The role of the AR in areas relevant to the physiological symptoms of PFS

Muscle atrophy and muscular dysfunction

Evidence regarding the ligand- and dose-dependent atrophic consequences of AR overexpression in muscle have been discussed in a previous section. Muscle AR is a major determinant of muscle mass and function. Owing to this, selective androgen receptor modulators are in development with a focus on therapeutic application to diseases including muscle wasting and cachexia ​(Narayanan et al., 2018; Srinath & Dobs, 2014)​. In mice with AR knockout in satellite cells, the precursor cells of skeletal muscle, limb maximal grip strength is decreased by 7% despite similar mass, with altered fiber-type distribution observed in soleus muscles. The weight of the perineal LABC muscle is markedly reduced, weighing 52 percent less than control animals ​(Dubois et al., 2014)​. Significant levator ani weight reduction occurs in inducible ARKO mice in adulthood independent of earlier AR expression ​(Wu et al., 2019)​. It is well appreciated that both the innervating lower motor neurons and the skeletal muscle of the LABC are exquisitely sensitive to androgens ​(Z. Yu, 2006)​, highly expressive of AR ​(D. Ashley Monks & Holmes, 2017; Narayanan et al., 2018)​ and androgen dependent for survival and function ​(N. Forger et al., 1993; N. G. Forger et al., 1992; Johansen et al., 2007; C. Jordan et al., 1997; C. L. Jordan et al., 1991; Douglas Ashley Monks et al., 2004; Schrøder, 1980; J. Xu et al., 2001)​. In female ovariectomized mice with consequently diminished pelvic muscles, two SARMs restored pelvic floor muscles to sham operated control weights, with a nonsignificant trend towards an overall increase in lean body mass ​(Ponnusamy et al., 2017)​. As a key site for histological analysis of AR-mediated toxicity ​(Nath et al., 2018)​, the pelvic floor muscle area is a promising site for biopsy and gene expression assay in PFS patients, as well as for less invasive study including EMG evaluation.

Defects in excitation contraction coupling and intracellular calcium homeostasis of skeletal muscle result in a wide range of myopathies including weakness, myalgia, cramping, muscle wasting, joint stiffness and exercise intolerance ​(Dowling et al., 2014)​. The AR is an important regulator of genes involved in muscle contraction, function, structure and calcium dynamics ​(Chivet et al., 2019)​. Using a computational biology approach, Chivet et al. identified androgen response elements in the enhancers, promoters, and 5’-untranslated regions of excitation-contraction coupling-related genes found to be dysregulated in their transcriptome analysis of AR100Q, AR113Q mice and SBMA patients. Restoration was achievable partly with castration and fully with suppression of polyQ AR using antisense oligonucleotides, suggesting a reversibility of the disruption. Importantly, these genes were found to be similarly dysregulated in castrated wild-type mice, establishing the key genes involved in muscle contraction as being under the regulation of androgen signaling ​(Chivet et al., 2019)​.

Myostatin is a growth factor that strongly inhibits muscle growth ​(McPherron et al., 1997)​, and is under the regulation of AR signaling. Dubois et al. reported a >6-fold decrease in myostatin expression in levator ani muscle of satellite ARKO mice, as well as significant downregulation in the gastrocnemius. Additionally, a reduction of myostatin mRNA levels in orchiectomised mice could be fully reversed with testosterone or DHT administration, demonstrating that myostatin is androgen regulated ​(Dubois et al., 2014)​. However, Mendler et al. reported a strong suppression of myostatin mRNA levels by androgens in the skeletal muscle of young male rats. Considering the presence of ARE on the myostatin gene and the induction of androgen receptor coregulators by myostatin, they speculate that a negative feedback-loop exists between myostatin and androgen pathways ​(Mendler et al., 2007)​.

