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Objective: We present the 1st case of prepubertal hyperandrogenism because of a defect in the conversion of cortisone (E) to cortisol (F) by hepatic11β-hydroxysteroid dehydrogenase type 1. Methods and Results: Clinical and anthropometric data were obtained. Serum androgens and gonadotropins with luteinizing hormone releasing hormone stimulation test, dexamethasone suppression test, and corticotropin-releasing hormone stimulation test were evaluated. Adrenal imaging and urinary steroid profiling by gas chromatography/mass spectrometry were employed. A 6.9-year-old boy presented with precocious pubarche, height (+2.6 SD), accelerated bone age (11.5 years), and Tanner stage 2 pubic hair and genitalia. Serum androgen levels were elevated and dexamethasone suppressible. Serum F was normal, but the E concentration was increased. Central precocious puberty and congenital adrenal hyperplasia were excluded. The excretion of androgen metabolites was moderately increased, but a highly increased tetrahydrocortisone (THE) and a diminished tetrahydrocortisol (THF + allo-THF) excretion was found with a [THF + allo-THF/ THE] ratio of 0.032 (normal controls 1.05 ± 0.17). The corticotropin-releasing hormone stimulation test showed an exaggerated adrenocorticotropic hormone response, suggesting a relative deficiency of F. Two months of hydrocortisone treatment (17.5 mg daily) failed to suppress androgens adequately. Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression. Conclusions: In the case of precocious pubarche and accelerated growth, the diagnosis of 11β-hydroxysteroid dehydrogenase type 1 deficiency (‘apparent cortisone reductase deficiency’) should be considered. The diagnosis is based on determinations of urinary steroid metabolites.

We studied 2 subjects with a 45,X/46,X,ring(Y) karyotype. Both of them were evaluated because of short stature and a subnormal rate of linear growth. One patient had additional features of the Ullrich-Turner syndrome. Both subjects had normal male external genitalia. Two copies of the pseudoautosomal gene, MIC2, were present in DNA of each individual. All sequences examined on the Y-specific portion of the short arm, including those for the sex-determining region Y (SRY) gene, were present. By contrast, portions of the long arm of the Y chromosome were missing from DNA of both subjects. In subject 1, deletion intervals 6 and 7 were missing. In subject 2, deletion interval 5, distal to 5B, was missing in addition to intervals 6 and 7. The most likely explanation for the ring formation in these subjects is a chromosomal break in the long arm and in the pseudoautosomal region of the short arm distal to MIC2 with subsequent ligation of the remaining sequences on the long arm and short arm. However, a complex rearrangement cannot be excluded.

Among a group of patients with abnormal sexual differentiation, we have identified two subjects who had a 46,XY karyotype, ambiguous genitalia, and well-developed Müllerian structures, but normal appearing testes. The presence of ambiguous genitalia and persistent Müllerian structures implied both Leydig cell and Sertoli cell dysfunction, hence, gonadal dysgenesis. However, the normal testicular histology suggested that the underlying abnormality was not a defect in testis determination itself but an abnormality in timing of gonadal ridge and testis development. In one of the two subjects genomic DNA was available. The sequence of the SRY gene was normal. Because rare patients with partial androgen insensitivity may have a similar phenotype, the AR gene was evaluated by denaturing gradient gel electrophoresis (DGGE) and was normal. Some subjects with mutation of the WT1 gene or with deletion of the distal short arm of chromosome 9 may have similar phenotypes. The WT1 gene was studied by single-strand conformation polymorphism (SSCP) analysis and was normal. In addition, there was no loss of heterozygosity of polymorphic markers in distal 9p. The gene for Müllerian inhibiting substance (MIS) was also studied by SSCP and was normal. Although the exact mechanism for the defect in the two subjects is unknown, it may be due to an abnormality in a gene or genes involved in the timing of gonadal ridge development.

