Aim: To study the effect of androgen and antiandrogen on the level of androgen receptor (AR) mRNA. Methods: The total RNA was extracted from the prostate and analyzed by slot blot analysis. The blots were hybridized w...Aim: To study the effect of androgen and antiandrogen on the level of androgen receptor (AR) mRNA. Methods: The total RNA was extracted from the prostate and analyzed by slot blot analysis. The blots were hybridized with AR cDNA probe and 1A probe (internal control) and autoradiography was performed. The intensity of signal was measured with a densitometer and the ratio of AR RNA and 1A RNA was calculated. Results: Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of AR mRNA. Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of AR mRNA. Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels Of AR mRNA. Conclusion: Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.展开更多
The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited toconsider the concept of compounds with selective androgenic effects for male hormone replacement therapy. T...The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited toconsider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The fullspectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosteronetreatment. To define for what indications certain androgenic properties are desired and undesired more insight in basicandrogen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds tooestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgenson biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology inageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiationand for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even beharmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven.For male contraception a progestational agent with strong androgenic properties might be an asset. For most of theandrogenic actions the critical levels of androgens are not well established. The latter is relevant since the large amountof androgen molecules required for its biological actions (as compared to oestrogens)is an impediment in androgenreplacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgenmolecules to the circulation poses problems for treatment modalities.展开更多
A growing body of literature has established the anabolic benefits of testosterone （T） therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men ...A growing body of literature has established the anabolic benefits of testosterone （T） therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently find a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5α-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease.展开更多
Significant disparities exist between genders for the development and progression of several gastrointestinal(GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatoc...Significant disparities exist between genders for the development and progression of several gastrointestinal(GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors(AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome- poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.展开更多
Benign prostatic hyperplasia(BPH)is a common urological condition in aging men.High levels of androgens,including testosterone(T)and dihydrotestosterone(DHT),are closely associated with BPH occurrence and development....Benign prostatic hyperplasia(BPH)is a common urological condition in aging men.High levels of androgens,including testosterone(T)and dihydrotestosterone(DHT),are closely associated with BPH occurrence and development.Currently,the main clinical drugs used for BPH treatment are 5α-reductase inhibitors andα-receptor blockers,both of which aim to decrease abnormal androgenic signaling while having several unignored side effects.Recently,various natural herbs,such as tonifying yang traditional Chinese medicine(TCM),have been found to have androgenic activities,some of which are also effective for BPH treatment.Here,we review the androgenic activities of phytoandrogens,together with their therapeutic effects in BPH,and summarize the mechanisms involved,providing evidence that such herbs serve as selective androgen receptor modulators.展开更多
Beyond regulation of male sexual function, the increasing evidence shows that androgens and androgen receptor (AR) have a variety of physiological and pathological effects on the skin. Skin cells express all androgen ...Beyond regulation of male sexual function, the increasing evidence shows that androgens and androgen receptor (AR) have a variety of physiological and pathological effects on the skin. Skin cells express all androgen metabolizing enzymes that are required for independent skin androgen synthesis and the development of hyperandrogenic related disorders such as acne, hirsutism and androgenetic alopecia. Targeting various elements of androgen function and metabolism is the major goal of medication design for the treatment of androgen-related diseases. Antiandrogen drugs such as clascoterone, flutamide could improve conditions. Even though the involvement of androgens and AR in skin diseases has been investigated for a long time, their molecular mechanisms in skin disorders remain largely insufficient. In this review, recent studies and advances on the role of androgens/AR in several skin-related diseases and their therapeutics are systematically summarized.展开更多
