Intermittent recombinant growth hormone treatment in short children born small for gestational age: four-year results of a randomized trial of two different treatment regimens.

BACKGROUND: Treatment of short children born small for gestational age SGA with recombinant human growth hormone r-hGH increases growth velocity during childhood. As in other indications, the growth velocity in these patients is more marked during the first year of treatment and then decreases. This study was undertaken to evaluate the efficacy of different r-hGH treatment schedules (67 microg/kg/day in a discontinuous or continuous regimen) during the second year of r-hGH treatment by comparing height velocity changes and total gain of height over a 4-year period. METHODS: 58 growth-retarded SGA children aged 2-5 years were randomized to a TOTO regimen (4 years alternating treatment (T) and observation (O), n = 30) or a TTOO regimen (2 years' treatment, followed by 2 years' observation, n = 28). Height velocity HV and total height gain were assessed during the 4-year study. RESULTS: In both groups, HV and HV standard deviation score HV-SDSCA increased during treatment and decreased during observation periods. Interruption of treatment in the TOTO group did not result in a better gain in height standard deviation score H-SDSCA when compared with the TTOO group. After 4 years of study, the gain in H-SDSCA was 1.4 + or - 01 in the TOTO group and 1.6 + or - 0.2 in the TTOO group leading to a mean height of -2.0 + or - 1.0 SDS and -2.0 + or - 0.8 SDS, respectively. The rate of bone maturation was similar in the two groups. CONCLUSIONS: In short SGA children, TOTO and TTOO regimens produced significant improvements in growth during r-hGH treatment. However, treatment interruption after 1 year did not influence the overall gain in height SDS when compared with 2 years' continuous treatment.

Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal.

In addition to its growth promoting effect, GH has profound metabolic effects that have not always been evaluated in longitudinal studies. We have recently shown that the effect of GH on body composition can be evaluated by magnetic resonance imaging measurement of adipose and muscle tissue cross-sectional (cs) areas in the thigh. The aim of this study was to evaluate the long-term effects of human GH (hGH) (0.2 IU/kg day) on muscle and adipose tissue mass during a 3-yr treatment period and after 1 year's withdrawal in short SGA (small for gestational age) children. Measurement of muscle and fat tissue mass by magnetic resonance imaging of the thighs was used to study the metabolic effect of hGH in 14 prepubertal short children born SGA. Results were compared with those of a control group of 7 normal children followed longitudinally. An increase of muscle tissue cs area was observed during the 3 yr of hGH treatment, an increase which was significantly different during the first 2 yr of treatment from that seen in controls (+31.2+/-2.6% and +18.1+/-1.8% during the 1st and 2nd year, respectively, vs. +9.1+/-2.6% change during 1 yr in controls). After a significant decrease in adipose tissue cs area during the first year of therapy (-16.4+/-3.4% vs. baseline values), an increase in adipose tissue cs area occurred during the second and third years. At the end of the third year, the muscle tissue cs area change was significantly greater in SGA-treated children, as compared with controls (+71.6+/-4.6% vs. 22.1+/-4.6%; P < 0.001), whereas the adipose tissue cs area change was similar in the two groups (+12.6+/-9.5% vs. +19.9+/-4.2%). After hGH withdrawal, the effects were opposite after 3 months, as compared with those observed after the first 3 months of hGH administration, whereas no additional significant change was seen after 1 yr off treatment, indicating the maintenance of muscle and adipose tissue mass. In conclusion, hGH administered to SGA children is effective in improving growth velocity and has long-term effects on muscle and adipose tissue mass. These effects may lead to speculation about the sensitivity of these tissues to GH. The physiological consequences of such effects must be evaluated.

Growth hormone in the treatment of short stature in young children with intrauterine growth retardation.

