E A Werder

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.

Excessive Thyrotropin Response to Thyrotropin-releasing Hormone in Pseudohypoparathyroidism

Extract: In 8 of 10 patients with pseudohypoparathyroidism, confirmed by increased immunoreactive plasma parathyroid hormone concentrations and/or defective urinary excretion of adenosine 3′,5′-monophosphate (cAMP) after parathyroid extract infusion, excessive plasma thyrotropin (thyroid-stimulating hormone) (TSH) response to thyrotropin-releasing hormone (TRH) injection was found. On the other hand, in all seven cases with idiopathic true hypoparathyroidism the TSH response was normal. In two of three patients with pseudopseudohypoparathyroidism, with normal or slightly low plasma calcium, normal or slightly high immunoreactive plasma parathyroid hormone concentration, and intermediate response of cAMP to parathyroid extract, the TSH response to TRH was increased. The results indicate that moderate primary hypothyroidism is frequently present in pseudohypoparathyroidism. Thyroid dysfunction may only be detectable with the use of TSH stimulation by TRH, since clinical signs and other studies of thyroid function did not definitely suggest hypothyroidism in our patients. The rise of TSH is suppressible by thyroxine treatment, but is not influenced by vitamin D treatment. The TSH response to TRH is significantly correlated with the decrease of tubular reabsorption of phosphate after parathyroid extract infusion in patients with pseudo- and pseudopseudohypoparathyroidism.Speculation: TSH stimulation by TRH may be a useful test for the further delineation of biochemical variants of pseudohypoparathyroidism.

HYPOGONADISM AND PARATHYROID ADENOMA IN CONGENITAL POIKILODERMA (ROTHMUND‐THOMSON SYNDROME)

In two adult patients with congenital poikiloderma (Rothmund‐Thomson syndrome) the following endocrine abnormalities were found: Patient 1, female, with short stature had primary amenorrhoea and did not develop secondary sexual characteristics. Despite lacking an oestrogen effect on the vaginal smear and the low urinary oestrogen excretion, basal LH and FSH and their response to LH‐RH were normal. At age 36 a parathyroid adenoma was diagnosed because of increased immunoreactive plasma parathyroid hormone and persistent hypercalcaemia. After removal of the tumour the patient remained normocalcaemic. The result of growth hormone response to insulin in the intermediate range was suggestive of partial deficiency. In patient 2, male, hypergonadotropic hypogonadism with small testes and high basal LH and FSH levels as well as increased LH and FSH response to LH‐RH were found. Plasma testosterone was normal. Endocrine abnormalities in previously published cases are summarized.

TREATMENT OF PRECOCIOUS PUBERTY IN GIRLS WITH INTRANASAL LHRH AGONIST (BUSERELIN)

Ten girls with idiopathic precocious puberty were treated for 1 - 3 years with Buserelin (B) intranasally at a daily dose of 200 - 900 ug. The data are compared to those obtained previously in 21 untreated and in. 13 girls with precocious puberty treated with cyproterone acetate (Pediat Res 8.248-256, 1974). B was clinically effective in suppressing menses in all but one girl who had low gonadotropins at onset. Breast size did not increase in 8, but pubic and axillary hair development progressed in 8 patients. Peak LH (170.3 ± 39.5 vs 99.1 ± 24.9 ug/1) and FSH (451 ± 73.4 vs 164.8 ± 29.1 ug/1) after LHRH were markedly suppressed during the first months of treatment and remained low thereafter. Basal LH increased intially (18.6 ± 3.8 vs 71.1 ± 17.0 ug/1) and persistently while basal FSH remain unchanged. Prl. E1. E2 levels were unaffected. DHEA gradually increased as seen in normal girls. Differences in height SDS at the beginning (1.72 ± 0.44). at 1 yr (2.01 ± 0.43) and at 2 years of treatment (1.95 ± 0.53) were minimal as were corresponding SDS for bone age (3.27 ± 0.53; 4.15 ± 0.54; 4.19 ± 0.53) and for height prediction related to target height (-1.20 ± 0.61; -1.40 ± 0.48; -173 ± 0.39). The data of statural and skeletal development of B-treated girls are not significantly different from those of untreated girls nor from those treated with cyproterone acetate.Supported by Swiss National Science Foundation grant 3.406.083.