Traumatic brain injury (TBI) is a worldwide public health problem. Populations with a growing number of vehicles are experiencing many traumas and accidents. The highest-risk group is young men. Significant advances i...Traumatic brain injury (TBI) is a worldwide public health problem. Populations with a growing number of vehicles are experiencing many traumas and accidents. The highest-risk group is young men. Significant advances in neurosurgery and intensive therapy have resulted in increased survival rates of TBI patients. These higher survival rates, in turn, have led to an increasingly higher number of patients with neurological, cognitive, clinical, and social problems. This lack of knowledge about TBI has been called by some “the silent epidemic”. In recent years, studies of patients with moderate and severe TBI are increasing. Glasgow Coma Scale ≤ 8 and abnormal pupils at admission are used to determine the prognosis of patients with moderate or severe TBI. Several biomarkers such as interleukins, thiobarbituric acid reactive species, and some hormones have been studied in an effort to aid prognosis. Testosterone plays a key role in men. Thus, an understanding of androgens in TBI is essential to follow these survivors of head trauma. This review will discuss the epidemiology of TBI, its association with male hypogonadism, and possible treatments.展开更多
Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conver...Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone （T） to estradiol （E2） by aromatase, or to dihydrotestosterone by 5（x-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of （high resolution） peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis.展开更多
Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we do...Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we do not have good experimental evidence to support the presumption that androgen administration improves physical function or athletic performance. Androgens do not increase specific force or whole body endurance measures. The anabolic effects of testosterone on the skeletal muscle are mediated through androgen receptor signaling. Testosterone promotes myogenic differentiation of multipotent mesenchymal stem cells and inhibits their differentiation into the adipogenic lineage. Testosterone binding to androgen receptor induces a conformational change in androgen receptor protein, causing it to associate with beta-catenin and TCF-4 and activate downstream Wnt target genes thus promoting myogenic differentiation. The adverse effects of androgens among athletes and recreational bodybuilders are under reported and include acne, deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma high-density lipoproteins （HDL） cholesterol level, suppression of spermatogenesis resulting in infertility, increase in liver enzymes, hepatic neoplasms, mood and behavioral disturbances, and long term suppression of the endogenous hypothalamic-pituitary-gonadal axis. Androgens are often used in combination with other drugs which may have serious adverse events of their own. In spite of effective methods for detecting androgen doping, the policies for screening of athletes are highly variable in different countries and organizations and even existing policies are not uniformly enforced.展开更多
Interest surrounds the role of sex-hormones in regulating brain function outside of reproductive behaviour. Declining androgen production in aging males has been associated with cognitive impairment, depression and in...Interest surrounds the role of sex-hormones in regulating brain function outside of reproductive behaviour. Declining androgen production in aging males has been associated with cognitive impairment, depression and increased risk of developing Alzheimer＇s disease. Indication for testosterone replacement therapy is based on biochemically determined low circulating testosterone combined with manifest symptoms. However, which aspects of age-related cognitive decline are attributable to low circulating testosterone remain ambiguous. Studies examining cognition in aging men receiving testosterone replacement therapy have yielded equivocal results. The exact role of testosterone in maintaining cognitive function and the underlying neural mechanisms are largely unknown, though it would appear to be domain specific. Cladty in this area will provide clinical direction toward addressing an increasing healthcare burden of mental health decline coincident with increasing longevity. The premise that androgens contribute to maintaining aspects of mental health in aging men by preserving hippocampal neurogenesis will be used as a forum in this review to discuss current knowledge and the need for further studies to better define testosterone replacement strategies for aging male health.展开更多
Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiratero...Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiraterone acetate and enzalutamide,has improved the survival of prostate cancer patients;however,a majority of these patients progress to castration-resistant prostate cancer(CRPC).The mechanisms of resistance to antiandrogen treatments are complex,including specific mutations,alternative splicing,and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways.In this review,we focus on the major mechanisms of acquired resistance to second generation antiandrogens,including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence.Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.展开更多
Objective To determine whether cyclosporine A(CsA)plus andronges was as effective as the current standard immunosuppressive therapy(IST)for transfusion-dependent nonsevere aplastic anemia(TD-NSAA).
