Androgen insensitivity syndrome

This is part of Rare diseases.

Diagnosis: Androgen insensitivity syndrome

Synonyms: AIS, Androgen resistance syndrome, Testicular feminisation syndrome


Publication date: 2014-12-22
Version: 3.0

The disease

Androgen insensitivity syndrome (AIS) is a disorder in which individuals whose chromosomes follow a normal male pattern (46, XY) respond poorly to male sex hormones (such as testosterone). It is the most commonly known reason why children born with normal levels of male sex hormones develop the external sex characteristics of females (feminisation). Androgen insensitivity syndrome thereby belongs to a group of sex development disorders.

There are two forms of the syndrome: complete androgen insensitivity syndrome (CAIS) and partial androgen insensitivity syndrome (PAIS). Children with the complete form have unambiguously female external genital development, and there is no question that these girls belong to the female sex. In partial androgen insensitivity the external genitals are feminised to various degrees, ranging from an abnormally placed urinary opening (hypospadias) to almost normal male development.

Androgen insensitivity syndrome was first described in 1948 by two American physicians, Minni Goldenberg and Alice Maxwell. The physician most closely associated with the syndrome, however, is American gynaecologist John Morris. In an article from 1953 he coined the term testicular feminisation syndrome, which explains the former name of the disorder, Morris syndrome.

Other disorders of sex development include congenital adrenal hyperplasia (CAH), in which individuals with female chromosomes (XX) develop as males (virilization). Separate information on congenital adrenal hyperplasia (in Swedish) is available in the Rare Disease Database of the Swedish Board of Health and Welfare. Less common causes of ambiguous sex development include deficiency of one of the enzymes required for normal production of male sex hormones, particularly testosterone.


There is no consistent data on the occurrence of androgen insensitivity syndrome. The incidence is usually reported to be between 1 and 5 per 100,000 births.

Approximately 10 to 20 Swedish children per year are born with a sex development disorder, some of whom are affected by partial androgen insensitivity syndrome. Complete insensitivity to male sex hormones is very rare.


Androgen insensitivity is usually caused by a mutation in the AR gene (Xq11-q12). This gene governs the production of (codes for) the androgen receptor, which is a protein that responds to signals from male sex hormones (androgens). In all, over 200 mutations in the androgen receptor (AR) gene have been described. Some of these mutations impair the ability of the androgen receptor to bind and mediate the effects of testosterone, which plays a role in many organs. A functioning receptor is crucial in the development of the male genitalia (the penis, scrotum, prostate, epididymides, and spermatic ducts). If there is no activity in the androgen receptor, no male genitals will develop. Androgen receptor activity is also required for the development of pubic and axillary hair, beard growth, and acne and perspiration odour in adults.

Partial androgen insensitivity is the most common type, and is associated with some degree of receptor activity. It is also possible that some cells in the body have normal receptors. In complete androgen insensitivity there is no androgen receptor activity. An AR mutation has been identified in almost 50 per cent of individuals with partial androgen insensitivity. It is likely that other factors may also cause partial androgen insensitivity.


Androgen insensitivity is caused by a mutated gene located on the X chromosome, which is one of the chromosomes determining sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50 per cent risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease cannot pass it on to his sons, but all his daughters will be carriers of the mutated gene. However, in androgen insensitivity syndrome this may not be relevant as individuals with the disorder are generally infertile.

Figure: X-linked recessive inheritance  via a healthy female carrier

Androgen insensitivity syndrome can also be caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder.


The type of androgen insensitivity syndrome determines the extent of symptoms.

In complete androgen insensitivity syndrome (CAIS), external development is unambiguously female and the diagnosis is not suspected until puberty, when menstruation fails to present. Occasionally the diagnosis is made before puberty, if a testis is found in association with surgery for inguinal hernia. Girls with CAIS develop little or no pubic or axillary hair. The vagina is short and blind-ended, as there is no developed uterus. The ovaries and Fallopian tubes are absent and there are no internal male genitalia (prostate, epididymides, or spermatic ducts). Testicles, however, are always present and appear normal. They may be located in the abdominal cavity or the groin and can produce normal amounts of testosterone but no sperm. As a consequence, the individual is infertile.

Partial androgen insensitivity syndrome (PAIS) may give rise to a variety of symptoms, and gender assignment is sometimes difficult. Hypospadias is very common, meaning that the urethra opens on the underside of the penis rather than on the top. The external genitals often have both male and female elements: the penis may resemble a large clitoris or the clitoris a small penis. The scrotum is divided and resembles the outer labia of a female.

