No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque.

BACKGROUND AND AIMS: Increased carotid artery intima-media thickness (IMT) and the presence of plaques have been shown to be predictors of cardiovascular disease. The cardiovascular risk in patients with overt thyroid diseases is related to increased risk of atherosclerosis, but there has been no clear evidence about subclinical disorders. We have assessed whether subclinical thyroid dysfunction is associated with arterial thickening and plaque. METHODS AND RESULTS: The SardiNIA study is a population-based survey on the Italian island of Sardinia. We reviewed data from 5815 subjects (aged 14-102 years), none of whom had overt hyperthyroidism or hypothyroidism or was taking thyroid medication. Serum thyrotropin (TSH), free thyroxine, together with carotid ultrasound IMT and the presence of common carotid plaques were analysed in all subjects. Possible association of IMT and carotid plaques with thyroid parameters was evaluated by univariate and multivariate analyses. IMT was significantly associated with age, sex, smoking, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol, pulse pressure (PP), history of arterial hypertension, diabetes, and previous cardiovascular events (p = 0.001 or lower, R(2) = 0.47). Carotid plaques were predicted by age, sex, LDL, PP, history of diabetes, previous cardiovascular events, and the use of statins (p = 0.029 or lower). Thyroid hormone was not predictive of carotid atherosclerosis when adjusted for confounders. CONCLUSION: Thyroid hormone is not associated with increased IMT or with the presence of carotid artery plaque. Our data do not support the idea that treating subclinical disorders might help to prevent arterial remodelling or carotid atherosclerosis.

An inhibition of the hypothalamic somatostatinergic tone is not the cause of the enhanced growth hormone response to growth hormone-releasing hormone in patients with liver cirrhosis.

Animal models of liver cirrhosis (LC) display a reduced hypothalamic somatostatinergic tone. To test whether a similar mechanism could explain the enhanced Growth Hormone (GH) secretory response to GH-Releasing Hormone (GHRH), which is seen in human LC, we studied the effect of the cholinesterase inhibitor pyridostigmine (PD), which is able to reduce the release of hypothalamic somatostatin (SS), on the GHRH-stimulated GH secretion. We considered that if PD were unable to increase GH secretion, this would constitute evidence of an already inhibited endogenous somatostatinergic tone. If proved, this in turn could explain the enhanced GH response to GHRH seen in LC. Ten LC patients and nine controls were given GHRH (100 microg, intravenously), or PD (120 mg, orally) plus GHRH. After GHRH alone, the GH peak was four times higher in LC than in controls (40.85+/-15.7 ng/ml in LC and 9.35+/-2.5 ng/ml in controls). In LC, PD administration markedly increased the GH response to GHRH (GH peak: 98.0+/-19.7 ng/ml; +240% vs. GHRH alone). The ability of PD to increase the GH response in patients with LC suggests that in this condition the enhanced GH response to GHRH is not due to a completely inhibited endogenous somatostatinergic tone. SS appears instead to maintain its modulator role on GH secretion in human LC, in contrast with what observed in animal models.

Helicobacter pylori CagA antibodies and thyroid function in latent autoimmune diabetes in adults.

OBJECTIVE: H. pylori infection is reportedly associated with autoimmune diseases such as chronic thyroiditis and autoimmune diabetes. The aim of this study is to determine the association between H. pylori infection and its virulent strain CagA with antibodies against thyroperoxidase (TPO Ab) and thyrotropin (TSH) in a cohort of latent autoimmune diabetes in adult (LADA) patients. PATIENTS AND METHODS: We included 234 LADA patients (53.8% women). Antibodies against H. pylori whole antigens and CagA, TPO Ab and TSH were assessed in all patients. RESULTS: Prevalence of IgG against H. pylori and GagA was 52.1% and 20.9% respectively. Antibodies against H. pylori were not associated with TPO Ab and TSH (rho = 0.067, p = 0.620 and rho = 0.156, p = 0.099, respectively). Antibodies against CagA showed a positive association with TSH and TPO Ab (respectively rho = 0.309, p = 0.036 and rho = 0.419, p = 0.037). Subjects with hypothyroidism (TSH ≥ 3.5 µU/ml) had an increased frequency of Ab anti CagA (p = 0.059). CONCLUSIONS: The infection by H. pylori strains expressing CagA is associated with increased TPO Ab and TSH levels in LADA patients, suggesting a possible mechanism involved in thyroid autoimmunity and dysfunction of the gland. Further research is needed to test this hypothesis.

Successful treatment of retrograde ejaculation with the alpha1-adrenergic agonist methoxamine: case study.

