A. Mancini

Corticotropin-releasing hormone inhibition of gonadotropin secretion during the menstrual cycle

To determine whether corticotropin-releasing hormone (CRH) exerts an inhibitory action on gonadotropin secretion in normal fertile women, the effects of CRH on luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol secretion were studied during the menstrual cycle. CRH had no effect on LH release during the midfollicular phase of the cycle. By contrast, IV injection of 100 micrograms CRH elicited significant decreases in LH concentrations during late follicular (-50%) and midluteal (-52%) phases of the cycle. LH concentrations decreased during the four-hours following injection of CRH and returned to those observed during the control period five hours after injection. Similarly, CRH elicited a significant decrease in FSH secretion during the midluteal phase of the cycle. CRH injection induced an increase in cortisol release during all phases of the cycle. These data demonstrate that exogenous CRH administration results in inhibition of gonadotropin secretion in late follicular and midluteal phases of the cycle. These results suggest that elevated endogenous CRH levels resulting in increased cortisol secretion could contribute to decreased gonadotropin secretion and, thus, disruption of reproductive function during stressful conditions in women.

Relationship between sperm cell ubiquinone and seminal parameters in subjects with and without varicocele

Summary. In a previous paper it was demonstrated that Coenzyme Q10, a lipidic molecule with important antioxidant properties, is present at remarkable levels in human seminal fluid, and shows a direct correlation with seminal parameters (sperm count and motility). In patients with varicocele, on the contrary, correlation with sperm motility was lacking and a higher proportion of Coenzyme Q10 was found in seminal plasma. In the present study, the levels of Coenzyme Q10 in the cell pellet of spermatozoa, obtained after centrifugation of semen, were evaluated. In nonvaricocele subjects it was observed that a higher concentration of Coenzyme Q 10 (expressed as ng of the molecule per million of cells) was present in the spermatozoa of oligospermic and asthenospermic patients (sperm count <20*106 spermatozoa ml−1, sperm motility <40%). This relationship was not observed in varicocele subjects, who also showed slightly lower intracellular absolute values of the coenzyme.

Cell cycle related proteins as prognostic parameters in radically resected non-small cell lung cancer

Background: Experimental evidence suggests that lung cancer development and progression can be linked to an increased proliferation rate. Aims/Methods: To evaluate the immunohistochemical expression of seven components of the cell cycle machinery in a series of well characterised non-small cell lung cancer (NSCLC) specimens (n u200a=u200a 105). Results: Multivariate analysis revealed that simultaneous loss of expression of three of these factors—cyclin D1, the cyclin dependent kinase inhibitor p16, and the tumour suppressor retinoblastoma protein Rb2/p130—correlated with survival, confirming the hypothesis that the cyclin D1–p16–retinoblastoma tumour suppressor pathway is inactivated in most lung cancer samples. Conclusions: These results suggest that loss of control of cell cycle checkpoints is a common occurrence in lung cancer and support the idea that functional cooperation between different cell cycle regulatory proteins constitutes another level of regulation in cell growth control and tumour suppression.

Effects of ghrelin administration on endocrine and metabolic parameters in obese women with polycystic ovary syndrome

Introduction: The novel peptide ghrelin displays multiple endocrine and non-endocrine actions. Its strong GH-releasing activity in humans has long been recognized. However, in obesity, ghrelin administration induces a blunted GH secretion, enhances glucose and reduces insulin levels. The effects of ghrelin administration have not been investigated in polycystic ovary syndrome (PCOS), which can be associated with obesity, hyperinsulinism, and GH hyposecretion. Leptin is a mediator for energy balance opposed to ghrelin; both of them are supposed to act as regulators of reproductive functions. Aim of the study: Evaluate the endocrine and metabolic response to ghrelin administration in PCOS obese patients compared to body mass index (BMI)-matched and normal weight women. Materials and methods: Nine obese PCOS patients (BMI: 35.4±1.2 kg/m2) (OB PCOS), 6 obese controls (BMI: 38.4±1.1 kg/m2) (Ob), and 6 normal-weight women (BMI: 23±0.6 kg/m2) (NW) were enrolled in the study. In all patients we performed: 1) basal hormonal evaluation including FSH, LH, estradiol, testosterone, androstenedione, DHEAS, SHBG, 17-hydroxyprogesterone (17OHP), IGF-I, free T3 (FT3), free T4 (FT4) and ghrelin levels; 2) metabolic evaluation as follows: concentration of non-esterified fatty acid (NEFA) and oral glucose tolerance test (OGTT) (75 g); homeostasis model assessment (HOMA); glucose and insulin response to ghrelin administration (1 µg/kg); 3) measurement of GH, PRL, TSH, and leptin levels after infusion of ghrelin. Results: Administration of ghrelin increased glucose and reduced insulin levels in both Ob and OB PCOS. Moreover, ghrelin enhanced GH and PRL levels in all groups but it did not modify TSH and leptin levels. GH peak and area under the curve (AUC) in OB PCOS and Ob were lower than controls (p<0.05). Similar PRL peak and AUC values were observed in all groups. Conclusions: In both obese and PCOS obese patients, leptin levels are not influenced by ghrelin administration. Moreover, the GH response after ghrelin administration is blunted. However, ghrelin exerts glucose-enhancing and insulin-lowering effects, the latter absent in NW.