Skeletal and dental problems

Bone-related complaints are frequent, and diagnosis of osteopenia and osteoporosis are reported by PFS patients. All aspects of body composition are determined by the actions of sex steroids including in the skeleton. Body composition is generally more robust in men, and the risk of osteoporosis is approximately half that of women ​(Vanderschueren et al., 2014)​. Hypogonadal men have lowered bone mineral density that is normalised by exogenous testosterone treatment ​(Behre et al., 1997)​. In addition to ER, appropriate AR signaling is independently required for adult bone health and maintenance ​(J.-F. Chen et al., 2019)​. AR is ubiquitously expressed in human bone marrow in both sexes ​(Mantalaris et al., 2001)​. Detailed tissue specific and global studies of ARKO in bone have revealed a critical regulatory role for androgens in bone health and maintenance on a compartmental basis ​(Vanderschueren et al., 2014)​. Men with complete or partial androgen insensitivity syndrome have a reduced final height that is intermediate between ordinary males and females, as well as reduced lumbar spine density that cannot be compensated by estrogen replacement ​(Danilovic et al., 2006)​. The dramatic reduction in lumbar bone density in androgen insensitivity syndrome patients is not seen in men with 5alpha redutase type II insufficiency syndrome ​(Sobel et al., 2006)​. In Asian men with prostate cancer, 12 months of ADT with either combined GnRH agonist and bicalutamide therapy or GnRH monotherapy induces the same significant loss of bone mineral density ​(Joung et al., 2017)​. Collectively, this illustrates a direct role of the AR in human bone maintenance. To account for the potential of the confounding influence on developmental influences in lifelong ARKO models, Wu et al. developed an inducible ARKO model, demonstrating appropriate AR expression in adulthood is crucial for bone maintenance in adult male mice. Both pre and post-pubertal AR inactivation resulted in significant decreases in the mid-diaphyseal cortical area and cortical thickness in the tibia, as well as trabecular bone volume fraction in the metaphyseal region ​(Wu et al., 2019)​. The reduced cortical thickness was seen to be a “phenocopy” of previously reported models of lifelong AR inactivation ​(Almeida et al., 2017)​.

In a transgenic mouse model, Wiren et al. explored the consequences of targeted AR overexpression in differentiated osteoblasts, demonstrating that excess AR signaling results in a significantly negative consequences on bone matrix quality, biomechanical competence, fragility and strength, while reducing turnover and inhibiting osteoblastic formation ​(Wiren et al., 2008)​. In line with these findings, Aro et al. locally delivered a SARM via an implanted sustained-release matrix in a rat bone marrow ablation model. Contrary to the stated hypothesis of an anabolic effect on intramedullary osteogenesis, only the lowest dose had a negligible anabolic effect, while all higher doses resulted in a dose-dependent decrease in new bone formation around the implant and the bone/implant contact. This was noted to be reflective of overexpression models ​(Aro et al., 2015)​. These findings support the suggestion of Vanderschueren et al that neither too high nor too low AR activity is favourable for bone. Steffens et al. have demonstrated in rats that, as with low levels of testosterone following orchidectomy, supraphysiological doses also increase ligature-induced periodontal bone loss ​(Joao P. Steffens et al., 2012; Joao Paulo Steffens et al., 2015)​, plausibly reflecting the curvilinear dose relationship of AR signaling ​(Gibson et al., 2018)​.

Tooth loss and gum problems are frequent in PFS patients, with many reports of rapid degeneration of teeth, gum recession and the condition causing the need to undergo gingival grafts. Similarly, significantly affected male patients have reported progressive alterations to the jaw structure after cessation. This is notably reported by two brothers who developed PFS after only two weeks of use. It is therefore again highly significant that several lines of evidence suggest periodontal and gingival tissues, tissues responsible for teeth structure and gum health, are dependent on androgens and specifically AR signaling. AR inhibition has been demonstrated to significantly increase peridontal bone loss and impairs bone repair in female rats and is regulatory of inflammatory markers in gingival tissue ​(João Paulo Steffens et al., 2018, 2019)​. Minocyline can stimulate 5alpha reductase in gingival tissue, and combinatory administration with finasteride has suggested that some of the anabolic response to minocycline in these tissues are attributed to the AR pathyway ​(Soory & Virdi, 1998)​. Parkar et al. analysed numerous human peridontal ligament and gingival tissue samples as well as cultured cells for expression of AR. In contrast to ER which was not detected, AR was readily detected in a high proportion of tissue and all fibroblasts, suggesting a high and direct sensitivity to androgens in these tissues with implications for inflammation, connective tissue and bone repair processes ​(Parkar et al., 1996)​. AR is also highly expressed in human tooth pulp, with a greater expression in males than females, and is subject to hormonal manipulation in vitro. T was observed to significantly reduce AR content in tooth pulp, while E2 or androstenedione increased AR mRNA. This suggests, as with bone, this tissue is highly androgen responsive ​(Dale et al., 2002)​. Wang et al. systematically examined the mandibles of castrated rhesus macaques in prime and old age against those of control animals to determine the impact of low androgens on bone and teeth. A prevalence of periodontitis, significant alveolar bone recession and severe temporomandibular joint osteoarthritis was observed in the old castrates. Faces were indicated to be generally narrower by reduced distance between rami. Cortical bone of the mandibular body and rami was thinner, and molar teeth were slender in castrates. These findings collectively suggest the importance of androgens to development and maintenance of facial structure, skeletal and dental health in macaques ​(Q. Wang et al., 2015)​. In addition, androgens exert a significant nociceptive behavioural response and are protective against temporomandibular joint pain in castrated male and female rats, but not sham-operated males. This was demonstrated to be mediated by the AR and is independent of aromatisation to estrogen or the organisational effects of androgens ​(Fanton et al., 2017)​.