To clarify the dependence of neural nitric oxide synthase mRNA (nNOSmRNA) and endothelial nitric oxide synthase mRNA (eNOSmRNA) on androgens (testosterone[T] and dihydrotestosterone [DHT]) Methods 160 male Sprague D...To clarify the dependence of neural nitric oxide synthase mRNA (nNOSmRNA) and endothelial nitric oxide synthase mRNA (eNOSmRNA) on androgens (testosterone[T] and dihydrotestosterone [DHT]) Methods 160 male Sprague Dawley (SD) rats were divided into Groups A (56 rats,5 weeks old),B (50rats,10 weeks old) and C (54 rats,58 weeks old) Groups A,B and C were all subdivided respectively into five Subgroups Subgroup 1: intact controls; Subgroup 2: castrated;Subgroup 3: castrated with testosterone undecanoate 25mg/kg·mon -1 ,intramuscular injection,Subgroup 4: castrated with testosterone undecanoate 50mg/kg·mon -1 ,intramuscular injection and Subgroup 5: treated with finasteride 4 5 mg/kg·day -1 ,orally Four and ten weeks after treatments described above,one half of the rats were killed Serum samples were taken for measurements of T, free testosterone (FT) and DHT by radioimmunoassay Penile samples were treated with liquid nitrogen and then stored at - 80℃ nNOSmRNA and eNOSmRNA were detected by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) and Dot blot Results There was no significant difference between Subgroup 1 and Subgroup 2 or Subgroup 5 in all Groups A, B and C The expression of penile eNOSmRNA of Group A was significantly increased (4weeks model) ( P <0 05) or increased (10 weeks model) ( P <0 05) in Subgroup 2 or 5 compared with those in Subgroup 1 There was no significant difference between Subgroup 1 and Subgroup 2 or Subgroup 5 of Group B in 4 weeks model ( P >0 05) There was an elevation when animals were castrated or treated with finasteride in the 10 weeks model The expression of penile eNOSmRNA of Group C was significantly increased (10 weeks model) ( P <0 05) or increased (4 weeks model) in Subgroup 2 compared with those in Subgroup 1 The production of eNOSmRNA in Subgroup 5 was also increased (including 4 and 10 week models) When T was supplied for castration, the penile eNOSmRNA was decreased to some extent;the greater the dose of T given,the lower penile eNOSmRNA was observed Conclusions The expression of eNOSmRNA in SD rat penile tissue increases while T or DHT diminishes Sometimes androgens modulate penile eNOSmRNA in opposite directions There is no correlation between the expression of nNOSmRNA and androgens (including T and DHT) Androgens give rise to penile erection probably not via the NOS pathway展开更多
Background 5a-Reductase inhibitors （5a-RI） act by inhibiting the conversion of testosterone to dihydrotestosterone （DHT）, thereby preventing DHT induced benign prostatic hyperplasia. The existing 5a-RIs can be cla...Background 5a-Reductase inhibitors （5a-RI） act by inhibiting the conversion of testosterone to dihydrotestosterone （DHT）, thereby preventing DHT induced benign prostatic hyperplasia. The existing 5a-RIs can be classified into two types： competitive and noncompetitive. Currently, limited evidence is available concerning the effect differences between the two types of 5a-RI on androgens. The purpose of this study was to assess the effects of competitive and noncompetitive 5a-RIs on serum and intra-prostatic androgens in beagle dogs. Methods Twenty beagles with spontaneous benign prostatic hyperplasia were randomly allocated into two groups： epristeride group （n=10） in which beagles were treated with epristeride at 1 mg/kg once a day for 3 months, and finasteride group （n=10） in which beagles were treated with finasteride at 1 mg/kg once a day for 3 months. The levels of intra-prostatic testosterone and DHT were measured before treatment and on day one after three months medication. Serum levels of testosterone and DHT were measured at the same time points. Changes in androgen levels before and after treatment were analyzed, and comparisons were made within each treatment group and between treatment groups. Results After 3-month treatment, serum and intra-prostatic DHT levels all decreased significantly in both the epristeride and finasteride groups. The change of DHT in serum was significantly higher in the finasteride group （-14% and -43% in epdsteride and finasteride groups respectively, with P〈0.001）; however there was no significant difference in the changes of intra-prostatic DHT between the two groups （-47% and -51% in epristeride and finasteride groups, respectively, P=0.304）. The decreases in DHT levels were accompanied by reciprocal increases in serum and intra-prostatic testosterone levels. Changes of testosterone were significantly higher in finasteride group both in serum （20% and 42% in epristeride and finasteride groups, respectively, P〈0.001） and in prostate tissue （18% and 29% in epristeride and finasteride groups, respectively, P=0.004）. Conclusions Two types of 5a-RI have similar effects in reducing DHT in prostate tissue in beagles. Competitive 5a-RI may reduce serum DHT to a greater scale, and significantly increase testosterone in beagle serum and prostate.展开更多
