Prolactin-lowering effect of luteinizing hormone-releasing hormone agonist administration in prolactinoma patients.

We studied the effect of LHRH agonist administration on serum PRL levels in five women with microprolactinomas and two women and a man with intrasellar macroprolactinomas. Each patient received either D-Trp6-LHRH or buserelin for 90 days. Serum PRL levels decreased significantly in the patients with microprolactinomas by 65%, from 156 +/- 93 (+/- SD) to 54 +/- 49 micrograms/L on day 90 (P = 0.011), but it did not decrease in the macroprolactinoma patients. Mean serum LH and FSH decreased by 43% and 62.5%, respectively, in all eight patients. There was no statistically significant correlation between the serum PRL and LH or FSH levels in the microprolactinoma patients. We conclude that LHRH agonists can counteract the hyperprolactinemia produced by microprolactinomas and that the effect probably is not exerted by an action on the gonadotrophs.

D-Trp6-luteinizing hormone-releasing hormone inhibits sulpiride-induced hyperprolactinemia in normal men.

The effect of a potent agonistic analog of LHRH, D-Trp6-LHRH, on hyperprolactinemia induced by sulpiride was studied in normal men. Six men received sulpiride (100 mg, twice daily, orally) for 44 days. D-Trp6-LHRH was given sc during the last 2 weeks of sulpiride administration; the dose was 500 micrograms on the first day and 100 micrograms daily for the subsequent 14 days. All men had high serum PRL levels before D-Trp6-LHRH administration (mean +/- SEM, 56 +/- 9 ng/mL), which decreased significantly after the first dose of the analog (45 +/- 5 ng/mL; P = 0.031) and also after 15 days of analog administration (41 +/- 6 ng/mL; P = 0.016). These data demonstrate that administration of LHRH agonist can inhibit the hyperprolactinemic effect of sulpiride, suggesting a direct action of the analog on the pituitary gland to modulate PRL secretion.

Effects of different proportions of carbohydrates, polysaccharides/monosaccharides, and different fibers on the metabolic control in diabetic rats.

Recent findings have suggested that diets with a high level of carbohydrates may impair the metabolic control of diabetes mellitus in humans. Moreover, other investigations have indicated that if the simple sugar content is increased in order to attain a proportion of polysaccharides/monosaccharides equal to 1, then neither the blood glucose nor the lipidic response show any change. We have studied the effect of increasing carbohydrates in the diet (59% v 82%), while maintaining cereal fiber levels constant (30%) and replacing cereal fiber in high carbohydrate diets by guar gum (30%) and lentil-derived leguminous fiber (30%) on the metabolic control of streptozotocin-induced diabetic rats. A study with different diets was performed for 3 weeks. An increase of carbohydrates in the diet produces an increase in the HbA1 concentration (1.9% v 3.9%, P less than 0.01) and in serum triglyceride levels (98.75 +/- 22.09 mg/dL v 144.50 +/- 3.52 mg/dL, P less than 0.05). Total cholesterol and HDL-cholesterol levels remained unchanged. The increase does not occur if the cereal fiber is replaced by lentil-derived leguminous fiber. In a second experiment, we substituted 50% of the complex carbohydrates in diets with 80% carbohydrates by glucose. Blood glucose, triglycerides, and HbA1 levels rose significantly in the four groups of rats that received diets containing 50% carbohydrates in glucose form. In addition, a test meal was carried out on day 19, consisting of 2.5 g of food/kg of wt. The maximum increase in blood glucose and the area below the glucose curve response was also significantly higher in the four groups of rats who received glucose in their diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of [D-Trp6]LHRH infusion on prolactin secretion by perifused rat pituitary cells.