Metabolic regulation

Androgens and the AR are increasingly appreciated as important regulators of metabolic function through actions across the body, and increasing evidence suggests an important influence on metabolic regulation through actions in neurons in hypothalamic and extra-hypothalamic sites in addition to peripheral tissues ​(Morford et al., 2018)​. As in broader evidence we have discussed, there appears to be a parabolic nature to androgen signaling in metabolic function, with high and low levels being detrimental in both sexes, although the parabola is shifted far to the right in males ​(Morford et al., 2018)​. Low androgens and androgen deprivation therapy for prostate cancer increase the risk of type 2 diabetes and obesity in men, and studies in humans and animal models have associated low androgens with hyperglycemia, decreased pancreatic β-cell function, impaired fasting glucose, glucose intolerance, altered lipid profiles and metabolic syndrome ​(Morford et al., 2018; G. Navarro et al., 2016; I.-C. Yu et al., 2014)​. Central AR knockout in males causes late-onset insulin resistance, glucose intolerance, lipid accumulation in the liver and visceral obesity ​(I.-C. Yu et al., 2012)​. ARKO also induces leptin resistance ​(Fan et al., 2008)​. AR CAG repeat length is positively correlated with higher body fat content, increased leptin and hyperinsulinemia in men ​(Zitzmann et al., 2003)​ owing to weaker AR signaling. Interestingly, the risk of type 2 diabetes was recently shown to be 30% greater over 11 years in men receiving either finasteride or dutasteride for BPH, without a difference between the drugs ​(Wei et al., 2019)​. Excessive androgen signaling is also detrimental to optimum metabolic function in males. Male powerlifters using anabolic steroids have diminished glucose tolerance secondary to insulin resistance when compared with non-steroid using athletes and sedentary weight men ​(COHEN & HICKMAN, 1987)​. In castrated rats administered high doses of testosterone, insulin resistance was observed, as with the castrated group. Castrated rats administered testosterone at a dosage that restored physiological levels abolished the perturbation of insulin sensitivity induced by castration, suggesting an appropriate “window” of androgen signaling is required for metabolic homeostasis in males ​(HOLMÄNG & BJÖRNTORP, 1992)​.

Hyperandrogenaemia in women results in metabolic effects strikingly coincident with hypogonadism in men, including predisposition to type 2 diabetes ​(Escobar-Morreale et al., 2014)​. In female mice fed a representative “Western” diet, chronic DHT administration predisposed subjects to type 2 diabetes due to activation of AR in the hypothalamus, which promoted hepatic insulin resistance. In these mice, increased AR signaling in pancreatic β cells increased mitochondrial oxygen consumption and caused insulin hypersecretion, oxidative injury, and predisposed to secondary β cell failure ​(G. Navarro et al., 2018)​. RNA-seq has identified a fold change >2 in the expression of 214 genes in AR-deficient islets, and that a third of these are proteins associated with cellular stress and inflammation, indicating a response to injury and emphasising the importance of appropriate AR signaling to β cell health ​(W. Xu et al., 2017)​. Another study in adult female rats showed hyperinsulinemia due to elevated DHT occurs without alteration in the number or size of pancreatic islets or change in β-cell area. Even though DHT treated females had higher insulin levels than controls, they exhibited glucose intolerance with elevated plasma glucose. Ins1 was shown to have an ARE-like sequence that bound to AR upon DHT treatment, suggesting functional regulation of insulin by the AR and androgen. Additionally, skeletal muscle Irβ, the major utiliser of glucose, was downregulated in this model ​(Mishra et al., 2018)​. Independent of obesity, female mice eating a normal diet administered low-dose DHT exhibit impaired whole-body glucose metabolism consisting of glucose intolerance, hepatocyte AR-mediated insulin resistance, impaired gluconeogenic capacity and hyperinsulinemia. This was in addition to observations pertaining to reproductive dysfunction including acyclicity, decreased corpora lutea, and increased atretic follicles that were beyond the scope of the study ​(Andrisse et al., 2016)​. Reflective of evidence in animal models, 50-90% of women with PCOS, a condition characterised by pathological hyperandrogenemia, display insulin resistance and glucose intolerance ​(Morford et al., 2018; W. Xu et al., 2019)​. Testosterone levels robustly correlate with the degree of insulin resistance and β-cell dysfunction in PCOS ​(Sahin et al., 2014; W. Xu et al., 2019)​. The Glucagon-Like Peptide-1 (GLP-1) receptor is widely expressed and also an important contributor to insulin and glucose homeostasis and β-cell proliferation ​(Bullock et al., 1996)​. Zhu et al recently demonstrated that GLP-1R expression is under the regulation of androgen signaling, and that this regulation was mediated by the DHT AR complex binding to an AR motif in the Glp1r gene promoter region ​(Zhu et al., 2019)​.

