Platelet cNOS activity is reduced in patients with IDDM and NIDDM.

Several studies in vitro and in vivo suggest that the nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to vascular alteration facilitating platelet-vascular wall interaction, adhesion of monocytes to endothelium, vascular smooth muscle proliferation and by decreasing endothelium-dependent vasodilation. In this study we evaluated the activity of the constitutive nitric oxide synthase (cNOS) in platelets of patients with insulin-dependent diabetes mellitus (IDDM) and with non-insulin-dependent diabetes mellitus (NIDDM). When compared to that of normal subjects, cNOS activity is significantly lower in patients with IDDM and with NIDDM (1.57 +/- 0.25 vs. 0.66 +/- 0.10 fmol/min/10(9) PLTs and 1.57 +/- 0.25 vs. 0.67 +/- 0.08, respectively; p<0.005). These data demonstrate that the platelet cNOS activity is decreased in diabetes mellitus.

Calcium blood level modulates endogenous nitric oxide action: effects of parathroidectomy in patients with hyperparathyroidism.

UNLABELLED: Platelet cyclic guanosine monophosphate (cGMP) is produced by soluble guanylate cyclase (sGC), the activity of which is modulated by the activity of nitric oxide (NO) constitutive synthase (cNOS) which, in turn, is activated by a calcium/calmodulin complex. In primary hyperparathyroidism (H-PTH) an increase in platelet free calcium levels is present. In this study we evaluate the platelet cGMP levels, as an expression of NO production, in the presence of 3-isobutyl-1-methylxanthine (IBMX) alone (IBMXcGMP) and after stimulation by ionomycine (IONO; IONOcGMP) and sodium nitroprusside (SNP; SNPcGMP), in eight subjects affected by H-PTH before and after removal of adenoma. Platelet cGMP levels were also measured in seven normal subjects. IBMXcGMP and IONOcGMP were elevated in H-PTH patients compared with normal subjects (1.9 +/- 0.3 vs 0.8 +/- 0.2 fmol/10(6) platelets and 2.7 +/- 0.4 vs 1.4 +/- 0.3; P < 0.02 and P < 0.05 respectively) but SNPcGMP was unaffected (3.9 +/- 0.6 vs 2.5 +/- 0.5). After parathyroidectomy, blood levels of intact parathyroid hormone (i-PTH), total calcium (t-Ca), IBMXcGMP and IONOcGMP all decreased (177.5 +/- 23.9 vs 45.0 +/- 8.8 pg/ml, P < 0.005; 6.5 +/- 0.5 vs 4.6 +/- 0.1 mEq/1, P < 0.005; 1.9 +/- 0.3 vs 0.8 +/- 0.2, P < 0.005; 2.7 +/- 0.4 vs 1.8 +/ 0.3, P < 0.05 respectively), while SNPcGMP was not modified (3.9 +/- 0.6 vs 4.3 +/- 0.9). t-Ca and i-PTH were directly correlated with IBMXcGMP (P < 0.02, rs = 0.613; P < 0.02, rs = 0.576 respectively) and i-PTH was also correlated with t-Ca (P < 0.001), rs = 0.840). IN CONCLUSION: (1) levels of IBMXcGMP and IONOcGMP are high in subjects with H-PTH; (2) after surgery both IBMXcGMP and IONOcGMP decrease to normal values. As IBMXcGMP expresses basal cGMP and IONOcGMP expresses the cGMP after cNOS stimulation, it can be speculated that the increase in NO production could be a mechanism to downregulate the vasoconstriction which may be caused by the high calcium levels in smooth muscle cells. After surgery, together with the normalization of calcium levels, NO production also returned to normal values.

[Hormonal control of sexual behavior in males and endocrinologic causes of sexual dysfunction]. / Il controllo ormonale del comportamento sessuale nel maschio e cause endocrinologiche di disfunzione sessuale.

