Maturation of the regulation of growth hormone secretion in young males with hypogonadotropic hypogonadism pharmacologically exposed to progressive increments in serum testosterone.

To study the onset of the action of gonadal sex steroids on the GH axis in spontaneous puberty, which is prolonged and sparingly predictable, we present a clinical investigative paradigm in which six previously untreated boys with isolated hypogonadotropic hypogonadism were exposed to progressively higher testosterone levels designed to mimic the androgen environment recognized during the early stages of puberty. We administered three incremental doses of testosterone (25-, 50-, and 100-mg im injections), each over a period of 4 weeks. Studies of overnight pulsatile GH secretion and GH responses to GHRH alone or combined with L-arginine (a functional somatostatin antagonist) were performed before testosterone administration and after each dose of testosterone. Serum testosterone, but not estrogen, levels increased progressively in all subjects during therapy. Deconvolution analysis of GH release profiles disclosed that GH secretory burst mass was stimulated significantly even by 25 mg testosterone. This parameter was not altered further by higher doses of testosterone. Spontaneous GH secretory burst number and amplitude increased significantly only after the 50- and 100-mg testosterone treatments, after which the serum GH response to GHRH and arginine also rose significantly. In contrast, the GH response to GHRH alone was not significantly affected by any dose of testosterone. Serum testosterone levels correlated significantly with the primary parameters of nocturnal GH secretion. In summary, our experimental model suggests that in males even very small increases in circulating testosterone occurring during the earliest stages of puberty are able to amplify pulsatile GH secretion. Our concomitant secretagogue data further suggest that testosterone exerts its action at different sites in the hypothalamo-somatotropic axis, i.e. directly at the pituitary level, and also at hypothalamic loci, possibly increasing both GHRH and somatostatin release.

Fish oil supplementation in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia is associated with premature coronary heart disease. In patients with familial hypercholesterolemia, monotherapy with hydroxymethylglutaril coenzyme. A reductase inhibitors rarely achieves the goal of desirable low-density lipoprotein levels. Epidemiological studies suggest that populations with a high dietary intake of marine n3 fatty acids are protected against coronary heart disease. Hepatic synthesis and secretion of very low density lipoproteins are reduced during fish oil supplementation while other effects on lipid and lipoprotein metabolism are controversial. Fourteen patients affected by familial heterozygous hypercholesterolemia on chronic treatment with simvastatin were enrolled in a double blind, placebo controlled, randomized crossover trial that evaluated the effect of fish oil ethyl ester (Esapent, 5.1 g/day) on lipid and lipoprotein serum concentrations. Total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apoprotein B, apoprotein AI, lipoprotein (a) did not show any significant variation during the four week treatment period with fish oil ethyl ester. The present data suggest that the possible favourable influence of fish oil on the progression of atherosclerosis in these high-risk patients might involve mechanisms which are different from lipid metabolism.

Pravastatin-associated myopathy. Report of a case.

A case of acute inflammatory myopathy associated with the use of pravastatin, a new hydrophilic 3-hydroxy-3 methylglutaril coenzyme A reductase inhibitor, is reported. The patient, a 69-year-old man was affected by non-insulin-dependent diabetes mellitus and hypertension. He assumed pravastatin (20 mg/day) because of hypercholesterolemia. He was admitted with acute myopathy of the lower limbs which resolved in a few days after pravastatin discontinuation. A previously unknown hypothyroidism, probably due to chronic autoimmune thyroiditis, was evidenced. Muscle biopsy (left gastrocnemius) revealed a perimysial and endomysial inflammatory infiltrate with a prevalence of CD4+ lymphocytes. While lovastatin and simvastatin have been associated with toxic myopathy, pravastatin-associated myopathy could represent a distinct, inflammatory entity.

Effects of a gluten-free diet on serum lipids and lipoprotein (a) levels in a group of patients with celiac disease.

The influence of nutrient absorption, caloric content, and diet on lipoprotein (a) [Lp(a)] concentration is uncertain. To our knowledge, there are no reports on Lp(a) behavior in malabsorption. Serum lipids and Lp(a) concentrations were evaluated in 17 celiac patients (5 male and 12 female patients; age range, 1-24 years) when the diagnosis was established and after a 3-month gluten-free diet. Mean total and low-density lipoprotein cholesterol did not show significant change, while mean high-density lipoprotein cholesterol rose and triglycerides decreased significantly after the diet. The Lp(a) concentration remained unchanged in all patients (median values, 35 mg/L before and 40 mg/L after the diet). Our results suggest that, in our patients, the lipoprotein profile was influenced by the gluten-free diet, while the Lp(a) concentration was not modified.

Lipoprotein (a) in thyroid dysfunction before and after treatment.