In very mild cases of PAIS, the external genitalia are unambiguously male, although the penis and scrotum are relatively small and beard growth is sparse. Breasts may develop in puberty. In most cases, fertility is impaired.


When a baby is born with ambiguous genitalia, congenital adrenal hyperplasia (CAH) must be promptly excluded as this condition requires immediate treatment. The diagnosis of androgen insensitivity syndrome is made on the basis of external signs, gynaecological examination, blood tests for measuring hormone levels and chromosome analysis. The diagnosis of complete androgen insensitivity is then confirmed by analysis of the androgen receptor gene.

Complete androgen insensitivity syndrome

In complete androgen insensitivity, genital development is unambiguously female, which means that the condition is usually not detected until pubic hair and menstruation fail to appear in puberty. An ultrasound scan is enough to raise strong suspicion of the syndrome, and further examinations and DNA analysis confirm the diagnosis. The presence of tender swellings (testicles) in the groin sometimes leads to earlier diagnosis.

Partial androgen insensitivity syndrome

Visibly atypical genitals enable early diagnosis of partial androgen insensitivity syndrome. External examination may still not be sufficient to determine whether, from a genetic perspective, the baby is a feminised boy or a girl that has become virilized owing to androgen exposure during the foetal period.

Gender assignment then requires extensive anatomic, genetic, and endocrinological assessment.

Children with androgen insensitivity have male sex chromosomes and produce male sex hormones, but their tissue response to these hormones is poor.

Almost all individuals with CAIS and almost half of those with PAIS have mutations in the AR gene, and DNA-based diagnosis is therefore possible in most cases of CAIS and sometimes in cases of PAIS.

At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation has been identified.


Within 24 hours of delivery, newborns with suspected androgen insensitivity must be referred to a university hospital with the required competence to examine and treat children with ambiguous sex development. The first step in this investigation is to exclude congenital adrenal hyperplasia (CAH), as this condition requires immediate treatment. The infant is then assessed by a multidisciplinary team consisting of specialists in paediatric endocrinology, paediatric surgery or urology, child psychiatry, gynaecology, and genetics. The parents are provided with information and support in preparation for the decision they have to make about gender assignment of the baby.

Difficult ethical issues sometimes arise with respect to gender assignment and making decisions about surgery. The timing and extent of surgical interventions are currently under debate, both nationally and internationally, as treatment has psychological implications and may affect sexuality. Treatment goals and planning vary from case to case, but Swedish guidelines specify that examinations and genital surgical procedures should be avoided between the ages of 2 and 12. In most cases, genital surgery is performed early, before the age of 6 months. Additional surgery may be carried out when the child reaches puberty. A number of adult women with the syndrome have stressed the importance of restricting early surgical intervention to a minimum, thereby enabling individuals with the syndrome to participate actively in decision-making that concerns their own bodies.

One option for avoiding surgery in girls with complete androgen insensitivity may be to lengthen the vagina using manual pressure dilation, which will gradually extend the vagina and thereby make sexual intercourse possible. This intervention is not begun until the girl is in her teens.

Babies with partial androgen insensitivity should be fully investigated as early as possible so that treatment goals can be drawn up. In order to facilitate the process of making an informed decision, the parents should be offered several opportunities to discuss the situation with specialist physicians and psychologists. The treatment is always individualised and involves careful decision-making. All interventions require parental consent and both parent and physicians are involved in planning treatment.

If it is decided that a child with partial androgen insensitivity is a girl, the testes are usually removed (gonadectomy). This intervention is performed to prevent pubertal virilization, as well as to prevent the development of gonadal tumours (the risk of testicular malignancies is elevated from the early teens onwards). In complete androgen insensitivity, it may be preferable to postpone gonadectomy as the testicles produce sufficient female hormones to encourage spontaneous breast development and female body shape in puberty. Apart from being valuable from a psychological perspective, delayed surgical intervention also enables the girl to take part in decisions relating to surgical treatment. In complete androgen insensitivity, there is no risk that testosterone from the testicles will virilise the girl. However, if gonadectomy is postponed, the girl must be carefully monitored for early detection of testicular tumours, although these are rare in cases of complete androgen insensitivity.

If the testicles have not been removed in girls with partial androgen insensitivity, it is important to detect possible signs of virilization in puberty. In girls whose testes have been removed, oestrogen replacement therapy is given from the age of 11 or 12. Surgical removal of the testicles is recommended for girls who are diagnosed later in childhood or in their teens.