Growth acceleration and bone maturation were studied in children with severe short stature and a history of intrauterine growth retardation (IUGR) to determine the effect of growth hormone (GH)-treatment. Patients were enrolled in an open randomized, multicenter trial and allocated to either the treated group (group 1, n = 38) or the control group (group 2, n = 31). Both groups were treated daily with 0.2 IU/kg/body weight during 3 years. The children in group 2 started the study with a 1-year observation period followed by a 3-year treatment period. At baseline, the mean age was 4.5 years, bone age was 3.3 years, height standard deviation score (SDS) was -3.4, height velocity (HV) SDS was -1.6. Auxologic data were measured every 3 months and bone age was assessed at the start of the study (baseline) and then every 12 months thereafter. After 1 year of treatment, linear HV in group 1 increased significantly in comparison with the pretreatment period (from 5.7 +/- 2.0 to 10.1 +/- 1.7 cm/year; p < 0.001). Increased HV was sustained during the 2nd and 3rd year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 years of growth hormone (GH) treatment in group 2. The mean height SDS for chronological age increased by 2.0 +/- 0.7 in the 2 groups after 3 years of treatment. Bone age remained retarded but increased with a mean of almost 4 years after 3 years of treatment in both groups. Even at a dose that is three times the replacement dose, treatment with recombinant human GH was well tolerated. From these results, we conclude that recombinant human GH treatment over 3 years can induce sustained catch-up growth in young children with severe short stature and a history of IUGR.

Three-year data from a comparative study with recombinant human growth hormone in the treatment of short stature in young children with intrauterine growth retardation.

Growth acceleration and bone maturation were studied for 3 y in 69 children with severe short stature and a history of intrauterine growth retardation (IUGR), to determine the effect of treatment with recombinant human growth hormone (r-hGH). The patients were enrolled in an open, multicentre trial and were randomly allocated to either the treated group (Group 1) or the control group (Group 2). The children in Group 1 were treated daily with 0.2 IU/kg/body weight (0.067 mg/kg) s.c., during 3 y and the children in Group 2 started the study with a 1-y observation period followed by a 3-y treatment period. At birth, their mean weight standard deviation score (SDS) was -2.5 and their mean length SDS -3.5. At baseline, the patients were prepubertal, non-GH deficient, with no known dysmorphic features. Mean age was 4.5 y, bone age was 3.3 y, height SDS was -3.4, height velocity (HV) SDS was -1.6, and body mass index SDS was -1.4. After 1 y of treatment, linear HV in Group 1 increased in comparison with the pre-treatment period (from 5.7 +/- 2.0 to 10.1 +/- 1.7 cm/y; p < 0.001) and with the first year of observation in Group 2 (p < 0.001). Increased HV was sustained during the second and third year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 y of GH treatment in Group 2. Mean height SDS for chronological age increased by 2.0 +/- 0.7 in the two groups after 3 y of treatment. HV after 1 y of treatment was negatively correlated with growth velocity at baseline. Bone age remained retarded but increased with a mean of almost 4 y after 3 y of treatment in both groups. Even at a dose that is three times the replacement dose treatment with r-hGH was well tolerated. From these results, we conclude that r-hGH treatment over 3 y can induce sustained catch-up growth in young children with severe short stature and a history of IUGR. Long-term studies are needed to assess ultimate effects on final height.

Specific abnormalities in a visual motor psychological test in short children with abnormal growth hormone secretion.

Forty short (< -2 SD) prepubertal children with no organic disease underwent two growth hormone (GH)-stimulation tests, a sleep test and a psychological assessment based on the Rey-Osterrieth figure that was scored for boundary-type errors (defined as non-developmental severe distortions or disrespect of boundaries) by a psychologist who had not met the child. Twenty-three children had normal endocrinological findings and 17 had abnormal GH secretion (4 with complete GH deficiency and 13 with normal GH response to pharmacological stimuli but abnormal nocturnal secretion). Seventeen children had normal results in the Rey-Osterrieth figure test and 23 made boundary-type errors. The biological and psychological analyses agreed in 32 cases, leading to a very significant (p < 0.0005) relation. This study reveals that short children with abnormal GH secretion, particularly low nocturnal secretion, show abnormalities independent of their developmental quotient in a visual motor psychological test.

Metabolism of vasopressin, oxytocin and their analogues [Mpa1, D-Arg8]-vasopressin (dDAVP) and [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin (antocin) in human kidney and liver homogenates.