Glucocorticoid steroids pleiotropically mediate a number of functions essential for life including stress-related and circadian functions, immune regulation, metabolic and energy regulation including gluconeogenesis, and control of glucose uptake ​(Kadmiel & Cidlowski, 2013)​. Spaanderman et al recently demonstrated that androgen receptor signaling strongly influences glucocorticoid receptor signaling in metabolic tissues. AR agonism was demonstrated to potentiate glucocorticoid signaling in white and brown adipocytes in vitro and in vivo, while AR antagonism attenuated GR in white adipose tissue and the liver. 11B-hydroxysteroid dehydrogenase type 1, critical to glucocorticoid homeostasis, was shown to be AR regulated. They also demonstrated increased glucocorticoid signalling enhanced fat mass and significantly reduced lean mass without significantly altering weight and induced hyperlipidaemia which was attenuated with the antiandrogen enzalutamide ​(Spaanderman et al., 2019)​.

Androgens, and appropriate proteomic quantity and status of AR, are crucially important to metabolic function and determinant of many aspects of metabolic health. Therefore, a dysregulated androgen receptor is a plausible mechanistic factor in the metabolic disturbances observed in PFS. Additionally, as recent findings implicate insulin receptor and glucagon-like peptide 1 expression in dopaminergic function and mood disorders (Mansur et al., 2018, 2019), the increasing appreciation of the regulation of androgen signaling upon metabolic systems may have functional relevance to the psychological disturbances in PFS.

Digestive complaints, dysmotility, bile acid synthesis and microbiome

Digestive complaints are frequent in PFS with dysmotility, diarrhoea, constipation, and pale stools well reported. Well appreciated sex differences exist in digestive conditions such as IBS, suggesting an influence of sex hormones ​(Y. S. Kim & Kim, 2018)​, and women are generally considered to be more disposed to functional gastroenterological disorders ​(Houghton et al., 2016)​. Interestingly, testosterone has been reported to be higher in male IBS patients than controls ​(B. J. Kim et al., 2008)​. González-Montelongo et al. demonstrated that the digestive tract is a key target of functionally relevant androgen action owing to the AR-mediated regulatory influence of intestinal smooth muscle transit ​(María C. González-Montelongo et al., 2010)​. Calcium sensitization and potentiation of contractile activity in ileal and colonic muscles is rapidly and powerfully induced by androgens at physiological concentrations through a strictly androgen-receptor dependent mechanism ​(Maria C. González-Montelongo et al., 2006; María C. González-Montelongo et al., 2010)​ that induces non-genomic cellular signal cascades. These in turn increase ornithine decarboxylase and intracellular polyamines ​(María C. González-Montelongo et al., 2013)​, important modulators of intestinal peristalsis ​(Sánchez et al., 2017)​.

Dysregulation of bile acid metabolism can result in malabsorption and hyperbilirubinemia ​(Chiang, 2013)​ which is a frequent serum abnormality reported by PFS patients. Aldo-keto reductase family 1 member D1 (AKR1D1), a Δ4-3-oxosteroid 5β-reductase, is required to synthesise bile acid from cholesterol ​(Chiang, 2013)​. Upregulation of Peroxisome Proliferator-activated Receptor α (PPARα) has been demonstrated to markedly decrease AKR1D1 promotor transactivation and expression in vitro in HepG2 cells and in vivo, disrupting bile acid homeostasis ​(Valanejad et al., 2018)​. PPARα also induces glucuronidation of bile acids, making this an important regulator of metabolism ​(Barbier et al., 2003)​. PPARα has been demonstrated to be under direct regulation by androgens ​(Collett et al., 2000; Zhang et al., 2012)​, and this suggests androgen receptor dysregulation may have functional consequences on bile acid synthesis and metabolism due to crosstalk between these pathways.

