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European Review For Medical and... Jun 2018We provide a review of the literature about the Androgen Insensitivity Syndrome (AIS), its onset and associated developmental anomalies and the genetic alterations... (Review)
Review
OBJECTIVE
We provide a review of the literature about the Androgen Insensitivity Syndrome (AIS), its onset and associated developmental anomalies and the genetic alterations causing it.
MATERIALS AND METHODS
We searched PubMed with a larger emphasis on the physiology, genetics and current management of AIS.
RESULTS
AIS is an X-linked recessive Disorder of Sex Development (DSD). It is caused by mutations of the Androgen Receptor, and their large amount and heterogeneity (missense and nonsense mutations, splicing variants, deletions, and insertions) are responsible for the wide spectrum of possible phenotypes of patients, divided into Partial AIS (PAIS) and Complete AIS (CAIS). Once the clinical and laboratory investigations have laid the foundation for a diagnostic hypothesis, it is important to identify the actual karyotype of the individual and search for the mutation in the Androgen Receptor to diagnose with certainty the syndrome. Alternatively, in the absence of such evidence, the diagnosis should more properly be an AIS-like condition, which we describe as well in our report.
CONCLUSIONS
The management of this DSD is based on pharmacotherapies, surgery and psychological support: all of them must be directed to facilitate the patient's life, considering his/her sexual identity.
Topics: Androgen-Insensitivity Syndrome; Humans; Male; Mutation; Receptors, Androgen
PubMed: 29949163
DOI: 10.26355/eurrev_201806_15272 -
Archives of Endocrinology and Metabolism 2018Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen... (Review)
Review
Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.
Topics: Androgen-Insensitivity Syndrome; Female; Hormone Replacement Therapy; Humans; Male; Phenotype
PubMed: 29768628
DOI: 10.20945/2359-3997000000031 -
Acta Pharmacologica Sinica Jan 2015Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and... (Review)
Review
Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.
Topics: Androgens; Animals; Drug Discovery; Humans; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 24909511
DOI: 10.1038/aps.2014.18 -
International Journal of Molecular... Jan 2021Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY... (Review)
Review
Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.
Topics: Androgen-Insensitivity Syndrome; Androgens; Chromosomes, Human, X; Female; Gonads; Hormone Replacement Therapy; Humans; Karyotype; Male; Mutation; Receptors, Androgen
PubMed: 33514065
DOI: 10.3390/ijms22031264 -
Journal of Neuroendocrinology Feb 2022Widespread sex differences in human brain structure and function have been reported. Research on animal models has demonstrated that sex differences in brain and... (Review)
Review
Widespread sex differences in human brain structure and function have been reported. Research on animal models has demonstrated that sex differences in brain and behavior are induced by steroid hormones during specific, hormone sensitive, developmental periods. It was shown that typical male neural and behavioral characteristics develop under the influence of testosterone, mostly acting during perinatal development. By contrast, typical female neural and behavioral characteristics may actually develop under the influence of estradiol during a specific prepubertal period. This review provides an overview of our current knowledge on the role of steroid hormones in the sexual differentiation of the human brain. Both clinical and neuroimaging data obtained in patients with altered androgen levels/actions (i.e., congenital adrenal hyperplasia or complete androgen insensitivity syndrome [CAIS]), point to an important role of (prenatal) androgens in inducing typical male neural and psychosexual characteristics in humans. In contrast to rodents, there appears to be no obvious role for estrogens in masculinizing the human brain. Furthermore, data from CAIS also suggest a contribution of sex chromosome genes to the development of the human brain. The final part of this review is dedicated to a brief discussion of gender incongruence, also known as gender dysphoria, which has been associated with an altered or less pronounced sexual differentiation of the brain.
Topics: Androgen-Insensitivity Syndrome; Androgens; Animals; Brain; Female; Gonadal Steroid Hormones; Humans; Male; Pregnancy; Sex Differentiation; Steroids
PubMed: 34708466
DOI: 10.1111/jne.13050 -
Italian Journal of Pediatrics Sep 2021In healthy adolescents, delayed pubarche is generally a benign condition that is caused by a physiological discrepancy between gonadarche and adrenarche. In presence of... (Review)
Review
In healthy adolescents, delayed pubarche is generally a benign condition that is caused by a physiological discrepancy between gonadarche and adrenarche. In presence of other clinical signs and symptoms, delayed pubarche can be caused by single or multiple hormones deficiency (such as adrenal insufficiency, panhypopituitarism and hypothyroidism) and/or genetic conditions (Turner syndrome, androgen insensitivity syndrome). Exposition to endocrine disruptors has also been described as a possible cause of delay of pubic hair development. Basic blood tests, karyotype and first level imaging studies are helpful in the differential diagnosis.
Topics: Addison Disease; Adolescent; Adrenal Insufficiency; Androgen-Insensitivity Syndrome; Endocrine Disruptors; Environmental Exposure; Female; Humans; Hypothyroidism; Male; Puberty, Delayed; Turner Syndrome
PubMed: 34488834
DOI: 10.1186/s13052-021-01134-0 -
European Journal of Endocrinology Apr 2022An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient...
Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.
An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.
Topics: Child; Female; Gonadal Steroid Hormones; Hormone Replacement Therapy; Humans; Hypogonadism; Male; Pituitary Diseases; Puberty; Puberty, Delayed; Testosterone; Young Adult
PubMed: 35353710
DOI: 10.1530/EJE-22-0073 -
Frontiers in Endocrinology 2019Congenital cryptorchidism (undescended testis) is one of the most common congenital urogenital malformations in boys. Prevalence of cryptorchidism at birth among boys... (Review)
Review
Congenital cryptorchidism (undescended testis) is one of the most common congenital urogenital malformations in boys. Prevalence of cryptorchidism at birth among boys born with normal birth weight ranges from 1.8 to 8.4%. Cryptorchidism is associated with a risk of low semen quality and an increased risk of testicular germ cell tumors. Testicular hormones, androgens and insulin-like peptide 3 (INSL3), have an essential role in the process of testicular descent from intra-abdominal position into the scrotum in fetal life. This explains the increased prevalence of cryptorchidism among boys with diseases or syndromes associated with congenitally decreased secretion or action of androgens, such as patients with congenital hypogonadism and partial androgen insensitivity syndrome. There is evidence to support that cryptorchidism is associated with decreased testicular hormone production later in life. It has been shown that cryptorchidism impairs long-term Sertoli cell function, but may also affect Leydig cells. Germ cell loss taking place in the cryptorchid testis is proportional to the duration of the condition, and therefore early orchiopexy to bring the testis into the scrotum is the standard treatment. However, the evidence for benefits of early orchiopexy for testicular endocrine function is controversial. The hormonal treatments using human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone (GnRH) to induce testicular descent have low success rates, and therefore they are not recommended by the current guidelines for management of cryptorchidism. However, more research is needed to assess the effects of hormonal treatments during infancy on future male reproductive health.
PubMed: 32010061
DOI: 10.3389/fendo.2019.00906