Information regarding the metabolic fate of the neurohypophyseal hormones arginine-vasopressin (AVP), oxytocin (OT) and their analogues in man is practically non-existent. The aim of the present study was to investigate the stability of oxytocin, vasopressin and their analogues dDAVP and [Mpa1-D-Tyr2(Et), Thr4, Orn8]-oxytocin (antocin) in human renal microvilli brush border membranes and in human liver membranes. After incubation the extent of degradation of the peptides was determined by reversed phase high-performance liquid chromatography (HPLC). The degradation of both AVP and OT was rapid in the presence of glutathione and human renal microvilli membranes. AVP, as well as dDAVP, was stable when incubated with microvilli membranes without glutathione, while OT was metabolized. The metabolization of the oxytocin analogue, antocin, also varied with the presence of glutathione. While in the absence of glutathione a more lipophilic peak eluted, a more hydrophilic peak was observed with glutathione on HPLC. The lipophilic peak was found to coelute with the truncated analogue [Mpa1, D-Tyr2 (Et), Thr4, desOrn8, Gly9]-oxytocin. No degradation occurred when the peptides were incubated with liver membranes. However, when using crude, unpurified liver homogenate degradation occurred for all peptides except antocin. The degradation of AVP in the human unpurified liver homogenate was as rapid as in the renal microvilli membranes. Similarly, OT was more rapidly degraded in human kidney microvilli membranes in the presence of glutathione than in the human crude liver homogenate, when using equal amounts of protein in the incubations. Thus, the present investigation indicates the existence of two possible metabolic pathways, in kidney microvilli, one for OT, which did not require the presence of reduced glutathione, and one for AVP, which required the presence of reduced glutathione. Liver degradation, on the other hand, requires the hepatocytes.

[Evaluation of dietary vitamin A intake in children with and without growth retardation]. / Evaluation de l'apport alimentaire en vitamine A chez l'enfant avec et sans retard statural.

BACKGROUND: A possible involvement of vitamin A in regulating physiological nocturnal growth hormone secretion has been recently suggested leading us to evaluate the daily vitamin A supply in prepubertal school children. POPULATION AND METHODS: A questionnaire including a list of foods containing vitamin A and/or beta-carotene was answered with the aid of the parents. Vitamin A supply was expressed in retinol-Equivalent and estimated as mean daily intake over a one-year period. Following this methodology, a study was conducted in 104 control school children with normal stature and 110 children with short stature. RESULTS: The total daily vitamin A intake (mean +/- SD: 1.197 micrograms +/- 799), retinol (675 micrograms +/- 628) and beta carotene (525 micrograms +/- 355) was above or equal to the recommended intake in more than 75% of the control children. In contrast, the total daily vitamin A intake (mean +/- SD: 787 micrograms +/- 850, P < 0.0002) retinol (436 micrograms +/- 670, P < 0.0004) and beta carotene (353 micrograms +/- 466, P < 0.002) was significantly decreased in those children with short stature, more than 35% of them having daily intake below the recommended one. The dietary vitamin A intake was also deficient when expressed as ER/1,000 calories (mean SD = 444 +/- 262) in the 46 children with short stature in whom the calorie intake had been evaluated for three days. CONCLUSIONS: This study confirms that annual dietary vitamin A intake can easily be measured in school children. Its results suggest that this intake, relatively deficient in children with short stature, could be correlated with deficient secretion of growth-hormone.

Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers.

OBJECTIVE: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor, was studied in six healthy, male volunteers aged 19-34 years, followed for 8 h after each drug administration. METHODS: For i.v. administration the subjects received 4 micrograms dDAVP. For intestinal administration 500 micrograms dDAVP was administered directly, in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and aprotinin was administered enterally at the constant rate of 5 ml.min-1 for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement of lipase, chymotrypsin and pH every 30 min for 5 h. RESULTS: The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified. After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml.min.kg-1. The mean bioavailability after duodenal administration of dDAVP+ aprotinin was 0.46% compared with 0.09% after duodenal administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of an enzyme inhibitor.

Metabolism of vasopressin, oxytocin, and their analogues in the human gastrointestinal tract.

