Advice on the Management of Ambiguous Genitalia to a Young Endocrinologist From Experienced Clinicians

Jean D. Wilson, M.D.; Marco A. Rivarola, M.D.; Berenice B. Mendonca, M.D., Ph.D.; Garry L. Warne, A.M., M.B.B.S., F.R.A.C.P.; Nathalie Josso, M.D., Ph.D.; Stenvert L.S. Drop, M.D., Ph.D.; Melvin M. Grumbach, M.D.


Semin Reprod Med. 2012;30(5):339-350. 

In This Article

Melvin M. Grumbach, M.D.

There are few events as profound as the birth of an infant and the immediate inquiry, Is it a girl or a boy? Phenotypic sex defines us male or female. From an early age the child knows his or her sex. The birth of an infant with ambiguous genitalia is a challenging, distressing event for the parents and the family and one with deep and lasting consequences.

The remarkable advances in knowledge over the past six decades in the field of sex determination and sex differentiation are a landmark in biomedical science. It has involved advances in embryology, developmental, cell and molecular biology, developmental endocrinology, steroid biochemistry, cytogenetics, classic genetics, molecular genetics, immunology, and behavioral science.[23–25]

One outcome of this extraordinary progress has been advances in prenatal diagnosis of sex and fetal disorders. Prenatal diagnosis performed in women at risk for harboring a fetus with a chromosomal disorder, genetic defect, or severe congenital malformation, or because of exposure to a known potent teratogen can lead to a discrepancy at birth between predicted sex and phenotypic sex. With the expanded application of prenatal diagnosis (including use of cell-free fetal DNA and RNA in maternal plasma), the discordance is a dilemma and a source of anxiety, distress, confusion, and concern to the new parents.

Among infants with ambiguous sexual development, it is import to establish a diagnosis as soon after birth as possible, not only for psychological and social reasons but also because of the dangers inherent in failure to recognize the salt-losing form of CAH ( Table 4 ).

Over the past two decades, considerable knowledge and insight have been obtained into psychosexual differentiation, sex and gender, and the long-term results of sex assignment in different types of ambiguous genitalia. Beginning more than three decades ago has been debate, controversy, and flux about the relative role of nature and nurture in the determination of gender identity—how one looks upon oneself as either male or female. To appreciate differences and similarities between sexes requires understanding the biologic bases of these differences and the many sex differences in nonreproductive organs. This debate has a profound influence on the decision of sex assignment in the newborn infant with ambiguous genitalia. For decades this decision was based in some clinics on the hypothesis of sexual neutrality at birth and that genes and androgens were not important, only nurture—experience, environment, and instinct—led to psychosexual differentiation. Accordingly, sex assignment in infants with a DSD depended heavily on surgical considerations with a bias toward feminine genitoplasty. However, a growing body of data emphasized the role of hormones and genes—nature in the control of sexual behavior. Prenatal brain exposure to androgens and the role of genes on the sex chromosomes (Y and X) and differential expression on autosomes ("brain/mind sex") are now recognized as important factors in gender identity.

It is important to appreciate the differences between sex and gender, terms that are inappropriately used by some interchangeably. It is now clear that biological and psychosocial factors are critical determinants of gender identity. However, clinical experience indicates that in a given infant with a DSD, there is uncertainty about whether either nature or nurture will be deterministic in establishing gender identity.

In summary, we make critical decisions with much uncertainty because of a paucity of outcome studies using stringent modern guidelines. Much of the present follow-up data on adults with DSD do not reflect current practice of group input in formulating recommendations, state-of-the-art surgical expertise, and parents who have sufficient knowledge and understanding to give truly informed consent.

The responsibility and goal of physicians in the management of patients with ambiguous genitalia are to establish a diagnosis promptly and, with the consent of the parents, assign a sex of rearing that is most compatible with a well-adjusted life and sexual adequacy ( Table 5 ). Early diagnosis and skillful management obviate many of the serious psychological and social problems of the patients and their parents, as well as the difficult decisions that may face the physician when the diagnosis is incorrect or the selection of sex is indecisive or delayed until childhood. Repeated, lucid, comprehensive discussion with the parents about the cause of their child's "atypical" genitalia, the natural history of other patients with similar pathophysiology, and the possible hormonal and therapeutic options available is critical to their coming to an informed decision on the sex of rearing of their infant. They need to be reassured that with modern diagnostic tests, a definitive diagnosis can be made expeditiously but that naming the baby, sending out birth announcements, and filing the birth certificate should be delayed ( Table 6 ).

The parents need support, reassurance, and counseling on how to deal with relatives and others. A simple explanation of the normal mechanisms of sex differentiation presented with illustrative material is useful. Introducing parents of children with a similar disorder and providing educational material including appropriate Web sites can help to assuage their concerns. The parents need to know that they will be supported by a group experienced in dealing with the clinical and psychosocial issues. For ongoing support, parents of DSD children need a psychiatrist or a psychologist who has knowledge of the pathogenesis and history of DSD and understands the complexities of gender identity.

The team approach of pediatric endocrinologist, pediatric surgeon, or urologist skilled in genitoplasty, psychiatrist/psychologist with knowledge of the functional and behavioral issues, pediatric nurse, social worker, and if appropriate, religious counselor is critical for the immediate and future care of the patient. It is useful to invite the family physician/pediatrician to participate in the discussion about their patient. It must be clearly stated that anatomical abnormalities can be surgically repaired, that hormone therapy can be given at an appropriate time, and that psychosocial support is available.

The physician and consultants recommend sex assignment, but the ultimate decision is that of the parents. Discussions must take into account parental concerns, religious views, ethical issues, cultural factors, social mores, and the parents' level of understanding. It is critical to explain what is known and what is not known about the long-term follow-up of patients with DSD and the results of reconstructive genital surgery in terms of genital sensitivity and sexual gratification and reproductive potential. Compassion and transparency by the team are essential in helping the parents make the decision about sex assignment.[25]

As mentioned earlier, there has been a vigorous challenge to the "modified psychosexual neutrality" at birth model as one issue in the decision to assign the sex of rearing and the timing and type of surgery. This re-examination has been highlighted by advances in diagnosis and understanding of the pathogenesis of DSD, by greater insight into the effect on the brain of exposure of the fetus to androgens, by new insight into sex-specific effects—for example, differential expression of brain genes independent of sex steroids—and by the voice of nonprofessional support groups, psychologists, ethicists, and social scientists. In addition, societal changes in attitude toward sexual differences and increased access to information through the worldwide web have had a salutary effect.

Reassignment of sex in infancy and childhood is always a difficult challenge for the patient, the parents, and the physicians involved. While easier in infancy than after 1 year of age, it should only be undertaken after deliberation and with provision for long-term psychiatric/psychological and clinical supervision and counseling.[26,27]