DSD-Life: Clinical European study on the outcome of surgical and hormonal therapy and psychological intervention in disorders of sex development (DSD)

Disorders of sex development (DSD) are a conglomerate of rare diseases with an
estimated total incidence of 1:4500. DSD are defined as a discrepancy of the
chromosomal, gonadal and phenotypic sex. The causes of DSD include disorders of
gonadal development in both sexes, gonadal disorders with decreased androgen
synthesis or function in XY males and disorders with elevated androgen
production in XX females.
Sex chromosome DSD consists mainly of disorders with gonadal dysgenesis
due to sex chromosome imbalances as Turner syndrome (45,X0 and mosaicism) in
females, Klinefelter syndrome (47,XXY) in males and individuals with mixed
gonadal dysgenesis (45,X0/46,XY) or individuals with chimeric DSD
(46,XX(46,XY). XY DSD comprises individuals with complete testicular dysgenesis
or gonadal dysgenesis, which is the result of disturbed testes development.
Severe prenatal androgen imbalances result in ambiguous genitalia at birth in
both sexes with DSD: in XY boys reduced prenatal androgen production or effect
and in XX girls increased prenatal androgens cause ambiguous genital
development. Furthermore, it is assumed that prenatal androgen priming of the
brain has an effect on psychosexual development. In some cases with ambiguous
genitalia taking the decision on sex of rearing is difficult. Genital
constructive surgery is needed for heterosexual intercourse in many cases.
Furthermore, corticoid or sex hormone substitution is needed in the majority of
individuals with DSD. Individuals with CAH need lifelong cortisone
(with/without aldosterone) substitution therapy to prevent life-threatening
events.
Individuals with DSD due to gonadal dysgenesis or disorders of sex
hormone synthesis need either estrogen or testosterone therapy starting at
puberty. Decision on estrogen or testosterone therapy in these patients depends
on the choice of sex of rearing. In addition to hormonal disturbances, many
individuals with DSD are infertile. Decision on the sex of rearing, genital
surgery and hormone therapies have a life-long impact on the affected
individuals. Furthermore, in the recent years, taking into account the
anticipated impact of DSD on psychosexual development, psychological
counselling to cope with the disorder has been recommended by the
multidisciplinary DSD treatment teams. So far, most research on DSD has been
focused on studies investigating the genetic cause, pathogenesis and
diagnostics of the disorders, but not the clinical outcome.
Treatment options in DSD are controversial and are questioned by many
adults with DSD. Treatment options include off label therapies and have not
been evaluated for long-term effectiveness and adverse effects. Furthermore,
there is great variation in the therapeutic approaches to DSD across Europe.
Clinical outcome studies in DSD are often limited by small numbers, a
mixture of diagnoses and different outcome measures. The so far largest
clinical outcome study has been performed from 2003-2008 in Germany (German
Clinical Evaluation Study, BMBF). Despite being the so far worldwide largest
clinical outcome study of DSD, conclusions of the study were also limited by
small patient numbers of known genetic entities. Different genetic entities
were summarized in subgroups reflecting the sex of rearing, the karyotype and
the androgenization level to obtain sufficient patient groups for statistical
analysis.
Moreover, in the last decade the issue of treatment of DSD, in
particular surgery, has reached a political level in several countries. In
2010, the Committee on the Elimination of Discrimination against Women (CEDAW)
of the United Nations Human Rights has advised governments to take charge of
the regulatory control of treatment in DSD. In 2011 e.g., the German Ethics
Committee (Deutscher Ethikrat) has been mandated to develop ethical
recommendations for the treatment of DSD. However, development of ethic
recommendations is also hampered by the lack of clinical evidence of treatment.
For these reasons the different treatment and intervention regimens in known
genetic entities should be investigated in a large cohort in the EU.

Objective 1: To improve clinical practice in the management of disorders of sex
development (DSD)

Objective 2: To develop accepted evidence-based clinical guidelines for a
better clinical care of patients with DSD affected by distinct genetic entities
for which no dedicated treatment is currently approved

DSD-Life is a descriptive observational study.
DSD-Life investigates and compares the long-term outcome of not evidence based
treatments such as 1. Sex assignment, 2. Surgery, 3. Hormone therapies, 4.
Psychological interventions in adolescents and adults (>= 16 years) that are
used in patients with various causes of DSD. An estimated total number of 1500
individuals with sex chromosome, XY DSD and XX DSD >= 16 years will be included
in the study from 14 clinical sites in Europe.
To investigate the main hypotheses the probands will answer questionnaires on
HRQOL and social - and psychological well-being.
To investigate the secondary hypotheses the patients will get a medical exam
including investigation of their hormonal and metabolic status, ultrasound of
the uterus, ovaries or testes, investigations of bone mineral density and body
composition. To investigate surgical outcome the probands will be offered a
standardized gynaecological/urological exam (optional) and/or a questionnaire
about satisfaction with the outcome of genital surgery.
Furthermore, the probands will answer questionnaires on sociodemographics,
psychosexual development, stigma, shame, previous and actual health care
situation including satisfaction, previous treatments including satisfaction
and a questionnaire investigating the patients* view of treatment with current
knowledge about their condition including also ethical considerations and
patients* rights.
The physician will fill in questionnaires regarding precise diagnosis,
presentation and phenotype at diagnosis, history of hormonal, surgical and
psychological therapies, previous and actual medical/psychiatric problems and
family history.

The individual benefit for the proband is that she/he obtains a thorough
medical check up and medical counselling including evaluation of metabolic
problems and complications after genital surgery. If the proband has no access
to a specialist for regular metabolic and/or gynaecologic/urologic follow-up
contacts to specialized endocrinologists or gynaecologist/urologist will be
promoted. If needed, assistance to find a psychologist for psychological
counselling or psychotherapy will be given. Moreover, the proband will be
instructed in self management of her/his condition by the study team.
There might be a psychological crisis of the probands when confronted again
with memories of earlier negative experiences with medical care which are
related to the disorder through the study. A psychologist is available for
psychological counselling and support if needed. The need and benefit of
psychotherapy for the individual proband will be evaluated and supported if
indicated.