Andrea Gallinelli

Corticotropin-releasing hormone modulates cytokines release in cultured human peripheral blood mononuclear cells.

Immune and neuroendocrine systems interact at various levels. In particular, either cytokines activate the hypothalamus-pituitary-adrenal axis (HPA) or corticotropin-releasing hormone (CRH) induces the release of beta-endorphin from peripheral human mononuclear cells. The aim of the present study was to investigate whether CRH may affect cytokine production and activity in human peripheral blood mononuclear cells (PBMC). Primary cultures of human PBMC and monocytes were used. They were incubated in presence of different doses of synthetic human CRH. Media were collected and interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) levels were measured by ELISA, while interferon-gamma (IFN-gamma) levels were measured by bioassay. In addition, phytohemoagglutinin-induced lymphocyte proliferation was evaluated by testing [3H]thymidine incorporation in the presence of various doses of CRH. CRH significantly increased IL-6 release from PBMC (p < 0.01). The addition of CRH to PBMC significantly decreased IFN-gamma levels, in a dose dependent manner (p < 0.01). No significant effect of CRH was observed on lymphocyte proliferation or IL-1 beta production. The present results suggest a role for CRH as a paracrine mediator for human immune cells, increasing the evidence of a clear correlation between immune and neuroendocrine system.

Pulsatile fluctuations of plasma‐gonadotropin‐releasing hormone and corticotropin‐releasing factor levels in healthy pregnant women

Several data emphasize the neuroendocrine aspects of human placenta. Classical hypophyseo‐tropic neurohormones are produced and secreted by the human placenta. Indeed, in contrast with non pregnant subjects, gonadotropin‐releasing hormone (GnRH) and corticotropin‐releasing factor (CRF) are measurable in maternal plasma during pregnancy. The aim of the present study was to investigate the characteristics of the secretory pattern of maternal plasma GnRH and CRF levels. A total of 25 healthy pregnant women participated in the present cross‐sectional study. Plasma levels of the two neurohormones were measured according to three different time‐intervals: 1) every five minutes for eight hours (n=4), 2) every ten minutes for four hours (n= 15), 3) every four hours for 24 hours (n =7). Following an acidic extraction plasma GnRH and CRF levels were measured by specific radioimmunoassay. Using two different algorithms (Detect and Cluster) a pulsatile pattern for both plasma GnRH and CRF levels was observed. Specific pulse frequency, amplitude, and duration were found. In the groups of women studied with a longer sampling interval, pulse frequency of GnRH or CRF levels did not differ between first and third trimester of gestation. However, amplitude of CRF pulses were significantly higher at term than at early stages of pregnancy (p≤0.01), while GnRH pulse amplitude was highest in women at first trimester of gestation. Evaluating the degree of concordance in all subjects, GnRH pulses significantly correlated with CRF pulses at 30 min. lag (p≤0.01). No significant circadian changes were found for any circulating neurohormone measured. The present study showed that maternal circulating neurohormone levels change according to a pulsatile pattern, probably reflecting the placental secretory events.

Effect of different chronic intermittent stressors and acetyl-l-carnitine on hypothalamic beta-endorphin and GnRH and on plasma testosterone levels in male rats.

Chronic stress affects the reproductive function by modifying the neuroendocrine homeostasis. The aim of the present study was to clarify the neuroendocrine and the gonadal changes following chronic intermittent stress in male rats and the action of a neuroactive drug, acetyl-l-carnitine (ALC). The effect of two different stressors, cold water swimming or ether, on central beta-endorphin (beta-EP) and GnRH contents, and on plasma testosterone levels was investigated. In addition, the response to an acute stress in chronically stressed rats, treated or untreated with ALC (10 mg/day/rat p.o.), was evaluated. The stressors were applied twice a day for 10 days, and rats were killed before, during and after the last stress session. Mediobasal hypothalamus (MBH) beta-EP and GnRH contents, and plasma testosterone levels were evaluated by radioimmunoassay. The following results were obtained: (1) both chronic swimming and ether stress caused a decrease in hypothalamic beta-EP contents; (2) MBH GnRH contents increased after chronic swimming stress but not after ether stress; (3) chronic swimming stress induced a twofold decrease in plasma testosterone levels, while no changes were observed after ether stress; (4) the treatment with ALC prevented the decrease in plasma testosterone levels after chronic swimming stress, and (5) acute stress in chronically stressed animals caused an increase in MBH-beta-EP. The present data showed that chronic swimming stress reduces the reproductive capacity and impairs the capacity to respond to the acute stress and that ALC modulates the hormonal changes to physical stress and prevents the antireproductive effect of chronic cold swimming.

Deficit of Galanin-Like Immunostaining in the Median Eminence of Adult Hypothyroid Rats

In this paper we describe the modification of the galanin (GAL)-like immunostaining in the hypothalamus of rats, which were made hypothyroid at 52 days after birth. On 21st day after the surgical ablation of the thyroid gland, the staining of the GAL-immunoreactive fibers in the median eminence decreased and on the 84th day disappeared almost totally. The GAL-immunoreactive distribution in other areas of the hypothalamus, e.g. the anterior hypothalamus and the dorsomedial nucleus, is only slightly affected by the absence of thyroid hormones, whereas the GAL-staining of medulla oblongata (vagal complex) is equal in both control and hypothyroid rats. In hypothyroid colchicine-treated rats, we were unable to stain GAL-immunoreactive neurons in the paraventricular nucleus (PVN). Oxytocin- and vasopressin-like material was present in the magnocellular neurons and the staining pattern in hypothyroid rats was the same as that of control animals. Our data show a marked reduction in the expression of the GAL-like immunoreactivity of the PVN and median eminence of adult hypothyroid rats. The possible role of this deficit in the pathogenesis of the GH secretion impairment that is observed in hypothyroid rats is discussed.