The condition of 46,XX maleness is characterized by testicular development in subjects who have two X chromosomes but who lack a normal Y chromosome. Several etiologies have been proposed to explain 46,XX maleness: 1) translocation of the testis-determining factor from the Y to the X chromosome, 2) mutation in an autosomal or X chromosome gene which permits testicular determination in the absence of TDF, and 3) undetected mosaicism with a Y-bearing cell line. We evaluated 10 affected subjects who were ascertained for different reasons and who had several distinct phenotypes. Six subjects had inherited sequences from the short arm of the Y chromosome including the sex-determining region Y gene (SRY). Five of the subjects were pubertal at the time of evaluation and had a phenotype similar to that of Klinefelter syndrome with evidence of Sertoli cell and Leydig cell dysfunction. One subject had evidence from Southern blot analysis and in situ hybridization for the presence of an intact Y chromosome in approximately 1% of cells. Three subjects lacked Y sequences by Southern blot analysis and by polymerase chain reaction amplification of SRY. These subjects were ascertained in the newborn period because of congenital anomalies. One had multiple anomalies including cardiac abnormalities; one had cardiac anomalies alone; and one had ambiguous genitalia. Our data confirm the genetic heterogeneity of 46,XX maleness, in which some subjects have SRY while other subjects lack it. In addition, there is phenotypic heterogeneity among subjects who lack SRY suggesting that there is also genetic heterogeneity within this subgroup.

Close linkage between HLA and the gene for 21-OH deficiency causing congenital virilizing adrenal hyperplasia (CVAH) has been well documented. HLA-A/B and HLA/GLO recombination data placed the CVAH gene within the HLA-A to GLO interval, with CVAH invariably segregating with HLA. HLA-A,B,C,DR and GLO typing and ACTH stimulation to determine carrier status was done on seven families. Carrier status correlated with the appropriate HLA haplotypes in all offspring, with two exceptions. Two intra-HLA recombinants were detected in one three-generation family. The father of the proband is homozygous for HLA-A2,Cw2,B27 but is a DR2/DR4 heterozygote. The CVAH gene segregated with DR2 in all but one of his offspring who is a carrier and is DR4. This finding is consistent with recombination between the CVAH gene and DR. Study of the father's family confirmed synteny of the CVAH gene and DR2. Three of four sibs of the father inherited this haplotype and were CVAH carrier, as was the paternal grandmother, whose other haplotype was A1, Bw44,DR1. One of the father's sibs was shown serologically to be a HLA-B/D maternal recombinant and a noncarrier. she inherited the A1,Bw44 of one maternal haplotype, but the DR2 of the other. In both recombinants in this family the CVAH gene segregated with the A to B interval, separate from D. While we cannot determine whether the CVAH gene is in the HLA-A to B or B to D interval, this is the first report of two intra-HLA recombinations in one family that unequivocally map the CVAH gene inside HLA-D.

Long-term, low-dosage androgen treatment of patients with Turner syndrome results in more rapid growth and significantly greater adult height than in control patients who receive only estrogen for pubertal development. Seventeen patients treated with oxandrolone for one year and ten treated for two years had significantly greater growth velocities during than before treatment. Mean adult height of 25 patients treated with oxandrolone, fluoxymesterone, or both was significantly taller than the height of adult patients with Turner syndrome treated with estrogen only. Excessive skeletal maturation was not generally observed.

2 Cases of childhood Cushing's disease have been treated with bilateral adrenalectomy and autotransplantation of adrenal tissue. Transplantation was unsuccessful in 1 case. In the other patient, replacement therapy was discontinued without any symptoms of hypo- or hyperadrenocorticism. Her urinary 17-hydroxycorticosteroids, free cortisol and aldosterone remain in the low normal range indicating functional adrenal tissue, probably a result of the transplant.

The effects of congenital adrenal hyperplasia on adult height and fertility were studied in 30 afflicted men. The patients' heights ranged from 150.0 to 178.6 cm (mean ±1 S.D. of 164.0±7.6), which is significantly lower than both the mean adult height for American men and that of the patients' parents (P

Gonadotropin levels in isolated blood samples, integrated plasma concentrations (IC), and timed urinary collections have been compared in 5 males with delayed puberty and 7 normal adult males. There was a significant correlation between urinary levels in 24-h collection and those in each of four shorter timed collections for both LH and FSH. Similarly, 24-h integrated plasma concentration and 4-h (0800–1200 h) integrated plasma concentration obtained on 10 additional subjects showed significant correlation. The 4-h integrated plasma concentrations correlated with single blood samples or the mean of three samples obtained at 0800, 1200, and 1600 h. These 4-h plasma samples also correlated significantly with all urine collections for FSH but only with the 2200-0800 h urine collection for LH. The study suggests that LH and FSH levels in urine samples collected over several hours correlate with 24-h urinary excretion and that levels in single blood samples estimate the 24-h plasma integrated concentr...