GONADAL FUNCTION IN YOUNG ADULTS AFTER SURGICAL TREATMENT OF CRYPTORCHIDISM

47 men who had been surgically treated for unilateral (UC,n=32) and bilateral cryptorchidism (BC,n=15) at 5-14 yrs were studied on follow-up at 16-28 yrs. In UC the volume of the operated testis was 11.9±0.7 ml (mean ± SEN) and of the contralateral testis 15.8± 0.7 ml. In BC the mean testicular volume was 11.3±0.9 ml. Sperm count was below 40 millions/ml in 12 UC (n=23) and 9 BC (n=13) with 5 of them below 1 million/ml. In all patients plasma LH and FSH were measured before and 10-120 tnin. after LHRH (25 ug/m2 i.v.). Basal FSH values were elevated in 5 UC and 10 BC, FSH response to LHRH was excessive in 2 UC and 8 BC. Basal LH values were within normal limits in all patients, but a high LH response was observed in 6 UC and 3 BC. Plasma testosterone was normal in all but 3 cases (2 UC, 1BC) where subnormal levels were found.This study reveals a high incidence of functional impairment of the germinal epithelium in cryptorchidism with compromised fertility in most cases with BC. Leydig cell function is affected in only a few cases of both UC and BC.

86 INCREASED PLASMA DHEA AND DHEAS AND ABSENT OR VERY LOW URINARY DHEAS, A NEW CAUSE OF HIRSUTISM (H)

3 Hirsute,unrelated girls(14.6-17.8yrs)with normal clitoris and regular(1) or irregular(2) menstruations were studied.Cortisol(12.2-22.7 ug/dl),testosterone(68-172),17αOH-progesterone (107-479), and androstenedione(120-459ng/dl)in plasma were normal or moderately increased,but DHEA(1023-1384ng/dl) was high. Also DHEAS (2730-6080 ng/ml) was high,indicating intact sulfokinase. In urine (capillary column gas chromatography), DHEAS was undetectable after helicase, acid or glucuronidase hydrolysis,and low (0.4mg/d,lpt), or absent(2) after ACTH, but 16α-OH-DHEAS was detectable before and after ACTH. Other conjucates were normal or slightly increased, and dexamethasone-suppressible.When DHEAS was added to urine, a peak appeared after helicase, excluding hydrolysis inhibition. When DHEAS was injected iv (50mg,2pts), DHEAS appeared in urine (0.9-2.9 mg/d). With the same dose given to 2 normal girls (17-18.4 yrs) with normal basal plasma DHEA(285 and 549ng/dl),more DHEAS (4.6-6.4 mg/d),and also some 16αOH-DHEAS appeared.Unconjugated urinary DHEA in the pts.was similar as or higher than in the controls. This new type of H appears to be due to an increased renal threshold for DHEAS, but not for other steroids.Based on plasma steroid results alone, such pts.could be erroneously considered to have mild 3β-hydroxysteroid dehydrogenase deficiency. Supported by Swiss National Science Foundation (Grant 3874083).

SHORT- AND LONG-TERM EFFECTS OF GH IN PATIENTS WITH NORMAL GROWTH DESPITE GH-DEFICIENCY AFTER REMOVAL OF CRANIOPHARYNGIOMA

Removal of craniopharyngioma usually results in panhypopituitarism. Nevertheless, a number of children grow normally or even excessively after extirpation of the tumor despite the proven lack of GH. These children did not undergo GH therapy, We studied the effects of short- and long-term administration of GH on growth and metabolism in 6 patients under regular hormonal replacement therapy. During the short-term GH 15N retention was not significantly stimulated (115.4 ± 9.6 % of basal balance, mean ± SEM) and not different from controls. In contrast, 15N retention was 210.3 ± 20.7 % in children with GH-deficiency of other causes. Long-term administration of GH (2 U/m2 s.c. per day during 12 months) did not influence growth velocity, but increased calf circumference and decreased body mass index and skin fold thickness in prepubertal patients. General well-being and strength improved impressively. IGF-I, IGFBP-3 and the 150 kD IGFBP-complex were decreased before and restored to normal during GH treatment. The reverse was observed for the 50 kD IGFBP-complex. Thus, growth velocity in these patients is not related to an2y of the usual indicators of the growth status and remains unexplained. Although GH therapy does not affect growth, it has other beneficial effects and is recommended for this group of patients with normal growth velocity in the absence of GH.

