Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Partial androgen insensitivity syndrome. Core disease mechanisms, molecula...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome

• Authors: Yiping Cheng, Yan Sun, Y. Ji, Dongqing Jiang, Guoxin Teng et al.
• Year: 2020
• Venue: Bioscience Reports
• URL: https://www.semanticscholar.org/paper/2b9b4c76dc7fafdafac1bbde29d6a89cb4e457e1
• DOI: 10.1042/BSR20200616
• PMID: 32338288
• PMCID: 7953519
• Citations: 7
• Summary: The phenotype of the patient with AIS may be caused by defects in both the AR and MAP3K1 signaling pathways, and whole-exome sequencing might reveal genetic variants that explain the heterogeneity of AIS.
• Evidence snippets:
• Snippet 1 (score: 0.521) > gene might act as a genetic modifier of the phenotype, as the patient has rudimentary Müllerian structures, which is uncommon in AIS. Therefore, we consider that the two pathogenic variants are the cause of AIS and that they are the exclusive causative agents of the phenotype of the described patient. Moreover, the confirmation of an AIS diagnosis by WES can reveal additional genetic variants to explain the heterogeneity of the disease. > AIS is highly heterogeneous and divided into three categories according to the degree of genital masculinization: mild androgen insensitivity syndrome (MAIS), partial androgen insensitivity syndrome (PAIS) and complete androgen insensitivity syndrome (CAIS). The clinical phenotypes range from a typical male habitus with mild spermatogenic defects and reduced secondary terminal hair to a full female habitus despite the presence of a Y chromosome. The correlation of genotype and phenotype has not yet been established. > AIS is a congenital disorder in which a defect in the AR gene leads to cellular resistance to androgens. More than 1000 AIS-causing mutations in the AR gene have been identified [24]. The types of AR gene variants include gene deletions, splice site mutations, premature stop codons and missense mutations, among others. The most common genetic abnormalities are missense mutations, which often occur in two important segments of the receptor protein: the DBD and LDB regions. Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity. > There are at least five potential mechanisms by which AR variants reduce or abolish AR function (Figure 6): androgen and AR binding disorders, androgen-AR complex and DNA-binding disorders, truncated AR proteins, altered ligand specificity and defective signal transduction downstream of AR. Impairment in androgen or DNA binding is the most common mechanism [25,26]. First, exons 5-8 and part of exon 4 encode the LBD, which includes residues 664-920 [27], and variants that cause androgen-AR-binding disorders are commonly reported in exons 4-8 [28,[29][30][31].

[2] [Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome].

• Authors: N. Kalinchenko, A. A. Kolodkina, V. Petrov, E. V. Vasiliev, A. Tiulpakov
• Year: 2019
• Venue: Problemy endokrinologii
• URL: https://www.semanticscholar.org/paper/85dfb56e658632c648c25d9ba3e79714f2653af1
• DOI: 10.14341/PROBL10166
• PMID: 32202729
• Citations: 1
• Summary: The phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene are described.
• Evidence snippets:
• Snippet 1 (score: 0.484) > Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.

[3] Phenotypic and molecular characteristics of androgen insensitivity syndrome patients

• Authors: Shimin Yuan, Ya-Nan Zhang, J. Du, Wen Li, C. Tu et al.
• Year: 2018
• Venue: Asian Journal of Andrology
• URL: https://www.semanticscholar.org/paper/44a0ebbf510a1f0d97912e5814e737f441017d73
• DOI: 10.4103/aja.aja_17_18
• PMID: 29785970
• PMCID: 6116692
• Citations: 21
• Summary: The spectrum of AR gene mutations is expanded and the usefulness ofAR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening is confirmed.
• Evidence snippets:
• Snippet 1 (score: 0.474) > Androgen insensitivity syndrome (AIS; OMIM# 300068) is a common 46,XY disorder of sex development (DSD) resulting from complete or partial resistance to the biological actions of androgens. Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty. 1 According to the degree of androgen responsiveness, AIS presents with a broad spectrum of defects in the external genitalia and can be subdivided into three phenotypes: complete androgen insensitivity syndrome (CAIS) with typical female external genitalia, partial androgen insensitivity syndrome (PAIS) with predominantly male or ambiguous external genitalia, and mild androgen insensitivity syndrome (MAIS) with typical male external genitalia or an isolated micropenis, but with gynecomastia at puberty and infertility in adulthood. 2 Of these categories, CAIS is the classic manifestation of AIS. The clinical diagnosis of CAIS is typically based on primary amenorrhea at puberty or inguinal hernia and labial swelling in a female infant with a 46,XY karyotype. 1 A pathogenic mutation of the androgen receptor gene (AR; OMIM# 313700) is the only established molecular cause of the X-linked recessive inherited disease. > The AR gene is located on chromosome Xq11-12 and contains eight exons that encode a protein of 920 amino acid residues. This protein functions as a steroid hormone-activated transcription factor and contains four major functional domains: the N-terminal