The effect of a superactive agonistic analog of luteinizing hormone-releasing hormone (LHRH), [D-Trp6]LHRH on prolactin (PRL) secretion by perifused rat pituitary cells was investigated. Constant infusion of [D-Trp6]LHRH (0.5 ng/min) for 2-3 h elicited a significant decrease in PRL secretion by these cells. This decrease in PRL release started ca. 30 min after the beginning of the infusion with the LHRH analog and lasted up to 1.5-2 h. [D-Trp6]LHRH significantly stimulated luteinizing hormone (LH) secretion during the first 30 min of peptide infusion; thereafter, LH levels began to return to control values. In animals pretreated in vivo with 50 micrograms of [D-Trp6]LHRH (s.c.) 1 h before sacrifice, PRL secretion by the rat pituitary cell perifusion system was significantly lower than vehicle-injected controls throughout the entire [D-Trp6]LHRH infusion period. On the other hand, thyrotropin-releasing hormone (TRH)-stimulated PRL secretion was slightly, but significantly imparied by [D-Trp6]LHRH infusion, while dopamine (DA) inhibition of PRL release was unaffected by this same treatment. These results reinforce previous observations of a modulatory effect of [D-Trp6]LHRH, probably mediated by pituitary gonadotrophs, on PRL secretion by the anterior pituitary. In addition, our findings suggest that basal PRL secretion by the lactotroph may be dependent on a normal function of the gonadotroph. The collected data from this and previous reports support the existence of a functional link between gonadotrophs and lactotrophs in the rat pituitary gland.

Behaviour modification in obese subjects with type 2 diabetes mellitus.

We have followed prospectively, 46 obese, type 2 diabetic patients for a 55-week period, in order to evaluate the efficiency of an educational programme based on behaviour modification to enhance weight loss and changes of other cardiovascular risk factors. No patient received pharmacological treatment during the study. At the end of the follow-up the patients obtained an average weight loss of 9.250 kg (range: 0.500-17.500 kg); the BMI was reduced from 34.2 +/- 0.8 kg/m2 to 30.6 +/- 1.1 kg/m2 (P less than 0.01); fasting serum glucose descended from 7.9 +/- 0.4 to 6.1 +/- 0.5 mM (P less than 0.05); SBP (systolic blood pressure) decreased from 145.7 +/- 3 to 126.4 +/- 5.1 mmHg (P less than 0.01); DBP (diastolic blood pressure) decreased from 83.5 +/- 2.5 to 65 +/- 2.6 mmHg (P less than 0.01); triglyceride levels were lowered from 164.5 +/- 12 to 109.7 +/- 10 mg/dl (P less than 0.01); HDL-cholesterol levels increased from 1.27 +/- 0.05 to 1.53 +/- 0.12 mM (P less than 0.01). Serum glucose 2 h after a 75 g glucose oral load decreased from 14.9 +/- 0.6 to 12.7 +/- 0.9 mM (P less than 0.05) on week 35 of follow-up. Twelve patients no longer presented a diabetic curve (8 normal oral glucose tolerance test (OGTT) curves, and 4 impaired glucose tolerance (IGT) curves). No significant changes in the parameters studied were obtained in the group of patients on conventional treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of pulse frequency and amplitude of D-Trp6-luteinizing hormone-releasing hormone on the pulsatile secretion of prolactin and LH.

This work analyzes the effect of the pulse amplitude and frequency of a potent LHRH analog, D-Trp6-LHRH, in a perfusion system of isolated rat pituitary cells. To this purpose, we studied the LH and PRL secretion in different conditions: basal secretion, secretion after increasing concentrations of D-Trp6-LHRL (0.001, 0.01, 0.1 and 1 nM) secretion in function of the pulses frequency (2,3, and 4 pulses per h) and amplitude (0.1, 1 and 10 nM). The principal findings were: 1. The basal LH and PRL secretions was pulsatile; 2. The stimulation of LH by the analog was not dose-dependent; 3. When more than 2 pulses per h were administered, a rapid desensitization of gonadotroph to release LH (at 20-30 min) occurred; 4. There was a loss of pulsatility of PRL secretion with an increase in the pulse frequency and amplitude of the D-Trp6-LHRH, which was produced parallelly to the desensitization of the gonadotroph to release LH. In summary, these findings suggest that a rapid loss of pulsatility of the PRL when the D-Trp6-LHRH pulse frequency and amplitude is increased might be due to the early desensitization of the gonadotroph to the analog.