Wound healing is a complex process involving four overlapping phases:haemostasis,inflammation,cell recruitment and matrix remodeling.In mouse models,surgical,pharmacological and genetic approaches targeting androgen a...Wound healing is a complex process involving four overlapping phases:haemostasis,inflammation,cell recruitment and matrix remodeling.In mouse models,surgical,pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-αproduction and reduce wound re-epithelization and matrix deposition,retarding cutaneous wound healing.Similarly,clinical studies have shown that cutaneous wound healing is slower in men compared to women.However,in major burn injury,which triggers not only local wound-healing processes but also systemic hypermetabolism,the role of androgens is poorly understood.Recent studies have claimed that a synthetic androgen,oxandrolone,increases protein synthesis,improves lean body mass and shortens length of hospital stay.However,the possible mechanisms by which oxandrolone regulates major burn injury have not been reported.In this review,we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing,as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.展开更多
Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),h...Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.展开更多
Androgens play an important role in prostate cancer development and progression.Androgen action is mediated through the androgen receptor(AR),a ligand-dependent DNA-binding transcription factor.AR is arguably the most...Androgens play an important role in prostate cancer development and progression.Androgen action is mediated through the androgen receptor(AR),a ligand-dependent DNA-binding transcription factor.AR is arguably the most important target for prostate cancer treatment.Current USA Food and Drug Administration(FDA)-approved AR inhibitors target the ligand-binding domain(LBD)and have exhibited efficacy in prostate cancer patients,particularly when used in combination with androgen deprivation therapy.Unfortunately,patients treated with the currently approved AR-targeting agents develop resistance and relapse with castration-resistant prostate cancer(CRPC).The major mechanism leading to CRPC involves reactivation of AR signaling mainly through AR gene amplification,mutation,and/or splice variants.To effectively inhibit the reactivated AR signaling,new approaches to target AR are being actively explored.These new approaches include novel small molecule inhibitors targeting various domains of AR and agents that can degrade AR.The present review provides a summary of the existing FDA-approved AR antagonists and the current development of some of the AR targeting agents.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
Objective To evaluate the association of GGN repeat polymorphism of androgen receptor(AR)with ovarian reserve and ovarian response in controlled ovarian stimulation(COS).Methods This genetic association study was cond...Objective To evaluate the association of GGN repeat polymorphism of androgen receptor(AR)with ovarian reserve and ovarian response in controlled ovarian stimulation(COS).Methods This genetic association study was conducted among a total of 361 women aged≤40 years with basal FSH≤12 U/L undergoing the GnRH-agonist long protocol for COS in a university affiliated IVF center.GGN repeat in the AR gene was analyzed with Sanger sequencing.The primary endpoint was the number of antral follicle counts(AFCs),and the secondary endpoints were stimulation days,total dose of gonadotropin(Gn)used,total number of retrieved oocytes,ovarian sensitivity index,and follicular output rate.Results The GGN repeat in exon 1 of the AR gene ranged from 13 to 24,and the median repeat length was 22.Based on the genotypes(S for GGN repeats<22,L for GGN repeats≥22),the patients were divided into 3 groups:SS,SL,and LL.Generalized regression analysis indicated that the number of AFCs in group SS was significantly lower than those in group SL(adjusted β=1.8,95%CI:0.2-3.4,P=0.024)and group LL(adjusted β=1.5,95%CI:0.2-2.7,P=0.021).No significant difference was observed in the number of AFCs between group SL and group LL(P>0.05).Generalized regression analysis indicated no significant differences in ovarian stimulation parameters among the 3 groups,either before or after adjusting for confounding factors(P>0.05).Conclusion GGN repeat length on the AR gene is associated with AFC but not with ovarian response in Chinese women,indicating that AR gene polymorphisms may affect ovarian reserve.展开更多
文摘Aim: To study the effect of androgen and antiandrogen on the level of androgen receptor (AR) mRNA. Methods: The total RNA was extracted from the prostate and analyzed by slot blot analysis. The blots were hybridized with AR cDNA probe and 1A probe (internal control) and autoradiography was performed. The intensity of signal was measured with a densitometer and the ratio of AR RNA and 1A RNA was calculated. Results: Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of AR mRNA. Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of AR mRNA. Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels Of AR mRNA. Conclusion: Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.
