Induction of follicle maturation and ovulation by gonadotropin administration in women with beta-thalassemia.

The objective of this paper was to assess the ability of gonadotropin administration to induce ovarian steroidogenesis, follicle maturation and ovulation in hypogonadal women affected by beta-thalassemia. Thirteen hypogonadal thalassemic women underwent a test with gonadotropin-releasing hormone (GnRH), with estimation of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. They were then administered human menopausal gonadotropin (hMG) for a period ranging from 11 to 15 days with a total dose variable from 3,300 to 4,200 IU. In each patient, the initial dosage of 300 IU daily, adopted for the first 9 days, was modified subsequently according to the ovarian morphology, as shown by serial echographic examinations and by serum estradiol levels. In those patients in whom a dominant follicle was evidenced and the occurrence of pregnancy could be excluded, induction of ovulation was attempted by administration of 10,000 IU of human chorionic gonadotropin (hCG). All patients displayed a reduced LH and FSH rise in response to GnRH. Upon hMG administration, they exhibited echographic evidence of follicular growth with a clear-cut increase of serum estradiol, which peaked between the 9th and the 16th day from the start of treatment. In two out of three patients in whom a dominant follicle developed, ovulation was induced successfully by hCG injection, as shown by the increase of serum progesterone and by the ultrasonographic demonstration of a corpus luteum. This study has shown that, by proper pharmacological stimulation, the steroidogenic function of the gonads and even ovulation can be reinstated in hypogonadal thalassemic women.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by phospholipid liposomes of the prolactin and cortisol response to insulin hypoglycemia in man.

This study was designed to further investigate the purported dopaminergic activity of phospholipid liposomes (PL) prepared from bovine cerebral extracts, and to obtain further indications about their pituitary or suprapituitary site of action. In eight normal subjects, we have studied the effects of PL administration (250 mg as IV bolus plus additional 250 mg infused IV over a 60-min period), compared to placebo, on the prolactin (PRL), cortisol and growth hormone (GH) response to an insulin tolerance test (ITT). In eight additional subjects, the effects of PL on the PRL and TSH response to TRH were evaluated. PL medication blunted the PRL and cortisol response in the ITT: significant differences, with respect to placebo administration, were observed between mean peak PRL values (51.9 +/- 13.63 SEM vs 83.4 +/- 26.35 ng/ml, P less than 0.05) and mean cortisol values at 120 min time (20.9 +/- 0.67 vs 26.7 +/- 2.46 micrograms/dl, P less than 0.05). In contrast, PL administration did not modify the ITT-related GH rise or the PRL and TSH release in response to TRH. These findings favour the view that PL are endowed with intrinsic biological activity which is dopamine-mediated, and point to the hypothalamus as their primary site of action.

Ineffectiveness of ceruletide to reduce food intake and body weight in obese women hospitalized for weight reduction and treated with a restricted diet. A double-blind study.

Ceruletide is a synthetic decapeptide closely resembling the 8-carboxy-terminal peptide of cholecystokinin (CCK-8) with which it shares several biological properties. In a double-blind study versus placebo, we evaluated the effects of ceruletide on self-rated hunger and food intake at lunch time, as well as on body weight in 14 obese women hospitalized for weight reduction and on a restricted diet. During two 6-day courses of treatment with ceruletide or placebo, ceruletide 0.3 microgram/kg b.wt. or an equivalent volume of its diluent were injected IM at 11.30 a.m., i.e., 30 min before lunch. Feelings of hunger were quantitated, using a visual analogue self-rating scale, prior to the injection of ceruletide or placebo and 30 min thereafter, i.e., just prior to the start of meal ingestion, as well as 2 hr after the start of the meal. Duration and caloric content of food ingested at lunch, as well as morning body weight, were recorded daily. Ceruletide, compared to placebo, did not significantly influence any of the above variables. However, in the first three experimental days, the increase in self-rated hunger from values before the injection to 30 min thereafter was less marked, though not significantly so (0.05 less than p less than 0.1), with ceruletide than with placebo. Thus, it appears that ceruletide, under the experimental conditions of the present study, was not effective in enhancing the patients' motivation to lose weight and to further restrict their food intake at lunch time.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of injectable bromocriptine in patients with Cushing's disease.

The therapeutic efficacy of sustained dopaminergic stimulation in Cushing's disease (CD), was investigated performing a three-month trial with monthly 50-100 mg injections of a bromocriptine depot preparation (Parlodel LAR, Sandoz) in six patients with CD. Dopaminergic treatment did not consistently influence pituitary-adrenal activity, as judged by plasma ACTH, cortisol and urinary free cortisol levels as well as by clinical findings. Interestingly, treatment with bromocriptine was associated with reappearance of menses in the three patients who were amenorrheic. In the five patients submitted to inferior petrosal sinus sampling, a parallelism between ACTH and PRL concentrations could be observed with a PRL rise, ipsilateral to that of ACTH, ensuing in three patients after administration of corticotropin-releasing hormone. In one patient a 55% reduction in the size of the pituitary adenoma was demonstrated by MRI carried out at the end of treatment. Our findings lead to the following conclusions: a) administration of depot injections of bromocriptine to patients with CD appears unable to correct hypercortisolism, although it can induce restoration of menses in amenorrheic patients; b) enhanced PRL concentrations at the pituitary level are probably involved in the amenorrhea often accompanying Cushing's disease.