74 GROWTH HORMONE INSUFFICIENCY ASSOCIATED WITH A SMALL NODULE OF THE PITUITARY STALK NEUROHYPOPHY SEAL ECTORY

Two prepubertal boys without any neurological signs nor diabetes insipidus were studied at age 12 and 15 years (bone age 9 and 12 years) because of declining height velocity. Arginine and insulin failed to induce GH release whereas TRH test results and cortisol response to insulin were normal. Skull radiographies did not show any abnormalities. On CT scan the pituitary stalk was suspected to be abnormal, but only with magnetic resonance imaging (MRI) a small round posterior nodule of the pituitary stalk was clearly demonstrated in both cases. Its qualitative appearance was equal to neurohypophyseal tissue. The lower part of the stalk was reduced to a filament leading to a hypoplastic pituitary gland which seemed to lack the posterior lobe. This suggests that in our patients the neurohypophysis may be located in an ectopic position attached to the pituitary stalk. Biopsy or surgical removal was avoided. The patients responded markedly to hGH therapy. At present, a malformation of the pituitary stalk seems to be a rare cause of GH insufficiency, but it is likely that a more extensive use of MRI for evaluation of apparent idiopathic hypopituitarism may reveal a higher incidence of such anomalies.

Effect of Delta-1-Testololactone(DT) in boys with pubertal gynecomastia (PG)

7 Boys with PG(mean age 15.4±1.1yrs),and 1 man (23yrs)with persistent G were treated with oral DT 450mg/d for 1.5 to 6 (mean 3.2)months without side-effects.In 2, PG disappeared after 3 and 4 months of DT,in 1 of them,it reappeared 6 months after discontinuation.In 5 others,glandular tissue became softer and/or smaller,and in 1, DT had no effect.Testicular volume did not change.The following steroid changes were observed:Gonadotropins before(b),and after(a)LHRH,and PRL were not influenced significantly:at first examination,LH was 21\[mnplus]4(b),and 110\[mnplus]31(a),FSH 83\[mnplus]32(b),and 182\[mnplus]88ug/l(a),and PRL 169\[mnplus]80mU/1. On DT,LH was 22\[mnplus]6(b),and 111\[mnplus]34(a),FSH 154\[mnplus]45(b),and 277\[mnplus]74 ug/l(a),and PRL 206\[mnplus]125mU/l.Although clinical results are variable and difficult to evaluate,it is concluded that DT might be useful in PG by increasing the androgen/estrogen ratios. Supported by the Swiss National Science Foundation (Grants No. 3.959-0.80,3.874-0.83,and 3.984-0.80).

17,20-Desmolase deficiency - clinical and biochemical heterogeneity

3 XY-individuals were studied at a pubertal age. No. 1 and 2 were the original patients (Zachmann et al., Clin.Endocr. 1,369, 1972) with intersexuality, raised as boys. No. 3 (unrelated) had female external genitalia and was raised as girl. 1 and 2 had male puberty, but 3 not. Serum testosterone (T) before and after HCG (5000 IU/m2) was (ng/dl):Androstenedione was low (62,76,29 ng/dl). 17OH-progesterone was normal or high (182, 212, 581 ng/dl) and increased after HCG (314, 381,1386 ng/dl), most in 3 with the lowest T. DHA before and after HCG was low in 1 and 2 (170-119,178-160 ng/dl), but normal in 3 (530-405 ng/dl). In urine, pregnanetriolone was present (0.62,0.32, 2.2mg/24h) and the 17-ketosteroids were normal or low (5.8,4.1,1.4 mg/24h). It is concluded that the degree of the defect may vary from partial (1 and 2) to marked (3) and that it may concern both, the Δ4-and Δ5-pathways (1 and 2), or the Δ4-pathway only (3).Supported by the Swiss National Science Foundation (Grant No. 3.959.080).