[4] The Glucocorticoid Resistance Syndrome. Two Cases of a Novel Pathogenic Variant in the Glucocorticoid Receptor Gene

• Authors: S. Mauri, Javier Nieto‐Moragas, María Obón, Josep Oriola
• Year: 2023
• Venue: JCEM Case Reports
• URL: https://www.semanticscholar.org/paper/c235337d68758a5c0be34cf84b2574c0f34cc1e5
• DOI: 10.1210/jcemcr/luad153
• PMID: 38170043
• PMCID: 10759794
• Citations: 5
• Summary: A mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome are described.
• Evidence snippets:
• Snippet 1 (score: 0.436) > Abstract Glucocorticoid resistance syndrome is a rare genetic condition characterized by generalized or partial target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal axis. Clinical manifestations may include mineralocorticoid and/or androgen excess without manifestations of Cushing syndrome. At a cellular level, glucocorticoid actions are mediated by the nuclear glucocorticoid receptor encoded by the NR3C1 gene. To date, only 33 glucocorticoid receptor loss-of-function pathogenic variants have been associated with glucocorticoid resistance syndrome. The NR3C1 gene has 2 known disease-causing mechanisms: haploinsufficiency and negative dominance. We describe a mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome. To date, no accurate genotype-phenotype correlation has been found.

[5] Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis

• Authors: Yajie Peng, Hui Zhu, B. Han, Yue Xu, Xuemeng Liu et al.
• Year: 2021
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/10bfaf772debd7b833a9c0a820696d4329d5881e
• DOI: 10.3389/fendo.2021.731107
• PMID: 34867780
• PMCID: 8637961
• Citations: 4
• Summary: Light is shed on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation and manual screening of tissue-specific gene expression.
• Evidence snippets:
• Snippet 1 (score: 0.432) > Background Androgen insensitivity syndrome (AIS) is a rare X-linked genetic disease and one of the causes of 46,XY disorder of sexual development. The unstraightforward diagnosis of AIS and the gender assignment dilemma still make a plague for this disorder due to the overlapping clinical phenotypes. Methods Peripheral blood mononuclear cells (PBMCs) of partial AIS (PAIS) patients and healthy controls were separated, and RNA-seq was performed to investigate transcriptome variance. Then, tissue-specific gene expression, functional enrichment, and protein–protein interaction (PPI) network analyses were performed; and the key modules were identified. Finally, the RNA expression of differentially expressed genes (DEGs) of interest was validated by quantitative real-time PCR (qRT-PCR). Results In our dataset, a total of 725 DEGs were captured, with functionally enriched reproduction and immune-related pathways and Gene Ontology (GO) functions. The most highly specific systems centered on hematologic/immune and reproductive/endocrine systems. We finally filtered out CCR1, PPBP, PF4, CLU, KMT2D, GP6, and SPARC by the key gene clusters of the PPI network and manual screening of tissue-specific gene expression. These genes provide novel insight into the pathogenesis of AIS in the immune system or metabolism and bring forward possible molecular markers for clinical screening. The qRT-PCR results showed a consistent trend in the expression levels of related genes between PAIS patients and healthy controls. Conclusion The present study sheds light on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation.

[6] Genotype and phenotype of Vietnamese patients with androgen insensitivity syndrome