The bioavailability from the gastrointestinal tract of peptides as large as nonapeptides is very low, which may be attributed to extensive lumenal and mucosal degradation. The aim of the present study was to investigate the stability of the neurohypophyseal hormones arginine-vasopressin (AVP), oxytocin (OT), and their synthetic analogues in human intestinal contents, small intestinal brush-border membranes, and gastric, rectal, and colonic plasma membranes. Peptides were incubated in gastrointestinal contents from healthy volunteers and in human intestinal mucosa homogenates. The extent of degradation was determined by reversed-phase high performance liquid chromatography (HPLC). AVP was rapidly degraded in the ileum fractions of the intestinal contents whereas 50% of the analogue 1-deamino-8-D-arginine vasopressin (dDAVP) remained intact after 35 min. The degradation was pH dependent, and a concentration-dependent inhibition was observed when aprotinin, a proteinase inhibitor, was preincubated with contents from the ileum. No degradation of AVP, dDAVP, or oxytocin analogues was observed in the mucosa homogenate from the stomach. The peptides were found to be rather slowly degraded by intestinal microvilli membranes and colonic and rectal plasma membranes. This degradation occurred essentially when reduced glutathione 10(-4) M was added to the incubations. In conclusion, the major enzymatic barrier to intestinal absorption of OT, VP, and their analogues is present in the intestinal juice and not in the mucosa, which, however, constitutes a major physical barrier to peptide transport.

Negative correlation between plasma GHRH values and growth velocity in short prepubertal children.

Numerous data suggest that impaired growth hormone secretion in short children is usually related to abnormal regulation of the hormone at the hypothalamic level. In order to improve our understanding of neurohypothalamic dysfunction in short children, we measured basal and peak (after L-dopa stimulation) plasma growth hormone-releasing hormone levels in 43 prepubertal children. Among them, in 23 children suspected of having hypothalamic growth hormone dysregulation, growth hormone-releasing hormone values were significantly higher than those observed in normal short stature children (n = 20), no longer correlated with peak growth hormone following L-dopa, and negatively correlated with growth velocity. This suggests that a predominant inhibitor of growth hormone secretion, such as an increase in somatostatin tone, might be prevalent in a large number of children with partial growth hormone deficiency and suspected hypothalamic growth hormone dysregulation.

Vitamin A deficiency and nocturnal growth hormone secretion in short children.

In the growth hormone (GH) neurosecretory dysfunction syndrome affecting slowly growing children with delayed bone age, low nocturnal GH secretion is accompanied by normal responses to pharmacological stimuli. We compared plasma vitamin A with physiological nocturnal and stimulated GH secretion in 68 short prepubertal children. Fasting plasma vitamin A correlated with nocturnal GH secretion but not with stimulated GH secretion. Total dietary vitamin A intake was significantly lower in short children with abnormal nocturnal GH secretion than in normal children and in endocrinologically-normal short children. 9 of 12 children with low nocturnal GH secretion and normal stimulated GH peaks who were supplemented with vitamin A 3000 micrograms for 3 months had increased nocturnal GH secretion.

Water-balance hormones during long-term follow-up of oral dDAVP treatment in diabetes insipidus.

The aim of the present study was to investigate the hormonal control of water-balance in children with diabetes insipidus and to assess safety and efficacy of long-term treatment with oral dDAVP. Plasma atrial natriuretic peptide, plasma renin activity, aldosterone, plasma and urinary cyclic 3'5'-guanosine monophosphate and urinary prostaglandin E2 were measured in eight patients (aged 3-21 y) with central diabetes insipidus. At baseline, 12 h after the last dDAVP dose, patients had hypotonic polyuria but normal plasma sodium concentrations and plasma osmolality relative to a control group. The mean plasma atrial natriuretic peptide concentration in patients (26.2 +/- 2.6 pg/ml) tended to be lower than in controls (36.5 +/- 8.2 pg/ml, mean +/- SEM), although the difference was not significant. Plasma cyclic 3'5' guanosine monophosphate was higher in controls (6.0 +/- 0.6 pmol/ml, mean +/- SEM) than in patients (3.8 +/- 0.3 pmol/ml). Aldosterone, plasma renin activity, urinary cyclic guanosine monophosphate and urinary prostaglandin E2 were similar in the two groups. During 3 h following dDAVP administration, atrial natriuretic peptide levels did not change in patients but decreased significantly in controls to 23.0 +/- 4.0 pg/ml. No adverse reactions, or circulating antibodies against dDAVP, were observed after 3.5 years of oral dDAVP treatment. The average oral dDAVP dosage was similar after 1 and 3.5 years of treatment (906 +/- 406 micrograms/24 h, mean +/- SD). Water-balance is not detectably different from normal in correctly treated diabetes insipidus patients in terms of plasma atrial natriuretic peptide, plasma renin activity and aldosterone levels. Long-term oral dDAVP treatment is safe and efficacious.