文摘The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited toconsider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The fullspectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosteronetreatment. To define for what indications certain androgenic properties are desired and undesired more insight in basicandrogen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds tooestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgenson biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology inageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiationand for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even beharmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven.For male contraception a progestational agent with strong androgenic properties might be an asset. For most of theandrogenic actions the critical levels of androgens are not well established. The latter is relevant since the large amountof androgen molecules required for its biological actions (as compared to oestrogens)is an impediment in androgenreplacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgenmolecules to the circulation poses problems for treatment modalities.
文摘A growing body of literature has established the anabolic benefits of testosterone （T） therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently find a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5α-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease.
文摘Significant disparities exist between genders for the development and progression of several gastrointestinal(GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors(AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome- poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer.
基金National Natural Science Foundation of China(82074105)National Key Research and Development Project of China(2021YFC1712904)Science and Technology Program of Tianjin(22ZXGBSY00020,21ZYJDJC00070).
文摘Benign prostatic hyperplasia(BPH)is a common urological condition in aging men.High levels of androgens,including testosterone(T)and dihydrotestosterone(DHT),are closely associated with BPH occurrence and development.Currently,the main clinical drugs used for BPH treatment are 5α-reductase inhibitors andα-receptor blockers,both of which aim to decrease abnormal androgenic signaling while having several unignored side effects.Recently,various natural herbs,such as tonifying yang traditional Chinese medicine(TCM),have been found to have androgenic activities,some of which are also effective for BPH treatment.Here,we review the androgenic activities of phytoandrogens,together with their therapeutic effects in BPH,and summarize the mechanisms involved,providing evidence that such herbs serve as selective androgen receptor modulators.
文摘Beyond regulation of male sexual function, the increasing evidence shows that androgens and androgen receptor (AR) have a variety of physiological and pathological effects on the skin. Skin cells express all androgen metabolizing enzymes that are required for independent skin androgen synthesis and the development of hyperandrogenic related disorders such as acne, hirsutism and androgenetic alopecia. Targeting various elements of androgen function and metabolism is the major goal of medication design for the treatment of androgen-related diseases. Antiandrogen drugs such as clascoterone, flutamide could improve conditions. Even though the involvement of androgens and AR in skin diseases has been investigated for a long time, their molecular mechanisms in skin disorders remain largely insufficient. In this review, recent studies and advances on the role of androgens/AR in several skin-related diseases and their therapeutics are systematically summarized.
文摘Traumatic brain injury (TBI) is a worldwide public health problem. Populations with a growing number of vehicles are experiencing many traumas and accidents. The highest-risk group is young men. Significant advances in neurosurgery and intensive therapy have resulted in increased survival rates of TBI patients. These higher survival rates, in turn, have led to an increasingly higher number of patients with neurological, cognitive, clinical, and social problems. This lack of knowledge about TBI has been called by some “the silent epidemic”. In recent years, studies of patients with moderate and severe TBI are increasing. Glasgow Coma Scale ≤ 8 and abnormal pupils at admission are used to determine the prognosis of patients with moderate or severe TBI. Several biomarkers such as interleukins, thiobarbituric acid reactive species, and some hormones have been studied in an effort to aid prognosis. Testosterone plays a key role in men. Thus, an understanding of androgens in TBI is essential to follow these survivors of head trauma. This review will discuss the epidemiology of TBI, its association with male hypogonadism, and possible treatments.
