mid-1990s, constituencies of affected intersex individuals have
criticized common practices in the management of disorders of sexual differentiation
(ie, objections to gender change, sexual dysfunction tied to genital
surgery, delay in full disclosure of medical information or barriers
to accessing medical charts).1-3 To address gaps in data
that guides clinical care, the National Institute of Child Health and
Human Development (NICHD) sponsored a Research Planning
Workshop on Intersex to: identify research areas needed to enhance
care of patients with intersex, discuss methodological and ethical
issues, consider how NICHD can assist in pursuing this research, and
attempt to reach a consensus, concerning specific projects.
of the Evidence:
Gender development. Long-term follow-up studies of intersex
patients demonstrate that the majority remain in their assigned
gender. However, this does not necessarily imply they are comfortable
with their gender identity. Studies typically have not assessed this
nuance nor factors that might account for gender dysphoria.
is general agreement that 46,XX patients with mild
hyperandrogenization or 46,XY patients with mild hypoandrogenization
should not be gender reassigned and that 46,XY patients with complete
androgen insensitivity should be assigned the female gender.
Although 46,XX patients with severe genital masculinization (Prader
stage 5) are typically assigned to the female gender to preserve
fertility, some believe that marked brain masculinization precludes
satisfactory psychosexual development. There is less guidance with
intersex conditions affecting 46,XY patients with intermediate
degrees of hypomasculinization or hormone-independent disorders.
Genital surgery. Surgeons aim to create a genital appearance
that conforms to the assigned gender, permits later penile-vaginal
intercourse, and/or preserves reproductive capacity. Masculinizing
surgery requiring neophallus construction and feminizing genitoplasty
and vaginoplasty remain significant surgical challenges. Although
clinicians and parents resist the call from patient advocacy groups
for a moratorium on all genital surgery, surgeons may be more
reluctant to operate on milder forms of genital ambiguity. Early
timing of genital surgery offers potential advantages of diminished
scarring and reduced negative psychological sequelae; however, this
must be balanced against ethical concerns associated with performing
surgery without patient consent.
Psychosocial management. Studies of psychosocial services and
intervention techniques specific to intersex patients have yet to be
for Future Research:
Clinical research. Most previous studies were characterized as
narrow in perspective ignoring the affected individual’s
developmental context, factors that contribute to gender-related
outcomes, or to quality of life (QOL). Little is known about family
socialization processes stemming from the birth of a child with
Basic research. Recent advances in identifying genes associated
with gonadal sexual differentiation hold the promise of precise
genetic diagnoses for some 46,XY patients with intersex who currently
cannot be definitively diagnosed. Genetic modulation of endocrine
and neuroendocrine function may lead to understanding
genotype-phenotype relationships. Brain imaging to assess genetic
and hormonal factors in sexual differentiation, may facilitate
improved gender assignment.
on experimental studies (ie, random assignment to treatment
conditions) are obvious. Nevertheless, there is much to be learned
from well-designed observational studies.
Retrospective versus prospective studies. Retrospective research
designs can be employed to elucidate the effects of genital surgery
on erotic sensitivity, the relationship between cosmetic appearance
and QOL, and the role of acceptance or rejection by a partner.
Prospective studies can address questions related to psychosocial
management, emotional benefits of support groups for patients and
families, and the effects of very early versus later surgery on
parental acceptance or rejection The importance of basic research in
the study of genital development was also highlighted. Open
questions include: factors other than testosterone controlling penile
growth, possible growth factors contributing to vaginal growth, the
potential value of growth factors in promoting growth of a
micropenis, and the relative benefits of early versus late surgery
for neuroplasticity. Emerging technologies of gene therapy for
genetic forms of intersex, stem cell therapy to overcome infertility,
and tissue engineering applied to genital conditions are plausible
Representative sampling. Substantial challenges exist to
recruiting nationally or regionally representative patient samples.
