Androgen Receptor, Implications for Health and Wellbeing: Natural History Study of Individuals With Androgen Insensitivity

Study Overview
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Brief Summary
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Background: Androgen effects in humans are usually (but not always) mediated by the androgen receptor which is coded for by the androgen receptor gene (AR gene). Androgen Insensitivity Syndrome (AIS) is a rare condition in which the body cannot sense the male hormones in the blood or tissue. Both women and men can be affected by AIS. Researchers want to learn more about the health of people with AIS over time. With a natural history study in individuals with AIS, data and tests may provide information regarding health risks (including the risks and benefits of gonadectomy and best ways to monitor for tumor) and optimal management of individuals with AIS as well as elucidate the role of the androgen receptor in human health. This study does not involve any interventions and we can provide clinical care while collecting data. Objective: The objective of this natural history study is to describe and define a comprehensive phenotype (characteristic) of patients with AIS based on confirmed androgen receptor (AR) gene difference. We will evaluate hormones, bone density and markers, cardiovascular and metabolic parameters, as well as quality of life and tumor formation risk and evaluation. The purpose is to obtain a better understanding of the overall health issues that people with AIS may have through the study procedures listed. Eligibility: People ages 0-99 with AIS and their adult relatives Design: Participants will go through a series of study procedures for data and specimen collection. This will be done to understand how AIS affects individuals since the androgen receptor is found in many tissues in the body including skin, bone, muscle, and the neurologic, immune and metabolic systems. All tests will be performed by skilled and trained study professionals. Participants will be screened with: Medical history Physical exam Medical record review Lab tests. Participants will have physical exams. Their body measurements will be taken. They will have blood and urine tests. They will have electrocardiograms to check heart health. They may complete questionnaires. They may have an Oral Glucose Tolerance Test. Participants may have x-rays taken of the hand, wrist, and other bones. Participants will have body scans to measure bone thickness. Participants will have magnetic resonance imaging (MRI) or sonogram of the pelvis. For MRI, they may get a contrast agent via intravenous (IV) catheter. Adult participants may have the following: MR elastography. It uses MRI and low-frequency vibrations to map stiffness of body tissues. MR spectroscopy. It uses MRI to take pictures of chemicals in the liver and body fat. Cardiac computed tomography scan. It uses x-rays to make pictures of the heart. Participants may get a contrast agent via IV. Optional genital exam. Participants will have visits every 1-2 years. Participation lasts indefinitely. Adult relatives will also be invited to participate but will have only 1 visit. It will include some of the above tests.

Detailed Description
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Androgen effects in humans are usually (but not always) mediated by the androgen receptor which is coded for by the androgen receptor gene (AR gene). Individuals with abnormalities of this receptor gene can present with androgen insensitivity syndrome (AIS). There are a variety of phenotypes including complete female phenotype (complete androgen insensitivity or CAIS), ambiguous genitalia in cases of partial androgen insensitivity (PAIS) and male phenotype associated with infertility of hypospadias in mild cases of AIS. Complete androgen insensitivity is a rare condition with an estimated incidence of 1:20,000-64,000, while PAIS is rarer still and mild AIS has likely not been studied enough to ascertain it s prevalence. Individuals with complete and partial AIS present some management conundrums as traditionally they have undergone gonadectomy in order to avoid gonadal tumors as well as pubertal virilization in girls with PAIS. Because this is a rare condition, little is known regarding the risks and benefits of gonadectomy, optimal hormone replacement after gonadectomy as well as general health in individuals with these conditions. Furthermore, the androgen receptor is found in many tissues in the body including skin, bone, muscle, and the neurologic, immune and metabolic systems. Finally, some testosterone effects may be through mechanisms other than AR receptor and these are not well understood. A natural history study in individuals with AIS may provide information regarding health risks and optimal management of individuals with AIS as well as elucidate the role of the androgen receptor in human health.