Pharmacokinetics of 1-deamino-8-D-arginine vasopressin after various routes of administration in healthy volunteers.

OBJECTIVE: We investigated the pharmacokinetics and biological effects of 1-deamino-8-D-arginine vasopressin (dDAVP) in healthy adults after intravenous, subcutaneous, intranasal, peroral, sublingual and intrarectal administration. DESIGN: Eight normal volunteers were studied over an 8-hour period after each drug administration, separated by at least one week. For intravenous and subcutaneous administration, the subjects received 2 micrograms of dDAVP. The intranasal and sublingual doses were 20 micrograms and the rectal dose was 50 micrograms. Oral administration of dDAVP was effected with a 200-micrograms tablet. MEASUREMENTS: Plasma and urinary levels of dDAVP were measured using a specific and sensitive radioimmunoassay. RESULTS: A significant increase of urine osmolality was observed after all routes of administration, except the sublingual and intrarectal for up to 8 hours after administration. After intravenous administration, the half-life of elimination (t1/2) of dDAVP was 78 +/- 10 minutes. An extensive adsorption of dDAVP to the plastic syringe was found with intravenous but not with subcutaneous administration. Using the area under the curve of dDAVP from the subcutaneous administration as a reference, bioavailability was found to be 3.4% after intranasal administration and 0.1% after oral administration. After sublingual and intrarectal routes of administration no detectable dDAVP was found in the blood; however, low amounts were found in the total 24-hour urine. CONCLUSION: The bioavailability of dDAVP seems lower than previously reported after intranasal and oral administration.

Urinary GH secretion correlates with plasma GH levels during sleep and GHRH stimulation tests but not during the L-dopa stimulation test in prepubertal children.

In order to assess the value of urinary growth hormone (GH) as a reflection of central GH release, 42 prepubertal children with short stature and without organic disease were studied. A nocturnal GH profile and L-dopa and GH-releasing hormone (GHRH) tests were performed. Urinary GH was measured by means of a direct immunoradiometric method we have developed, using two monoclonal antibodies. Nocturnal urinary GH values correlated positively with plasma GH values expressed as the area under the curve (r = 0.76; p = 0.0001) or mean peak amplitude (r = 0.73; p = 0.0001). Also, urinary GH values correlated positively with peak plasma GH levels during the GHRH test (r = 0.64; p = 0.001). In contrast, no correlation was observed between peak plasma GH and urinary GH during the L-dopa test (r = 0.29; p = 0.11). This suggests a specific but as yet undetermined effect of L-dopa on urinary GH secretion.

Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man.

The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i.v. administration the subjects received 4 micrograms dDAVP. For intestinal administration 400 micrograms dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i.v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml.min-1.kg-1, amount excreted in urine 2.0 micrograms and renal clearance was 0.8 ml.min-1.kg-1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02-0.35%). f was 0.24% after duodenal application (range 0.04-0.62%), 0.19% after jejunal (range 0.01-0.41%), 0.03% after distal ileal (range 0.01-0.08%), 0.04% after proximal colonic (range 0.01-0.12%) and 0.04% after rectal (0.01-0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.

Effect of hypertonic saline infusion on the level of immunoreactive dynorphin in extracted human plasma.