Increased estradiol levels in venous occlusive disorder: a possible functional mechanism of venous leakage.

Venous insufficiency of the corpora cavernosa is the second most common cause of erectile dysfunction (ED). A functional insufficiency of the venous system has been hypothesised, but the cause is still unclear. To evaluate a possible endocrine mechanism, we have studied hormone profile in a group of nine patients with pure venous-leakage (VL) compared with a control group of 15 patients with ED of different origin. Prolactin, testosterone and gonadotropin levels did not differ among the two groups, while estradiol (E2) plasma concentration was significantly higher in VL patients compared to controls. Our data support the hypothesis that the steroid environment, in particular estradiol level, can influence venous vascular tone (via VEGF or NO), thus affecting venous leakage dysfunction. This point can explain a possible link between the high estradiol levels and a functional insufficiency of the venous system in ED.

Coenzyme Q10 levels in human seminal fluid: diagnostic and clinical implications.

The levels of Coenzyme Q10 (CoQ10) were determined by HPLC in seminal fluid samples obtained from 77 patients who performed a standard semen analysis for infertility, previous phlogosis or varicocele. CoQ10 was determined in total seminal fluid (n = 60), in seminal plasma (n = 44) and in the cell pellet (n = 37). The molecule, in total fluid, showed a linear correlation with sperm count and motility. In the pellet of spermatozoa, a trend toward an inverse correlation between CoQ10 (expressed as ng/10(6) cells) and semen parameters could be observed. A different pattern was shown in varicocele patients, in whom, in total fluid, the correlation between CoQ10 and sperm count was preserved, but the one between CoQ10 and sperm motility was lacking; moreover, a higher proportion of CoQ10 was present in seminal plasma, and the inverse trend between cellular CoQ10 and sperm count and motility was not observed. These data suggest a pathophysiological role of ubiquinone in human seminal fluid and a molecular defect in the spermatozoa of varicocele patients.

Sex-related naloxone influence on growth hormone-releasing hormone-induced growth hormone secretion in normal subjects

The effect of opiate-receptor antagonist naloxone on growth hormone (GH) release after growth hormone-releasing hormone (GHRH) 1-44 administration was investigated in ten normal men and 18 normal women during different phases of their menstrual cycle. Naloxone was infused at a rate of 1.6 mg/h in women and 1.6- and 3.2 mg/h in men, starting one hour before GHRH administration (50 micrograms iv as a bolus). On different day sessions, naloxone, GHRH, or saline were administered as controls. Naloxone infusion reduced the GHRH-induced GH release in normal women. The mean % inhibition of peak GH response was 83% during follicular phase, 46.5% during periovulatory phase, and 77.6% during luteal phase. On the contrary, in normal men, both doses of naloxone infusion were ineffective in blunting the GH response to GHRH. Our studies indicate that naloxone infusion was capable of inhibiting GH release induced by direct stimulation with GHRH in normal women, suggesting an opiate-antagonist action at the anterior pituitary level. The absence of such an effect in normal men strongly indicates a sex dependence of naloxone effects and suggests a role of the sexual steroid environment in opioid modulation of pituitary hormone secretion.

Biphasic effect of estradiol on luteinzing hormone response to gonadotropin-releasing hormone in castrated men

This study was designed to investigate the possibility that in men estradiol (E2) has a stimulatory effect on the gonadotropin response to GnRH. Nine castrated adult men, who presented extremely low testosterone (T) concentrations, received 5 mg/day estradiol benzoate (E2B) i.m. every 24 hr for several days, starting 5 days after orchidectomy. During E2B treatment the pituitary responsiveness to GnRH (100 micrograms given as an iv bolus) was tested after 24, 48, 72, 96, 120, and 144 hrs of E2B administration. The pituitary responsiveness to GnRH was also tested in untreated men from day 5 to day 10 following bilateral orchidectomy. In the E2B-treated subjects the increased serum estradiol concentrations induced an initial decrease and a subsequent increase of the LH response to GnRH. The responses were decreased after 24 hr of treatment; thereafter, the LH responses were progressively increased and were markedly augmented after 120 hr of E2B treatment. On the contrary, during treatment the FSH response to GnRH was preferentially blunted. In the untreated castrated men the LH and FSH responses to GnRH increased progressively from day 5 to day 10 after orchidectomy, but decreased responses were never observed during this period of observation. The maximum LH concentrations, which occurred at 30-60 min following GnRH in untreated castrated men, did not occur until 120-150 min in the E2B treated men.