Androgen dysregulation has been well demonstrated to induce changes in the microbiome composition, including mice models of hyperandrogenemia, castrated mice and PCa patients undergoing multiple different antiandrogen therapies ​(Guo et al., 2016; Harada et al., 2016; Sfanos et al., 2018; Sherman et al., 2018)​. The absence of species does not appear to affect the influence of androgens on composition ​(Torres et al., 2019)​. Additionally, the microbiome composition of Finasteride treated rats is shown to differ from control animals ​(Diviccaro et al., 2019)​.

Immune system and wound healing

For many patients PFS entails an alteration of immune responses, including intraindividual changes in the incidences of viral infection, fungal infections and the modulation of allergies. Various studies have highlighted essential androgen regulation of the immune system ​(Lai, Lai, et al., 2012)​. Data indicates an extensive role for the AR in haematopoiesis ​(Mantalaris et al., 2001)​, and immune cell lines including neutrophils, mast cells, macrophages, B cells, T and Treg cells express AR ​(W. Chen et al., 2010; Ma et al., 2019; Mantalaris et al., 2001; Viselli et al., 1997; Walecki et al., 2015)​. Rodent studies have indicated that androgen signaling directly influences differentiation and function of T and B cells, central to the adaptive immune system, and possibly contributes to sex differences in autoimmune disorders ​(Gubbels Bupp & Jorgensen, 2018)​. Androgens and the AR have an increasingly appreciated role in thymopoiesis and T cell transcriptional function partly by modulation of thymic epithelial cells and affect thymic size and output ​(M. A. Brown & Su, 2019)​. Kadel and Kovats, reviewing the understanding of the regulation of sex hormones and viral immunity, suggest that receptor expression may underlie numbers of and functional regulation of innate immune cells in response to hormones ​(Kadel & Kovats, 2018)​. Further, sex differences in epigenetically imprinted regions of open or closed chromatin in hematopoietic stem cells may exist, and the sex-divergent epigenome may be responsive to the sex hormone environment ​(M. A. Brown & Su, 2019; Kadel & Kovats, 2018)​.

Neutrophils are significantly the most abundant granulocyte and form an vital part of the innate immune system, responding rapidly through chemotaxis to clear bacterial and fungal infections ​(Desai & Lionakis, 2018; Lai, Lai, et al., 2012)​. As well as phagocytic removal of cellular debris and pathogens, neutrophils secrete and scavenge a number of cytokines and chemokines that recruit and activate macrophages and monocytes in resolution of inflammation ​(Gordon & Taylor, 2005; Jones et al., 2016; Pham, 2006; Rittirsch et al., 2008)​. In men and women neutrophils strongly express AR at all stages of granulopoiesis from myeloblasts to mature neutrophils ​(Mantalaris et al., 2001)​. In humans, neutropenia can occur with antiandrogen treatment ​(Eaton & Blackmore, 2001; McDonnell & Livingston, 1994)​ but neutrophil counts decrease more moderately following castration ​(Chuang et al., 2009)​.

With both in vivo and in vitro studies, Chuang et al. demonstrated that the AR exerts a direct and profound effect upon which neutrophil homeostasis is critically dependent. AR knockout mice are significantly more susceptible to infection. A 90% reduction of neutrophils is observed in male AR knockout and Tfm mice compared with wild type, while castration results in a less significant neutrophil reduction in blood and bone marrow, reflecting human findings. Exogenous androgens restored neutrophil levels in castrated WT mice, but not Tfm or AR knockout mice. Female mice have normal neutrophil levels in the presence of ten-fold lower androgen levels than males, whereas female AR knockout mice are neutropenic, suggesting a direct importance of the AR rather than androgens. It was further demonstrated that loss of AR results in defects in terminal differentiation of neutrophils, and AR restoration in AR knockout granulocyte-macrophage progenitor cells rescued the neutrophil maturation process. AR was also shown to be significantly important to neutrophil production mechanistically by regulation of granulocyte-colony stimulating factor (G-CSF) signaling. Loss of AR in granulocytes leads to suppression of G-CSF resulting from an increase in protein inhibitor of activated STAT protein 3 (PIAS3) binding to STAT3, which is rescued by AR in a dose-dependent manner, apparently without dependence on androgens. Thus, AR is required for G-CSF induction of ERK activation and consequent proliferation of granulocytes ​(Chuang et al., 2009)​. Higher androgen levels have been demonstrated to impair the bactericidal abilities of neutrophils and increase the expression of anti-inflammatory cytokines IL10 and TGFβ1 in a rat model of bacterial prostate inflammation, prolonging the inflammatory response ​(Scalerandi et al., 2018)​.

