible explanation, with IIH potentially representing a distinctive manifestation of these sex specific differences ​(O’Reilly et al., 2019)​. Interestingly, male IIH patients are more likely to have symptoms typically associated with androgen insufficiency including obstructive sleep apnoea, erectile dysfunction and loss of libido ​(Fraser et al., 2010)​. As well, androgen deprivation therapy or hypogonadism can induce IIH symptomatology ​(Valcamonico et al., 2013)​. Although in males the metabolic parabola of AR signaling is shifted far to the right compared with females ​(Ding et al., 2006; Morford et al., 2018)​, significant increases in AR signaling in men are likely to recapitulate this symptomatology, and we therefore consider it plausible IIH occurs in PFS and contributes to commonly reported symptoms, including feelings of intense pressure in the head. In this context, it is of interest that the pilot study of Melcangi et al. evaluating CSF methylation in PFS patients and controls found only one member of the control group with methylation of SRD5A2, and this patient had normal-pressure hydrocephalus. The majority of PFS patient samples exhibited variable methylation of this gene ​(Melcangi et al., 2019)​.

Methylation of SRD5AR2

It is of interest that SRD5A2 was reported to be methylated in most CSF samples in a cohort of PFS patients. Interestingly, symptoms and severity per validated scales were found not to correlate to the observed methylation profiles ​(Melcangi et al., 2019)​. This is unlikely to represent a key factor in the pathological presentation when considering the symptomatic profile, novel factors of the condition and the lack of significant overlap between PFS and 5 alpha reductase insufficiency ​(Brinkmann et al., 2007; Imperato-McGinley et al., 1974)​.

5 alpha reductase type II is localised to many areas abundant in dopamine neurons and sites of projection, and finasteride has been considered for application in conditions associated with increased dopaminergic signaling including Parkinson’s disease, Tourette’s syndrome and schizophrenia ​(Castelli et al., 2013)​. Reduced D2 dopamine receptor binding in the nucleus accumbens has been reported in 5ar2 knockout mice. This was accompanied with behavioural deficits in aggressive, dominance, mating behaviours, along with reduced novelty seeking and risk taking. No anxiety-like, motoric or processing deficits were observed in these mice, and 5ar2 deficiency is not associated with sensorimotor deficit nor abnormalities in anxiety-like or reward-related behaviours ​(Mosher et al., 2018)​. Further, sexual desire is usually normal in human patients ​(Brinkmann et al., 2007)​. A role in neurosteroidgenesis could have some symptomatic relevance given their behavioural influences ​(Edinger & Frye, 2005; Ratner et al., 2019)​. However, hypotheses regarding the pathological alterations in PFS being localised to the nervous system do not plausibly account for the symptoms of patients, nor take appropriate account of reported evidence from investigations of peripheral tissues.

Evidence suggests that the methylation status of SRD5A2 is under regulatory influence of androgen signaling. Both serum DHT and SRD5A2 mRNA in seminal vesicles have been demonstrated to significantly increase in inducible ARKO mice, demonstrating that SRD5A2 is regulated by the AR through local negative feedback ​(Wu et al., 2019)​. 5ar2 expression in the rat brain has been demonstrated to be under feed-forward regulation of androgens ​(Torres & Ortega, 2003)​. In the frog Silurana tropicalis, Bissegger and Langlois demonstrated that while SRD5A2 was not altered at the mRNA level, DNA methylation of SRD5A2 significantly increased in the testes and ovaries following treatment with DHT, suggesting androgen modulation of epigenetic mechanisms in both sexes. The methylation statuses of SRD5A1 and SRD5A3 were not changed following androgen exposure ​(Bissegger & Langlois, 2016)​.

One possible mechanistic influence of androgen signaling on methylation of SRD5A2 is the role of androgens in inflammatory regulation and a consequential influence on the methyltransferase enzyme DNA methyltransferase 1 (DNMT1). Kang et al. found a majority of BPH samples have methylation of the SRD5A2 promoter, with strong correlation between methylation and low or absent expression of 5alpha reductase 2 ​(Kang et al., 2018)​. Ge et al. reported that, in human prostate samples, DNMT1 regulates methylation of SRD5A2. The methylation of the promotor was shown to be increased by inflammatory mediators such as tumor necrosis factor α (TNF-α), Nuclear factor-kappa B (NF-κB), and Interleukin-6 (IL-6) which upregulate DNMT1 expression. Inhibition of TNF-α restored the expression of SRD5A2 ​(Ge et al., 2015)​. In prostate cancer cells, androgen signaling crosstalk exists with inflammatory signaling (Malinen et al., 2017). As previously discussed, the AR has an upregulatory effect on TNF-α expression and is thus suppressive of cutaneous wound healing ​(Lai et al., 2009)​. DHT activates macrophage TNF-α secretion through AR signaling in prostatic urethral tissue ​(Zhao et al., 2017)​. In the CNS, epigenetic macrophage activation increases proinflammatory cytokines and chemokines, including TNF-α and IL-6 ​(Yin et al., 2017)​.

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