Filippo Ninni

Plasma brain-derived neurotrophic factor daily variations in men: correlation with cortisol circadian rhythm

Expression and secretion of neurotrophins, including brain-derived neurotrophic factor (BDNF), are regulated also by neuronal activity. Data available in the literature suggest that BDNF central levels are influenced by light and dark. Diurnal changes of BDNF mRNA and protein contents have been demonstrated in the rat central nervous system. Based on these pieces of evidence, we investigated the hypothesis of a possible diurnal variation of BDNF circulating levels in human males. Moreover, we looked for a possible correlation with cortisol circadian rhythm, since both BDNF and cortisol are implicated in the maintenance of cerebral functions. In this study, 34 healthy young male volunteers were included. Five blood samples were drawn from each subject thrice in a month at regular 4-h intervals (0800, 1200, 1600, 2000, and 2400 h). BDNF and cortisol were measured in all samples. BDNF was determined by ELISA method. Our results show that plasma BDNF levels, as well as cortisol levels, are significantly higher in the morning when compared with the night (P<0.001), with a trend of constant decrease during the day. Furthermore, plasma BDNF and cortisol are positively correlated (Spearman index=0.8466). The present study is the first to demonstrate the presence of a diurnal rhythm of BDNF in humans. Moreover, the correlation found out between BDNF and cortisol circadian trend allows us to speculate that these two factors may be physiologically co-regulated, in order to maintain the homeostasis of integrated cerebral activities.

Progesterone and progestins: Effects on brain, allopregnanolone and β-endorphin

Abstract The increased use of hormonal therapies over the last years has led to improve the knowledge of pharmacological, biochemical and metabolic properties of several progestins and their effects in target tissues, such as the central nervous system. Progesterone and synthetic progestational agents are able to modulate the synthesis and release of several neurotransmitters and neuropeptides in response to specific physiological and pathological stimuli. While these actions may relay on differential activation of progesterone receptor or recruitment of intracellular pathways, some of the differences found between synthetic progestins may depend on the specific conversion to neuroactive steroids, such as the 3-α, 5-α reduced metabolite, allopregnanolone. This is a potent endogenous steroid that rapidly affects the excitability of neurons and glia cells through direct modulation of the GABA-A receptors activity exerting hypnotic/sedative, anxiolytic, anaesthetic and anticonvulsive properties. Estrogens increase the CNS and serum levels of allopregnanolone and the addition of certain but not all synthetic progestins determines a further increase in allopregnanolone levels, suggesting that the metabolism into this reduced product is related to the chemical structure of progestin molecule used. In addition, depending on specific progestin molecule used, different interaction are found with the estradiol-induced beta-endorphin synthesis and release, showing that diverse progestins have specific and divergent actions on the opiatergic system. These results highlight the concept that natural and synthetic progesterone receptor agonists may systematically induce different biological actions in CNS. This may have far-reaching implications for the clinical effects and related indications of each compound.

Office Vaginoscopic Hysteroscopy in Infertile Women: Effects of Gynecologist Experience, Instrument Size, and Distention Medium on Patient Discomfort

STUDY OBJECTIVE To assess the roles of instrument diameter (5.0- or 3.5-mm external sheath), uterine distention medium (carbon dioxide [CO(2)] or saline solution), and hysteroscopist experience in diagnostic hysteroscopy. DESIGN Prospective, randomized, multicenter trial (Canadian Task Force classification I). SETTING Two university medical centers in Italy. PATIENTS One hundred eighty-four women attending an infertility clinic. INTERVENTIONS Patients were randomly assigned to undergo conventional hysteroscopy (group 1, n = 92) or minihysteroscopy (group 2, n = 92) with CO(2) or saline solution as distention medium. The procedures were performed by hysteroscopists with varying degrees of experience. Patient discomfort was analyzed using the visual analog score. Procedure complications and patient satisfaction rate were also recorded. MEASUREMENTS AND MAIN RESULTS Independent of hysteroscopist experience, less pain, fewer complications, and higher satisfaction rates were observed with minihysteroscopy. In addition, procedures in which saline solution was used resulted in less pain and fewer complications than those in which CO(2) was used, but only when performed by inexperienced hysteroscopists. CONCLUSION Instrument diameter and hysteroscopist experience, but not the distention medium, seem to be the primary variables that affect the perception of discomfort during office hysteroscopy.