Slowed wound healing is very frequently reported in PFS. As with immune differences, sex differences exist in the speed of cutaneous wound healing, with males healing slower than females ​(Taylor et al., 2002)​. Higher androgen levels are observed to be inhibitory of cutaneous wound healing ​(Ashcroft & Mills, 2002; Fimmel & Zouboulis, 2005)​, and DHT is more potently inhibitory of upon re-epithelialization than testosterone ​(Gilliver et al., 2009)​. In line with findings in dermal wound healing, androgens were demonstrated to prolong healing in castrated rats administered testosterone following urethral surgery. Those administered testosterone had significantly increased neutrophils, higher macrophage counts, significantly higher immunomodulators such as TNFα, TGFβ-1, VEGFα and IL-10, a more intense and longer inflammatory phase and an increase in myofibroblast proliferation and collagen tissue deposition in the delayed proliferative phase ​(Hofer et al., 2015)​. Following prostate resection, both castration ​(X.-J. Wang et al., 2017)​ and finasteride ​(Ruizhe Zhao et al., 2017)​ were seen to speed wound healing and induce re-epithelialization, while DHT enhanced macrophages TNF-α secretion through AR signaling. This extended the inflammatory phase, delaying and weakening the anti-inflammatory stage.

Mechanistic studies have revealed that the AR, and not androgens, are critical to the suppression of wound healing ​(Lai, Chang, et al., 2012)​. AR knockout males have markedly accelerated wound healing that is not reversed with DHT administration ​(Lai et al., 2009)​, demonstrating increased reepithelialisation, keratinocyte proliferation and matrix deposition. By contrast, AR knockout does not affect the wound healing rate in female mice ​(Yiwei Wang et al., 2016)​. In a model of autoimmune myocarditis, AR suppression with the AR degrader ASC-J9 promoted anti-inflammatory cytokines and M2 macrophage polarization via STAT3/SOCS3 regulation, suggesting ASC-J9s potential as a protective therapeutic in inflammatory cardiomyopathy ​(Ma et al., 2019)​. Local AR antagonists and degraders including ASC-J9 are reported to speed wound healing ​(Lai et al., 2009; Toraldo et al., 2012; Yiwei Wang et al., 2016)​. While AR has an upregulatory effect on TNF-α and CCR2 expression, suppressing cutaneous wound healing ​(Lai et al., 2009)​, TNF-α has been shown to increase in ARKO mice ​(Bourghardt et al., 2010)​. Androgens have been reported to be inhibitory of inflammatory cytokine production after haemorrhagic shock and burns ​(Lai, Lai, et al., 2012)​. In contrast to the discussed studies, testosterone has been shown to reduce TNF-α and IL-1β in hypogonadal men ​(Kalinchenko et al., 2010; Malkin et al., 2004)​. Men and women with rheumatoid arthritis have significantly decreased androgen levels in synovial fluid of inflamed tissue ​(Cutolo, 2009)​.

Considering the increased inflammatory markers in hypogonadism and the anti-inflammatory influence of testosterone in hypogonadal men, Traish et al. suggest that androgens may be necessary in maintaining inflammatory homeostasis ​(Traish et al., 2018)​. This would be in agreement with a “bell curve” effect of androgen signaling on cellular homeostasis and consistent with Gibson’s description of the new appreciation of testosterone as a “goldilocks molecule” ​(Gibson et al., 2018)​.