If gender assignment is male, analysis of tissue from the testicles (testicle biopsy) should be performed in order to detect early-stage testicular cancer, which requires treatment. In some cases testosterone supplements may be considered in puberty.

Teenagers and adults with the syndrome may feel uncomfortable about their lack of pubic hair. Topical testosterone treatment sometimes stimulates hair growth.

Having a child with a sex development disorder is an emotionally trying experience for the parents. Under these circumstances it is important how and by whom the parents are informed about the condition, and that they are given well-informed answers to their questions. Information must be given by staff with knowledge and experience of the condition, and should comprise medical facts presented lucidly, treatment options, and future prospects. The parents will be better able to support their child if they have had the opportunity to deal with their own thoughts and emotions, and if they learn as much as possible about the condition. Psychological support is an integral part of treatment.

The child needs continuous age-appropriate information and psychological support. Development should be monitored closely, facilitating contact as new questions and problems arise. The need for psychological support may increase in puberty. Teenage girls should be given the opportunity to meet an experienced gynaecologist to discuss the condition and future plans, including surgical options and fertility issues.

Girls with the syndrome whose external female genitalia are unambiguously female, and whose testicles produce enough female sex hormones for breasts and female body shape to develop, usually do not seek medical care until they fail to menstruate. This means that both the girl and her parents are completely unprepared for the news that she was born with male sex chromosomes and without internal genitalia. Information about the condition should therefore be given in stages at a number of appointments with an endocrinologist and/or gynaecologist with experience in disorders of sex development, possibly together with an experienced child psychiatrist, psychologist, or medical social worker. Surgical interventions must not be planned until the family is fully informed and the girl is able to express her own wishes. The current recommendation is to remove the testes in individuals with partial androgen insensitivity for the purpose of cancer prevention. (Although sources vary, the risk of developing gonadal tumours is estimated at between 2 and 10 per cent in complete androgen insensitivity and considerably higher in partial androgen insensitivity). This intervention is followed by hormone replacement therapy to maintain breast development, healthy vaginal tissue, and normal bone density. It is important that the girl herself is fully informed and that she takes part in the decision to remove the testicles. A growing number of adult women with complete androgen insensitivity have protested against the fact that their testes were removed without their informed consent.

Adults with the syndrome need continued contact with a physician knowledgeable about the condition, as well as psychological support.

Practical advice


National and regional resources in Sweden

Initial investigation may be performed by specialists at Swedish university hospital departments of paediatric endocrinology. Multidisciplinary assessment and treatment teams (consisting of specialists in paediatric endocrinology, paediatric surgery or urology, gynaecology, genetics, and paediatric psychiatry) have been formed at Astrid Lindgren Children’s Hospital, Karolinska University Hospital in Stockholm, tel: +46 8 517 700 00, at Queen Silvia Children's Hospital, Sahlgrenska University Hospital in Gothenburg, tel: +46 31 343 10 00, and at the Centre for Reproductive Medicine in Malmö, tel: +46 40 33 10 00. The Centre for Reproductive Medicine is the result of cooperation between the university hospitals in Lund and Malmö. In all these care units, the team coordinator is usually a paediatric endocrinologist.

Resource personnel

Paediatric endocrinology

Professor Emeritus Sten Ivarsson, email: stenanders.ivarsson@telia.com, and Associate Professor Johan Svensson, email: johan.svensson@med.lu.se, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00.

Professor Emeritus Martin Ritzén, email: martin.ritzen@ki.se, and Associate Professor Anna Nordenström, email: anna.nordenstrom@ki.se, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 775 79.

Professor Olle Söder, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 751 24, email: olle.soder@ki.se.

Specialist Physician Annika Reims, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: annika.reims@vgregion.se.

Paediatric surgery/urology

Senior physician Gundela Holmdahl, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: gundela.holmdahl@vgregion.se.

Professor emeritus Göran Läckgren, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: goran.lackgren@kbh.uu.se.

Professor Agneta Nordenskjöld, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 777 05, email: agneta.nordenskjold@ki.se.

Christina Clementson Kockum, MD, PhD, Paediatric Surgery Clinic, Children's Hospital, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00, email: christina.clementsonkockum@skane.se.

Professor Henry Svensson, Plastic Surgery Clinic, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00, email: henry.svensson@med.lu.se.