Serum gonadotropins in 5 females with Turner syndrome have been evaluated using a 24-hour constant withdrawal pump. A sleep-related increase in gonadotropin levels was documented among patients at an early to midpubertal age but not among older individuals, a phenomenon observed among normal individuals.

Clinical observations suggest that estrogen levels above physiologic plasma concentration can result in pathologic endometrial changes. Patients with feminizing ovarian tumors and those with the polycystic ovary syndrome who have excessive amounts of endogenous estrogens have a high incidence of endometrial cancer.1-4 Several investigators have noted the development of atypical hyperplasia and adenocarcinoma in women receiving prolonged treatment with various estrogen preparations, including the sequential oral contraceptives.5-11 Until recently, the association of exogenous estrogens with carcinoma of the endometrium had been based on clinical impression, but convincing epidemiological data had been lacking. Recent reports by Smith et al.12 and Ziel and Finkle13 indicate that the risk of endometrial cancer is 5 to 14 times greater in women taking exogenous estrogens. Patients with hypogonadism are frequently treated with estrogenic substances to initiate the development of breasts and menstrual bleeding. Most of these patients are then maintained on estrogenic preparations for years. Therefore, this group of subjects provides a model for the study of possible development of endometnial changes in response to estrogen therapy. To date, there have been 12 reported cases of endometrial adenocarcinoma in gonadal dysgenesis patients who received estrogen therapy.14-19 Eleven of these women were known to have received diethylstilbestrol; one patient was taking a sequential ethinyl estradiol-dimethisterone preparation at the time of the study and had previously taken an unknown estrogen preparation for four years. This article presents information about the relationship of estrogen therapy and endometrial histology in 43 hypogonadal patients followed up in the Pediatric Endocrine Clinic and the Department of Gynecology and Obstetrics at The Johns Hopkins Hospital, Baltimore.

A 17-yr-old female presented with marked menstrual irregularities since menarche at age 13 yr and severe hirsutism, particularly facial, since puberty. Her disorder was shown to be related to a mild 21-hydroxylase deficiency and she was diagnosed to have an attenuated (so-called acquired) form of congenital virilizing adrenal hyperplasia. HLA typing and ACTH testing of her parents and siblings provided evidence of a linkage between HLA and 21-hydroxylase deficiency loci. Similar observations have been made previously for the salt-losing and simple virilizing forms of congenital virilizing adrenal hyperplasia, suggesting that these two as well as the attenuated forms are allelic in regard to the 21-hydroxylase deficiency gene.

Fifty-eight children with cryptorchidism have been given hCG stimulation testing, 31 with bilateral cryptorchidism, 22 with unilateral, and 5 with prior unsuccessful orchiopexy. Hormonal studies were carried out prior to and following stimulation. In bilateral cryptorchidism, bilateral descent was observed in 32 percent of cases and in unilateral, the success rate was 55 percent. From their data, the authors concluded that hCG is not indicated if patients present elevated LH and FSH levels or if the basal T levels are in the pubertal range. In the other subjects, the hCG test will permit the determination of the presence or absence of testosterone production and in some cases it results in testicular descent. Finally, in cases of failure that require surgery, the hCG will stimulate tissue growth enhancing the success of orchiopexy.