The role of androgens in the male sex differentiation, in the genesis and preservation of the erectile function is summarized. In sex differentiation, testosterone acts on genitalia and central nervous system (CNS). In CNS sexual steroids exert a morphogenetic action during neuronal development. At the pubertal age, the increase of testosterone leads to the development of sex characteristics, the onset of libido and the beginning of the nocturnal spontaneous erectile function. Spontaneous erections are androgen-dependent, and they are impaired in androgen deficiency. Normal androgen levels lead to make voluntary erections. However, in the human species, cortical influences may greatly affect what could be possible to occur in relation to the hormonal situation. Endocrine causes of sexual dysfunction are responsible for about 20-25% of the total; among these primary and secondary hypogonadisms are the most frequent and they are to be managed with causal treatments and androgen replacement therapy. Therefore, androgen treatments are not useful in functional sex disorders and they may be at risk on prostatic tissue. Andropause is related to a progressive reduction of testicular function, principally due to vascular disorders, with low-normal androgen levels. On the basis of these observations it is underlined that in the human species the androgen presence is a necessary but not sufficient condition for a correct sex function.

Administration of glutathione in patients with type 2 diabetes mellitus increases the platelet constitutive nitric oxide synthase activity and reduces PAI-1.

Several studies suggest that nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to cardiovascular mortality. Furthermore, NO synthesis is impaired in glutathione (GSH)-depleted human umbilical vein endothelial cells and GSH is reduced in patients with type 2 diabetes mellitus (T2DM). We tested the hypothesis that treatment with GSH may improve platelet constitutive NO sinthase (cNOS) activity in patients with T2DM. Fifteen patients with T2DM underwent a treatment with GSH 600 mg/day i.m. for 10 days. With respect to the basal values on the 10th day of treatment, the red blood cell GSH concentration and platelets cNOS increased (1.4+/-0.1 vs 1.9+/-0.1 micromol/10(10) RBC, p<0.001 and 0.7+/-0.1 vs 2.9+/-0.2 fmol x min(-1) x 10(-9) PLTs, p<0.001, respectively) and the plasma PAI-1 levels diminished (81.4+/-3.7 vs 68.7+/-4.0 ng/ml, p<0.002). A negative correlation between the cNOS and the PAI-1 was found on the basal values. After a wash-out of 30 days the values of red blood cell GSH concentration, platelet cNOS activity and PAI-1 Ag returned to the basal levels. These data suggest that the administration of GSH, in patients with T2DM, is able to improve platelet cNOS activity together with a reduction of PAI-1.

Platelet cyclic guanosine monophosphate production during menstrual cycle in healthy women.

UNLABELLED: The incidence of cardiovascular disease among women during their reproductive years is considerably less than in men and this difference decreases after menopause. Since in cultured endothelial cells and in platelets E2 increases nitric oxide (NO) production, it is possible that their cardioprotective effect may be mediated by NO. The aim of this study was to evaluate platelet cyclic guanosine monophosphate (cGMP), as a marker of NO production, during menstrual cycle. Fifteen women aged 26-40 yr were studied to evaluate: LH, FSH, E2, P and cGMP on the 5th follicular and 22nd luteal day of the cycle and during the ovulatory period. Platelet cGMP was evaluated in basal condition (3-isobuthyl 1-methylxanthine-IBMX) and with ionomycine (IONO) and sodium nitroprusside (SNP). RESULTS: LH, FSH, E2 and P demonstrated the typical patterns of ovulatory cycle. During follicular and luteal IBMX, SNP and IONO phase were homogeneous while they increased during the ovulatory period. A correlation between IBMX cGMP and E2 (p<0.002, rs=0.456) was found. In conclusion the data show an increase in platelet cGMP during the ovulatory period and a correlation between E2 and cGMP suggesting that E2 modulates NO production. The cardioprotective effect of E2 may be, at least in part, mediated by the increase in NO production.

Repeated administration of growth hormone-releasing hormone with or without previous administration of pyridostigmine in insulin-dependent diabetes mellitus.