• Authors: V. Dũng, M. Fukami, C. T. B. Ngọc, Bùi Phương Thảo, N. Khánh et al.
• Year: 2013
• Venue: International Journal of Pediatric Endocrinology
• URL: https://www.semanticscholar.org/paper/b0aa73b6d8e6147c51f4c4346817d70c4db38af6
• DOI: 10.1186/1687-9856-2013-S1-P194
• PMCID: 3850449
• Summary: Five different mutations of AR were identified from 7 cases of 3 unrelated families including three novel ones and two reported mutation in the AR gene that may provide new insights into the molecular mechanisms of AIS.
• Evidence snippets:
• Snippet 1 (score: 0.431) > Androgen insensitivity syndrome (AIS) is the most common specific cause of 46,XY disorder in sex development. The androgen signaling pathway is complex but so far, the only gene linked with AIS is the androgen receptor (AR). Mutations in the AR are found in most subjects with complete AIS but in partial AIS, the rate has varied 28–73%, depending on the case selection. More than over 800 entries of mutations causing AIS, representing over 500 different AR mutations from more than 850 patients with AIS have been reported. We aim to describe clinical manifestations and to identify mutation of AR in Vietnamese patients with AIS. > This case series study included 12 patients from 9 unrelated families with AIS. The gonadal position and external genitalia were evaluated clinicaly and using ultrasound. The mutation analysis of AR was performed using PCR and direct sequencing. > The age of diagnosis was 1 to 83 years old. 8/12 cases were complete androgen insensitivity syndrome (CAIS) (female external genitalia) and 4 cases were predominantly female partial AIS phenotype. Four cases had two labial testes, six cases had inguinal testes and 2 cases had abdominal testes. Five different mutations of AR were identified from 7 cases of 3 unrelated families including three novel ones. The novel missense mutation p.L701F (c.2103G>T) was identified in a patient of 83 year of age. The novel missense mutation p.L705F (c.2113C>T) was identified in two sibs. The novel mutation p. W752S (c. 2256 G>T) was identified in a child with CAIS phenotype and had family history. The reported missense mutation p.V747M was identified in two sibs. The reported mutation p.V867M (c.2599 G>A) was identified in a child with female phenotype. > Our study identified three novel and two reported mutation in the AR gene that may provide us new insights into the molecular mechanisms of AIS. The expanded database of these mutations should benefit patients in the diagnosis and treatment of this syndrome.

[7] The role of androgens and global and tissue-specific androgen receptor expression on body composition, exercise adaptation, and performance

• Authors: Sabrina Tzivia Barsky, D. A. Monks
• Year: 2025
• Venue: Biology of Sex Differences
• URL: https://www.semanticscholar.org/paper/7426826fc1f798d8afecfd9acef3bb3272f5eb79
• DOI: 10.1186/s13293-025-00707-6
• PMID: 40269952
• PMCID: 12016402
• Citations: 10
• Summary: The understood mechanisms of action of AR and its interactions with exercise, specifically on outcomes of body composition and muscle function, and the global- and tissue-specific role of AR in regulating skeletal muscle, adipose, and bone morphology are summarized.
• Evidence snippets:
• Snippet 1 (score: 0.411) > Clinical observations of androgen insensitivity syndrome were first presented by Morris in 1953 [162] (then described as testicular feminization) in humans, and later in rats [163] and mice [33]. Cases of androgen insensitivity can be classified as complete, partial, or mild, and diagnoses are made by observation of female external genitalia in a XY karyotype male fetus (ie., complete androgen insensitivity), gynecomastia and atypical genitalia at puberty (ie., partial androgen insensitivity), or unaffected genitalia yet presence of male infertility (ie., mild androgen insensitivity). Complete androgen insensitivity was discovered and propagated in a substrain of rats, lending an in vivo model to study the molecular underpinnings of androgen insensitivity and the influence of lost AR function on sex development, aptly named the testicular feminized (Tfm) rat. Tfm males develop testes, which remain undescended in the inguinal canal, appearing to have immature Sertoli cells limiting the progression of spermatogenesis [164] and hyperplasia of Leydig cells allowing for normal to excess androgen production [165]. Additionally, Tfm males do not develop male accessory sex organs (ie., prostate, epididymis, ductus deferens, seminal vesicles). Studies attempting to identify mechanisms of androgen insensitivity in the Tfm rat revealed that cytoplasmic AR was decreased in target organs [166,167] and had reduced binding capacity for androgens [168], which resulted from a single base mutation in the AR gene [169]. The limitations in the Tfm model included male sterility and no opportunity to study females with complete aberrant AR function, as female carriers of Tfm are genetic mosaics for androgen insensitivity [170]. This brought forth the production of the androgen receptor knockout mouse (ARKO) [68].