Dynorphin-A and its related peptides are derived from prodynorphin, one of the three known endogenous opioid precursors. The prodynorphin gene is expressed in the vasopressinergic magnocellular neurons of the hypothalamus, while its peptide products are present in the vasopressin (AVP) neurosecretory vesicles of the neurohypophysis. The concentration of immunoreactive (IR) dynorphin is orders of magnitude higher in the neurohypophysis than in any other tissue, suggesting that perhaps the prodynorphin-derived peptides are secreted from the hypothalamic-neurohypophyseal unit into the general circulation. Experiments in rats have shown that osmotic stimuli increase both AVP and prodynorphin in the hypothalamus. To determine whether human hypothalamic prodynorphin is also under osmotic regulation, we measured plasma IR-dynorphin, plasma IR-AVP, and serum sodium immediately before and during the infusion of normal or hypertonic saline in normal human volunteers. Because of the unusual susceptibility of the prodynorphin-derived peptides to cleavage by endopeptidases, we also developed an appropriate plasma dynorphin extraction technique. We found that the IR-dynorphin present in human plasma was composed of 6K- and 4K-sized peptides and that no larger than 6K or smaller than 4K dynorphins were present. The infusion of normal saline did not have any significant effect on plasma IR-dynorphin, while 3% hypertonic saline increased its plasma levels. Thus, the mean IR-dynorphin level in the plasma of the volunteers infused with normal saline was 40.3 +/- 6.4 fmol/mL (mean +/- SE; n = 6) at zero time; after 30 min of infusion, plasma IR-dynorphin was 36.0 +/- 6.3, after 60 min it was 29.9 +/- 5, after 90 min it was 36.0 +/- 4.7, after 120 min it was 36.8 +/- 3.2, and after 150 min it was 36.0 +/- 6.1. The plasma IR-dynorphin level in the volunteers infused with hypertonic saline was 31.7 +/- 3.5 fmol/mL (mean +/- SE; n = 10) at zero time. After 30 min of infusion it increased to 37.4 +/- 3.8, after 60 min to 46.4 +/- 7.7, after 90 min to 56.2 +/- 9.1, after 120 min to 53.6 +/- 8.7, and after 150 min to 99.0 +/- 14.2. The increase in plasma IR-dynorphin with time was significant (P less than 0.0001) and correlated positively with serum sodium and plasma AVP. The physiological role of the prodynorphin-derived peptides of the hypothalamic-neurohypophyseal unit is not yet known.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma of the prostate with Cushing's syndrome. A case report with histochemical and chemical demonstration of immunoreactive corticotropin-releasing hormone in plasma and tumoral tissue.

A case is described of a patient with a small-cell prostatic carcinoma containing immunoreactive CRH, in conjunction with ACTH-dependent Cushing's syndrome. The serum concentrations of CRH, ACTH, beta-endorphin and calcitonin were all found to be above normal. Post-mortem examination revealed a prostatic tumour with multiple metastases, and a diffuse hyperplasia of pituitary corticotropic cells and adrenal cortical cells. In sections of the primary prostatic tumour, immunoreactive cells were demonstrable with antisera raised against human CRH, TSH, calcitonin and somatostatin, but not with antisera against ACTH or beta-endorphin. By radioimmunoassay the CRH-like material could also be demonstrated in extract of the prostatic tumour and the material from both plasma and tumour extract eluted at the position of human CRH on gel chromatography (Sephadex G-75). These findings provide support for the interpretation that the patient's Cushing's syndrome was due to a CRH-producing prostatic tumour. Finally, the origin and the clinical significance of the neuroendocrine cells in the prostatic carcinoma is discussed.

[Central diabetes insipidus in the very young child. Treatment with oral desmopressin]. / Diabète insipide central chez le très jeune enfant. Traitement par une préparation orale de la DDAVP.

Neonatal diabetes insipidus (DI) is extremely rare. An efficacious substitutive treatment can be particularly difficult to ensure. We have treated two children with central DI, revealed during the neonatal period, successively with an intranasal preparation of desmopressin at one month of age and with an oral preparation at one and 3 years respectively. We conclude that oral treatment with desmopressin is possible, secure and effective in DI presenting in the first months of life. This new form of administration seems even better for younger children when the difficulties of intranasal administration can be responsible for severe complications. As with the intranasal form, the doses given orally are very variable and individual.