M. Zachmann

Genetic Mapping of the 21-Hydroxylase-Deficiency Gene within the HLA Linkage Group

To document further the proposed genetic linkage between congenital adrenal hyperplasia due to 21-hydroxylase deficiency and HLA, 34 unrelated families from New York and Zurich, with a total of 48 patients, 48 siblings and their parents, were studied. All patients were HLA genotypically different from the healthy sibs; when two or more children were affected in the same sibship they were always HLA-B identical. The gene for 21-hydroxylase deficiency was separated by genetic recombination from the HLA-A locus and from the locus for glyoxalase I-polymorphism. No HLA-A, HLA-B or HLA-C antigen was selectively increased among the 34 unrelated patients. Lod-score analysis for HLA-B:21-hydroxylase deficiency gave a peak for theta approximately 0.00 at 5.20 for females and 4.30 for males, giving a total peak lod score of 9.5 at theta approximately 0.00 when male and female lod scores were combined. Close genetic linkage between HLA-B and 21-hydroxylase deficiency was thus established.

Bayley-Pinneau, Roche-Wainer-Thissen, and Tanner height predictions in normal children and in patients with various patholgoic conditions

Bayley-Pinneau, Roche-Wainer-Thissen, and Tanner height predictions at various chronologic ages were compared with final adult height in 56 normal subjects and in 34 patients with abnormal growth pattern (11 with familial tall stature, 7 with idiopathic precicious puberty, 6 with Turner syndrome, and 10 with primordial small stature or Silver-Russell syndrome). The two recent methods (Roche-Wainer-Thissen and Tanner) gave very accurate results and were superior to the Bayley-Pinneau method in normal subjects and in patients with familial tall stature. However, they overestimated adult height grossly in precocious puberty and moderately in Turner syndrome and in primordial small stature. It is concluded that calculations based on coefficients and regression equations obtained from normal children (as in the Roche-Wainer-Thissen and Tanner methods) can only be used in normal children or in patients with normal growth potential under adequate treatment. Calculations based on percentages of adult height (as in the Bayley-Pinneau method) are preferable in conditions in which the growth potential in relation to bone maturation is inherently reduced and cannot be corrected by treatment.

Interrelation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism

The present study evaluates the modifying effect of growth hormone on the growth-promoting action of testosterone in boys at pubertal bone age. Growth and bone maturation were analyzed in 42 boys with primary or secondary Leydig cell insufficiency who had been treated with testosterone in an attempt to induce puberty and the accompanying growth spurt. The dosage given was considered normal or high for physiologic replacement therapy at puberty. Sixteen boys had normal GH secretion (seven had isolated gonadotropin deficiency, nine had congenital anorchia); 26 were GH and Gn deficient (20 idiopathic, six craniopharyngiomas). Of the GH-deficient patients, 12 received hGH simultaneously, while 14 received only testosterone. Results from each group were compared with the normal pubertal growth spurt in 15 untreated healthy boys. In isolated Gn deficiency and in congenital anorchia, the growth rates increased to above normal during the first six months of treatment, indicating that the testosterone dosage was probably too high for the beginning of puberty. During two subsequent six-month treatment periods, the rates leveled off close to normal. The same was true in the GH- and Gn-deficient patients on adequate hGH replacement. For contrast, there was minimal or no stimulation of growth when an even higher testosterone dose was given to GH- and Gn-deficient boys without hGH therapy. Bone maturation was normal in the boys with normal GH secretion or with hGH replacement, but was subnormal in the GH-deficient boys not treated with hGH. We conclude that testosterone exerts its full growth-promoting action only in the presence of normal endogenous GH secretion or with sufficient hGH replacement and that both hormones should be continued simultaneously until final adult height is achieved.

STEROID 17, 20‐DESMOLASE DEFICIENCY: A NEW CAUSE OF MALE PSEUDOHERMAPHRODITISM

In a child with male pseudohermaphroditism (ambiguous external genitalia, XY sex chromosomal constitution and normal adrenocortical function), incubations of testicular tissue with pregnenolone/progesterone, 17α‐hydroxy‐pregnenolone/17α‐hydroxyprogesterone and androstenedione/dehydroepiandrosterone showed that testosterone could be formed from androstenedione and dehydroepiandrosterone only, but not from other substrates. In urine, testosterone did not increase after HCG, but small amounts of pregnanetriolone were found, which increased after HCG and ACTH. There was no DHA increment after ACTH.

Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance

SummaryThe syndrome of type A insulin resistance is encountered in young women and is characterized by glucose intolerance or frank diabetes mellitus, endogenous hyperinsulinism, insensitivity to insulin administration, acanthosis nigricans and virilization. The insulin resistance is due to reduced cellular insulin binding because of a lack of or defective binding sites and/or because the interaction with the tyrosine kinase of the β-subunit is hindered. This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 μg/kg body weight to three women with type A insulin resistance. An immediate but slow fall of blood glucose was observed. The glucose disappearance rate was 28.0 μmol/min, i.e. considerably lower than that seen in healthy subjects. The markedly elevated insulin and C-peptide levels fell in a parallel manner to blood glucose but not to normal levels. The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. We suggest that the potential of recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth.

