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Six 46,XX patients with congenital adrenal hyperplasia (CAH) presented with genital ambiguity, five so severe that initial gender assignment was male. Once diagnosis was realized, parents were involved in evaluation and chose sex re-assignment as female. To date, these girls and their parents all indicate satisfaction with their decision for a female sex of rearing. The girls have a female gender identity with behavior characteristics known for females with CAH. Thus, while outcome is satisfactory, it is realized that for most, expression of sexual orientation and adult life adjustments have not yet occurred.

Premature pubarche (PP) appears to be a risk factor for the subsequent development of polycystic ovary syndrome (PCOS) during or after puberty. The clinical manifestations due to hyperandrogenism are influenced by androgen production, androgen metabolism, and androgen receptor activity. Glucuronidation by the UDP-glucuronyltransferase 2B (UGT2B) family of enzymes is one mechanism through which androgens are inactivated. Two variants differing by the amino acid at codon 85 have been described for UGT2B15, a member of this family. Both variants show similar substrate specificities. However, for the substrates alpha-androstanediol (alpha-diol) and dihydrotestosterone (DHT), the D85 variant has a lower Vmax than the Y85 variant. We compared the frequencies of these variants in 69 patients with PP, 46 adolescent girls with hyperandrogenism (HA), and 88 healthy controls to determine whether the frequency of the D85 variant was increased among patients with hyperandrogenism. Allele frequencies were comparable in children with PP, adolescent girls with HA, and healthy control subjects. Although D85 and Y85 appear to be common variants, we cannot exclude the possibility that the UGT2B15 gene represents a minor modifying locus.

Monozygotic female twins with congenital adrenal hyperplasia due to 21-hydroxylase deficiency are described and evaluated over the first 6 years of life. Despite appropriate steroids, NaCl, and fludrocortisone therapies, there was significant fluctuation in the suppression of adrenal steroid secretion. Advanced bone maturation in both was noted. For the first time, molecular genetic analysis was performed and documented that the twins were compound heterozygotes for two different mutations: the maternal allele carried the 8-bp deletion mutation, whereas the paternal allele carried the 1172N missense mutation. Parental DNA samples confirmed that the mutations were on different alleles.

The treatment of intersex patients, including any patient born with genital ambiguity, is being reassessed. The re-evaluation is primarily focused upon the indications for and age of genital surgery, the impact of prenatal androgen levels upon gender development, and the potential for maximum sexual responsiveness as an adult. As a background to document changes in genital surgery for females with 21-hydroxylase congenital adrenal hyperplasia, this report is a review of surgical treatment of this most common form of genital ambiguity. Results document changes in the 1960s from clitorectomy to clitoroplasty using more refined techniques, but more interestingly a choice by parents against any surgery during childhood. This shift preceded the current impetus from intersex support groups. It appears to result from an appreciation by parents of variation in female genital configurations plus a realization that the clitoris will regress with the withdrawal of excessive androgens with relative size diminishing as growth proceeds. The primary impetus for this shift apparently has not been to preserve the vascular and neural supply to enhance sexual responsiveness, since parents in the past assumed that such could be preserved with appropriate surgical techniques.

The phenotypic heterogeneity recognized in congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency appears to extend to 21hydroxylase (CYP21) mutation carriers. To begin the search for modifying loci responsible for this phenotypic heterogeneity, we performed CYP21 genotype analysis and assays for three candidate modifier loci on genomic DNA samples obtained from 30 adolescent girls with hyperandrogenism, 14 healthy control women, and 15 female obligate CYP21 mutation carriers. The frequency of heterozygosity for CYP21 mutations was increased in women with symptomatic hyperandrogenism (10/30) compared to healthy controls (1/14). There were no significant differences in the frequencies of the modifier variants among the three groups. Although the small sample size precludes strong conclusions, CYP21 nonsense mutation carriers tend to be asymptomatic while missense mutation carriers, i.e. V281L, appear to manifest a PCOS phenotype. Evaluation of additional modifying loci in larger series of patients will help identify new genetic markers associated with PCOS.

Nutritional status and body composition influence the development and maintenance of reproductive competence in mammals. It has been suggested that leptin concentrations communicate nutritional status to the neuroendocrine reproductive axis. To determine the interrelationship between circulating gonadotropin and leptin concentrations, leptin concentrations were measured in 39 children treated for GnRH dependent precocious or untimely puberty. Leptin concentrations were obtained during pubertal suppression with GnRH analogue therapy and during spontaneous pubertal gonadotropin secretion. The status of gonadotropin secretion (suppressed vs not suppressed) was verified by simultaneous GnRH stimulation tests and sex steroid concentrations. Leptin concentrations were similar at both time-points and correlated only with body mass index. Thus, no relationship was apparent between circulating concentrations of gonadotropins, sex steroids, and leptin.