文摘Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone （T） to estradiol （E2） by aromatase, or to dihydrotestosterone by 5（x-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of （high resolution） peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis.
文摘Androgen doping in power sports is undeniably rampant worldwide. There is strong evidence that androgen administration in men increases skeletal muscle mass, maximal voluntary strength and muscle power. However, we do not have good experimental evidence to support the presumption that androgen administration improves physical function or athletic performance. Androgens do not increase specific force or whole body endurance measures. The anabolic effects of testosterone on the skeletal muscle are mediated through androgen receptor signaling. Testosterone promotes myogenic differentiation of multipotent mesenchymal stem cells and inhibits their differentiation into the adipogenic lineage. Testosterone binding to androgen receptor induces a conformational change in androgen receptor protein, causing it to associate with beta-catenin and TCF-4 and activate downstream Wnt target genes thus promoting myogenic differentiation. The adverse effects of androgens among athletes and recreational bodybuilders are under reported and include acne, deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma high-density lipoproteins （HDL） cholesterol level, suppression of spermatogenesis resulting in infertility, increase in liver enzymes, hepatic neoplasms, mood and behavioral disturbances, and long term suppression of the endogenous hypothalamic-pituitary-gonadal axis. Androgens are often used in combination with other drugs which may have serious adverse events of their own. In spite of effective methods for detecting androgen doping, the policies for screening of athletes are highly variable in different countries and organizations and even existing policies are not uniformly enforced.
基金supported by a National Health and Medical Research Council (Australia) postdoctoral fellowship
文摘Interest surrounds the role of sex-hormones in regulating brain function outside of reproductive behaviour. Declining androgen production in aging males has been associated with cognitive impairment, depression and increased risk of developing Alzheimer＇s disease. Indication for testosterone replacement therapy is based on biochemically determined low circulating testosterone combined with manifest symptoms. However, which aspects of age-related cognitive decline are attributable to low circulating testosterone remain ambiguous. Studies examining cognition in aging men receiving testosterone replacement therapy have yielded equivocal results. The exact role of testosterone in maintaining cognitive function and the underlying neural mechanisms are largely unknown, though it would appear to be domain specific. Cladty in this area will provide clinical direction toward addressing an increasing healthcare burden of mental health decline coincident with increasing longevity. The premise that androgens contribute to maintaining aspects of mental health in aging men by preserving hippocampal neurogenesis will be used as a forum in this review to discuss current knowledge and the need for further studies to better define testosterone replacement strategies for aging male health.
基金Efforts are supported by the Department of Defense Grant(W81XWH-18-1-0618 and W81XWH-19-1-0720)to Gupta S.Kushwaha PP acknowledges financial support from University Grants Commission,India in the form of CSIR-UGC Senior Research fellowshipKumar S acknowledges University Grants Commission,India+2 种基金Department of Science and Technology,India for providing financial support in the form of UGC-BSR Research Start-Up-Grant[F.30-372/2017(BSR)]DST-SERB Grant(EEQ/2016/000350)respectively.Kumar S acknowledges Central University of Punjab,Bathinda,India for providing Research Seed Money Grant(GP-25)Singh AK,Prajapati KS,and Shuaib M acknowledge CSIR-India,DBT-India and DST-India funding agencies respectively for providing financial assistance in the form of Junior Research Fellowship.
文摘Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiraterone acetate and enzalutamide,has improved the survival of prostate cancer patients;however,a majority of these patients progress to castration-resistant prostate cancer(CRPC).The mechanisms of resistance to antiandrogen treatments are complex,including specific mutations,alternative splicing,and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways.In this review,we focus on the major mechanisms of acquired resistance to second generation antiandrogens,including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence.Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.
文摘Objective To determine whether cyclosporine A(CsA)plus andronges was as effective as the current standard immunosuppressive therapy(IST)for transfusion-dependent nonsevere aplastic anemia(TD-NSAA).