Evidence for a modulatory role of catecholamines on hypothalamic somatostatin in the rat.

The influence of catecholamines (CA) on hypothalamic somatostatin (HPT-SRIF) was investigated in rats by using several drugs which interfere with brain CA metabolism. Depletion of brain CA stores by alpha-methyl-rho-tyrosine (AMT) increased HPT-SRIF, while augmented brain CA levels following L-dopa administration decreased HPT-SRIF content. Blockade of dopamine beta-hydroxylase activity by disulfiram depleted brain noradrenaline (NA) and decreased HPT-SRIF. The selective increase in brain NA stores caused by threo-dihydroxyphenylserine (DOPS) also produced an increase in HPT-SRIF. Increased dopamine (DA) and decreased NA levels after disulfiram + L-dopa (1 h) treatment did not modify HPT-SRIF, whereas unaltered NA and greatly increased DA levels following disulfiram + L-dopa (2 h) treatment produced a drastic reduction of HPT-SRIF. The results suggest that DA and NA exert an influence on HPT-SRIF, supporting previous observations.

Epidermal growth factor receptors in human breast and endometrial carcinomas.

The incidence and levels of epidermal growth factor receptor (EGFR) were studied in 67 breast tumors and 22 endometrial carcinomas. Estrogen receptors (ER) were also measured in all samples and progesterone receptors (PR) were analyzed in 57 breast samples and 21 endometrial tumors. A high level of EGFR expression is found in both breast and endometrial carcinomas, although the incidence of EGFR content is greater in breast carcinomas. 36% of breast tumors had EGFR at levels 3-49.5 fmol/mg membrane protein, whereas this percentage of positivity was 27% for endometrial tumors. In 51% of breast carcinoma and 73% of endometrial tumors, there was a positive ER content, whereas 53% of breast tumors and 62% of endometrial carcinomas were positive. A clear inverse relationship between EGFR content and ER and PR status has been observed in breast tumors. Our data confirm the previously described inverse correlation between expression of EGFR and estrogen receptors in human breast cancer. We also show here that there is a similar inverse relationship between EGFR content and ER levels in endometrial tumors.

Evidence of abnormal dopaminergic control of prolactin in patients with hypothalamic and pituitary tumors.

Prolactin secretion was investigated in an attempt to identify the patterns of responses in different types of tumors. Forty four patients were studied: thirty patients with prolactinomas (Group 2); nine patients with growth-hormone (GH)-adrenocorticotropic hormone (ACTH)-secreting pituitary tumors and hypothalamic tumors (Group 3); and five patients with non-secreting pituitary tumors (Group 4). A control group (Group 1) consisted of 60 healthy subjects (30 males and 30 females). All were submitted to testing by nomifensine (Nom), domperidone (Dom) and thyrotropin releasing hormone (TRH). The prolactin levels were measured by radioimmunoassay (RIA). In group 2 the suppression of PRL with Nom and the stimulation with Dom and TRH were significantly lower than in the control group (p less than 0.001). There was no statistically significant difference between groups 2 and 3 in the suppression with Nom. The increase with Dom in group 3 was significantly greater than that in group 2 (p less than 0.001) and less than that in the control group (p less than 0.005). The rise in PRL with TRH was also significantly higher in group 3 than in group 2 (p less than 0.001) and similar to that of the control group. Group 4 gave the same results as the control group to all 3 tests. Our results indicate a dopaminergic irregularity in the hypothalamic and GH-ACTH-secreting pituitary tumors, thus supporting a hypothalamic etiopathogenesis of these tumors. The normality of the GH-ACTH-secreting pituitary tumors and hypothalamic tumor responses to TRH is one more factor in differentiating these from prolactinomas. The normal response of the non-secreting tumors may involve a primary pituitary etiology of these tumors.