[8] Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole‐exome sequencing

• Authors: O. Naumova, S. Rychkov, O. Burenkova, M. Solodunova, Irina V Polyanskaya et al.
• Year: 2020
• Venue: Clinical Case Reports
• URL: https://www.semanticscholar.org/paper/c134cee557e957216c151c8394e6748c5ac2407d
• DOI: 10.1002/ccr3.3286
• PMID: 33363845
• PMCID: 7752474
• Citations: 1
• Summary: The study shows that whole‐exome sequencing is a promising approach to detect novel variants—and gene candidates in DSD, that, as a future direction, may improve the diagnostic gene panels for this heterogeneous disorder.
• Evidence snippets:
• Snippet 1 (score: 0.407) > This study, utilizing whole-exome sequencing (WES), reports on a previously detected disease-related variant in the androgen receptor gene AR [c.528C>A (p.Ser176Arg)] and novel candidate variants in the DHCR24, BMPR1B, NODAL, and WDR48 genes detected in the genome of a 15-month-old child diagnosed with MPH, manifested as partial androgen insensitivity syndrome (AIS). 46,XY disorder of sexual development (DSD)-or male pseudohermaphroditism according to formerly used nomenclature-is a condition defined by the presence of female-like or incompletely differentiated external genitalia in an individual with a Y chromosome. It is the most diverse type of DSD concerning to both clinical manifestations and etiology. The molecular etiology of 46,XY DSD is almost always attributed to genetic lesions that might be delineated as cytogenic alterations and gene mutations. 1 The former is usually manifested | 2889 NAUMOVA et Al. > as 45,X/46,XY mosaicism, while the latter as mutations that disrupt either the production of androgens or tissue response to androgens. > Androgen resistance is one of the most common causes of 46,XY DSD; it is manifested as AIS and classified based on clinical phenotypes into three categories: complete (CAIS), partial (PAIS), and mild (MAIS) forms. In most cases, this is an X-linked disease due to alterations to the androgen receptor gene AR, whose variety of damaging effects may partly determine the severity of AIS. 2,3 Besides, AIS may also be related to a deficit in AR coactivators caused by mutations in the relevant genes, such as NR5A1 encoding the steroidogenic factor-1 protein, 4 which among other functions promotes the transcription of steroidogenic enzymes and steroidal receptors. Other possible molecular causes of the DSD are related to deficiencies in key enzymes controlling the androgens' production associated with various deleterious variants in the relevant genes: Cytochrome P450 17α-hydroxylase (CYP17A1) and 17β-hydroxysteroid dehydrogenase

[9] A novel androgen resistance gene mutation (p.G590W) in complete androgen insensitivity syndrome: Emphasizing the need for early gonadectomy and integrated patient care

• Authors: Hai-yan Sun, Xu Wang, Li-Xian Wang, Hui Zhang
• Year: 2025
• Venue: The Journal of International Medical Research
• URL: https://www.semanticscholar.org/paper/3561243c5f38d987d3d1b3624d342298e4d25a47
• DOI: 10.1177/03000605251350626
• PMID: 40552659
• PMCID: 12188037
• Citations: 1
• Summary: The case of a 30-year-old woman who was diagnosed with complete androgen insensitivity syndrome at 18 years of age during evaluation for primary amenorrhea and later presented with a palpable abdominal mass underscores the importance of genetic analysis, early prophylactic gonadectomy, and multidisciplinary care in managing complete androgen insensitivity syndrome to mitigate tumor risk and optimize outcomes.
• Evidence snippets:
• Snippet 1 (score: 0.405) > ][3] The AR gene encodes a nuclear receptor that is critical for mediating androgen signaling. 4 ][7] CAIS results from mutations causing complete receptor dysfunction, characterized by female external genitalia despite a 46,XY karyotype. In contrast, PAIS and MAIS involve partial receptor impairment, leading to a range of phenotypes from ambiguous genitalia (PAIS) to mild undervirilization and infertility (MAIS). Individuals with CAIS typically present with primary amenorrhea, absent or rudimentary Mu¨llerian structures, female external genitalia, and a short blind-ending vagina, with gonads frequently located intra-abdominally or in the inguinal region. 8,9 utations in the AR gene associated with CAIS are highly heterogeneous, encompassing missense, nonsense, and frameshift mutations as well as and splicesite alterations. 10 Clinical phenotypes vary considerably depending on the mutation type, with frameshift and nonsense mutations typically associated with more severe androgen insensitivity phenotypes due to complete loss of receptor function, while missense mutations may produce a spectrum of phenotypic outcomes dependent on the specific location and functional domain affected. To date, hundreds of such mutations have been documented in the Androgen Receptor Mutation Database (http://androgendb.mcgill.ca/), many of which are linked to severe androgen insensitivity phenotypes. However, novel pathogenic variants continue to be identified, underscoring the complexity of the genotype-phenotype relationships in CAIS. Characterizing these novel variants is essential for advancing our understanding of the molecular mechanisms underlying AR dysfunction and for developing improved diagnostic, prognostic, and therapeutic strategies. > A significant clinical challenge in managing CAIS is the heightened risk of gonadal germ cell tumors, 11 particularly seminomas, arising due to undescended or dysgenetic gonads. Recent systematic reviews suggest malignancy risks ranging from 15% to as high as 30% in patients with CAIS, underscoring the importance of timely prophylactic gonadectomy to prevent tumor development and progression. 12