文摘To clarify the dependence of neural nitric oxide synthase mRNA (nNOSmRNA) and endothelial nitric oxide synthase mRNA (eNOSmRNA) on androgens (testosterone[T] and dihydrotestosterone [DHT]) Methods 160 male Sprague Dawley (SD) rats were divided into Groups A (56 rats,5 weeks old),B (50rats,10 weeks old) and C (54 rats,58 weeks old) Groups A,B and C were all subdivided respectively into five Subgroups Subgroup 1: intact controls; Subgroup 2: castrated;Subgroup 3: castrated with testosterone undecanoate 25mg/kg·mon -1 ,intramuscular injection,Subgroup 4: castrated with testosterone undecanoate 50mg/kg·mon -1 ,intramuscular injection and Subgroup 5: treated with finasteride 4 5 mg/kg·day -1 ,orally Four and ten weeks after treatments described above,one half of the rats were killed Serum samples were taken for measurements of T, free testosterone (FT) and DHT by radioimmunoassay Penile samples were treated with liquid nitrogen and then stored at - 80℃ nNOSmRNA and eNOSmRNA were detected by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) and Dot blot Results There was no significant difference between Subgroup 1 and Subgroup 2 or Subgroup 5 in all Groups A, B and C The expression of penile eNOSmRNA of Group A was significantly increased (4weeks model) ( P <0 05) or increased (10 weeks model) ( P <0 05) in Subgroup 2 or 5 compared with those in Subgroup 1 There was no significant difference between Subgroup 1 and Subgroup 2 or Subgroup 5 of Group B in 4 weeks model ( P >0 05) There was an elevation when animals were castrated or treated with finasteride in the 10 weeks model The expression of penile eNOSmRNA of Group C was significantly increased (10 weeks model) ( P <0 05) or increased (4 weeks model) in Subgroup 2 compared with those in Subgroup 1 The production of eNOSmRNA in Subgroup 5 was also increased (including 4 and 10 week models) When T was supplied for castration, the penile eNOSmRNA was decreased to some extent;the greater the dose of T given,the lower penile eNOSmRNA was observed Conclusions The expression of eNOSmRNA in SD rat penile tissue increases while T or DHT diminishes Sometimes androgens modulate penile eNOSmRNA in opposite directions There is no correlation between the expression of nNOSmRNA and androgens (including T and DHT) Androgens give rise to penile erection probably not via the NOS pathway
文摘Background 5a-Reductase inhibitors （5a-RI） act by inhibiting the conversion of testosterone to dihydrotestosterone （DHT）, thereby preventing DHT induced benign prostatic hyperplasia. The existing 5a-RIs can be classified into two types： competitive and noncompetitive. Currently, limited evidence is available concerning the effect differences between the two types of 5a-RI on androgens. The purpose of this study was to assess the effects of competitive and noncompetitive 5a-RIs on serum and intra-prostatic androgens in beagle dogs. Methods Twenty beagles with spontaneous benign prostatic hyperplasia were randomly allocated into two groups： epristeride group （n=10） in which beagles were treated with epristeride at 1 mg/kg once a day for 3 months, and finasteride group （n=10） in which beagles were treated with finasteride at 1 mg/kg once a day for 3 months. The levels of intra-prostatic testosterone and DHT were measured before treatment and on day one after three months medication. Serum levels of testosterone and DHT were measured at the same time points. Changes in androgen levels before and after treatment were analyzed, and comparisons were made within each treatment group and between treatment groups. Results After 3-month treatment, serum and intra-prostatic DHT levels all decreased significantly in both the epristeride and finasteride groups. The change of DHT in serum was significantly higher in the finasteride group （-14% and -43% in epdsteride and finasteride groups respectively, with P〈0.001）; however there was no significant difference in the changes of intra-prostatic DHT between the two groups （-47% and -51% in epristeride and finasteride groups, respectively, P=0.304）. The decreases in DHT levels were accompanied by reciprocal increases in serum and intra-prostatic testosterone levels. Changes of testosterone were significantly higher in finasteride group both in serum （20% and 42% in epristeride and finasteride groups, respectively, P〈0.001） and in prostate tissue （18% and 29% in epristeride and finasteride groups, respectively, P=0.004）. Conclusions Two types of 5a-RI have similar effects in reducing DHT in prostate tissue in beagles. Competitive 5a-RI may reduce serum DHT to a greater scale, and significantly increase testosterone in beagle serum and prostate.