Impact of long-term naltrexone treatment on growth hormone and insulin secretion in hyperandrogenic and normal obese patients

The growth hormone (GH) response to stimulation tests is impaired in obesity. Moreover, obese patients exhibit a paradoxical increase of GH to GH-releasing hormone (GHRH) stimulation after food ingestion; this paradoxical response is reversed by naloxone infusion. On the other hand, beta-endorphin seems to exert profound effects on insulin release. Recent studies also demonstrated an impairment of GH response to several stimuli in polycystic ovary syndrome (PCOS), a condition associated with obesity, hyperinsulinism, and insulin resistance. Chronic inhibition of opioid tone by the opioid antagonist naltrexone (NTX) is able to reduce the insulin response to an oral glucose tolerance test (OGTT) in hyperinsulinemic PCOS patients. Since insulin and GH may reciprocally influence their secretion and the opioid system may have a role in the pathogenesis of hyperinsulinemia and reduced GH secretion, we have explored the involvement of these neuroendocrine mechanisms in essential obesity and in obesity associated with hyperandrogenism by a long-term treatment with an opiate antagonist. We tested seven obese patients affected by PCOS, seven matched women with essential obesity (EO), and five non-obese control subjects. All patients, in the follicular phase, underwent an OGTT (75 g) and basal hormone assay. Two days later, patients were subjected to a GHRH test. The patients then had 4 weeks of treatment with NTX 50 mg/d. Following continuation of the treatment, OGTT and GHRH tests were repeated. Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) plasma concentrations were also determined in the basal condition before and after NTX treatment. NTX treatment reduced fasting insulin levels in patients with EO (P < .05) and restored a normal GH response to GHRH without affecting IGF-1 and IGFBP-3 levels. In PCOS subjects, NTX reduced the insulin response to a glucose load and failed to modify the blunted GH response to GHRH. Our data suggest a significant difference in opioid system function in PCOS and EO subjects, indicating a particular form of obesity in PCOS. The opiate antagonist treatment in EO may act through the reduction of negative insulin feedback on GH secretion. In PCOS patients, the failure to improve GH secretion in obese hyperandrogenized patients may be related to a high opioidergic tone or to the inhibitory predominance of other neurotransmitters.

Evaluation of pre- and postprandial growth hormone (GH)-releasing hormone-induced GH response in subjects with persistent body weight normalisation after biliopancreatic diversion

BACKGROUND: Obesity is characterised by growth hormone (GH) abnormalities, including a blunted response to stimulation and a ‘paradoxical’ increase after meals. The blunted GH release is reversed by a surgical intestinal bypass procedure. However, this does not mean that normal GH dynamics have been restored. The present study assessed whether post-surgical weight reduction in obese patients normalised the modulation of GH release produced by metabolic fuels.SUBJECTS: Ten obese female subjects, aged 23–54u2005y, were studied before and after biliopancreatic diversion (BPD). All patients, after surgery, had experienced a significant reduction in body weight (mean body mass index (BMI) 25.78±1.01u2005kg/m2 vs 44.68±1.73u2005kg/m2). Two groups were also studied as controls: Ten normal body weight female subjects and ten patients suffering from anorexia nervosa (AN, mean BMI 17.46±1.12u2005kg/m2).MEASUREMENTS: We have studied the GH response to a GH releasing hormone (GHRH) bolus (1u2005μg/kg iv, at 13.00u2005h) before and after a standard meal.RESULTS: In post-BPD subjects, the GH response to GHRH in the fasting state, was clearly augmented in comparison with the pre-BPD values (peak values 18.06±4.56 vs 3.24±0.68u2005μg/L). In post-BPD subjects the postprandial GH response was further augmented in comparison with the fasting test (peak 30.12±4.99u2005μg/L, P<0.05). This pattern was similar to that observed in anorexic patients.CONCLUSION: The surgical procedure restores a normal GH response to GHRH in the fasting state, but the ‘paradoxical’ GH response after meals remains present, suggesting a persistent GH derangement in such patients, which is not related to body weight per se. The surgical procedure makes obese patients similar to anorexics, in the relationships between metabolic fuels and GH secretion. The persistence of the GH postprandial response to GHRH in post-BPD subjects suggests a role for metabolic fuels in the regulation of somatostatin (SRIF) secretion.