We treated two patients affected by retrograde ejaculation (RE) with the pure alpha1-adrenergic agonist methoxamine; the drug was self-administered intramuscularly by the patients 30 min prior to intercourse or masturbation. A previous trial with oral imipramine had been ineffective in both patients. Sperm count increased substantially, particularly in the first patient who had insulin-dependent diabetes and was seeking fertility. In this patient, total ejaculated sperm increased from 22 millions to 488 and 419.5 millions on two different occasions, with good motility; two clinical pregnancies were obtained in the partner of this patient after 3 and 4 months of treatment, respectively. The second patient did not desire fertility. In both patients, no side effects were seen except for slight piloerection; blood pressure values increased slightly, and heart rate was unchanged. We conclude that self-administered methoxamine can be a useful, noninvasive and inexpensive treatment of RE, when oral agents are ineffective.

Domperidone, an extracerebral inhibitor of dopamine receptors, stimulates thyrotropin and prolactin release in man.

Domperidone, an extracerebral dopamine receptor antagonist, was given im to 12 normal subjects and to a group of patients with subclinical hypothyroidism to study its effect on PRL and TSH secretion. Domperidone induced in all subjects a quick and marked increment of serum PRL. At 180 min, the levels remained high. A small but significant increase of TSH was also observed in normal as well as in hypothyroid subjects. Since domperidone does not cross the blood-brain barrier, the hormonal changes observed may be mediated through the pituitary and median eminence, tissues which lie outside of the blood-brain barrier.

Suppression of thyrotropin (TSH) and prolactin (PRL) release by pyridoxine in chronic primary hypothyroidism.

A single iv dose of pyridoxine (V) (300 mg) caused a significant decrease in the concentration of serum thyrotropin (TSH) in 6 patients with primary hypothyroidism. There was no consistent change in serum thyroxine and triiodothyronine concentrations suring the experiment. The serum prolactin (PRL) levels were also suppressed by pyridoxine administration. These findings suggest that pyridoxine inhibits TSH secretion as well PRL by a direct action on the hypothalamus or pituitary gland.

On the role of dopamine receptors in the naloxone-induced hormonal changes in man.

To assess the role of dopamine receptors in naloxone-induced hormonal changes, the effects of dopamine and metoclopramide on anterior pituitary hormone secretion were studied during the infusion of the opiate blocker in normal men. Naloxone stimulated LH and cortisol secretion in all subjects, whereas FSH, TSH, PRL, and GH did not change. The infusion of dopamine completely suppressed the naloxone-induced LH rise; on the contrary, metoclopramide failed to alter the magnitude of the increments in LH observed during the infusion of the opiate blocker. The cortisol response to naloxone remained unchanged during dopamine and metoclopramide infusion. Metoclopramide stimulated PRL and TSH release during naloxone treatment, whereas dopamine suppressed PRL and TSH secretion. The data do not suggest a participation of dopamine receptors in the naloxone-induced hormonal changes in man and confirm a suppressive effect of dopamine infusion on LH release in humans.

Participation of cholinergic muscarinic receptors in glucagon- and arginine-mediated growth hormone secretion in man.

To investigate the participation of cholinergic receptors in glucagon- and arginine-induced GH and PRL secretion, glucagon (1 mg, sc) and arginine (30 mg over 30 min) were administered to a group of normal subjects. On a different occasion, both tests were repeated after premedication with 40 mg pirenzepine, a muscarinic blocker, given iv 5 min before the test substances. Pirenzepine completely suppressed the glucagon- and arginine-induced GH rise in all subjects. The PRL response to arginine was not altered by pirenzepine. The results suggest that cholinergic muscarinic receptors regulate the GH response to glucagon and arginine in man.

Effect of pyridoxine on human hypophyseal trophic hormone release: a possible stimulation of hypothalamic dopaminergic pathway.

A single dose of pyridoxine (300 mg iv) produced significant rises in peak levels of immunoreactive growth hormone GH and significant decrease of plasma prolactin PRL in 8 hospitalized healthy subjects. Serum glucose, luteinizing hormone LH, follicle stimulating hormone FSH and thyrotropin TSH were not altered significantly. In addition, in 5 acromegalic patients who were studied with both L-dopa and pyridoxine, inhibition of GH secretion followed either agent in a similar pattern. These data suggest a hypothalamic dopaminergic effect of pyridoxine.

Enhancement of insulin-induced prolactin secretion by fluoxetine in man.

Fluoxetine hydrochloride, a specific inhibitor of serotonin reuptake, was given orally to five adult males to study its effect on fasting and insulin-stimulated release of PRL. A 3-day course of fluoxetine (30 mg daily) had no demonstrable effect on fasting PRL levels. Fluoxetine significantly enhanced insulin-induced PRL release. These data suggest that serotoninergic pathways have little or no part in the control of spontaneous PRL secretion in man, whereas they may play a role in insulin-stimulated PRL release.

Action of metergoline in suppressing prolactin release induced by mechanical breast emptying.