In insulin dependent diabetes mellitus (IDDM) either elevated growth hormone (GH) levels or abnormal responses to specific as well as unspecific stimuli have been reported. As hyperglycemia is known to blunt GH response to various stimuli, a normal GH response to GHRH in presence of hyperglycemia should also be considered inappropriate. To investigate the mechanism underlying this inappropriate GH response, in 9 patients with IDDM, selected for normal GH response to GHRH, we studied the GH response to two consecutive GHRH boluses (1 microgram/kg), the second of which preceded 30 min before by pyridostigmine (120 mg p.o.). Seven age matched normal volunteers were evaluated as control group. Basal plasma glucose and serum GH levels were significantly higher in patients with IDDM than in normal subjects (184.4 +/- 9.6 vs 86.2 +/- 4.4 mg/dl, p < 0.01 and 2.4 +/- 1.0 vs 1.0 +/- 0.4 microgram/l, p < 0.01 respectively). Both in normal subjects and in patients with IDDM the GH response to the second consecutive GHRH administration was lower than that of the first GHRH bolus (delta AUC: 82.5 +/- 28.3 vs 401.1 +/- 131.2 micrograms/l/h, p < 0.05 and 77.2 +/- 30.4 vs 336.8 +/- 60.0 p < 0.02, respectively). Pyridostigmine was able to restore the blunted GH responsiveness to the second GHRH administration in both groups, but this response was found higher in normal than in diabetic subjects (delta AUC: 1250.8 +/- 136.2 vs 527.5 +/- 147.6, p < 0.01). Since the GH-releasing effect of PD is likely to be mediated by the inhibition of hypothalamic somatostatin release, our results suggest that there is also an impaired somatostatin tone in hyperglycemic type 1 diabetic patients with normal GH response to GHRH.

Postmenopausal virilization in a woman with gonadotropin dependent ovarian hyperthecosis.

We report a case of a 66-yr-old woman with progressive hair balding, hirsutism and virilization. Gonadotropins and estradiol levels were in the postmenopausal range; total testosterone (TT), free testosterone (FT) and 17-hydroxyprogesterone (17-OHP) were elevated with dehydroepiandrosterone sulphate, androstendione and cortisol serum levels in the normal range, as 24-hr free urinary cortisol. TT, FT and 17-OHP were normalized, and FSH and LH fell to premenopausal levels on 18th day after a single i.m. injection of the GnRH analogue (GnRHa), triptorelin. Then, a diagnosis of hyperandrogenism of ovarian origin was made and bilateral ovariectomy was performed. Histological study of gonadal tissue revealed diffuse stromal hyperplasia of both ovaries with occasional nests of luteinized cells. With immunoperoxidase techniques these cells stained positively for testosterone and progesterone. One month after surgery, androgen levels were normalized together with regression of most of the clinical signs of virilization. In conclusion, our patient showed a severe virilization developed after menopause; hormonal investigations suggested a gonadotropin dependent ovarian hyperandrogenism, confirmed by histological examination; the presence of luteinized cells in the ovarian stroma was responsible for hyperandrogenism, as confirmed by the immunoperoxidase technique.

The altered plasma amino acid pattern is responsible for the paradoxical growth hormone response to the oral glucose tolerance test in liver cirrhosis.

OBJECTIVE: An increased basal growth hormone (GH) secretion and a parodoxical GH response to the oral glucose tolerance test (OGTT) have been reported in patients with liver cirrhosis. It has been suggested that the ratio between branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) (BCAA/ AAA ratio) may determine in part the brain concentration of the AAAs, since the BCAAs compete with the AAAs for entry across the blood-brain barrier, leading to the accumulation of false neurotransmitters such as octopamine and phenylethanolamine, which are able to stimulate GH secretion (via alpha 2-adrenergic stimulation). In this study we investigated the role of amino acids, particularly the BCAA/AAA ratio, in the paradoxical response of GH to the OGTT in patients with liver cirrhosis. PATIENTS AND DESIGN: Twelve non-diabetic patients with biopsy-proven cirrhosis of the liver underwent an OGTT. Three of the five patients with a paradoxical response of GH to the OGTT underwent a second oral glucose administration associated with an infusion of BCAA solution from -30 min until 180 min. RESULTS: During the OGTT, glucose and insulin levels increased from 4.8 +/- 0.2 to 9.6 +/- 0.7 mmol/l (P < 0.001) and from 18.8 +/- 2.6 to 104.4 +/- 13.8 mU/l (P < 0.005), respectively. GH levels increased from 8.6 +/- 2.6 to 22.4 +/- 10.8 mU/l although not significantly. Five patients had a paradoxical GH response to the OGTT. A negative correlation between serum GH values and BCAA/AAA ratio in the plasma at every time point of the OGTT was found. After co-administration of glucose and BCAA in three patients the BCAA/AAAs ratio increased, abolishing the paradoxical GH secretion. CONCLUSIONS: Our data suggest that in liver cirrhosis the altered BCAA/AAA ratio may influence the altered basal GH secretion and the paradoxical GH response to the OGTT, probably by an increase of adrenergic mediators in the brain. Moreover, the increase of BCAA/AAA ratio seems to be able to abolish the GH paradoxical response to the OGTT.