NICHD Research Planning Workshop on Intersex
© 2005 Prime Health Consultants, Inc.
Since the 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.
Status of the Evidence:
a) 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.
There 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.
b) 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.
c) Psychosocial management. Studies of psychosocial services and intervention techniques specific to intersex patients have yet to be conducted.
Focus for Future Research:
a) 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 intersex.
b) 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.
Research Design:
Constraints on experimental studies (ie, random assignment to treatment conditions) are obvious. Nevertheless, there is much to be learned from well-designed observational studies.
a) 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 options.
b) 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.
Assessment:
A 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 techniques.
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 recommended.
Research Ethical Issues:
Despite 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.
Meyer-Bahlburg HFL, Blizzard RM. Conference Proceedings: Research on Intersex: Summary of a Planning Workshop. Endocrinologist 2004;14:59-69.
Editor’s 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
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