Primary intrasellar germinoma with synchronous pineal tumor.

Germinomas arising within the sella turcica are extremely rare. The association of intrasellar and a pineal region tumours is even more unusual. We report a 30-year-old man with germinomas in the sellar and pineal region.

Effect of the infusion of p-Glu-His-Ala-OH, analog of the anorexigenic peptide, on the insulin response induced by intravenous glucose. Preliminary results with obese subjects.

The effect of the intravenous infusion of peptide p-Glu-His-Ala-OH, analog of the postulated anorexigenic peptide, on the insulinaemic response to an intravenous bolus of 20 g glucose was studied in 6 obese patients (body mass index 43.12 +/- 5.77 kg/m2). The infusion of the peptide reduced the insulinaemic response (p < 0.05) without modifying either the C-peptide or the glucose response. This decreased insulinaemic response is associated with a greater hepatic extraction of insulin (86.45 +/- 1.1% vs 82.1 +/- 1.2%; p 0.05), determined in terms of the molar ratio of the C-peptide to insulin) but not with a smaller pancreatic secretion (determined as C-peptide levels). Our results confirm that the infusion of the peptide increases the hepatic insulin extraction without its effect being mediated by any intestinal factor. Its therapeutic application remains to be determined.

Selective inhibition of sleep related growth hormone release by Phe-4-somatostatin.

We have compared the effects of somatostatin (SS) and the somatostatin analog Phe-4-SS on nocturnal GH secretion in three normal male volunteers, 20 to 23 years of age. Subjects were studied in our sleep laboratory on 5 consecutive nights. Nights 1 and 2 were used for adaptation. On the third night (control night), all patients exhibited a typical GH peak accompanying slow-wave sleep, with maximum GH levels from 9.2 to 27 ng/ml. Insulin, glucagon and glucose levels were episodic and sleep-independent. On night 4, subjects received SS infusion at a rate of 3 micrograms/min, which inhibited GH levels consistently below 2.4 ng/ml. In two cases a post-infusion rebound of GH levels was observed. During SS infusion all three subjects showed a significant decrease in insulin levels (p less than 0.0005), followed by an immediate rebound after infusion was stopped. Glucagon levels fell significantly during infusion (p less than 0.001, p less than 0.025 and p less than 0.00025 respectively). Glucose was significantly higher than on control night in subject No. 3 (p less than 0.0005) and similar to control night in subjects 1 and 2. On the fifth night, Phe-4-SS was infused at a rate of 0.75 microgram/min. GH levels decreased significantly as compared to control night in all three subjects and remained virtually constant throughout the night. Insulin levels were diminished in subject No. 1 (p less than 0.0005), but were comparable to control values in subjects 2 and 3. Cessation of analog infusion was followed by a rebound in insulin levels in all three subjects. Glucagon values were not significantly lowered and the rebound effect was not apparent. Glucose levels were higher in response to Phe-4-SS than on control night, and fell below infusion values (p less than 0.001) after administration was discontinued. It was concluded that Phe-4-SS inhibits nocturnal secretion of GH more selectively than SS, but its effect is not more prolonged than that of SS.

Association of a thyrotropin-secreting pituitary adenoma and a thyroid follicular carcinoma.

The different factors involved as etiological agents in thyroid cancer have in common long term thyroid follicle stimulation. On this base, a patient with a TSH-producing pituitary adenoma could be at high risk for developing thyroid cancer. A patient consulting for a single thyroid nodule was studied in our unit. He was diagnosed as having a TSH-producing pituitary adenoma and the Thyroid nodule was shown to be a follicular carcinoma following removed. We speculate that elevated TSH levels could have contributed to neoplastic transformation of the thyroid in this patient.