One-year therapy with 10 mg/day DHEA alone or in combination with HRT in postmenopausal women: Effects on hormonal milieu

The purpose of this study was to evaluate the effects on hormonal milieu of 1-year therapy with 10 mg/day oral dehydroepiandrosterone (DHEA) or 50 microg transdermal estradiol plus 100 mg/day oral micronized progesterone in a group of 20 healthy postmenopausal women (age=50-58 and years since menopause (ysm)=1-6) and also the effects observed by combining these two therapies in a group of 12 postmenopausal women (age=54-61 and ysm=6-10) characterized by lower baseline DHEA and DHEAS levels (<2.40 and <0.55 microg/ml, respectively). DHEA produced a significant rise in androgens levels, whereas HRT did not. Moreover, DHEA alone induced a significantly lower increase in estrogens and beta-endorphin levels and a higher decrease in cortisol levels than HRT. DHEA and HRT also produced a significant similar increase in allopregnanolone levels. DHEA plus HRT induced a significantly higher increase in testosterone and estradiol and a lower increase in allopregnanolone and beta-endorphin levels and a significantly lower decrease in cortisol levels than HRT alone treated group. A similar increase was observed in progesterone and SHBG levels in all groups. These results suggest that 10-mg DHEA seems to be the proper dose to replace androgen deficiency in subjects with reduced Delta-5 androgens plasma levels. However, the aging process and the number of years since menopause may further modulate the effects of hormone therapy on hormonal milieu.

Sex Differences in Brain and Plasma β-Endorphin Content following Testosterone, Dihydrotestosterone and Estradiol Administration to Gonadectomized Rats

Aims: The present study aims at evaluating the effect of a 2-week treatment with testosterone (T), dihydrotestosterone (DHT) and estradiol valerate (E2V) on brain and plasma β-endorphin (β-END) concentrations in gonadectomized rats of both sexes. Methods: Eight groups of female and 8 groups of male Wistar rats were included. For each sex, 1 group of gonad-intact and 1 group of gonadectomized rats were employed as controls (placebo). The other groups received subcutaneous T at the doses of 10 and 100 μg/kg/day (female rats) or 1 and 5 mg/kg/day (male rats). Subcutaneous DHT was administered at the doses of 1, 10, 100 μg/kg/day (female rats) or 0.1, 1 and 5 mg/kg/day (male rats). E2V was administered subcutaneously at 0.05 mg/kg/day. β-END levels were measured in different brain areas and plasma. Results: Ovariectomy (OVX) induced a significant decrease in β-END in all brain areas analyzed as well as in plasma. Orchidectomy (OCX) reduced opioid concentration in the hypothalamus, anterior pituitary and neurointermediate lobe. In OVX rats, T replacement as well as E2V significantly increased β-END concentration in all brain areas and in plasma. In the OCX group, T and E2V did not influence β-END concentrations in different hypothalamic areas. However, they produced a significant rise in β-END levels in the hypothalamus, neurointermediate lobe, anterior pituitary and plasma. Conversely, DHT replacement did not affect β-END levels at any dose administered, either in males or females. Conclusions: The sensitivity of the endogenous opiatergic system to T administration seems to be sex-related. This effect is particularly evident in the brains of female animals where this endogenous endorphin elicits a much greater response than it does in males that have undergone gonadal steroid depletion and subsequent T replacement.

Spontaneous Cornual Pregnancy after Homolateral Salpingectomy for an Earlier Tubal Pregnancy: A Case Report and Literature Review

Cornual pregnancy is an infrequent pathological condition with severe prognosis if not adequately recognized. Ipsilateral salpingectomy represents a unique risk factor for this clinical entity. This article reports a laparoscopically treated spontaneous cornual pregnancy after homolateral salpingectomy for an earlier tubal pregnancy in a condition of hemodynamic instability as a result of cornual rupture. We include a review of the literature, underlining the feasibility of a laparoscopic approach and new treatment options combining medical and surgical tools with specific attention to their impact on future fertility and on risk of uterine rupture in a future pregnancy.