[10] Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

• Authors: Aasems Jacob, Rishi Raj, Derek B. Allison, Zin W. Myint
• Year: 2021
• Venue: Cancers
• URL: https://www.semanticscholar.org/paper/93d425f8fbbccd8b90f442fbef73e8e7508c3ee3
• DOI: 10.3390/cancers13215417
• PMID: 34771580
• PMCID: 8582395
• Citations: 105
• Influential citations: 3
• Summary: This review article details the current evidence on clinically relevant driver mechanisms, relevant biomarkers, and treatment modalities to overcome resistance of androgen receptor (AR) in prostate cancer.
• Evidence snippets:
• Snippet 1 (score: 0.405) > Simple Summary Early-stage and castration-sensitive prostate cancer (PCa) growth is solely mediated by androgen signaling pathways. AR signaling inhibitors (ARSIs) have significantly improved clinical outcomes among men with PCa. In the metastatic castration-resistant PCa, there is presence of both androgen-dependent and androgen-independent cells driving the tumor growth. Despite the use of ARSIs, disease progression ultimately occurs in all patients with PCa and is due to genetic alterations in ARs, resulting in the outgrowth of androgen-independent cells. The possible mechanisms include development of AR splice variants of which AR-V7 is more common, AR point mutations, and AR overexpression. In addition, restoration of downstream signaling through alternate pathways can also lead to androgen-independent growth of PCa. Therapeutic strategies to overcome these resistance mechanisms and establish predictive biomarkers are still in clinical trials. This review article details the current evidence on clinically relevant driver mechanisms, relevant biomarkers, and treatment modalities to overcome resistance. Abstract Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

[11] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

• Authors: R. Ragusa, P. Bufano, A. Tognetti, M. Laurino, Chiara Caselli
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
• DOI: 10.3390/ijms26062571
• PMID: 40141213
• PMCID: 11942187
• Citations: 6
• Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
• Evidence snippets:
• Snippet 1 (score: 0.391) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[12] Hormone resistance and hypersensitivity: From genetics to clinical management

• Authors: S. Mathur
• Year: 2015
• Venue: The Indian Journal of Medical Research
• URL: https://www.semanticscholar.org/paper/92089b8daf83a6eccb54f0f51ef5c99a5545ccf8
• DOI: 10.4103/0971-5916.164279
• PMCID: 4613450
• Citations: 8
• Summary: This book is a compilation of presentations during the workshop on ‘Hormone Resistance and Hypersensitivity: From Genetics to Clinical Management’ held in Genoa, Italy, in May 2012 and is a good attempt to present information on clinical genetics of hormone resistance and sensitivity disorders.
• Evidence snippets:
• Snippet 1 (score: 0.389) > This book is the 24th volume of the ongoing series ‘Endocrine Development’, edited by P. -E. Mullis. This book comprises 14 articles contributed by different authors and is a compilation of presentations during the workshop on ‘Hormone Resistance and Hypersensitivity: From Genetics to Clinical Management’ held in Genoa, Italy, in May 2012. In the preface, the editors have rightly emphasized that the meeting provided a unique opportunity for an updated and perspective view of this exciting topic. > Though disorders of end organ resistance and hypersensitivity to hormones are rare, but availability of powerful genetic/epigenetic technologies has catalysed translational research in the field of pathogenesis of these disorders. The clinical application of their findings is the development of highly sensitive and specific molecular diagnostic tests for these disorders. This book is an excellent compilation of genotype-phenotype correlations of these paediatric endocrinology disorders. > Each of the articles in this book is on a specific hormone disorder. Each article describes the pathophysiology and clinical phenotype first, followed by compilation of available evidences of molecular genetic defects underlying the hormone resistance syndrome and lastly genotype-phenotype correlations and their therapeutic implications are discussed. > The first article is on thyroid hormone transporters and resistance. Physiology of thyroid hormone action, transportation specifically by MCT8 and MCT10 and their mutations are discussed. A brief overview of the thyroid hormone receptor is also given in this article. The second article is about the pseudohypoparathyroidism types-I and II and genetics and epigenetics of GNAS complex and PRKAR locus. The pathophysiologic role of their mutations and altered expression due to epigenetic changes is described. The third and fourth chapters are respectively on gonadotropin and androgen insensitivity and outline the clinical and genetic correlations between their receptor mutations and various reproductive hormonal disorders. > The next three chapters are respectively on the molecular mechanism of glucocorticoid receptor action from sensitivity to resistance, ACTH resistance and its defects and generalized glucocorticoid resistance (Chrousos syndrome) and sensitivity. > The eighth chapter is on pseudohypoaldosteronism (PHA) and describes its three types and renal sodium channel, and NR3C2 mutations