Ten women were studied during the first post-partum week. Mechanical breast emptying with a breast pump for 30 min induced a marked increase in plasma prolactin (PRL) reaching a maximum 30 min after the beginning of stimulation. In all patients oral administration of the antiserotonin agent metergoline, 8 mg daily for two days, completely blocked any PRL secretion induced by breast stimulation. These results confirm the inhibitory effect of metergoline on PRL release.

Growth hormone and prolactin release in acromegalic patients following metergoline administration.

In six acromegalite patients oral administration of 4 mg of metergoline, an antiserotonin agent, produced a fall in plasma growth hormone (GH) and prolactin (PRL) concentrations. In the same patients this inhibitory effect was observed after administration of dopaminergic drugs, L-Dopa and 2-Br-alpha-ergocryptine. Both GH and PRL levels remained suppressed during a 6 day course of treatmnt with metergoline. These results are consistent with the hypothesis that the inhibitory effect of netergoline on GH and PRL release is determined by inactivation of serotonin receptors in the hypothalamus or at the pituitary.

Opioids stimulate growth hormone (GH) release in man independently of GH-releasing hormone.

The Met-enkephalin analog DAMME [D-Ala2,MePhe4-Met-enkephalin-(o)-o1, FK 33-824] can stimulate GH secretion in man. In this study we investigated the effects of the guanyl derivative of DAMME (G-DAMME) on the serum GH response to an analog of GHRH in normal men. GHRH-(1-29)NH2 and G-DAMME each induced a rise in serum GH, and the increase was greater when both were given together. Since the GHRH-(1-29)NH2 dose (100 micrograms) used was a maximally stimulatory one, these results suggest that the enhancing effect of G-DAMME on GHRH-induced GH release may be mediated through inhibition of somatostatin release.

Participation of endogenous opiates in regulation of the hypothalamic-pituitary-testicular axis in normal men.

To assess the influence of endogenous opioids on human gonadotropin secretion, integrated concentrations of gonadotropins during 24-h naloxone infusion (2.08 mg/h) were examined in a group of six normal men. Naloxone significantly stimulated LH secretion in all subjects, whereas serum FSH levels were similar during both saline and naloxone infusion. Serum testosterone, dihydrotestosterone, and 17 alpha-hydroxyprogesterone levels increased during the infusion of naloxone, but the delta 4-androstenedione concentration was not modified. The frequency and amplitude of LH secretory episodes were clearly increased when an equal amount of the drug was given and LH concentrations were measured every 15 min for 6 h. The results suggest the endogenous opioids inhibit the hypothalamic-pituitary-gonadal axis in normal men.

Cholinergic receptor control mechanisms for L-dopa, apomorphine, and clonidine-induced growth hormone secretion in man.

The effect of pirenzepine, an anticholinergic agent, on GH release induced by L-dopa (500 mg po), apomorphine (0.75 mg sc), and clonidine (0.150 mg iv) administration was studied in a group of normal men. Pirenzepine, a cholinergic muscarinic antagonist, completely blocked the GH rise induced by dopamine- and adreno-receptor stimulation. In contrast, the PRL-inhibiting action of L-dopa was not modified by the cholinergic antagonist. The data suggest that acetylcholine and its receptors are important regulators of the neurosecretory mechanisms that control GH secretion in man.

Spontaneous nocturnal growth hormone secretion in anorexia nervosa.

In anorexia nervosa, serum GH levels are increased under basal conditions and respond abnormally to provocative stimuli. We report here, for the first time, an analysis of pulsatile GH secretion in these patients performed by Cluster algorithm. Seven anorectic and six normal weight, healthy women underwent serial blood sampling at 20-min intervals form 2030-0830 h for GH estimation. The total area under the curve (AUC; micrograms per L/min) was elevated 4-fold in anorectic patients compared to controls (4743.0 +/- 1520.09 vs. 1148.6 +/- 519.27; P < 0.01), largely due to an increase in the non-pulsatile fraction (3212.5 +/- 990.45 vs. 378.7 +/- 123.27; P < 0.01). Accordingly, the valley mean value was higher in anorectic than in control subjects (5.9 +/- 2.25 vs. 1.0 +/- 1.30 micrograms/L; P < 0.01). Furthermore, pulsatile AUC was also greater in anorectic patients (1530.4 +/- 654.72 vs. 769.8 +/- 404.02; P < 0.01) due to a significant increase in GH peak frequency (5.0 +/- 0.81 vs. 3.0 +/- 0.89; P < 0.01). No correlations were observed in these patients between body mass index and any of the parameters of spontaneous GH release, whereas a positive correlation was found between insulin-like growth factor I levels and pulsatile AUC (r2 = 0.583; P < 0.05), peak height (r2 = 0.743; P = 0.01), peak increment (r2 = 0.801; P < 0.01), and GH valley mean (r2 = 0.576; P < 0.05). In conclusion, it appears that the enhanced GH secretion in anorexia nervosa is the result of an increased frequency of secretory pulses superimposed on enhanced tonic GH secretion. Although this latter is consistent with a reduction of hypothalamic SRIH tone, the former may be accounted for by an increased number of GHRH discharges. Considering that in normal weight and obese subjects parameters of GH release are negatively correlated with adiposity indexes, the lack of such a negative correlation in our patients suggests that the enhancement of spontaneous GH release in anorectic patients is not merely the consequence of malnutrition-dependent impairment of insulin-like growth factor I production, but reflects a more complex hypothalamic dysregulation of GH release.