Inhibition of growth hormone and glucagon release by Phe-4-somatostatin in patients with acromegaly.

We have studied growth hormone (GH), insulin (I), glucagon (Gl) and glucose in basal conditions, after somatostatin (SS) (3 micrograms/ml) and Phe-4-SS (0.75 microgram/ml) infusion and IV bolus of the latter in 3 acromegalic patients. In two patients, Phe-4-SS inhibited glucagon and growth hormone secretion in a similar way as SS, without modifying insulin secretion. These effects were short-lived and ceased after the infusion was stopped. From these results it appears that Phe-4-SS is both more potent and more specific than SS with respect to inhibition of GH and glucagon release, but it does not have prolonged biological action. Lack of suppression of GH by SS or Phe-4-SS in the acromegalic patient with post-surgical recurrence of the disease could be due to the existence of receptor abnormalities, and suggests a diversity in the physiopathology of the disease.

Índice glucémico y tratamiento nutricional de las personas con diabetes mellitus / Glycemic index and nutritional treatment in persons with diabetes

Desde hace más de 20 años ha existido interés en analizar los niveles posprandiales de glucosa después de la ingestión de alimentos ricos en carbohidratos. El objetivo de estos análisis era realizar un listado de alimentos ordenados en función de la respuesta glucémica posprandial. Este parámetro se denominó índice glucémico, que Jenkins definió como la relación entre el área bajo la curva de la respuesta glucémica posprandial producida por la ingestión de 50 g de carbohidratos suministrados por un alimento concreto y un alimento patrón (glucosa o pan), y multiplicado por 100. En teoría, la elección de alimentos con bajo índice glucémico podría ser útil para el tratamiento nutricional de la persona con diabetes. Sin embargo, la utilidad de dicho índice ha sido cuestionada recientemente.Los trabajos disponibles en la actualidad no demuestran ningún beneficio sobre el control de la diabetes en personas con diabetes tipo 1 o tipo 2 cuando reciben alimentos con bajo índice glucémico en comparación con los de alto índice glucémico. El tratamiento nutricional de la persona con diabetes debe basarse en su alimentación habitual y debe utilizarse como la base del tratamiento farmacológico y su estilo de vida. Desde el punto de vista clínico, debe considerarse prioritario seleccionar los alimentos por su contenido en carbohidratos más que por su índice glucémico. En esta revisión analizamos la utilidad del índice glucémico desde la perspectiva de la medicina basada en la evidencia (AU)

Progresión de la retinopatía diabética después de instaurar un tratamiento intensivo de insulina con infusión continua. A propósito de 2 casos

Se ha calculado que alrededor de 135 millones de personas padecen de diabetes mellitus y se espera que la cantidad se incremente al doble en las siguientes dos décadas. La retinopatía diabética es la causa más frecuente de ceguera en la población en edad productiva en los países desarrollados. Se requiere un adecuado control glicémico y de las alteraciones metabólicas asociadas para prevenir la aparición o enlentecer la progresión de la retinopatia. Sin embargo, se ha visto que la terapia intensiva con insulina puede provocar un empeoramiento inicial de la retinopatía cuando esta existe previamente a la intensificación del tratamiento insulínico. Se presenta dos casos de pacientes con diabetes mellitus tipo 1 con retinopaia no proliferativa que después de comenzar el tratamiento con sistemas de infusión continua de insulina y al obtenerse un adecuado control glicémico y metabólico, presentaron un empeoramiento de su retinopatía que precisó fotocoagulación. Se discuten algunas terapias alternativas previas o conjuntas al estricto control glicémico con el objetivo de prevenir un deterioro visual. Si tenemos en cuenta que la utilización de los sistemas de infusión continua de insulina son accesibles en todo el territorio nacional desde abril de 2004, estos datos habria que tenerlos en cuenta antes de aplicarlos a personas con diabetes tipo 1 que tengan retinopatía (AU)