MEDICAL & ACADEMIC RESEARCH

Please find following various papers published on the subject of Androgen Insensitivity Syndrome (AIS) and intersex.

Click on any of the headings to see the full article (where available). Please also see our page on the Management of Infants with Ambiguous Genitalia for more scholarly information.

Ethical Principles for the Management of Infants with Disorders of Sex Development.

Gillam LH, Hewitt JK, Warne GL. Children's Bioethics Centre, Royal Children's Hospital, Melbourne, Vic., Australia. Horm Res Paediatr. 2010 Aug 12.

Abstract: The Fifth World Congress on Family Law and Children's Rights (Halifax, August 2009) adopted a resolution endorsing a new set of ethical guidelines for the management of infants and children with disorders of sex development (DSD). The ethical principles developed by our group were the basis for the Halifax Resolution. In this paper, we outline these principles and explain their basis. The principles are intended as the ethical foundation for treatment decisions for DSD, especially decisions about type and timing of genital surgery for infants and young children. These principles were formulated by an analytic review of clinician reasoning in particular cases, in relation to established principles of bioethics, in a process consistent with the Rawlsian concept of reflective equilibrium as the method for building ethical theory. The principles we propose are: (1) minimising physical risk to child; (2) minimising psychosocial risk to child; (3) preserving potential for fertility; (4) preserving or promoting capacity to have satisfying sexual relations; (5) leaving options open for the future, and (6) respecting the parents' wishes and beliefs.

Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK

R M Vinerb, Y Teoh, D M Williams, M N Patterson & I A Hughes Archive of Diseases in Childhood 1997; 77:305-309

OBJECTIVE A two year survey of androgen insensitivity syndrome (AIS) to assess current diagnostic and management strategies.

METHODS Cases were ascertained by inclusion on the British Paediatric Surveillance Unit monthly report card for 24 months.

RESULTS Fifty one of 139 notifications were confirmed as AIS; 29 cases were complete AIS and 22 cases partial AIS. Seventy six per cent of complete AIS presented with an inguinal hernia, and half the complete AIS patients had an established family history of the disorder. Presentation in the partial AIS group was through ambiguous or undermasculinised genitalia; 59% of partial AIS were raised as male.

CONCLUSIONS The importance of karyotyping girls with inguinal hernias is confirmed, and further attention should be given to genetic counselling for families of complete AIS patients. A large number of cases were misreported as partial AIS, emphasising the importance of undertaking a comprehensive diagnostic evaluation in intersex states. A large percentage of children with partial AIS were raised as boys despite severe genital undermasculinisation, indicating the current lack of validated measures that predict genital response to androgen treatment. The management of AIS is discussed and diagnostic guidelines provided to improve the diagnostic yield in AIS.  

Male Gender Identity in Complete Androgen Insensitivity Syndrome

Guy T'Sjoen, Griet De Cuypere, Stan Monstrey, Piet Hoebeke, F. Kenneth Freedman, Mahesh Appari, Paul-Martin Holterhus, John Van Borsel and Martine Cools Archives of Sexual Behaviour April 01, 2010. 

Abstract: Women and girls with complete androgen insensitivity syndrome (CAIS) invariably have a female typical core gender identity. In this case report, we describe the first case of male gender identity in a CAIS individual raised female leading to complete sex reassignment involving both androgen treatment and phalloplasty. CAIS was diagnosed at age 17, based on an unambiguously female phenotype, a 46,XY karyotype, and a 2660delT androgen receptor (AR) gene mutation, leading to a premature stop in codon 807. Bilateral gonadectomy was performed but a short period of estrogen treatment induced a negative emotional reaction and treatment was stopped. Since the age of 3, childhood-onset cross gender behavior had been noticed. After a period of psychotherapy, persisting male gender identity was confirmed. There was no psychiatric co-morbidity and there was an excellent real life experience. Testosterone substitution was started, however without inducing any of the desired secondary male characteristics. A subcutaneous mastectomy was performed and the patient received phalloplasty by left forearm free flap and scrotoplasty. Testosterone treatment was continued, without inducing virilization, and bone density remained normal. The patient qualifies as female-to-male transsexual and was treated according to the Standards of Care by the World Professional Association for Transgender Health with good outcome. However, we do not believe that female sex of rearing as a standard procedure should be questioned in CAIS. Our case challenges the role of a functional AR pathway in the development of male gender identity.  