Neuroendocrine effects of chronic administration of sodium valproate in epileptic patients.

In 10 untreated epileptic patients, we evaluated the functional integrity of the hypothalamic-pituitary axis before and during chronic treatment with sodium valproate, a gamma-aminobutyric acid-mimetic compound. The GH response to L-dopa (250-500 mg po) was absent in 3 and severely impaired in 2 of the 10 patients though being, on the average, only slightly lower in the epileptic subjects than in normal controls. Conversely, the GH rise following GHRH (0.5 micrograms/kg body weight, iv) was normal in 9 of the patients. A significant blunting of the GH response to L-dopa occurred in the 7 patients initially responsive after 6 month of sodium valproate (P less than 0.05). The GH response to GHRH also underwent an evident though not significant attenuation. The ACTH and the ACTH/cortisol elevations elicited by metyrapone (35 mg/kg body weight infused over 4 h), and by CRH (1 microgram/kg body weight, iv), respectively, normal before treatment, were significantly impaired (P less than 0.05, less than 0.01) during antiepileptic therapy. Prolactin and TSH dynamics following metoclopramide (0.1 mg/kg body weight, iv) and TRH (200 micrograms iv) remained normal over the whole study period. Growth arrest ensued in 1 patient after 6 months of sodium valproate and disappeared after drug withdrawal. These observations point to a defective hypothalamic control of GH secretion in some epileptic patients. They also indicate that chronic administration of sodium valproate, hence activation of central gamma-aminobutyric acid system, results in a blunting of the stimulated GH and ACTH secretion. Occasionally, a reversible arrest of skeletal growth may also ensue.

Effect of chronic treatment with biosynthetic growth hormone (GH) on the GH response to double GH-releasing hormone administration in children with short stature.

Growth hormone (GH) exerts a negative feedback on its own secretion through direct and indirect mechanisms. Normal children, unlike adults, display consecutive GH responses after repeated GH-releasing hormone (GHRH) administration. In this study, we investigated the effects of long-term GH administration on this peculiar secretory pattern. Eight children with severe short stature and impaired GH responses to suprapituitary provocative stimuli associated with normal GH responsiveness to GHRH, underwent, while on chronic treatment with biosynthetic GH and on the 10th day following drug withdrawal, a double bolus GHRH test (two GHRH injections of 1 microg/kg b.w. given as i.v. boluses two hours apart). During GH therapy the GH response to the first GHRH bolus appeared to be reduced, though not significantly so, compared to that observed at diagnosis; after treatment withdrawal, this response returned quite similar to pretreatment. Both during and after treatment, the GH response to the second GHRH bolus was comparable for magnitude to that evoked by the first application. In conclusion, even prolonged treatments with rhGH do not induce persisting alterations of the physiological mechanisms subserving GH regulation.

Evidence against a self-inhibition of ACTH secretion in man.

To ascertain the physiological relevance of an autoregulation of adrenocorticotropin hormone(ACTH) secretion in man, we studied the effect of alsactide (beta-Ala1, Lys17-ACTH1-17-4-amino-N-butylamide), a synthetic ACTH analogue with potent steroidogenic activity but not recognized in the endogenous ACTH immunoassay, on plasma ACTH pattern in patients with Addison's disease. Three experimental models were employed as follows: (a) in 6 patients, whose steroid replacement therapy had been discontinued 36 h previously, we compared the effect of alsactide, administered at two dose levels (10 or 100 micrograms i.v. als bolus followed by the same dose infused over 2 h, and of placebo, on the plasma ACTH pattern; (b) the previous experiment was repeated in 4 patients in whom cortone replacement therapy was substituted for 3 days with dexamethasone, 0.5-1.5 mg daily p.o., so as to lower plasma ACTH levels to within the high normal range; (c) in 4 patients off therapy for 36 h, we evaluated the ACTH response to synthetic ovine corticotropin-releasing factor, 1 microgram/kg body weight injected intravenously, occurring during concomitant administration of alsactide, 100 micrograms i.v. as bolus plus 100 micrograms infused over 2 h, or placebo. Compared to placebo, alsactide did not significantly affect the pattern of ACTH under any of the experimental conditions investigated. Collectively, our findings, although they have to be interpreted with caution, do not support the idea that a self-regulation mechanism plays an important role in the control of ACTH secretion in man.

Effect of chronic treatment with octreotide nasal powder on serum levels of growth hormone, insulin-like growth factor I, insulin-like growth factor binding proteins 1 and 3 in acromegalic patients.