Professor Trond Diseth, Paediatric Psychiatry Unit, Department of Paediatrics, Oslo University Hospital, 0027 Oslo, Norway. Tel: +47 2307 00 00, email: trond.diseth@rikshospitalet.no.

Professor emeritus Per-Anders Rydelius, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden. Tel +46 8 517 772 06, email: per-anders.rydelius@kbh.ki.se.

Dr Louise Frisén, PhD, Department of Neuroscience, Karolinska institutet, Stockholm, email: louise.frisen@ki.se.


Professor emerita Kerstin Hagenfeldt, email: kerstin.hagenfeldt@telia.se, and Professor Angelica Lindén-Hirschberg, email:
angelica.linden-hirschberg@karolinska.se, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Professor Martin Stjernquist, Department of Obstetrics and Gynaecology, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 40 33 10 00, email: martin.stjernquist@med.lu.se.


Professor Niklas Dahl, Department of Clinical Genetics, The Rudbeck Laboratory, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 00 00, email: niklas.dahl@igp.uu.se.

Associate Professor Yvonne Lundberg Giwercman, CRC, Lund University, SE-205 02 Malmö, Sweden. Tel: +46 40 39 11 03, email: yvonne.giwercman@med.lu.se.

Dr. Maria Soller, PhD, Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00, email: maria.soller@skane.se.

Professor Anna Wedell, Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 700 00, email: anna.wedell@ki.se.

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations etc.

INIS is a Swedish support group for intersex individuals with DSD (Disorders of Sex Development, i.e. congenital conditions characterised by chromosomal, gonadal or anatomic abnormalities in sex development). Email: kontakta@inis-org.se, Internet: www.inis-org.se.

Courses, exchanges of experience for personnel


Research and Development

Research aiming to explain the cause and treatment of sex development disorders is ongoing at Astrid Lindgren Children’s Hospital and the Department of Clinical Genetics at Karolinska University Hospital in Stockholm.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under "Mer hos oss" in the column on the right-hand side.

Information from INIS, the Swedish support group for intersex individuals with DSD and their families: www.inis-org.se.

Information from the Androgen Insensitivity Support Group in Great Britain: www.aissg.org.

Information from the North-American patient association Accord Alliance: www.accordalliance.org.

The Intersex Society of North America (ISNA) is another North-American patient association. It closed down in 2008 when Accord Alliance was formed, but there is still a great deal of information on the website: www.isna.org.


Brown J, Warne G. Practical management of the intersex infant. J Pediatr Endocrinol Metab 2005; 18: 3-23.

Hjort O. Clinical and molecular aspects of androgen insensitivity. Endocr Dev 2013; 24: 33-40.

Mattila AK, Fagerholm R, Santtila P, Miettinen PJ, Taskinen S. Gender identity and gender role organisation in female assigned patients with disorders of sex development. J Urol 2012; 188: 1930-1934.

Morris JM, Mahesh VB. Further observations on the syndrome, “testicular feminization”. Am J Obstet Gynecol 1963, 15; 87: 731-748.

Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome - a review. J Pediatr Adolesc Gynecol 2008; 21: 305-310.

Purves JT, Miles-Thomas J, Migeon C, Gearhart JP. Complete androgen insensitivity: the role of the surgeon. J Urol 2008; 180: 1716-1719.

Rey RA, Grinspon RP. Normal male sexual differentation and aetiology of disorders of sex development. Best Pract Res Clin Endocrinol Metab 2011; 25: 221-238.

Ritzén M, Gustavson K-H, Wedell A. Genetisk och somatisk könsdifferentiering. I: Sexologi, tredje upplagan, red P O Lundberg, Liber Förlag 2010; 19-30.

Thyen U, Richter-Appelt H, Wiesemann C, Holterhus PM, Hiort O. Deciding on gender in children with intersex conditions: considerations and controversies. Treat Endocrinol 2005; 4: 1-8.

Wedell A, Ritzén M, Nordenskjöld A. Pojke eller flicka? Molekylära mekanismer vid könsdifferentiering. Läkartidningen 1997: 449-457, 2000.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: androgen insensitivity syndrome, AIS

GeneReviews (University of Washington)
www.genetests.org (select "GeneReviews", then "Titles")
Search: androgen insensitivity syndrome, AIS

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Martin Ritzén, Astrid Lindgren Children's Hospital, Sweden.

Associate Professor Anna Nordenström, Astrid Lindgren Children's Hospital, Stockholm, has also been involved in revising the material.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-12-22
Version: 3.0
Publication date of the Swedish version: 2013-06-03

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.