46,XY Intersex Individuals: Phenotype and Etiologic Classification, Knowledge of Condition, and Satisfaction with Knowledge in Adulthood

Claude J. Migeon, Amy B. Wisniewski, Terry R. Brown, John A. Rock, Heino F.L. Meyer-Bahlburg, John Money, and Gary D. Berkovitz, Pediatrics 2002; 110: e32.

The AISSG Australia was recently asked to review this paper for a television network preparing a documentary on the treatment of children with intersex conditions. Here is a copy of Tony Briffa's letter:

Thank you for contacting the AIS Support Group Australia (AISSGA) for a comment about this study.

The AISSGA is pleased Johns Hopkins is conducting research on the treatment of children with intersex conditions. Unfortunately, follow-up studies and research on a number of important issues for those affected by intersex conditions, such as osteoporosis and hormone replacement therapy, is severely lacking.

While the AISSGA is pleased this study shows that approximately three out of four children with intersex conditions are happy with the gender they were assigned at birth, we support the child's right to physical integrity and are deeply concerned for those children who are not happy with the gender they were assigned - particularly if they have undergone irreversible medical intervention. A failure rate of 25% is not acceptable.

There are also those individuals with intersex conditions that are happy with the gender they were raised, but still grieve for the bodies they were born with.

Doctors need to realise that the genitals of children with intersex conditions are never a medical problem.

The results of the companion study that showed half the participants knew little about their condition demonstrates the importance of full disclosure. It also raises doubts as to their ability to comment on the success of their gender assignment.

The focus on the medical management of children with intersex conditions should be on: obtaining an accurate diagnosis, providing professional counselling, peer support, accurate and timely information, permitting the parents time to reflect on all treatment options available, informing the child in stages about their condition and seeking their consent for any medical intervention when they are old enough to make these important decisions for themselves.

The AISSGA's preferred treatment paradigm is attached to this email. Please feel free to distribute or quote it.

I hope this information has helped. Thanks once again for the opportunity to comment about the study.

Best wishes,

Tony Briffa

Novel (60%) and Recurrent (40%) Androgen Receptor Gene Mutations in a Series of 59 Patients with a 46,XY Disorder of Sex Development

The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 4 1876-1888

Copyright © 2010 by The Endocrine Society

L. Audi, et. al

Background: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS).

Objective: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients.

Setting: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis.

Methods: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients.

Results: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel.

Conclusions: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

Concomitant Mutations in the P450 Oxidoreductase and Androgen Receptor Genes Presenting with 46,XY Disordered Sex Development and Androgenization at Adrenarche

Jan Idkowiak, et al.

Centre for Endocrinology, Diabetes, and Metabolism (J.I., V.D., N.R., D.M.H., C.H.L.S., N.K., W.A.), School of Clinical and Experimental Medicine, University of Birmingham, Birmingham BI5 2TT, United Kingdom; Departments of Biochemistry and Experimental Medicine (E.M.M.) and Metabolic Diseases, Endocrinology, and Diabetology (M.S.-C.), The Children's Memorial Health Institute, 04-730 Warsaw, Poland; Department of Paediatrics (J.D.D., I.A.H.), Addenbrooke's Hospital, University of Cambridge, Cambridge DB2 2OO, United Kingdom

Address all correspondence and requests for reprints to: Professor Wiebke Arlt, M.D., D.Sc., F.R.C.P., Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. E-mail: w.arlt@bham.ac.uk.

Context: Undervirilization in males, i.e. 46,XY disordered sex development (46,XY DSD), is commonly caused by either lack of androgen action due to mutant androgen receptor (AR) or deficient androgen synthesis, e.g. due to mutations in 17{alpha}-hydroxylase (CYP17A1). Like all other microsomal cytochrome P450 (CYP) enzymes, CYP17A1 requires electron transfer from P450 oxidoreductase (POR).

Objective: The objective of the study was to analyze the clinical and biochemical phenotype in a 46,XY individual carrying concomitant POR and AR mutations and to dissect their impact on phenotypic expression.

