Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

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.

Human androgen deficiency： insights gained from androgen receptor knockout mouse models

The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor （AR） through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout （ARKO） models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immune and hemopoetic system, bone, muscle, adipose tissue, the prostate and the brain. This review focuses on the insights that have been gained into human androgen deficiency through the use of ARKO mouse models at each of these sites of action, and highlights the strengths and limitations of these Cre-loxP mouse models that should be considered to ensure accurate interpretation of the phenotype.

Novel mutation in the ligand-binding domain of the androgen receptor gene （1790p） associated with complete androgen insensitivity syndrome

Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.

Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway

Objective This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients.Methods Through various techniques,such as Argonaute immunoprecipitation,luciferase assays,and ChIP,this study confirmed the positive effects of androgen receptor(AR)on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models.Results The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level,which in turn required changes in miRNA-23a-3p.Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR.Conclusion This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.

In vivo modulation of androgen receptor by androgens

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.

Detection of androgen receptor (AR) and AR-V7 in small cell prostate carcinoma: Diagnostic and therapeutic implications

Objective:Small cell prostate carcinoma(SCPC)is a rare and highly malignant subtype of prostate cancer.SCPC frequently lacks androgen receptor(AR)and prostate-specific antigen(PSA)expression,and often responds poorly to androgen deprivation therapy(ADT).AR splice variant-7(AR-V7)is a truncated AR protein implicated in resistance to AR-targeting therapies.AR-V7 expression in castration-resistant prostate cancers has been evaluated extensively,and blood-based detection of AR-V7 has been associated with lack of response to abiraterone and enzalutamide.However,whether AR-V7 is expressed in SCPC is not known.Methods:Using validated antibodies,we performed immunohistochemistry(IHC)assay for the full-length AR(AR-FL)and(AR-V7)on post-ADT surgical SCPC specimens.Results:Seventy-five percent(9/12)of the specimens showed positive staining for the AR-FL with various intensities.Thirty-three percent(4/12)of the specimens showed positive staining for AR-V7.Among the specimens with positive AR-V7 staining,two samples displayed very weak staining,one sample showed weak-to-moderate staining,and one sample showed strong staining.All positive specimens displayed a heterogeneous pattern of AR-FL/AR-V7 staining.All specimens positive for AR-V7 were also positive for AR-FL.Conclusion:The study findings support the existence of measurable AR-FL and AR-V7 proteins in SCPC specimens.The results also have implications in detection of AR-V7 in specimens obtained through systemic sampling approaches such as circulating tumor cells.A positive AR-V7 finding by blood-based tests is not impossible in patients with SCPC who often demonstrate low PSA values.

Regulation of androgen receptor variants in prostate cancer

Aberrant activation of androgen receptor(AR)signaling occurs in patients treated with AR-targeted therapies,contributing to the development of castration-resistant prostate cancer(CRPC)and therapeutic resistance.Over the past decade,many AR variants(AR-Vs)have been identified in prostate cancer cell lines and clinical CRPC specimens.These AR-Vs lack the COOH-terminal ligand-binding domain(LBD),and may mediate constitutively active AR signaling acquired following AR-targeting therapies.AR splice variant-7(AR-V7),one of the most well characterized AR-Vs,can be reliably measured in tissue and liquid biopsy specimens,and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies(NHT)such as abiraterone and enzalutamide in men with metastatic CRPC(mCRPC).Given the important clinical implication of AR-Vs,this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer.With regard to the molecular origin of AR-Vs,it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling.Therapeutic targeting of the AR axis may result in active transcription of the AR gene,elevated activities of certain components of the mRNA splicing machinery,as well as AR genomic alterations,all of which may explain the molecular origin of AR-Vs.Although a unified hypothesis is currently lacking,existing data suggest that elevated expression of AR-Vs,which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed,is driven by both genomic and epigenomic features acquired in the development of CRPC.