Dry Eye

Dry eye problems are extremely well reported in anecdotes on our forum and from post-finasteride, Accutane and SSRI patients. Androgens play a direct role in the development of lacrimal gland inflammation and aqueous-deficient dry eye disease ​(Morthen et al., 2019)​. Androgen deficiency is a major cause of dry eye, and this is particularly prevalent in women following the menopausal decrease in androgen levels ​(K. Li et al., 2017)​. Androgen administration alleviates dry eye symptoms and increases tear flow in Sjogren syndrome patients, suppresses inflammation in mice models of dry eye, and completely resolves symptoms in dry eye dogs ​(Morthen et al., 2019)​. Complete androgen insensitivity syndrome causes dry eye, meibomian gland dysfunction, lipid tear film layer instability and decreased mucous levels in humans ​(Mantelli et al., 2006)​. Finasteride has been used to generate a rat model of androgen deficient dry eye, downregulating the AR, disrupting androgen-influenced inflammatory homeostasis, and significantly increasing levels of the inflammatory cytokines IL-1β, IL-4, IL-6, IL-10, MMP-8, FasL and TNF-α in the lacrimal glands as compared with control rats ​(K. Li et al., 2017; S. Singh et al., 2014)​.

The androgen receptor mRNA and protein have been identified in epithelial cell nuclei of the human meibomian glands, lacrimal glands, cornea and conjunctiva ​(Rocha, 2000; Wickham et al., 2000)​. DHT has been demonstrated to significantly regulate the expression of approximately 3,000 genes in immortalized human meibomian gland and conjunctival epithelial cells ​(Khandelwal et al., 2012)​, including many related to inflammation and mucus production.

The testosterone-induced regulation of numerous immune related gene expressions in the lacrimal tissue of Sjogren syndrome and diabetic mouse models differed considerably, with a significant inflammatory effect of androgens in the diabetic mice model as opposed to the anti-inflammatory response seen in the Sjogren’s syndrome model. AR status was hypothesised as a possible mediating “on/off switch” for the microenvironment-dependent response ​(Morthen et al., 2019)​. Interestingly, hyperandrogenic PCOS patients experience dry eye, tear reduction and meibomian gland dysfunction ​(Baser et al., 2016; Bonini et al., 2007; Yuksel et al., 2015)​, lending further support to the suggestion that appropriate androgen signaling is required for inflammatory homeostasis. Local AR dysregulation in PFS could underlie the dry eyes and tear-related symptoms reported by patients.

Skin

Skin is an androgen-sensitive organ ​(Ashcroft & Mills, 2002)​ and a major target of androgen action. The AR is expressed in human skin fibroblasts, basal cells, sebocytes, pilosebaceous units, sweat gland secretory cells, dermal papilla, and keratinocytes ​(Alesci & Bornstein, 2000; Pelletier & Ren, 2004)​. The AR has been shown to have a profound and determinant effect on the collagen content of the skin of the adult mouse in both genders ​(Markova et al., 2004)​. Immunohistochemical staining has shown that AR staining intensity and immunoreactivity correlates strongly with the height of the apocrine sweat secretory epithelium ​(Beier et al., 2004)​, and as low epithelium is associated with inactivity, this would suggest AR signaling has a direct role in sweat secretion ​(Ceruti et al., 2018)​. Androgens have been understood to be a leading factor in acne pathogenesis for nearly a century ​(J. B. HAMILTON, 1941)​, and androgen signaling influences both the sebaceous gland activity and inflammation associated with acne ​(Lai, Chang, et al., 2012)​. Comprised of sebocytes, the sebaceous gland is are important in production of sebum, the lipids comprising which are important in skin barrier function, water resistance, sun damage and UV resistance, and establishment of the commensal bacterial flora of the skin ​(Szöllősi et al., 2017)​. The sebaceous gland is capable of synthesising pregnenolone from cholesterol via p450 side chain cleavage ​(Thiboutot et al., 2003)​ as well as metabolising androgens through enzymes including hydroxysteroid dehydrogenases and 5 alpha reductase type 1 ​(Szöllősi et al., 2017)​. The proliferative effects of androgens on sebocytes are dependent on the physiological site of localisation ​(Akamatsu et al., 1992)​. Recent in vitro investigation has demonstrated differentiation of immature sebocytes is under strong AR regulation, and lipid synthesis and storage is induced by androgens in an AR-dependent process. This was demonstrated to be independent of the presence of serum or other cofactors ​(Barrault et al., 2015)​.

Alteration in skin pigmentation and tanning response is very commonly reported in PFS patients and a case of PFS involving significant vitiligo was reported by Motofei et al. ​(Motofei et al., 2017)​. Early observations by Hamilton noted a poor tanning response to ultraviolet radiation in castrated men, and testosterone treatment would improve melanisation ​(J. HAMILTON, 1948)​. Androgens and the AR are involved in melanocyte biology and function, and melanocytes synthesise DHT ​(Slominski et al., 2004)​. Genital skin increases in pigmentation at puberty, and this increase in pigmentation is not seen in hypogonadal men ​(Köhn et al., 2000)​.