Methods: We characterized the clinical and biochemical phenotype, genetic identification, and functional analysis of POR missense mutation by yeast micrososomal coexpression assays for CYP17A1, CYP21A2 and CYP19A1 activities.

Results: The patient presented neonatally with 46,XY DSD and was diagnosed as partial androgen insensitivity syndrome carrying a disease causing AR mutation (p.Q798E). She was raised as a girl and gonadectomized at the age of 4 yr. At 9 yr progressive clitoral enlargement prompted reassessment. Urinary steroid analysis was indicative of POR deficiency, but surprisingly androgen production was normal. Genetic analysis identified compound heterozygous POR mutations (p.601fsX12/p.Y607C). In vitro analysis confirmed p.Y607C as a pathogenic mutation with differential inhibition of steroidogenic CYP enzymes.

Conclusion: Both mutant AR and POR are likely to contribute to the neonatal presentation with 46,XY DSD. Virilization at the time of adrenarche appears to suggest an age-dependent, diminishing disruptive effect of both mutant proteins. This case further highlights the importance to assess both gonadal and adrenal function in patients with 46,XY DSD.

Ed's note: Adrenarche is the onset of androgen dependent signs of puberty in boys or girls, including pubic hair, axillary hair, acne, and adult body odor.

Androgen Receptor Gene Mutations in a Series of 59 Patients with a 46,XY Disorder of Sex Development

L. Audi et al Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 4

Background: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS).

Objective: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients.

Setting: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. Methods: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients.

Results: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. Conclusions: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel. 

Sexual Function in Adult Women with Complete Androgen Insensitivity Syndrome

Dr Catherine L Minto, MB ChB, & Miss Sarah Creighton, MD MRCOG.
University College London Hospitals, Department of Obstetrics and Gynaecology, London WC1E, UK.

BACKGROUND: Women with complete androgen insensitivity syndrome (CAIS) have always been presented as unequivocally feminine women with normal sexual function. However they have both physical and psychological factors that might predispose them to suffer sexual dysfunction, eg: shorter than average vaginas, an inability to respond to androgens and anxieties or concerns about their condition, which could impact on self esteem, body image, sensuality and sexual function.

METHODS: This was a questionnaire study and retrospective hospital notes review, looking at sexual function in XY females with a diagnosis of CAIS. The questionnaire comprised details on diagnosis and treatment and a modified sexual function inventory (GRISS) which provided scores encompassing seven areas of female sexual function. All respondents were invited for a clinical examination and all hospital notes were collected and analysed for details of diagnosis and treatments.

RESULTS: 62 women with a current diagnosis and clinical features compatible with CAIS completed and returned the questionnaire. 21/62 (34%) were examined. 17/62 (27%) were patients and 45/62 (73%) were recruited through the AISSG (Androgen Insensitivity Syndrome Support Group). 6/62 (10%) had never been sexually active, and 2/62 did not complete the sexual function questionnaire, leaving sexual function data on 54 women. Global mean sexual function scores were worse than the population average. Mean scores were worst for infrequent sexual activity, non-communication with partner about sexual activity and difficulty with vaginal penetration.

CONCLUSIONS: Sexual dysfunction is common in CAIS, most significantly in the areas of difficulty with vaginal penetration, infrequency and non-communication.

Long Term Sexual Function in Intersex Conditions with Ambiguous Genitalia

Dr Catherine L Minto, MB ChB, Miss Sarah Creighton, MD
MRCOG & Mr Christopher Woodhouse, FRCS.

University College London Hospitals, Department of Urology and Obstetrics and Gynaecology, London WC1E, UK.

BACKGROUND: Current management for intersex conditions includes clitoral reduction surgery for those patients with ambiguous genitalia who are being raised female. Evaluation of this management is difficult due to the scarcity of long term outcome data looking at sexual function and other outcomes.

METHODS: This was a questionnaire study combined with a retrospective hospital notes review. The questionnaire comprised detail on diagnosis and treatment along with a modified sexual function inventory (GRISS) which provided scores encompassing seven areas of female sexual function. All hospital notes were collected and analysed for diagnosis and surgical detail.

All respondents were invited for clinical examination.