Studies on Androgen Receptor mRNA expression in Pancreas,Hypothalamus and Ovary of Androgen Sterilized Rats

Objective To investigate the androgen receptor （AR） mRNA expression in pancreas, hypothalamus and ovary of androgen sterilized rats （ASR）.Methods ASR model was established by subcutaneous injection of testosterone propionate to SD female rats at the age of 9 days. Around the age of 106 days （proestrus）, all rats were killed, serum Δ4-andronestedione （Δ 4-A）, total testosterone （TT）, free testosterone （FT）, insulin （Ins） and C-peptide （C-P） were measured by radioimmunoassay （RIA）. Total RNA in pancreas, hypothalamus and ovary were extracted and the amount of AR mRNA was quantitatedly analyzed by RT-PCR with single base mutant template as inner standard. Results Serum concentrations of Δ4-A, TT, FT, Ins and C-P in ASR model rats were significantly higher than those in control group （P〈0.05, P〈0.01）. The expression of AR mRNA in pancreas, hypothalamus and ovary increased significantly （P〈0. 05, P〈0.01） of model rats as compared with control group. Conclusion The elevated serum androgen levels in ASR model could enhance the expression of AR mRNA levels in pancreas, hypothalamus and ovary, which further induce hyperinsulinemia and anovulation.

Identification of neuron selective androgen receptor inhibitors

AIM To identify neuron-selective androgen receptor(AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy(SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell typeselective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuronselective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-q PCR of AR-regulated genes and immunohistochemistry.RESULTS We identified the thiazole class of antibiotics as com-pounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that sh RNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the association between beta-catenin and AR. Treatment of rats with thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles. CONCLUSION Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can inhibit AR signaling selectively in motor neurons and may be useful in the treatment or prevention of SBMA symptoms.

Phenotypic heterogeneity of mutations in androgen receptor gene

Androgen receptor （AR） gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat （CAG and GGN） length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.

nfluence of immune inflammation on androgen receptor expression in benign prostatic hyperplasia tissue

This study was designed to investigate the association between immune inflammation and androgen receptor （AR） expression in benign prostatic hyperplasia （BPH）. We retrospectively analyzed 105 prostatectomy specimens. An immune inflammation score for each specimen was defined by combining three immunohistochemical markers （CD4, CD8 and CD20）. The immunohistochemical markers were CD4 and CD8 for T lymphocytes, CD20 for B lymphocytes and AR antibody for the AR in BPH samples. Rates of CD4, CD8, CD20 and AR expression in BPH were 20 （19.0%）, 21 （20.0%）, 101 （96.2%） and 48 （45.7%）, respectively. Total prostate volume （TPV） was higher in the immune inflammation group than in the non-immune inflammation group （62.7 ml vs. 49.2 ml, t=-2.482, P〈0.05）. Patients in the immune inflammation group had a higher serum prostate-specific antigen （PSA） than those in the non-inflammation group （7.5 ng m1-1 vs. 5.4 ng m1-1, t=-2.771, P〈0.05）. Specifically, the immune inflammation group showed a higher rate of AR expression than the non-inflammation group （56.1% vs. 28.2%, χ2=7.665, P〈0.05）. Our study revealed a strong association between immune inflammation and TPV, serum PSA and AR expression in BPH tissue. Prostate hyperplasia caused by an immune inflammatory process may contribute to BPH progression over time. Therefore, the inflammatory response involved in BPH may be a prime therapeutic target.

Androgen insensitivity syndrome： do trinucleotide repeats in androgen receptor gene have any role？

Aim： To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome （AIS） phenotype. Methods： We analyzed lengths of androgen receptor （AR）-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction （PCR） amplification followed by allelic genotyping to determine allele length. Results： Our study revealed significantly shorter mean lengths of CAG repeats in patients （mean 18.25 repeats, range 14-26 repeats） in comparison to the controls （mean 22.57 repeats, range 12-39 repeats） （two-tailed P 〈 0.0001）. GGN repeats, however, did not differ significantly between patients （mean 21.48 repeats） and controls （mean 21.21 repeats） （two- tailed P = 0.474）. Among patients＇ groups, the mean number of CAG repeats in partial androgen insensitivity cases （mean 15.83 repeats） was significantly less than in complete androgen insensitivity cases （mean 19.46 repeats） （two- tailed P 〈 0.0001）. Conclusion： The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity.