Official Title
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Androgen Receptor, Implications for Health and Wellbeing: Natural History Study of Individuals With Androgen Insensitivity

Conditions
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Androgen Insensitivity Syndrome, Metabolic Parameters in AIS, CAIS, PAIS and MAIS, Tumor Formation in AIS, CAIS, PAIS and MAIS, Sexual Function AIS, CAIS, PAIS and MAIS

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Inclusion Criteria for AIS subjects In order to be eligible to participate in this study, an individual must meet all the following criteria: Individuals ages 0-99 years old with known androgen insensitivity based on pathologic androgen receptor gene mutation or based on clinical diagnosis of complete androgen insensitivity (CAIS) based on 46 XY karyotype, presence of testis, absence of uterus, high testosterone without signs of virilization at birth or during purberty and/or multipl members in the family also presenting with clinical CAIS. Identify as male or female Patients with both complete, partial and mild androgen insensitivity are eligible Stated willingness to comply with all study procedures and availability for the duration of the study Ability of subject or guardian to understand and the willingness to sign and date a written informed consent document. Inclusion Criteria for Relative of AIS subjects 1) Adult Relatives of patients with AIS EXCLUSION CRITERIA: Exclusion Criteria for AIS subjects An individual who meets any of the following criteria will be excluded from participation in this study: Patients with other diagnosis such as partial or complete gonadal dysgenesis, 5-alpha reductase deficiency, and 46 XY. If, following a diagnostic work-up, a patient is determined to have causes for 46 XY DSD other than androgen insensitivity; they will no longer be followed on this protocol. They will have the opportunity to continue care with the team under the Data Collection Protocol or may be referred to an expert or multidisciplinary DSD team in the community Patients with significant non-endocrine medical conditions. Exclusion Criteria for Relative of AIS subjects 1) Patients with significant non-endocrine medical conditions. INCLUSION OF VULNERABLE PARTICIPANTS Participation of Children Children will be included in this protocol as AIS is often diagnosed early in life and has effects on puberty and development. Every effort will be made to protect children s rights and safety. Participation of Employees NIH employees may be enrolled in this study as this population meets the study entry criteria. Neither participation nor refusal to participate as a subject in the research will have an effect, either beneficial or adverse, on the participant s employment or position at NIH.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Female subjects relatives who are carriers of the AR gene difference<br>We will enroll 50 female subjects relatives AIS subjects who are carriers of the AR gene difference | |
| Female subjects relatives who are not carriers of the AR gene<br>We will enroll 50 female subjects relatives of AIS subjects who are not carriers of the AR gene. | |
| Healthy male subjects relatives<br>We will enroll 50 healthy male subjects of AIS relative subjects | |
| Subjects with androgen receptor mutations<br>500 Subjects with confirmed androgen receptor mutations | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define and describe a comprehensive phenotype in 500 patients with androgen insensitivity | Primary Objectives: To define and describe a comprehensive phenotype of patients with androgen insensitivity (based on confirmed androgen receptor (AR) gene difference), including hormonal, metabolic, immunologic, and cardiovascular aspects of the disease, as well as quality life and tumor formation risk and evaluation | End of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Bone Health in individuals with Androgen Insensitivity | DEXA scans and bone metabolism markers will be evaluated longitudinally in all individuals with AIS. Comparison between family members who are carriers and non-carriers of the AR gene difference, those with mild, partial and complete androgen insensitivity will allow for evaluation of the effect of androgen receptor abnormalities on bone mineral density and growth as well as develop normative data for DEXA scan interpretation in this population. Physiatry measurements will allow evaluation of muscle skeletal unit inferences. | End of study | 
| Metabolic assessment in individuals with Androgen Insensitivity | Metabolic parameters including laboratory evaluation as well as novel endometabolic imaging will be performed. Imaging will include MR spectography of liver fat and body composition, MR elastography for fibrosis assessment, and coronary wall imaging using CT angiography, and MRI evaluation of endothelial function to evaluate for artherosclerosis | End of study | 
| Gonadal Tumor evaluation in individuals with Androgen Insensitivity | A) MRI and Ultrasound imaging will be performed to describe the typical appearance of testes on ultrasound and magnetic resonance imaging (MRI) in young individuals with CAIS. B) Evaluate gonadal tumor markers as a tool to assess for gonadal tumor C) Gonadectomy tissue evaluation in order to: Investigate the histology and pathophysiology of gonadal tumor formation and assess the state of spermatogenesis in testis of individuals with androgen receptor abnormalities | End of study | 
| Quality of life measures (QoL) in individuals with Androgen Insensitivity | Quality of life questionnaires will be administered during each patient visit | End of study | 
| Effects of hormone therapy in individuals with Androgen Insensitivity | Evaluate different types and delivery of hormone replacement therapy on quality of life, sexual function, bone health and metabolic parameters in individuals who have undergone gonadectomy | End of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Androgen insensitivity syndrome (AIS), Complete androgen insensitivity (CAIS), Partial androgen insensitivity (PAIS), Mild androgen insensitivity syndrome (MAIS), Natural History