Ruth Illig

CONGENITAL BILATERAL ANORCHIA IN CHILDHOOD: A CLINICAL, ENDOCRINE AND THERAPEUTIC EVALUATION OF TWENTY‐ONE CASES

An evaluation of twenty‐one boys, including a discordant pair of identical twins, is presented in whom bilateral anorchia was found with a negative family history and without history of breech presentation or of postnatal testicular trauma, torsion or orchitis. The most likely cause is prenatal testicular torsion. The incidence of the condition in our hospital is 1 in 177 cases of cryptorchidism. Prepubertal growth was normal beofore treatment, and testosterone replacement therapy allowed a normal pjubertal growth spurt and skeletal maturation. Although demonstrable basal urinary tstosterone was found in the subjects with a postpubertal bone age, most patients tested showed no increase after stimulation with human chorionic gonadotrophin. In the presence of a normal penis and scrotum, such findings, together with a high basal FSH and an increased response of plasma LH to LHRH, make surgical exploration unnecessary. In the rare patient who shows a positive but subnormal response of testosterone to HCG, Leydig cells are presumed to be present either ectopically or in rudimentary testes, and further surgical exploration is indicated.

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.

Success, relapse and failure after intranasal LHRH treatment of cryptorchidism in 55 prepubertal boys

Synthetic LHRH was given intranasally to 55 prepubertal boys with 67 undescended testes. After a 4–5 week period while receiving a daily dose of 1.2 mg complete testicular descent was seen in 24 testes. Follow-up over 6 to 24 months showed relapse in 4 boys who responded successfully to a second trial with LHRH. In boys with insufficient or no response to an initial trial further treatment with LHRH in 11 cases or HCG in 5 cases also was without effect. Surgical correction after unsuccessful LHRH treatment in 32 boys with 35 undescended testes showed anatomical abnormalities in 28 testes, mostly an open processus vaginalis with or without hernia. Because of its simple and painless administration and the absence of unwanted side effects, intranasal LHRH is well-suited as initial treatment of cryptorchidism, particularly in young children.

EFFECT OF INTRANASAL LHRH THERAPY ON PLASMA LH, FSH AND TESTOSTERONE, AND RELATION TO CLINICAL RESULTS IN PREPUBERTAL BOYS WITH CRYPTORCHIDISM

Synthetic LHRH (HOE 471) administered intranasally over a period of 4 weeks for treatment of uni‐ or bilateral cryptorchidism in nineteen otherwise healthy prepubertal boys led to increased basal and peak LH values and to markedly decreased peak FSH values in the i.v. LHRH test. Basal testosterone remained unchanged. Sixteen cryptorchid boys treated with placebo served as a control group. The reduced FSH response to i.v. LHRH could be due to induction of a gonadal feedback mechanism rather than pituitary depletion of FSH, in view of the favourable therapeutic effect and the increased LH secretion seen in some of our patients. Pretreatment LHRH tests were available in twenty successfully and in twenty‐eight unsuccessfully treated boys. LH values were similar in both groups, whereas FSH peak values were significantly higher in boys who responded successfully to subsequent therapy. Testicular descent occurred most readily in boys with a large pool of easily releasable FSH and without a significant rise in testosterone (in contrast to HCG treatment). We suggest that FSH induces changes that potentiate the local action of testosterone.

Defects of Growth Hormone Genes

Human growth hormone (GH) is a 191-amino-acid polypeptide hormone whose production and release by somatotropes of the anterior pituitary is under complex hormonal control. Production of GH is increased by glucocorticoid, thyroid hormone, and growth-hormone-releasing factor (GRF) at least in part by stimulation of transcription of the GH gene.(1) Release of GH into the peripheral circulation is controlled by at least two hypothalamic factors: GRF, which stimulates, and somatostatin, which inhibits its release.(2–5) In turn, these hypothalamic factors are modulated by various influences originating in the central nervous system (CNS).(6) Because of the complexity of these interactions which control the synthesis and release of GH, GH deficiency could be caused by disorders at the level of the CNS, the hypothalamus, or the anterior pituitary. Thus, a wide variety of disorders including CNS developmental defects such as septooptic dysplasia, head trauma, histiocytosis X, tumors, or irradiation can cause GH deficiency.(6,7)

LACK OF BROMOCRIPTINE-INDUCED REDUCTION OF GROWTH PREDICTION IN TALL ADOLESCENTS

It has been suggested that bromocriptine treatment of tall girls and boys reduces growth prediction by inhibiton of growth hormone secretion (J Clin Endocr Metab 58.1022-1026.1984). We have treated 15 girls and 5 boys (chron age 10.1-14.6 years. bone age 11.0-14.0 years) with bromocriptine (2×2.5 mg/day) over a period of 1.14 ± 0.31 years (0.6-1.75).Results (paired Wilcoxon rank test): The differences between the mean adult height prediction before and after bromocriptine were -0.8 ± 3.5 cm according to Bailey-Pinneau (p = 0.433) and +0.2 ± 2.5 cm according to Tanner Mark I (p = 0.586). The mean peak GH values after TRH i.v. were 53.0 ± 50.2 mU/l before, and 59.0 ± 50.2 mU/l during bromocriptine treatment (p = 0.314). The wide range of the GH results most probably reflects physiological variations in this age group. Our results are essentially negative. Moreover, the concept, that bromocriptine reduces GH secretion, seems doubtful: in 6 of our patients we have measured plasma GH after 2.5 mg of bromocriptine and found a significant increase within the first three hours.Our results do not support the data from the literature. We conclude, that bromocriptine is ineffective in reducing adult height of tall girls and boys.Supported by Swiss National Science Foundation grant 3.906.083.