RESULTS: 37 intersex women, over 18 years old, all with ambiguous genitalia at birth or in childhood, completed the questionnaire. 11 were patients, 26 were recruited through the UK AISSG (Androgen Insensitivity Syndrome Support Group). 16/37 (43%) attended for a clinical examination. 10/37 (29%) had had clitoral surgery deferred and so had currently not undergone clitoral surgery, of which 1/10 (10%) had never been sexually active. Of the 27/37 (73%) who had undergone clitoral surgery, 9/27 (33%) had never been sexually active, leaving sexual function data on 18 subjects who had undergone clitoral surgery and 9 subjects who have virilised female genitalia and have not undergone clitoral surgery. Mean global sexual function scores were worse in the group with clitoral surgery. On looking at orgasm scores alone, the group with clitoral surgery had scores significantly abnormal for difficulty with orgasm, with 5/18 (28%) having complete anorgasmia.

CONCLUSIONS: This study shows that clitoral surgery can damage adult sexual function.

Cosmetic and Anatomical Outcomes Following Feminising Childhood Surgery for Intersex Conditions

Miss Sarah Creighton MD MRCOG, Dr Catherine L Minto MB ChB & Mr Stuart J Steele FRCOG & FRCS.

Department of Gynaecology, University College London Hospitals, London WC1E, UK.

BACKGROUND: The immediate aim of feminising genitoplasty in the management of ambiguous genitalia is to make the cosmetic appearance look as female as possible. In the long term the vagina must also be adequate for menstruation and intercourse. There is increasing awareness amongst patients and clinicians that the outcome of this surgery may be unsatisfactory. This study evaluates the cosmetic and anatomical outcome of feminising genital surgery.

METHODS: 45 girls were examined under anaesthetic. All had undergone reconstructive genital surgery in childhood for intersex conditions. The external cosmetic appearance was evaluated and a recommendation made as to further intervention. In all cases previous surgical notes were reviewed.

RESULTS: The age range was 7.5-19.5 years (mean 15 years). The cosmetic result was good or satisfactory in 62% of patients. However, in 98% of patients further intervention was deemed necessary. Of these, 23% required dilators and 77% surgery. 60% had undergone one previous procedure. The rest had two or more prior genital operations and one child had undergone six prior genital procedures. All patients who had undergone prior vaginoplasty required further treatment to the vagina.

CONCLUSION: Most children undergoing feminising surgery require further treatment in puberty and this must be made clear to the parents. Vaginal surgery should be deferred until puberty unless there is a risk of haematocolpos. The requirement for clitoral surgery should be carefully considered on an individual basis.

"The Sexes: New Insights into the X and Y Chromosomes"

The distance between Mars and Venus might be closer than previously thought.

By Bob Beale, The Scientist 15[15]:18, Jul. 23, 2001

Jarring Bodies: Thoughts on the Display of Unusual Anatomies

By Dreger, A. D. 2000. Perspectives in Biology and Medicine. 43 ( 2): 161-172.

As in the 19th century, a given physician's examination and display of a patient is as much about establishing that physician's place within the institutions of medicine as it is about establishing the patient's disease within the nosologies of medicine. Dreger discusses the ways in which intersexed people have been examined and displayed in the 19th and 20th centuries.

Re-membering a queer body

By Morgan Holmes. Published in Undercurrents (May 1994: 11-13) by the Faculty of Environmental Studies, York University, 4700 Keele St., North York, Ontario, Canada, M3J 1P3.

What follows is the text of Morgan’s article followed by some correspondence between an AISSG USA member, Morgan and Cheryl Chase, Director of the Intersex Society of North America (ISNA).

The medical construction of gender: Case management of intersexed infants

Kessler, S. J. 1990. Signs: Journal of Women in Culture and Society. 16 (1): 3-26

"The process and guidelines by which decisions about gender (re)construction are made [in intersex case management] reveal the model for the social construction of gender generally. Moreover, in the face of apparently incontrovertible evidence - infants born with some combination of 'female' and 'male' reproductive and sexual features - physicians hold an incorrigible belief and insistence upon female and males as the only 'natural' options. This paradox highlights and calls into question the idea that female and male are biological givens compelling a culture of two genders."

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