[13] Network analysis of an in vitro model of androgen-resistance in prostate cancer

• Authors: S. Detchokul, Aparna Elangovan, E. Crampin, Melissa J. Davis, A. Frauman
• Year: 2015
• Venue: BMC Cancer
• URL: https://www.semanticscholar.org/paper/b1ceea1ad550c95910c1b68491f4fb638c8aedd3
• DOI: 10.1186/s12885-015-1884-7
• PMID: 26553226
• PMCID: 4640359
• Citations: 6
• Summary: An in vitro model of androgen-resistance is developed to characterise molecular changes occurring as androgen resistance evolves over time and reveals several potential mechanisms and network interactions, including cooperative behaviours of other nuclear receptors, in particular the subfamily of steroid hormone receptors such as PGR and alteration to gene expression in both the MAPK and PI3K-Akt signalling pathways.
• Evidence snippets:
• Snippet 1 (score: 0.387) > We used a published clinical dataset [10] to determine whether our cell line model of androgen insensitivity displays molecular features in common with human disease. We found 213 genes were differentially expressed in both experiments. This highlights that while there are definite differences in the molecular phenotypes of our data, our model nonethe-less recapitulates molecular features found in advanced human disease. We also examined the pathways that are enriched for differentially expressed genes in each experiment, and found that differential expression in both datasets converged at the pathway level (full results Additional file 1: Table S1 and S2); in particular, two related pathways, MAPK and PI3K signalling are both strongly implicated by the differentially expressed genes of both datasets. Previous reports adopting disease-associated gene network and pathway analyses in PCa have revealed novel regulatory mechanisms and were more powerful than the analysis of gene expression level alone [20][21][22][23][24].

[14] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.386) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[15] Serial evaluation of gonads of complete androgen insensitivity syndrome from birth to puberty: Is gonadectomy necessary?

• Authors: Yuko Ueda, F. Matsumoto, Futoshi Matsui, S. Matsuyama
• Year: 2025
• Venue: Urology Case Reports
• URL: https://www.semanticscholar.org/paper/1306e066c6fea2070a19ada9e508756f42c6d839
• DOI: 10.1016/j.eucr.2025.103068
• PMID: 40496184
• PMCID: 12148651
• Citations: 1
• Summary: A rare case of CAIS diagnosed shortly after birth, prompted by a discrepancy between the karyotype identified through amniocentesis and the phenotype at birth is reported.
• Evidence snippets:
• Snippet 1 (score: 0.383) > Androgen insensitivity syndrome is an X-linked recessive genetic disorder caused by mutations in the androgen receptor (AR) gene. The syndrome is classified into mild (MAIS), partial (PAIS), and complete (CAIS) forms. CAIS is characterized by female external genitalia and a 46, XY karyotype, whereas PAIS manifests with a varying degree of genital ambiguity, including bifid scrotum, clitoromegaly, micropenis, and hypospadias. MAIS is typically asymptomatic, with infertility being the primary clinical manifestation. 1 CAIS is typically diagnosed based on primary amenorrhea during puberty or inguinal swelling during infancy. With the advancement of prenatal testing, early diagnosis based on the discrepancy between fetal karyotypes and phenotypes has been increasingly reported. 2 According to molecular testing, the estimated prevalence of CAIS ranges from 1 in 20,400 to 1 in 99,000 genetic males. 1 Gonadectomy is recommended for individuals with CAIS at various ages to reduce the risk of gonadal malignancies. However, the indications for and optimal timing of gonadectomy remain controversial. Although the risk of malignancy increases with age, reports of invasive testicular germ cell tumors (GCTs) in females with CAIS remain scarce. 3 erein, we present a case of CAIS that was diagnosed soon after birth owing to the discordance of karyotype in amniocentesis and the phenotype at birth. Early diagnosis of CAIS enables serial evaluation of the gonad, from birth to puberty, offering valuable insights into the progression of testicular tumors.

