We used to call them hermaphrodites

Abstract

Sex is just as complicated as humans are. What seems a rather straightforward concept—with an unequivocal answer to the proverbial delivery room question, “Is it a boy or a girl?”—is in reality full of nuances and complexities, just like any human trait. From a biological standpoint, the appearance of the external genitalia is only one parameter among many, including chromosomal constitution, the sequence of sex-determining genes, gonadal structure, the profile of gonadal hormones, and the internal reproductive structures. One of the pillars of the modern scientific method is to test models and try to prove them wrong.1 However, sex and sexuality have long been an exception to modern standards of science because of the perceived consequences of scientific findings on controversial social debates. Human sexual anatomy was categorized into five types in the 19th century. An individual could be a female or a male (with typical feminine or masculine external genitalia, respectively), a female or male pseudohermaphrodite, or a true hermaphrodite. Male or female pseudohermaphrodite—terms no longer appropriate— referred to individuals with ambiguous external genitalia, a blurring between masculine and feminine features, and the presence of either testes or ovaries. True hermaphrodites have both testicular and ovarian tissue. As noted by Dreger,2 this model, centered on the gonadal anatomy, was adopted by clinicians, and all patients born with ambiguous genitalia were traditionally classified into one of these categories. For example, individuals born with Congenital Adrenal Hyperplasia have been categorized as female pseudohermaphrodites. However, scientific advances of the past half century have shown that this model, taking into consideration exclusively the type of gonads, is inaccurate. The early embryological experiments of Jost in 1947 suggested that sex development can be viewed as a two-phase process: sex determination (the orientation of an originally undifferentiated and bipotential gonad into either testis or ovary) and sex differentiation (the development of external and internal genitalia). It took a little more than 40 years to identify the main molecular trigger of sex determination, the Y-linked, DNA-binding and -bending transcription factor SRY.3,4 Mutations in SRY in XY individuals cause gonadal dysgenesis and a female phenotype, providing strong genetic evidence that it is a major sex-determining gene. However, few patients with disorders of sex determination can be explained by mutations in SRY, indicating the existence of other sex-determining genes that have been progressively identified since 1990.5 As for sex differentiation, most genes that have been well characterized code either for hormonal biosynthetic enzymes or hormone receptors. The sheer number of genes involved in sex development, the variety of their products, and the diversity of their function has led to the notion of sex as a complex trait in which “molecular sex” influences the various steps of sex determination and sex differentiation. The spectacular molecular advances in our understanding of sex now warrant a reevaluation of the standard classification, which has become too vague to be efficient for the accurate analysis of outcomes data. From a patient’s perspective, the nomenclature has two main issues. One is gender labeling, which is often psychologically harmful to the patient. For instance, a woman with androgen insensitivity syndrome would find herself being called a male pseudohermaphrodite, in complete contradiction to her phenotypic sex and, most probably, gender identity. In addition, inclusion of gender in a diagnostic label increases confusion for the parents and even the medical team at the time of gender assignment decisions. The other issue is the comparison of a patient to a mythological creature. There is something eerie about being called by the name of a monstrous fusion of two divine creatures, Hermes and Aphrodite. The fantasies attached to the word “hermaphrodite” have also given rise to a whole industry catering to individuals with paraphilias, looking for sexual gratification with a mythical image of a Man/Woman. Why has the gonado-centric model not changed throughout the years? First, it provided an intellectual frame that seemed to function. Even if it was a biased biological view, many disorders could be classified according to this model. Second, it is only relatively recently that the genetic mechanisms of sex development started to be deciphered. More importantly, there was no compelling reason to rapidly change the system. The patients’ outcomes were unexplored, and their collective existence was essentially invisible. However, in the early 1990s, patient-based intersex advocacy movements started challenging and questioning physicians and their practices, including the traditional nomenclature. In October 2005, under the auspices of the Lawson Wilkins Pediatric Endocrine Society (USA) and the European Society From the Department of Human Genetics, University of California Los Angeles School of Medicine, Los Angeles, California; UCL Instistute of Child Health, London, United Kingdom; Pediatric Endocrinology, Riley Hospital, Indiana University, Indianapolis, Indiana; Human Molecular Genetics, Prince Henry’s Institute of Medical Research, Melbourne, Australia; Laboratoire de Biochimie Endocrinienne et Moleculaire, Hopital Debrousse, Lyon, France; University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pediatrics, Medical University of Lubeck, Lubeck, Germany.