Dynamic evaluation of prolactin secretion during the early hours of life in human newborns.

PRL secretion was evaluated in 30 human newborns during the early hours of life. Both levodopa and pyridoxine administration failed to suppress PRL release in all subjects. Synthetic TRH elicited a constant, prompt increase in PRL levels. No significant changes were observed after somatostatin injections. These results demonstrate normal pituitary PRL reserve in newborns. The failure to respond to levodopa and pyridoxine administration might reflect partial immaturity of the pituitary dopaminergic receptors.

Effect of LRH on gonadotropin secretion in newborn male infants.

The concentrations of LH and FSH were measured in eight male newborn babies, aged 4-6 h, before and after the administration of 25 micrograms synthetic LHR. A comparison was performed with six control newborns receiving normal saline. Both LH and FSH rose significantly in all subjects after LHR administration. Their values were significantly higher than those observed during the control study. These data demonstrate sensitivity of the pituitary gonadotropes to synthetic LHR and a pubertal-type response to LH in the early hours of human life.

Naloxone administration does not affect gonadotropin secretion in agonadal men either basally or during testosterone treatment.

Naloxone administration has no effect on plasma gonadotropin levels of agonadal men. The present study was designed to evaluate whether testosterone replacement therapy could restore LH responsiveness to naloxone in such men. We measured plasma LH and FSH levels at 15-min intervals during naloxone infusion (8 mg in 1 min followed by 12 mg in 3 h) and for the following 3 h in a group of agonadal men both before and after at least 2 months of three different schedules of testosterone replacement therapy: 1) testosterone undecanoate, 40 mg three times a day by mouth; 2) testosterone enanthate 200 mg im every 2 weeks; and 3) testosterone enanthate 100 mg im once a week. Mean plasma gonadotropin levels as well as LH pulse frequency did not vary during naloxone infusion vs. placebo either basally or during each testosterone regimen. These results suggest that long term testosterone therapy does not affect the altered opioid modulation of gonadotropin secretion which is present in agonadal men.

Effects of different dopaminergic antagonists on bromocriptine-induced inhibition of norepinephrine release.

In this study we evaluated the effects of placebo or acute bromocriptine (BC) administration (2.5 mg orally) on plasma catecholamines, systolic and diastolic blood pressure (BP), heart rate, and plasma PRL in six normal subjects [group I, mean age 33.2 +/- 5.4 (SD) yr] in the supine as well as upright position. BC induced a significant decrease in plasma norepinephrine in the supine [167.7 +/- 16.8 (SEM) vs. 101.9 +/- 33.7 pg/ml, P less than 0.005] and upright positions [397.3 +/- 27.7 vs. 211.3 +/- 26.7 pg/ml, P less than 0.005], a decrease in systolic and diastolic BP and a decrease in plasma PRL (P less than 0.01). After standing, epinephrine levels increased significantly (53.6 +/- 11.8 vs. 226.4 +/- 71.0 pg/ml, P less than 0.05). The study was repeated in a second group of seven normal subjects (mean age, 32.3 +/- 12.9 yr) after placebo or metoclopramide (20 mg orally) plus BC. In this group metoclopramide, a central and peripheral antidopaminergic agent, counteracted the BC-induced effects found in group I, both in the basal and stimulated conditions. Plasma PRL increased significantly (P less than 0.025). Finally, to assess the effect of peripheral dopaminergic blockade on BC-induced changes in sympathetic outflow, we repeated the study in seven normal subjects (group III, mean age, 30.1 +/- 5.0 yr) after placebo or domperidone (20 mg orally) plus BC. Domperidone blocked the effects of BC on norepinephrine and BP in the supine position. On standing there was a significant decrease in systolic (P less than 0.05) and diastolic (P less than 0.05) BP and an increase in epinephrine levels (58.9 +/- 12.2 vs. 109.8 +/- 24.6 pg/ml, P less than 0.05) was still observed. Plasma PRL increased significantly (P less than 0.025). The results of this study suggest that the inhibition of sympathetic outflow induced by BC is peripherally mediated. As peripheral dopamine receptor blockade did not counteract all the effects after BC during standing, dopaminergic modulation of central reflex sympathetic activation is suggested.