Color Doppler and hormone replacement therapy: The role of thromboxane and plasma viscosity

The aim of the study was to evaluate the plasma thromboxane and plasma viscosity in relation with Doppler flow parameters in postmenopausal patients treated with hormone replacement therapy. Thirty-two postmenopausal (follicle-stimulating hormone > 40 IU/l and estradiol < 100 pmol/l) women (mean age +/- SD, 54.7 +/- 2.9 years) participated in the study and were submitted to continuous estradiol transdermal supplementation and 12-day courses of medroxyprogesterone acetate every second month. Doppler resistances at the level of the uterine and internal carotid arteries, thromboxane plasma levels and plasma viscosity were analyzed in basal condition and after 1, 3 and 6 months. During hormone supplementation, the pulsatility index significantly decreased at the level of the analyzed arteries. Similarly, plasma thromboxane levels and plasma viscosity were significantly reduced. Significant correlations were found between thromboxane plasma concentrations, plasma viscosity and uterine artery resistances. Thus hormone replacement therapy seems to be responsible for both direct and indirect modifications at the level of the vessel wall physiology.

Acetyl-L-Carnitine Effect on Pituitary and Plasma β-Endorphin Responsiveness to Different Chronic Intermittent Stressors

The aims of the present study were: 1) to compare the effect of two different chronic intermittent stressors i.e. cold‐swimming versus ether, on the pituitary opioidergic system; 2) to evaluate the response of pituitary and plasma β‐endorphin (βS‐EP) to an acute stress in chronically stressed rats; and 3) to evaluate the effect of acetyl‐l‐carnitine treatment (10 mg/day/rat per os at night) on pituitary and plasma β‐EP changes induced by two different types of chronic stress. The stressors were applied twice a day for 10 days. Rats were killed either before, during or after the last swimming or ether stress session. β‐EP was measured by radioimmunoassay in anterior pituitary and in neurointermediate lobe extracts and in plasma. The following observations were made; 1) Chronic intermittent cold‐swimming stress increased anterior pituitary contents and plasma β‐EP levels; 2) both chronic intermittent cold‐swimming stress and ether stress caused an increase of neurointermediate lobe β‐EP contents; 3) as in control animals, rats exposed to chronic intermittent swimming stress reduced pituitary β‐EP contents and raised plasma β‐EP levels in response to the last acute swimming stress; 4) in contrast to control animals, rats exposed to chronic intermittent ether stress did not show any significant response of the pituitary‐plasma opioidergic system to the last acute ether session; 5) the acetyl‐l‐carnitine treatment counteracted the changes evoked by chronic intermittent cold‐swimming stress on the pituitary and plasma β‐EP levels. The present data show that chronic intermittent ether stress impairs the capacity to respond to the acute stress and that acetyl‐l‐carnitine may modulate the changes of β‐EP levels following chronic cold‐swimming stress exposure.

Secretion and Putative Role of Activin and CRF in Human Parturitiona

The endocrine mechanisms regulating human parturition are not well defined. Several studies have indicated that human placenta has the capacity to produce hormonal substances that may play a fundamental role in the physiology of pregnancy. The capacity of hormonal production in placental cells is critical in providing a favorable uterine environment at implantation, and in regulating growth during pregnancy. I Appropriate neuroendocrine signals involved in the initiation of labor, originating from placenta and fetal membranes, have also been suggested. A good deal of evidence indicates that different local factors participate in the mechanisms regulating myometrial contractile activity. Placental or decidual or amniotic hormonal products may act locally or are released in the maternal circulation or in amniotic fluid. In particular, a new group of molecules has been described in the various intrauterine tissues, the hypothalamic hypophysiotropic hormones: corticotropin-releasing factor (CRF), activin, inhibin, gonadotropin-releasing hormone (GnRH), and somatostatin. They have local action, in some respects comparable to the organization of the hypothalamus-pituitary-target organ axes.2 A possible role for some of these neuroendocrine factors at parturition has been also suggested by recent investigations. The end of pregnancy and initiation of labor must be preceded by the ability of the uterus to contract. This last phase of pregnancy may involve a complex set of maternal and fetal factors. As for hormonal changes, it is known that progesterone and estrogen as well as prostaglandins, oxytocin, cortisol, endothelin and sympathomimetic amines may play a role in the events of labor. Until now attention has been mainly paid to oxytocin. Increased oxytocin release, decreased activity of oxytocinase, and a change in the number of oxytocin

Placental Stress Factors and Human Parturition

Human parturition is a complex process whose mechanisms represent a fascinating interplay among fetus, placenta, and mother. Our recent studies suggest that endocrine changes in the uteroplacental environment are important factors accounting for the initiation and maintenance of labor, and human placenta appears to play a pivotal role both for the production and modulation of various of these endocrine substances. Indeed, human labor and parturition represent a stressful situation both for the mother and the fetus, requiring a series of adaptative reactions, which are dependent upon the activation of a series of nervous, endocrine, metabolic, cardiovascular, and respiratory homeostatic modifications. To face the stress of labor and parturition an activation of stress pathways has an adaptative significance, preserving maternal/fetal well-being. Human placenta produces a network of stress factors intimately involved in these processes, and therefore may be proposed as a major organ in the stress pathway control at the moment of parturition, acting systematically and locally, capable of controlling the cascade of intrauterine events leading to parturition (prostaglandin synthesis, control of uterine contractility).