Inhibitory Effects of Cypermethrin on Interactions of the Androgen Receptor with Coactivators ARA70 and ARA55

Objective The purpose of this study was to investigate the anti-androgenic mechanism of cypermethrin involving coactivators.Methods Mammalian two-hybrid assays were performed to study the effects of cypermethrin on interactions of the androgen receptor(AR)with the coactivators androgen receptor-associated protein70(ARA70)and androgen receptor-associated protein 55(ARA55).Results The results showed that AR–ARA70 and AR–ARA55 interactions were remarkably enhanced by dihydrotestosterone(DHT,P≤0.05).Cypermethrin inhibited DHT-induced AR–ARA70 and AR–ARA55 interactions significantly(P≤0.05).Conclusion The study indicates that cypermethrin exhibits inhibitory effects on AR transcription associated with repression of AR–ARA70 and AR–ARA55 interactions in a ligand-dependent manner.The data show novel anti-androgenic mechanisms of cypermethrin that contribute to male reproductive toxicology.

Correlations between Expression of Estrogen and Androgen Receptors and the Clinical Characteristics of Prolactinoma~*

Objective： To study the correlations between estrogen receptor （ER） and androgen receptor （AR） and the clinical presentations of prolactinoma and investigate the effect of ER and AR expression on the pathogenesis of prolactinoma in sexual difference. Methods： The clinical data of 30 patients who had undergone transsphenoidal operations in Tongji Hospital from December 2000 to December 2001 were reviewed retrospectively. The clinical information included sex, age, serum-prolactin, size, tumor invasiveness, history of use of bromocriptine and frequency of recurrence. In 20 out of the 30 patients, the ER and AR expression was detected by using immunohistochemistry method. With help of Chi-square test, the relationship between ER, AR and the clinical presentations was analyzed. Results： The statistical values revealed that there was no significant correlation between the ER and AR expression levels with the clinical presentations such as sex, age, tumor size or tumor invasiveness among the 20 patients studied （P〉0.05）. Conclusion： The expression of ER or AR is not influenced by the clinical data of prolactinoma such as sex, age, tumor diameter or extent of tumor invasiveness. The tumor is more aggressive in males than in females. In maroadenoma or tumor with hyperprolactineamia （〉200 ng/mL） simple surgical treatment can＇t successfully cure the prolactinoma. Post-operative bromocriptine therapy can＇t be determined by the sex of the patients, but is greatly related to the tumor size and serum-prolactin level before operation.

Complete androgen insensitivity syndrome caused by the c.2678C>T mutation in the androgen receptor gene:A case report

BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene(AR).However,the underlying molecular mechanisms for the majority of AR variants remain unclear.In this study,we identified a point variant in three patients with complete androgen insensitivity syndrome(CAIS),summarized the correlation analysis,and performed a literature review.CASE SUMMARY The proband was raised as a girl.In infancy,she was first referred to hospital with a right inguinal hernia.Ultrasonography revealed the absence of a uterus and ovaries,and a testis-like structure located at the inguinal canal.Further diagnostic workup detected a 46,XY karyotype,and fluorescence in situ hybridization analysis showed the presence of the SRY gene.Histological analysis revealed the excised tissue to be testicular.Twelve years later,she was admitted to our hospital with a lack of breast development.Her pubic hair and breasts were Tanner stage I.She had normal female external genitalia.Blood hormone tests showed normal testosterone levels,low estradiol levels,and high gonadotropin levels.Her two siblings underwent similar examinations,and all three had a rare hemizygous missense mutation in AR:c.2678C>T.In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells.CONCLUSION This case of CAIS was caused by an AR variant(c.2678C>T).Functional studies showed impaired nuclear translocation ability of the mutant protein.

Targeting androgen receptor and trail： a novel treatment paradigm for breast cancer

OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.

Expression of estrogen receptor alpha,nerve growth factor,interleukin-2,and androgen receptor in the cerebellum of ovariectomized rats following soybean isoflavone treatment

