Androgen insensitivity syndrome medical therapy: Difference between revisions
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===Surveillance=== | ===Surveillance=== | ||
Periodic reevaluation for [[gynecomastia]] during [[puberty]] in individuals assigned a male sex; monitoring of [[bone mineral density]] (BMD) through DEXA scanning in adults. <ref name="pmid20301602">{{cite journal |vauthors=Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, Gottlieb B, Trifiro MA |title= |journal= |volume= |issue= |pages= |year= |pmid=20301602 |doi= |url=}}</ref> | Periodic reevaluation for [[gynecomastia]] during [[puberty]] in individuals assigned a male sex; monitoring of [[bone mineral density]] (BMD) through [[DEXA scan|DEXA]] scanning in adults. <ref name="pmid20301602">{{cite journal |vauthors=Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, Gottlieb B, Trifiro MA |title= |journal= |volume= |issue= |pages= |year= |pmid=20301602 |doi= |url=}}</ref> | ||
===Evaluation of relatives at risk=== | ===Evaluation of relatives at risk=== | ||
In an apparently asymptomatic older or younger sibling who has normal external female genitalia and who has not yet undergone [[menarche]], a [[karyotype]] can be done first. For those phenotypic females who have a 46,XY [[karyotype]], molecular genetic testing for the known [[androgen receptor]] (AR) variant in the family can be pursued next. If the [[androgen receptor]] (AR) variant in the family is not known, androgen binding assays could be considered. | In an apparently asymptomatic older or younger sibling who has normal external female genitalia and who has not yet undergone [[menarche]], a [[karyotype]] can be done first. For those phenotypic females who have a 46,XY [[karyotype]], molecular genetic testing for the known [[androgen receptor]] ([[Androgen receptor|AR]]) variant in the family can be pursued next. If the [[androgen receptor]] ([[Androgen receptor|AR]]) variant in the family is not known, androgen binding assays could be considered. | ||
===Genetic counseling=== | ===Genetic counseling=== | ||
*Androgen receptor | *[[androgen receptor]] ([[Androgen receptor|AR]]) mutations are inherited and transmitted in an X-linked manner. | ||
*In XY-offspring, 50% are affected and XX offspring 50% of them are a healthy carrier. <ref name="pmid28670533">{{cite journal |vauthors=Akella RR |title=Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity |journal=Indian J Endocrinol Metab |volume=21 |issue=4 |pages=520–523 |year=2017 |pmid=28670533 |pmc=5477437 |doi=10.4103/ijem.IJEM_345_16 |url=}}</ref> | *In XY-offspring, 50% are affected and XX offspring 50% of them are a healthy carrier. <ref name="pmid28670533">{{cite journal |vauthors=Akella RR |title=Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity |journal=Indian J Endocrinol Metab |volume=21 |issue=4 |pages=520–523 |year=2017 |pmid=28670533 |pmc=5477437 |doi=10.4103/ijem.IJEM_345_16 |url=}}</ref> | ||
*Affected 46,XY individuals are almost always [[infertile]]. | *Affected 46,XY individuals are almost always [[infertile]]. | ||
Revision as of 20:50, 23 August 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]
Overview
A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who choose to retain the gonads are at risk of developing germ cell tumors for which sensitive circulating tumor markers may soon become available.
Medical Therapy
General management
Management of androgen insensitivity syndrome should address: [1]
- Functional issues
- Sexual issues
- Psychological issues such as disclosure
- Gonadectomy and subsequent hormone replacement
- Creation of a functional vagina, and provision of genetic advice.
- Care needs to be individualised, flexible, and holistic.
- Management is dependent wholly on a multidisciplinary team.
Specific management based on the type of AIS
Management of CAIS
Treatment of manifestations:
- In order to prevent testicular malignancy, treatment of CAIS may include either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood.
- Additional treatment for CAIS may include vaginal dilatation to avoid dyspareunia.
- Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery.[2]
- 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.[2]
- Hormone Replacement Therapy: Starting dose of 2 μg daily from roughly 11 years of age. This dose is increased in increments of 2–4 μg over about 2 years to reach a daily dose of 30 μg. Thereafter, and in women who have a gonadectomy after puberty, several preparations are available, including the natural estrogen estradiol, which can be given orally or transdermally. Synthetic estrogens can be given in the form of the combined oral contraceptive pill. Some evidence supports the use of natural estrogens as transdermal hormone replacement therapy because this administration method might be more physiological than oral delivery. [1]
Management of PAIS
- Treatment of PAIS in individuals with predominantly female genitalia is similar to treatment of CAIS, but is more likely to include prepubertal gonadectomy to help avoid increasing clitoromegaly at the time of puberty.
- In individuals with PAIS and ambiguous or predominantly male genitalia, the tendency has been for parents and healthcare professionals to assign sex of rearing after an expert evaluation has been completed.
- Individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair. [1]
- Individuals with PAIS who are raised as females and who undergo gonadectomy after puberty may need combined estrogen and androgen replacement therapy. [1]
Management of MAIS
- Males with MAIS may require mammoplasty for gynecomastia.
- A trial of androgen pharmacotherapy may help improve virilization in infancy.
- It is best if the diagnosis of AIS is explained to the affected individual and family in an empathic environment, with both professional and family support.
Psychosocial management
Psychosocial support is central to the multidisciplinary approach to management of complete androgen insensitivity syndrome. Presenting adolescents and parents of children with the disorder will have to make important decisions at diagnosis about treatments and the timing and extent of any surgical interventions. Concerns should focus on assimilation of the disconnect between chromosomal, gonadal, and phenotypic sex and its implications. Most centers caring for patients with disorders of sex development (DSD) provide specialist psychological support.[1]
Prevention of secondary manifestations
Regular weight-bearing exercises and supplemental calcium and vitamin D are recommended to optimize bone health; bisphosphonate therapy may be indicated for those with evidence of decreased bone mineral density and/or multiple fractures. [3]
Surveillance
Periodic reevaluation for gynecomastia during puberty in individuals assigned a male sex; monitoring of bone mineral density (BMD) through DEXA scanning in adults. [3]
Evaluation of relatives at risk
In an apparently asymptomatic older or younger sibling who has normal external female genitalia and who has not yet undergone menarche, a karyotype can be done first. For those phenotypic females who have a 46,XY karyotype, molecular genetic testing for the known androgen receptor (AR) variant in the family can be pursued next. If the androgen receptor (AR) variant in the family is not known, androgen binding assays could be considered.
Genetic counseling
- androgen receptor (AR) mutations are inherited and transmitted in an X-linked manner.
- In XY-offspring, 50% are affected and XX offspring 50% of them are a healthy carrier. [4]
- Affected 46,XY individuals are almost always infertile.
- The risk of transmission is negligible in sporadic cases. [4]
- In any case of de novo mutation of the AR gene, germline mosaicism cannot be excluded and while counseling the families has to be handled cautiously. [4]
- Each offspring of a female known to carry an androgen receptor (AR) pathogenic variant (heterozygote) is at a 25% risk for each of the following:
- Having a 46,XY karyotype and being affected
- Having a 46,XY karyotype and being unaffected
- Having a 46,XX karyotype and being a carrier
- Having a 46,XX karyotype and not being a carrier
- Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J (2012). "Androgen insensitivity syndrome". Lancet. 380 (9851): 1419–28. doi:10.1016/S0140-6736(12)60071-3. PMID 22698698.
- ↑ 2.0 2.1 Hughes IA, Werner R, Bunch T, Hiort O (2012). "Androgen insensitivity syndrome". Semin Reprod Med. 30 (5): 432–42. doi:10.1055/s-0032-1324728. PMID 23044881.
- ↑ 3.0 3.1 Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean L, Bird TD, Ledbetter N, Mefford HC, Smith R, Stephens K, Gottlieb B, Trifiro MA. PMID 20301602. Vancouver style error: initials (help); Missing or empty
|title=(help) - ↑ 4.0 4.1 4.2 Akella RR (2017). "Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity". Indian J Endocrinol Metab. 21 (4): 520–523. doi:10.4103/ijem.IJEM_345_16. PMC 5477437. PMID 28670533.