文摘Wound healing is a complex process involving four overlapping phases:haemostasis,inflammation,cell recruitment and matrix remodeling.In mouse models,surgical,pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-αproduction and reduce wound re-epithelization and matrix deposition,retarding cutaneous wound healing.Similarly,clinical studies have shown that cutaneous wound healing is slower in men compared to women.However,in major burn injury,which triggers not only local wound-healing processes but also systemic hypermetabolism,the role of androgens is poorly understood.Recent studies have claimed that a synthetic androgen,oxandrolone,increases protein synthesis,improves lean body mass and shortens length of hospital stay.However,the possible mechanisms by which oxandrolone regulates major burn injury have not been reported.In this review,we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing,as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.
基金supported by the Health and Medical Research Fund,Food and Health Bureau,Hong Kong SAR Government(HMRF 07180186).
文摘Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.
基金supported in part by DOD Idea Development Award(HT9425-23-1-0295)NIH grants(R01 CA265897 and R21 CA280467)by the Department of Urology,University of Pittsburgh School of Medicine,Pittsburgh,PA,USA。
文摘Androgens play an important role in prostate cancer development and progression.Androgen action is mediated through the androgen receptor(AR),a ligand-dependent DNA-binding transcription factor.AR is arguably the most important target for prostate cancer treatment.Current USA Food and Drug Administration(FDA)-approved AR inhibitors target the ligand-binding domain(LBD)and have exhibited efficacy in prostate cancer patients,particularly when used in combination with androgen deprivation therapy.Unfortunately,patients treated with the currently approved AR-targeting agents develop resistance and relapse with castration-resistant prostate cancer(CRPC).The major mechanism leading to CRPC involves reactivation of AR signaling mainly through AR gene amplification,mutation,and/or splice variants.To effectively inhibit the reactivated AR signaling,new approaches to target AR are being actively explored.These new approaches include novel small molecule inhibitors targeting various domains of AR and agents that can degrade AR.The present review provides a summary of the existing FDA-approved AR antagonists and the current development of some of the AR targeting agents.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
文摘Objective To evaluate the association of GGN repeat polymorphism of androgen receptor(AR)with ovarian reserve and ovarian response in controlled ovarian stimulation(COS).Methods This genetic association study was conducted among a total of 361 women aged≤40 years with basal FSH≤12 U/L undergoing the GnRH-agonist long protocol for COS in a university affiliated IVF center.GGN repeat in the AR gene was analyzed with Sanger sequencing.The primary endpoint was the number of antral follicle counts(AFCs),and the secondary endpoints were stimulation days,total dose of gonadotropin(Gn)used,total number of retrieved oocytes,ovarian sensitivity index,and follicular output rate.Results The GGN repeat in exon 1 of the AR gene ranged from 13 to 24,and the median repeat length was 22.Based on the genotypes(S for GGN repeats<22,L for GGN repeats≥22),the patients were divided into 3 groups:SS,SL,and LL.Generalized regression analysis indicated that the number of AFCs in group SS was significantly lower than those in group SL(adjusted β=1.8,95%CI:0.2-3.4,P=0.024)and group LL(adjusted β=1.5,95%CI:0.2-2.7,P=0.021).No significant difference was observed in the number of AFCs between group SL and group LL(P>0.05).Generalized regression analysis indicated no significant differences in ovarian stimulation parameters among the 3 groups,either before or after adjusting for confounding factors(P>0.05).Conclusion GGN repeat length on the AR gene is associated with AFC but not with ovarian response in Chinese women,indicating that AR gene polymorphisms may affect ovarian reserve.