DISPARITY OF PITUITARY AND BIOSYNTHETIC GROWTH HORMONE IN ANTIGENICITY AND GROWTH RESPONSE OBSERVED IN TWO BROTHERS WITH ISOLATED GH DEFICIENCY |[lpar]|IGHD|[rpar]| TYPE IA

Two boys with IGHD due to GH-N gene deletion developed antibodies (Ab) to exogenous GH. The younger boy A (age 3 y, height -5.8SD at start of R) with high Ab titres did not grow during therapy with pit-GH. After 2 y without Rx and a decrease of Ab titres he showed a tremendous growth response to treatment with bio-methionyl-GH and only a moderate rise of Ab titres. The older boy B (age 9.5 y, height -7.8SD) with low Ab titres showed a normal growth rate during treatment with pit-GH and bio-methionyl-GH.Scatchard analysis with bio-methionyl-GH showed a lower binding capacity. This, and the lesser antigenicity of bio-GH may explain the therapeutical success in these 2 patients with IGHD type IA.

73 EUROPEAN COLLABORATIVE STUDY ON MENTAL DEVELOPMENT IN CHILDREN WITH CONGENITAL HYPOTHYROIDISM (CH) DIAGNOSED BY NEONATAL THYROID SCREENING

In an effort to obtain, large numbers of data on mental development in children with C H, questionnaires were sent (after previous inquiries) to 28 screening centers in 15 European countries. Thanks to the collaboration of many collegues and psychologists, we have received, so far individual data of 648 children with C H. The data comprises developmental/intelligence quotients (total, subscores) obtained at the ages of 6 months (n=189), 12 m (n=365), 24 m (n=254), 36 m (n=139), 48 m (n=125), 60 m (n=61), 72 m (n=19), and 84 m (n=17). Further data are to be expected during the next weeks.Developmental/intelligence quotients will be analyzed by the standard deviation score method where applicable, and related to various factors, such as exact diagnosis (athyroidism/ectopic thyroid/others), age at onset of therapy, socio-economic status, pre/peri/postnatal risk factors, and associated findings. Being able to pool a large number of data, this study should yield valid information about the significance of these factors for the mental outcome of children with C H.Supported by the Swiss National Science Foundation Grant No, 3,906.0.83 and 3.971.0.82.

Is a decreased LH response to LHRH in prepubertal boys with cryptorchidism predictive of permanent gonadotropin deficiency|[quest]|

Among more than 300 prepubertal boys with uni- or bilateral cryptorchidism, 15 with low LH response to LHRH (peak LH ug/l LER 907: 30.1 ± 7.8 SD) could be followed up to the age of 12 - 16.5 years and had at least 2 further LHRH tests (25 ug/m2 i.v.). At that age, all had signs of spontaneous puberty (testes ⋜3 ml and/or pubes Tanner stage ⋜2); peak LH values were 102.3 ± 40.7 SD (difference first/last LH peak p <0.001 in 14 boys). In 10 of them the rise of LH response appeared at pubes 2 - 3, in 4 at pubes 4 - 5. In one boy with testes of 20 ml and pubes 5 at the age of 14.4 years, LH peak values remained <40, comparable to patients with persistent gonadotropin deficiency. Before puberty, peak FSH values were low in half of these patients; during puberty, 13 boys had normal and 2 increased FSH values.Our results show that LH deficiency - suggested to be a causative factor of cryptorchidism - is present in this group of patients. However, it seems to be of transient nature as demonstrated by the rise of LH response and the occurance of spontaneous puberty.Supported by the Swiss National Foundation Grant No. 3.984.080

STUDIES of GROWH HORMONE BINDING AND INSULIN LIKE METABOLIC EFFECT IN ISOLATED RAT ADIPOCYTES

Adipocytes isolated by collagenase digestion from normal rat epididymal(EP), subcutaneous(SC), or retroperitoneal(RP) locations were selected for a study of human growth hormone(hGH) binding and metabolic activity. Scatchard analysis of 125-I-hGH binding was linear; binding affinities ranged from 2.1-3.5 × 109 M−1 and were not different, but the number of binding sites per cell were highest in EP(8,300), followed by SC(6,700), p<.05, and then RP fat(2,700), p<.01. The metabolic response of fat cells was evaluated by the incorporation of 14-C(U) glucose into adipocytes(without pre-incubation). With pituitary hGH, basal and maximally stimulated glucose incorporation was: EP=202±9 to 265±18 (31% increase, p<.05), SC=97±6 to 111±8 (17% increase), and RP=96±10 to 104±9 nMoles/106 cells(7% increase). Similar studies following biosynthetic hGH (supplied by Kabi Vitram) showed: EP=243±13 to 301±21(24% increase, p<.025), SC=120±17 to 139±31 (18% increase), and RP=110±10 to 104±12 nMoles/106 cells. Addition of hGH antibodies blocked the glucose incorporation in EP adipocytes using both pituitary and biosynthetic hGH, while insulin antibodies did not prevent this increase. We conclude that this insulin-like metabolic effect is caused by hGH, not an insulin-like impurity. EP fat cells demonstrated the highest number of binding sites and glucose incorporation, followed by SC and then RP fat cells. These results suggest different metabolic responses to hGH for adipose tissue from different locations.