Pubertal growth in patients with androgen insensitivity: Indirect evidence for the importance of estrogens in pubertal growth of girls

Spontaneous pubertal growth was studied in eight patients with the syndrome of androgen insensitivity to obtain information on the growth-promoting action of estrogens. In one additional patient (who had a gonadectomy before puberty), the effect of exogenous estrogens was studied. Mean age at peak height velocity (12.7 years) was closer to that in normal girls than to that in normal boys. Mean peak height velocity (7.4 cm/yr) was as in normal giris (7.3 cm/yr), but was lower than in normal boys (9.3 cm/yr). Bone age corresponded normal men (−0.6 SD), but higher than in normal women (+1.4 SD). In the better to male standards. Mean adult height (172.3 cm) was lower than in patient who had a gonadectomy, estrogen replacement caused a higher peak height velocity (12 cm/yr), but lower adult height (160.5 cm) than in the patients with intact gonads who received no treatments. We conclude than in normal giris, the pubertal growth spurt also results from the action of estrogens rather than of adrenal androgens. To ensure normal pubertal growth, physiologic estrogen replacement in hypogonadal females should be started at a bone age of about 11 years, and should not be delayed in the hope of achieving a greater mature height.

Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance.

Twelve children with documented Prader-Labhart-Willi syndrome were treated with human growth hormone (24 U/m2/week) during 1 year. The children were divided into three groups: group 1: overweight and prepubertal (n = 6, age 3.8–7.0 years); group 2: underweight and prepubertal (n = 3, age 0.6–4.1 years); group 3: pubertal (n = 3, age 9.2–14.6 years). In group 1, height increased from -1.7 SD to -0.6 SD, while weight decreased from 1.1 SD to 0.4 SD, with a dramatic drop in weight for height from 3.8 SD to 1.2 SD. Hand length increased from -1.5 SD to -0.4 SD and foot length from -2.5 SD to -1.4 SD. Body fat, measured by dual X-ray energy absorptiometry, dropped by a third, whereas muscle mass increased by a fourth. Physical capability (Wingate test) improved considerably. The children were reported to be much more active and capable. In group 2, similar changes were seen, but weight for height increased, probably because muscle mass increase exceeded fat mass decrease. Changes in group 3 were similar as in group 1, even though far less distinct.ConclusionGrowth hormone treatment in Prader-Labhart-Willi syndrome led to dramatic changes: distinct increase in growth velocity, height and muscle mass, as well as an improvement in physical performance. Fat mass and weight for height decreased in the initially overweight children, and weight for height increased in underweight children.

Experience with long-term therapy in congenital adrenal hyperplasia

The experience with treatment of 93 cases of congenital adrenal hyperplasia due to 21-hydroxylase deficiency has beenanalyzed with respect to growth, bone maturation, and steriod excretion. Doses of hydrocortisone, cortisone, and prednisone have been established which produce optimal effects, and the question of the time of day when such doses are best administered is discussed. The present experience leads us to recommend oral hydrocortisone in a dose of 25 mg. per square meter of body surface area as the basis of therapy. The danger of over- or undertreating patients appears to be minimized by giving the larger part of the dose in the morning.

Treatment of precocious puberty with cyproterone acetate.

Extract: Cyproterone acetate, an antiandrogenic steroid with inhibitory effects on gonadotropin secretion, was given to 13 girls and 6 boys with precocious puberty for periods of 1–3 years in a daily dose of 70 mg/m2 body surface area. Treatment was started at a mean chronologic age of 6.65 years in girls and 6.21 years in boys.No side effects were noted and the compound had a beneficial effect on the clinical signs of precocious puberty with the exception of increased growth velocity. Testicular size remained unchanged during treatment. In one boy high testosterone concentration in plasma was reduced to prepubertal levels.For analysis of the effect of treatment on growth the standard deviation score method was used. The data for height, bone age, height for bone age, and height prediction were compared with those obtained from 21 girls and 11 boys with precocious puberty who did not receive cyproterone acetate. No significant differences between treatment and control groups were found. It is concluded that cyproterone acetate in the dosage used is without effect on growth and would therefore be expected not to prevent short adult stature in patients with precocious puberty.Speculation: From the present study it is evident that cyproterone acetate at the dosage used does not diminish the rate of skeletal maturation, but that with other respects it is effective through its antiandrogenic and gonadotropin-inhibiting properties. This may indicate that in precocious puberty, bone maturation is more sensitive to the action of androgens and less suppressible than the secondary sex characteristics or behavioral changes. Whether earlier treatment and/or higher doses would also inhibit bone maturation remains uncertain.

Results of Transsphenoidal Extirpation of Craniopharyngiomas and Rathke's Cysts

Fourteen patients undergoing transsphenoidal extirpation of craniopharyngiomas or Rathkes cysts underwent endocrinological evaluation before and after surgery. One patient died during the procedure because of uncontrollable arterial bleeding. The other patients were followed for up to 16 years (average, 8.5 years). One patient had recurrence of tumor 12 years after surgery. Another patient, the only one operated on because of a recurrent craniopharyngioma after previous radiation therapy, died 2 years after the transsphenoidal operation. No patient recovered pituitary functions that had been lost before surgery. One patient, who had an isolated growth hormone deficiency, and another, who had panhypopituitarism with sustained antidiuretic hormone secretion, had no change postoperatively from their preoperative endocrine status. The other 11 patients lost pituitary function and required pharmacological replacement of one to four pituitary hormones.