Alterations of the lipid profile are a well known phenomenon in thyroid dysfunction. Thyroid hormones regulate lipid metabolism through various mechanisms, but a key role is played by the LDL receptor pathway. Thyroid hormone influence on Lipoprotein (a) (Lp[a]) metabolism is unknown; therefore we studied Lp(a) concentrations in a group of 29 hypothyroid patients with post-surgical hypothyroidism and in a group of 14 hyperthyroid subjects with Graves' disease before and after the thyroid function was normalized by treatment. In hypothyroid patients total and LDL-cholesterol markedly decreased after T4 treatment (342 +/- 78 mg/dl before and 193 +/- 46 mg/dl after; 225 +/- 72 mg/dl before, 111 +/- 43 mg/dl after respectively, p < 0.001). Also HDL-cholesterol and triglycerides decreased (from 75 +/- 22 mg/dl to 56 +/- 18 mg/dl and from 182 +/- 87 mg/dl to 112 +/- 42 mg/dl respectively, p < 0.001). Lp(a) showed minor but not significant variations (median values 80 mg/l before 55 mg/l after treatment, p: N.S.). In hyperthyroid patients total and LDL-cholesterol increased after methimazole treatment (from 148 +/- 49 mg/dl before to 254 +/- 67 mg/dl after and from 87 +/- 38 mg/dl before to 178 +/- 51 mg/dl after, p < 0.001). HDL-cholesterol increased (from 39 +/- 9 to 50 +/- 15, p < 0.01) while triglycerides were unchanged. Lp(a) levels slightly rose (median values 57 mg/l before 84 mg/l after treatment, p < 0.05). These data suggest that the influence of thyroid hormones on Lp(a) metabolism is of minor entity and probably does not operate through the LDL receptor pathway.

Primary empty sella syndrome and hypogonadotropic hypogonadism in young male patients.

Twelve male patients with absence of pubertal development and hypogonadotropic hypogonadism underwent a contrast-enhanced computed tomography of the sellar region and dynamic endocrine testing consisting of insulin-induced hypoglycemia, GnRH and TRH test. In two patients, clinically indistinguishable from the others, the presence of an empty sella turcica was demonstrated. They also showed, in comparison with patients with normal sellar morphology, an absent prolactin response to hypoglycemia with otherwise normal pituitary function. Empty sella, either due to congenital incompetence of the diaphragma sellae or to pituitary shrinkage due to regressive changes by hemorrhage, infarction and possibly autoimmune phenomena, may rarely be associated with hypogonadotropic hypogonadism.

Pyridostigmine enhances even if it does not normalize the growth hormone responses to growth hormone-releasing hormone in patients with Cushing's disease.

Subjects with Cushing's disease have diminished growth hormone (GH) response to growth hormone-releasing hormone (GHRH). The aim of our study was to investigate the underlying mechanism of this diminished GH response in these patients using pyridostigmine (PD), an acetylcholinesterase inhibitor, which is reported to increase GH secretion by reducing somatostatin tone. Eight subjects with untreated Cushing's disease (caused by a pituitary adenoma) and 6 control subjects received GHRH 100 micrograms in 1 ml of saline, as intravenous bolus injection 60 min after (1) placebo (2 tablets, p.o.) or (2) PD (120 mg, p.o.). After GHRH plus placebo, the GH peak (mean +/- SEM) was significantly lower in subjects with Cushing's disease (2.4 +/- 0.5 micrograms/l) compared to control subjects (25.1 +/- 1.8 micrograms/l, p less than 0.05). After GHRH plus PD, the GH peak was significantly enhanced both in subjects with Cushing's disease (7.1 +/- 2.3 micrograms/l, p less than 0.05) and in control subjects (42.3 +/- 4.3 micrograms/l, p less than 0.05). In patients with Cushing's disease, the GH response to GHRH plus PD was lower with respect to the GH response to GHRH alone in normal subjects. We conclude that hypercortisolism may cause a decrease in central cholinergic tone which is in turn hypothesized to be responsible of an enhanced somatostatin release from the hypothalamus. However, other metabolic or central nervous system alterations may act synergistically with hypercortisolism in causing GH inhibition in patients with Cushing's disease.

[Hypopituitarism secondary to suprasellar giant carotido-ophthalmic aneurysm. Normalization of the hypophyseal function after neurosurgical depression of the aneurysm]. / Ipopituitarismo secondario ad aneurisma gigante carotido-oftalmico soprasellare. Normalizzazione della funzione ipofisaria dopo decompressione neurochirurgica dell'aneurisma.

A 49-year-old man presented with a 6-month history of weight loss, muscular weakness, easy fatigue, impotence, decreased visual acuity, campimetry defects. The results of radiologic and endocrine testing disclosed the presence of pituitary dysfunction due to pituitary stalk section caused by a giant suprasellar aneurysm extending into the sellar region. After the neurosurgical decompression of the aneurysm a progressive normalization of all pituitary functions was demonstrated. In this case, the preoperative finding of a preserved pituitary integrity with acute and prolonged endocrine testing demonstrated to be predictable of a recovery of the hypothalamo-pituitary axis after the removal of the mass effect caused by the giant aneurysm.

Severe microvascular disease in type II diabetes of early onset. A family study.

Both early onset and late onset type II diabetes were present in one family of nine siblings. The three early onset type II diabetic siblings showed severe microvascular complications: proliferative retinopathy, diabetic nephropathy, and peripheral neuropathy. Early onset type II diabetes was not associated with any particular HLA haplotype. Early onset type II diabetes could be considered a clinical and genetic disease entity different from MODY type diabetes.