A variety of mild forms of congenital adrenal hyperplasia (CAH) due to partial 21-hydroxylase deficiency have recently been described. We report two families in whom members presented with CAH with various degrees of enzyme deficiency. In family A, two children had the classical salt-losing CAH. Their male sibling and mother presented a very mild asymptomatic form of CAH, characterized by elevated basal plasma levels of 17-hydroxyprogesterone (17-OHP) and exaggerated responses of progesterone and 17-OHP to ACTH stimulation. The Hormonal profile and HLA types of these two individuals suggested allelic compounds, having one mutant gene for classical CAH and another for a mild form. In family B, the proband presented an attenuated form of CAH, manifested by amenorrhea and hirsutism, elevated basal levels of plasma 17-OHP and androgens, as well as markedly increased ACTH response. Two of her four siblings had the same ad HLA type, elevated basal plasma 17-OHP levels, and increased ACTH response. Their father, their paternal aunt, and their paternal uncle had the ab HLA type and normal basal plasma 17-OHP but markedly increased ACTH response. The haplotypes a, b, and d were considered to be linked to a mutation resulting in mild 21-hydroxylase deficiency, the homozygotes with ab HLA type having a milder form of CAH than the homozygotes with the ad HLA type. The wide spectrum of clinical and hormonal characteristics among homozygotes for the 21-hydroxylase deficiency trait suggests that their is a continuum of degree of enzyme deficiency. Furthermore, it suggests that most nonclassical subjects are allelic compounds for variable degrees of severity in the mutation at the 21-hydroxylase locus. More specifically, the study of families A and B shows that the so-called cryptic and attenuated forms of CAH have the same pathophysiological basis.

The circadian variation of 17-hydroxyprogesterone levels in 3 male obligatory carriers of 21-hydroxylase deficiency (salt-losing form) was not significantly different from that of normal noncarrier male subjects.

Two teen-age XY brothers with mental retardation, short stature, obesity, genital abnormalities, and contractures of their hands are described. They have generalized osteoporosis and a history of frequent fractures. Their endocrinologic evaluation was normal except for mild glucose intolerance and delayed, but normal puberty. Although these brothers are similar to individuals with Prader-Willi syndrome, their unusual hand contractures, clinically significant osteoporosis, and lack of hypotonia indicate that they represent a different entity.

The time of onset and progression of pubertal development has been documented in seven male patients with Addison's disease. Two patients developed associated autoimmune problems before puberty and were excluded from further study. The mean age of the onset of puberty among the remaining five patients was 12.3 +/- 0.4 yr, not different than the 11.4 +/- 0.4 yr reported for normal American boys. Integrated plasma levels of testosterone, androstenedione, 17-hydroxyprogesterone, progesterone, and dehydroepiandrosterone were also determined in three Addisonian patients who had no associated autoimmune disease before puberty and their study date. Results were compared with integrated plasma levels from three other groups: four agonadal males, four normal adult males, and three pubertal boys. Integrated plasma levels of these steroids confirm that in a male, testosterone is essentially testicular in origin, dehydroepiandrosterone is mainly adrenal in origin, and androstenedione and 17-hydroxyprogesterone are derived from both sources.

Fifty-one patients with gonadal dysgenesis receiving estrogen-progesterone replacement therapy for periods of six months to twenty years were studied. Endometrial biopsies or dilatation and curettage were obtained in forty-seven patients. One patient on diethylstilbesterol had atypical endometrial hyperplasia which progressed to adenoepidermoid carcinoma. Six patients had benign cystic hyperplasia. Endometrial abnormalities occurred in patients with a duration of estrogen therapy greater than 3-5/12 years and who received a total lifetime estrogen dose exceeding 2500 mg of conjugated estrogen or its equivalent. Five patients who developed endometrial hyperplasia had taken cyclic estrogen-progesterone therapy; the sixth took unopposed estrogen therapy. Total nuclear estradiol binding was measured in six patients with Turner Syndrome and nine control women. Two of the Turner patients had endometrial hyperplasia. Nuclear binding in these two subjects did not differ from that of the other patients with Turner Syndrome. Nuclear binding in the Turner patients (range 3-101/DPM ng DNA) was not different from that of nine control women at comparable stages of the menstrual cycle (34-429 DPM/ng DNA). Cytoplasmic binding of estradiol was not different in two patients with Turner Syndrome with hyperplasia from the four without.

• We report the clinical and hormonal findings in two boys with isosexual precocity secondary to Leydig cell tumor of the testis. The hormonal profile at the initial evaluation was quite different in the two cases suggesting differences in steroid biosynthesis by the tumors. These differences indicate that a dexamethasone suppression test may be required to differentiate between Leydig cell tumors and congenital virilizing adrenal hyperplasia with adrenal rest tissue located within the testes. (Am J Dis Child132:494-497, 1978)

Adrenal steroids have been measured before and after acute IV ACTH stimulation (100 u CortrosynR) in 25 prepubertally aged children with excessive virilization (pubic hair ± genital, somatic or skeletal growth excess).