[16] Androgen receptor roles in spermatogenesis and infertility.

• Authors: L. O’Hara, Lee B. Smith
• Year: 2015
• Venue: Best practice & research. Clinical endocrinology & metabolism
• URL: https://www.semanticscholar.org/paper/a906fc64845c10728725d782e8c78c5bb52bbfea
• DOI: 10.1016/j.beem.2015.04.006
• PMID: 26303086
• Citations: 217
• Influential citations: 5
• Summary: These models have pinpointed the steps of spermatogenesis that require AR signalling and detail the essential nature of androgens in the promotion of male fertility.
• Evidence snippets:
• Snippet 1 (score: 0.382) > As of October 2014, more than 1100 mutations in human AR have been identified [65].Although some AR mutations are associated with non-testicular phenotypes such as prostate cancer, premature ovarian failure and Kennedy's disease, approximately 90% result in androgen insensitivity syndrome (AIS).AIS presents as a spectrum of masculinisation disorders in XY individuals from a fully female external phenotype present in complete androgen insensitivity syndrome (CAIS) through undervirilised male phenotype in partial androgen insensitivity syndrome (PAIS) to normal male genitals but infertility seen in mild androgen insensitivity syndrome (MAIS).PAIS and CAIS are discussed further in the chapter on androgen insensitivity syndrome by Mongan et al., in this issue of Best Practice and Research Clinical Endocrinology and Metabolism. > In contrast to more severe forms of AIS, patients with MAIS have normal genitalia and may present with infertility as the first or only symptom.Investigation into Ar mutations should be prompted when a high androgen sensitivity index (ASI, the LH to testosterone ratio) is seen as there is a positive correlation between the two [66].The location of the mutation in the AR gene and the type of the mutation correlates with the resulting severity of the AIS phenotype.Most premature termination mutations result in a truncated AR protein and complete AIS.Single base substitutions can results in all grades of AIS, depending on what effect the substitution has on the amino acid sequence and three dimensional structure of the protein and therefore how much of the function is retained.Exon 1 of AR encodes the N-terminal domain which codes for more than half the AR protein, but only about 25% of total loss of function mutations occur in this domain.While mutations in exon 1 such as premature termination mutations or deletions generally result in CAIS due to a truncation of the protein, 22 of 39 of the single-base substitution mutations in exon 1 that result in a form of AIS results in MAIS, implying that missense mutations in this domain have a mild effect on AR function.

[17] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

• Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
• Year: 2015
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
• DOI: 10.1186/s13023-015-0242-9
• PMID: 25874378
• PMCID: 4358699
• Citations: 93
• Influential citations: 5
• Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
• Evidence snippets:
• Snippet 1 (score: 0.382) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[18] A Novel Mutation in the Androgen Receptor Gene of Female Patients with 46,XY Karyotype

• Authors: I. N. Uslu, Nuriye Gokce, Gülsevinç Aksoy, N. Inandiklioğlu, B. Yuksel et al.
• Year: 2025
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/d3cdd1b57391c53f510eb8437c1d6c67bff8cc9c
• DOI: 10.3390/cimb47050349
• PMID: 40699748
• PMCID: 12110714
• Citations: 1
• Summary: A novel missense mutation (c.2246C>T) in the AR gene in five members of a CAIS-affected family, which has not been previously reported in the literature is identified.
• Evidence snippets:
• Snippet 1 (score: 0.380) > This novel mutation is a single-nucleotide substitution (T to G) mutation [25]. Advances in next-generation sequencing have recently led to the discovery of additional mutations responsible for CAIS. Furthermore, the wide variability in genotype-phenotype correlation has prompted investigations into other potential mechanisms contributing to specific forms of partial androgen insensitivity [24]. Another study recently have showed a rare missense mutation 2170C>T (p.Pro274Ser) in AR gene resulting CAIS [26]. In our study, we identified a novel mutation and our finding highlights the importance of genetic analysis in diagnosing AIS and improving the understanding of genotype-phenotype correlations. > These findings not only enhance our understanding of AR-related disorders, but also lay the foundation for future research exploring the functional and clinical implications of AR mutations, potentially guiding targeted therapeutic strategies for CAIS. > This study has several limitations that should be acknowledged. First, the sample size was limited to a single family, consisting of only five individuals, which restricts the generalizability of our findings. Second, the absence of long-term clinical follow-up data for the affected individuals limits our understanding of potential phenotypic variability or late-onset complications associated with this novel mutation. Future studies involving larger cohorts and functional analyses are needed to confirm the pathogenicity of this novel AR gene variant, and to better understand its clinical implications.