Cooper et al. reported three cases of myotonic dystrophy – a disease associated with low androgen levels – exhibiting androgen dependent diseases including acne, hidradenitis suppurativa, androgenetic alopecia and keratosis pilaris. They speculated a functional difference in AR may account for the frontal balding in myotonic dystrophy, and that in androgen-mediated conditions, the peripheral response to androgens differs between individuals, mediated by peripheral androgen receptors, with absolute levels of circulating androgens being of limited importance ​(Cooper et al., 2003)​.

Mitochondrial function

With broad physiological relevance, AR is an important regulator of overall mitochondrial function and is suggested to impact gene transcription through retrograde signaling ​(Bajpai et al., 2019)​. Testosterone had been hypothesised to regulate mitochondrial function owing to prior data including serum levels correlating with oxidative phosphorylation gene expression in skeletal muscle ​(Pitteloud et al., 2005)​. In a significant contribution to the understanding of the nonclassical role of the AR, Bajpai et al. demonstrated that the AR contains a mitochondrial localisation sequence and is imported into the mitochondria independent of association with ligand where it localises and regulates multiple processes via signaling cascades. Through a number of studies, they elucidated several roles for the AR in regulation of mitochondria. AR negatively regulates assembly factors of, and destabilises, oxidative phosphorylation supercomplexes. The AR is regulatory of the enzymatic activity of oxidative phosphorylation complexes and a large number of oxidative phosphorylation subunits. The AR regulates mitochondrial protein translation through control of the expression of nuclear ribosomal genes in the mitochondria. AR expression was shown to negatively correlate with mitochondrial DNA content and to TFAM (transcription factor A mitochondrial) protein content, which is regulatory of mitochondrial DNA. Mitochondrial stress was demonstrated to increase expression of the AR and its import into the mitochondria, suggesting an intricate link between both ​(Bajpai et al., 2019)​. Taken together, the well demonstrated impact on mitochondrial function would suggest aberrant AR signaling is capable of inducing significant mitochondrial dysfunction, which in turn could result in numerous detrimental effects at the cellular and consequently systemic level. This is of significance to the mechanistic overlap of wild-type gene amplification and polyglutamine expansion ​(D. A. Monks et al., 2007)​ with consideration as to the aforementioned implication of mitochondrial dysfunction in SBMA. Beyond an indispensable role in cellular energy production, metabolism, apoptosis and proliferation ​(van der Bliek et al., 2017)​, mitochondria play a major role in aspects of health and disease ​(Chakrabarty et al., 2018; Ru‑Zhou Zhao et al., 2019)​ including t-cell and macrophage immune response ​(Liu & Ho, 2018)​, neurodegeneration and neuroprotection ​(Darryll M.A. Oliver & P. Hemachandra Reddy, 2019; P. A. Li et al., 2017)​, sensorineural hearing loss ​(Kamogashira et al., 2015)​, cardiomyopathy ​(Lorenzo et al., 2013)​, atherosclerosis ​(Hulsmans et al., 2012)​, macular degeneration ​(E. E. Brown et al., 2018)​, periodontitis ​(Y. Chen et al., 2019)​, non-alcoholic fatty liver disease ​(Simões et al., 2018)​, cancer ​(Higuchi et al., 2005; K. K. Singh & Modica-Napolitano, 2017)​, and normal aging ​(Y. Wang & Hekimi, 2015)​.

LH/T Deregulation

PFS patients often report atypical hormonal profiles, and in cases who had profiles from before exposure to finasteride, a significantly altered hormonal milieu is frequently apparent. Curiously, PFS patients commonly report LH disproportionately low in relation to Testosterone levels, and this has been noted in a studied cohort ​(Di Loreto, 2011)​. A feedback loop of hypothalamic gonadotropin-releasing hormone (GnRH) and subsequent LH release from the pituitary stimulate male testosterone synthesis, which in turn negatively regulates GnRH release by acting on steroid receptors in Kiss1/NKB/Dynorphin (KNDy) neurons ​(V. M. Navarro et al., 2011; Ruka et al., 2016; Smith et al., 2005)​. Neural ARKO male mice show elevated levels of T ​(Raskin et al., 2009)​, and evidence from ERa knockout additionally illustrates that the AR plays the primary role in negative-feedback regulation of hypothalamic LH release ​(Wersinger et al., 1999)​.

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