BACKGROUND： Studies have shown that estrogen receptor alpha （ERα）, nerve growth factor （NGF）, interleukin-2 （IL-2）, and androgen receptor （AR） expression in the cerebellum decreases when estrogen levels decrease in vivo. Soybean isoflavone, a type of non-steroid estrogen with similar molecular structure and function to estradiol, exhibits estrogen-like characteristics. OBJECTIVE： To investigate the effects of various doses of soybean isoflavone on expression of ERa, NGF, IL-2, and AR in the cerebellum of ovariectomized rat, and to determine whether there is a dose-dependent effect.DESIGN, TIME AND SETTING： Controlled trial at the cellular and molecular level. The study was performed at the Experimental Animal Engineering Center, College of Veterinary Medicine, Sichuan Agricultural University from July 2006 to May 2008. MATERIALS： Soybean isoflavone, comprised of daidzin, genistein and isoflavone, was provided by Taiyuan Yuantai Biochemical Industry, China. The ERα, NGF, IL-2, and AR in situ hybridization kit, rabbit anti-rat ERa, NGF, IL-2, and AR monoclonal antibodies, and SABC kit were purchased from Wuhan Boster Biological Technology, China. METHODS： A total of 50 female, Sprague Dawley rats, aged 3 months, were randomly assigned to 5 groups, with 10 animals in each group. With the exception of the sham-operation group （abdominal cavity opening alone）, all rats underwent bilateral ovariectomy. At 14 days after surgery, rats in the high-, middle-, and low-dose soybean isoflavone groups were subcutaneously injected with 1.5, 1.0, and 0.5 mg/kg soybean isoflavone, respectively, every 2 days for 6 consecutive weeks. Rats in the sham-operation and ovariectomized groups were subcutaneously injected with absolute alcohol （0.5 mL/kg）. MAIN OUTCOME MEASURES： Expression levels and distribution of ERα, NGF, IL-2, and AR in the cerebellum were detected by immunohistochemistry and in situ hybridization. RESULTS： Compared with the sham-operation group, immunoreactive products and hybridization signals of ERa, NGF, IL-2, and AR were significantly decreased in the cerebellar cortex and nuclei of ovariectomized rats （P 〈 0.05 or P 〈 0.01）, but increased following soybean isoflavone treatment. In particular, levels of the high-dose soybean isoflavone group were almost restored to levels of the sham-operation group （P 〉 0.05）. The immunoreactive products were primarily located in the cytoplasm and neurites, and rarely in the cell membrane and nuclei. However, the hybridization signals were predominantly located in the nuclei, but rarely in the cytoplasm, cell membrane, or neurites. CONCLUSION： Soybean isoflavone upregulated ERα, NGF, IL-2, and AR protein and gene expression in a dose-dependent manner, and played an important role in sustaining and protecting structure and function of cerebellar neurons. Moreover, the similarity of expression patterns of these molecules indicated that they were mutually interactive during the regulation of soybean isoflavone to the cerebellum.

Computational Investigation on the Allosteric Modulation of Androgen Receptor

Androgens have similar structures with different biological activities. To identify molecular determinants responsible for the activity difference, we have docked six steroidal androgens to the binding site or the surface of androgen receptor by using molecular docking with computational investigation. The energy was calculated respectively based on the QM （quantum mechanics） and MM （molecular mechanics） methods. The result shows that the allosteric modulation of androgen receptor plays an important role in the binding process between androgens and receptor. The open state receptor is less stable than the close state one, but the latter is more favorable for binding with androgens. It is worthy of note that when the androgen receptors binding or without binding with androgen are in close state, they are difficult to return to their open state. This phenomenon is an exception of the well known two-state model theory in which the two states are reversible. Whether the internal of close state androgen receptor has a combination of androgen or not, the androgen receptor surface can be combined with another androgen, and their surface binding energies could be very close. The result is consistent with the experimental observations, but this phenomenon of continuous combination from open state is also an exception of the two-state model theory.

Study of Androgen and Androgen Receptor in Relation to Insulin Resistance in Polycystic Ovary Syndrome

In order to investigate the relationship between serum testosterone level and expression of androgen receptors in ovary in relation to insulin resistance in polycystic ovary syndrome (PCOS). Serum testosterone levels were determined by radioimmunoassay in 17 patients with PCOS and 20 cases as control group. The expression of androgen receptor in ovary was detected by immunohistochemistry method. The results showed that serum testosterone level \[(3.1±1.5) nmol/L\] and insulin resistance index (0.85±0.49) in patients with PCOS were significantly higher than in control group (P<0.05), and showed a positive relation (r=0.65, P<0.01). The expression levels of androgen receptor in ovary of patients with PCOS were significantly higher than that in control group(P<0.05). The optical density value was positively related with insulin resistance index (r=0.59, P<0.01). It was concluded that androgen and androgen receptor could accelerate insulin resistance and the interaction of them might aggravate the pathophysiological change in PCOS.

Androgens/Androgen Receptor in the Management of Skin Diseases

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.