Octreotide nasal powder is a delivery system of the somatostatin analogue developed to overcome the inconvenience of repeated subcutaneous administrations. Eight patients with clinically active acromegaly were treated for three months with octreotide nasal powder which was administered at the initial dosage of 0.125 mg tid, doubling the dosage up to 2 mg tid in order to obtain a mean GH value below 5 micrograms/l during 8 daytime hours. In 4 of these patients, treatment was prolonged till the sixth month. Blood samples were taken on days 15, 29, 43, 55, 90, 120, 150, 180 for GH, IGF-I, IGFBP-3, IGFBP-1 and insulin measurements. Before treatment, mean daytime GH and morning IGF-I serum levels were both increased but not correlated with each other. Serum IGFBP-3 levels were higher than normal and positively correlated with those of GH, IGF-I and insulin. Insulin levels were elevated and positively correlated with those of GH but not with those of IGF-I and IGFBP-1. Serum IGFBP-1 levels were in the low normal range and not correlated with any of the other parameters. Treatment with octreotide nasal powder induced in all patients a marked decrease of GH which lowered below 5 micrograms/l in 7/8 patients and IGF-I levels, which fell within the normal range in 1 patient. Serum IGFBP-3 and insulin concentrations decreased by 26% and 71%, respectively, and those of IGFBP-1 underwent an only transient increase in 5/8 patients. Opposite changes of insulin and IGFBP-1 levels, with a decrease of the former followed by an increase of the latter were noted during the 8 hours following an octreotide nasal insufflation. During chronic octreotide treatment, positive correlations were found between GH and IGF-I, GH and IGFBP-3, IGF-I and IGFBP-3, insulin and IGFBP-3 and insulin and IGF-I. An improvement of the clinical picture was registered in all patients after a few days of octreotide nasal powder administration. Treatment was well tolerated, with only mild side effects and no significant changes in the nasal mucosa, and the patients' compliance was excellent.

Evaluation of hypothalamic-pituitary function in patients with thalassemia major.

The increased survival of patients with thalassemia major, made possible by more adequate therapeutic regimens, has emphasized the importance of the endocrine abnormalities often associated with this disease. In twelve thalassemic patients, we evaluated the hypothalamic-pituitary function by measuring plasma levels of anterior pituitary hormones under basal conditions and in the course of provocative tests. An impairment of growth hormone (GH) secretion was demonstrated in a considerable proportion (7/12) of these patients. In some of them failure of GH response to insulin-hypoglycemia and normal hormone rise after growth hormone-releasing hormone indicate a hypothalamic defect. A defective prolactin secretion was observed in the female hypogonadic but not in the male thalassemic patients. This abnormality appears to be dependent on estrogen deficiency rather than on a hypothalamic-pituitary dysfunction. In our series a high prevalence (8/12) of hypogonadism was also noticed. In these cases, the low gonadotropin levels and their unresponsiveness to gonadotropin-releasing hormone are compatible with a hypothalamic and/or pituitary damage. Lastly, the enhanced ACTH responses to the stimuli associated to a reduced cortisol release suggest the existence, in these patients, of a diminished adrenocortical reserve. On the whole, this study has shown several derangements of the hypothalamic-pituitary function in thalassemia. This emphasizes the need for careful endocrine surveillance in this disease.

Treatment with biosynthetic growth hormone of short thalassaemic patients with impaired growth hormone secretion.

OBJECTIVE: Impairment of linear growth is a common clinical feature in patients with beta-thalassaemia major. Although growth hormone secretion appears to be normal in many short thalassaemic patients, it proves to be deficient in some of them. In these cases, administration of biosynthetic growth hormone seems justified. The aim of this study was to evaluate the effect of such treatment in a group of patients with beta-thalassaemia major presenting with growth failure and impairment of growth hormone secretion. DESIGN: Recombinant human growth hormone, 0.6 U/kg body weight per week, given subcutaneously in three divided doses, was administered for 12 months. PATIENTS: Eight prepubertal patients with beta-thalassaemia major, presenting with severe growth retardation and impaired growth hormone secretion in response to provocative stimuli (insulin-induced hypoglycaemia, L-dopa and growth hormone-releasing hormone), were investigated. MEASUREMENTS: Height and pubertal stage of the patients, as well as plasma levels of insulin-like growth factor I, were determined before, during and after biosynthetic growth hormone treatment. RESULTS: During the first 6 months of therapy, a significant increase of growth velocity was observed, from a mean pretreatment value of 2.1 +/- 0.45 cm/year to a value of 4.8 +/- 0.66 cm/year (P less than 0.002). Mean growth rate at 12 months (4.1 +/- 0.50 cm/year), though slightly decreased in comparison to that recorded at 6 months, was still significantly higher than basal (P less than 0.001). A significant increase in plasma levels of insulin-like growth factor I was recorded during treatment (2.82 +/- 0.47 vs 0.96 +/- 0.22 U/ml, P less than 0.005). No side-effects, adverse reactions or alterations in routine laboratory examinations ensued during or after therapy. CONCLUSIONS: It appears from these data that biosynthetic growth hormone administration is worth serious consideration in patients with beta-thalassaemia major presenting growth retardation and impaired growth hormone secretion.