Androgen Insensitivity Syndrome

Abstract

The androgen insensitivity syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of androgens. Three categories are recognized: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), mild androgen insensitivity syndrome (MAIS). The androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients (www.androgendb.mcgill.ca/). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups.

Novel Frem1-Related Mouse Phenotypes and Evidence of Genetic Interactions with Gata4 and Slit3

“…A complete inability to respond to androgens–as seen in complete androgen insensitivity syndrome (OMIM #300068)–can cause male fetuses to develop female external genitalia [58]. Since eyes2 male mice have male external genitalia and are fertile, we can assume that they are able to produce and respond to androgens in utero .…”

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

“…When dysregulated, however, AR activity is central to the onset, development and progression to metastasis of prostate cancer (PCa), the most common cancer diagnosed in males worldwide (Matias et al 2000, Gottlieb et al 2004, Knudsen & Penning 2010, Arora & Barbieri 2018, Centenera et al 2018, Cioni et al 2018, Li et al 2018, Nevedomskaya et al 2018, Paschalis et al 2018. In addition, AR mutations are linked to disorders of male sexual differentiation and development termed androgen insensitivity syndromes (AIS) (Hughes et al 2012, Mongan et al 2015, Gibson et al 2018 and to the rare adult-onset hereditary neurodegenerative disorder known as spinal and bulbar muscular atrophy (SBMA or Kennedy's disease; OMIM #313200) (Spada et al 1991, Badders et al 2018, Cortes & La Spada 2018, Lieberman 2018, Pennuto & Rinaldi 2018. Finally, AR malfunction is also associated to androgenic alopecia or loss of scalp hair and skin malignancies (Ellis et al 2001, Clocchiatti et al 2018.…”

Endocrine control of spermatogenesis: Role of FSH and LH/ testosterone

“…Mice in which AR has been knocked out prenatally (i.e., ARKO mice) are infertile. [77][78][79][80][81][82] Interpretation of the significance of these findings, however, are confounded by the failure in these mice of the testis to descend into the scrotum due to the absence of AR signaling during prepubertal development. This problem is eliminated by postpuberal ablation of AR in adult mice expressing a tamoxifen inducible Cre recombinase and in these animals spermatogenesis is arrested with a virtual absence of sperm in the epididymis and testis 50 d after deletion of the receptor.…”

“…37 As in the rodent, humans bearing loss of function mutations in AR are infertile. 77,[80][81][82] Activation of LH-testosterone signaling prior to the onset of puberty, on the other hand, leads to the precocious onset of spermatogenesis. In the human, reports of activating mutations in LHb or LH-R and Leydig cell tumors are shown to be associated with precocious puberty.…”