[19] Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies

• Authors: M. A. Sánchez-Garrido, M. Tena-Sempere
• Year: 2020
• Venue: Molecular Metabolism
• URL: https://www.semanticscholar.org/paper/243f4163baea41e10b23ec24cef1772fabf40f4e
• DOI: 10.1016/j.molmet.2020.01.001
• PMID: 32244180
• PMCID: 7115104
• Citations: 419
• Influential citations: 15
• Summary: Androgen excess plays a prominent role in the development of metabolic disturbances associated withPCOS, with a discernible impact on key peripheral metabolic tissues and the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance.
• Evidence snippets:
• Snippet 1 (score: 0.378) > Importantly, the prevalence of these metabolic comorbidities is high in women with this disorder [11,12], and the concurrence of overweight or obesity and PCOS exacerbates not only metabolic complications [6,7], but also reproductive derangements associated with this endocrinopathy [13,14]. The pathophysiological mechanisms of PCOS are complex and not fully understood [10,15,16]. Several lines of evidence suggest that developmental, environmental, genetic, and epigenetic mechanisms are involved in the etiology of this endocrine disorder [17,18]. Although many aspects of its pathophysiology remain obscure, it is widely accepted that hyperandrogenism plays a fundamental role in the development of most of the reproductive and metabolic perturbations associated with PCOS. Androgen excess has a deleterious impact on metabolic homeostasis in women with PCOS, acting on different metabolic tissues such as the adipose tissue, liver, muscle, and pancreas as well as on the brain. However, a better understanding of the molecular mechanisms underlying the metabolic actions of androgens in PCOS is needed. This study reviews the current literature to provide an overview of the main pathogenic mechanisms that may underlie metabolic dysregulation commonly linked to PCOS, with particular attention to the potential molecular mechanisms responsible for the metabolic impact of androgen excess in selective tissues. Special emphasis was placed on discussing findings from studies of various female rodent models of hyperandrogenism generated by exposures to different types of androgens at various doses and administration windows, which resulted in a multiplicity of PCOS-like symptoms resembling the heterogenous clinical presentation of the syndrome. In addition, data from other species (for example, sheep and non-human primates) have been also included when relevant. Finally, a brief recap is provided on the current therapeutic strategies for managing the metabolic complications of PCOS, which are urgently necessary for more effective treatment options, in particular subsets of PCOS patients.

[20] Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

• Authors: Ryan M. Samuel, Homa Majd, Mikayla N Richter, Z. Ghazizadeh, S. Zekavat et al.
• Year: 2020
• Venue: Cell Stem Cell
• URL: https://www.semanticscholar.org/paper/f4766a510363f3ff641596b5978ea169a1d4f2fd
• DOI: 10.1016/j.stem.2020.11.009
• PMID: 33232663
• PMCID: 7670929
• Citations: 167
• Influential citations: 5
• Summary: It is demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity, and antiandrogenic drugs as candidate therapeutics for COVID-19 are identified.
• Evidence snippets:
• Snippet 1 (score: 0.377) > The diverse pharmacokinetic properties in these candidates may enable the development of drugs with improved distribution to disease-relevant tissues. Further experiments are needed to validate these compounds and characterize their pharmacokinetic and pharmacodynamic properties in vitro and in vivo. > A common characteristic among our validated hit compounds is their ability to target androgen signaling. Analysis of disease outcomes in COVID-19 patients in two independent cohorts revealed a significant association between elevated free androgen and COVID-19 complications, pointing to a possible link between androgen-mediated ACE2 regulation and disease severity. Pathway and gene target analysis on compounds that reduce ACE2 levels also highlighted the regulatory roles of peptidase pathways. Interestingly, protein interaction maps suggested a possible crosstalk between AR signaling pathways, inflammatory markers, and peptidases relevant to the viral receptor and co-receptors, offering insights into alternative pathways involved in ACE2 regulation. > Our FDA drug screen data revealed that many commonly used medications modulate ACE2 levels and could affect disease severity in COVID-19 patients. Further studies evaluating the relationships between these drugs and disease outcomes will be necessary to assess potential clinical impact and the need to substitute medications that might pose a heightened risk for COVID-19 patients. > In conclusion, our results provide key insights into ACE2 regulatory mechanisms, present strong molecular and clinical evidence for the role of androgen signaling in SARS-CoV-2 infection, and identify therapeutic candidates for the treatment of COVID-19.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.