Findings based on incomplete samples may not represent the total
eligible group. Recruitment through patient support groups
introduces additional self-selection biases.
c) Control groups. Identifying appropriate comparison groups
in long-term follow-up studies demands careful consideration. For
instance, surveys of community samples show sexual dysfunction occurs
in a significant, but small number of women. It would therefore be
misleading to assume that anything less than full sexual function
indicates morbidity associated with surgery. Contemporary,
population-based control groups for studies of both gender-related
outcomes and other aspects of QOL need to be applied.
d) Clinic-limited study samples versus cross-clinic aggregation.
Small sample sizes recruited from single sites may be adequate to
address narrow research questions. Research design requirements with
adequate statistical power to test complex multivariate hypotheses
require larger sample sizes. Additional considerations include
aggregation strategies and associated challenges, as well as the role
of individual clinicians whose patients might be persuaded to
participate in multi-center studies.
crucial principle in clinical treatment research demands separating
those providing treatment from those performing the outcome
evaluation. Since approximately half 46,XY intersex patients are
undiagnosed, immediate molecular genetic investigations are required.
Thus, centralized laboratories capable of performing sophisticated
genetic work (similar to the NIH’s Alliance for Cellular
Signaling) are needed. There is also a need to uniformly characterize
preoperative reproductive system anatomy, provide standardized
assessment of genital status at birth, and classify genital surgical
A detailed characterization of the clinical care received (ie,
categorizing prescribed hormone treatments and information regarding
treatment compliance), is important. Medical clinics need to be
characterized regarding their use of an interdisciplinary team and
the presence of a psychosocial component to patient-family care.
Thus, there was a strong consensus that patients with intersex should
be evaluated and treated at centers of excellence. This would enhance
care and facilitate research data collection.
With regard to assessing psychosocial outcomes, many well-developed
measures are available (eg, gender role behavior, sexual functioning,
psychiatric disorders, health-related QOL, family functioning, and
gender identity). However, there is a need to modify and/or creat
these specifically for intersex patients. Finally, the use of
multiple informants (eg, patients, parents or other relatives,
martial partners) in evaluating psychosocial outcomes is strongly
extensive secular changes in clinical practice regarding disclosing
medical information to patients, there are intersex adults who lack
fundamental facts about their condition and medical history.
Recruiting these individuals to follow-up studies could be associated
with potential emotional harm. A medical ethicist concluded that
conducting studies with only partial disclosure is ethically
permissible and provided several recommendations on study design.
Currently, there is a trend toward full disclosure of medical
information to the patient commensurate with the patient’s
cognitive development. Approaches toward achieving this goal were
discussed. However, the authors noted that members of the
multidisciplinary meeting could not arrive at full consensus. Thus,
the report represents a compromise summary rather than a consensus.
HFL, Blizzard RM. Conference Proceedings: Research on
Intersex: Summary of a Planning Workshop. Endocrinologist
Comment: As a participant in this workshop who has closely
followed the on-going (and often harsh) debate regarding clinical
care of patients with intersex, I was buoyed by the broad range of
professional and advocacy interests represented. The presence of
NICHD leadership will hopefully promote awareness of the urgent need
for systematic inquiry in this contentious field. Details of the
proceedings may also serve as a roadmap to investigators and a primer
to potential reviewers of research grants. The dearth of
investigators virtually ensures that researchers without firsthand
experience in this area will review grant proposals. Rather than
serving as a barrier to funding, this could encourage investigators
to examine more closely the links between research in intersex and
related topics in basic and clinical research. As the proceedings
illustrate, multidisciplinary approaches are likely to result in
advances in understanding and improved clinical care.
Challenges posed by the differing perspectives should not be
underestimated. Moreover, “turf” issues could always
scuttle the development of essential collaborations. In the
short-term, it is promising that this initiative resulted in funding
on psychosexual differentiation.
On-going pilot projects, and planned full-scale research studies
flowing from these, appear to manifest in spirit and action the
motivation for convening the Research Workshop on Intersex.
David E. Sandberg, PhD
References - (linked to )
- Berenbaum SA Growth Genet Horm 2003; 19:1-6
- Root Ar, Blizzard RM. Growth Genet Horm 2003;6-7.
- Blizzard RM. Pediatrics 2002;110:616-21.