Effects of nomegestrol acetate administration on central and peripheral beta-endorphin and allopregnanolone in ovx rats

The aim of this study was to investigate the effects of nomegestrol acetate (NOMAc) on the central nervous system by analyzing the neurosteroid allopregnanolone and the opioid beta-endorphin (beta-endorphin). 104 Wistar female rats were used in this study; one group of fertile and one group of ovariectomized rats were used as control. The others were ovariectomized and they underwent a 2-week oral treatment of NOMAc (0.05, 0.1, 0.2, 0.5, 1mg/kg/day), alone or with 0.05 mg/kg/day of estradiol valerate (E2V). Allopregnanolone and beta-endorphin were assessed in different brain areas and in circulation. Ovariectomy decreased allopregnanolone anywhere except in the adrenal gland and E2V reversed the effects of ovariectomy. 0.5 and 1mg/kg/day of NOMAc increased allopregnanolone levels in hippocampus. Combined administration of 1mg/kg/day of NOMAc plus E2V induced a further increase of allopregnanolone levels in hippocampus, hypothalamus, and anterior pituitary. NOMAc (1mg/kg/day) decreased the adrenal content of allopregnanolone, both by itself and associated with E2V. NOMAc increased hippocampal and hypothalamic content of beta-endorphin at the highest doses, and it increased positively E2V action, at 1mg/kg/day, also in anterior pituitary and plasma. These findings reinforce the clinical data regarding the capability of NOMAc to modulate the pathways involved in mood and behaviour. In fact, due to the NOMAc action on hippocampus, hypothalamus, and anterior pituitary, our results highlight the selectivity of NOMAc on part of the limbic system and the anterior pituitary, regarding both allopregnanolone and beta-endorphin.

ORIGINAL RESEARCH—BASIC SCIENCE: Sexually Dimorphic Effects of Testosterone Administration on Brain Allopregnanolone in Gonadectomized Rats

INTRODUCTION Clinical and biological evidences have shown a wide range of neuroactive effects of testosterone administration. AIM Evaluation of the effects of 2-weeks treatment with testosterone (T), Dihydrotestosterone (DHT), and estradiol valerate (E2V) on brain and serum allopregnanolone (AP) in gonadectomized rats of both sexes. MAIN OUTCOME MEASURES AP levels were measured in frontal and parietal lobe, hippocampus, hypothalamus, anterior pituitary, and in serum. METHODS Eight groups of Wistar female and eight groups of Wistar male rats were included. For each sex, one group of fertile and one group of gonadectomized rats were employed as control receiving placebo. The others groups received subcutaneous T at the dose of 10 microg/kg/day and 100 microg/kg/day for female rats, and 1 mg/kg/day and 5 mg/kg/day for male rats, or DHT at the doses of 1 microg/kg/day, 10 microg/kg/day, and 100 microg/kg/day for females, and 0, 1 microg/kg/day, 1 mg/kg/day and 5 mg/kg/day for males, or E2V (0.05 mg/Kg/day). RESULTS Ovariectomy (OVX) and orchidectomy (OCX) induced a significant decrease in AP in all brain areas analyzed, as well as in serum. In OVX rats, T replacement, as well as E2V, significantly increased AP content in all brain areas and in plasma. In OCX, T and E2V did not actively result in influencing AP concentration in frontal and parietal lobe, while it produced a significant rise in AP levels in the hippocampus, hypothalamus, anterior pituitary, and serum. Conversely, DHT replacement had no affect on AP levels anywhere or at any administered dose, either in males or in female rats. CONCLUSIONS Gender difference and T therapy affect brain AP synthesis/release during the reproductive aging. This effect becomes particularly evident in the brain of ovariectomized animals, where the content of this specific neurosteroid is much more responsive than male animals to testosterone replacement.

ORIGINAL RESEARCHORIGINAL RESEARCH—BASIC SCIENCE: Sexually Dimorphic Effects of Testosterone Administration on Brain Allopregnanolone in Gonadectomized Rats

INTRODUCTION Clinical and biological evidences have shown a wide range of neuroactive effects of testosterone administration. AIM Evaluation of the effects of 2-weeks treatment with testosterone (T), Dihydrotestosterone (DHT), and estradiol valerate (E2V) on brain and serum allopregnanolone (AP) in gonadectomized rats of both sexes. MAIN OUTCOME MEASURES AP levels were measured in frontal and parietal lobe, hippocampus, hypothalamus, anterior pituitary, and in serum. METHODS Eight groups of Wistar female and eight groups of Wistar male rats were included. For each sex, one group of fertile and one group of gonadectomized rats were employed as control receiving placebo. The others groups received subcutaneous T at the dose of 10 microg/kg/day and 100 microg/kg/day for female rats, and 1 mg/kg/day and 5 mg/kg/day for male rats, or DHT at the doses of 1 microg/kg/day, 10 microg/kg/day, and 100 microg/kg/day for females, and 0, 1 microg/kg/day, 1 mg/kg/day and 5 mg/kg/day for males, or E2V (0.05 mg/Kg/day). RESULTS Ovariectomy (OVX) and orchidectomy (OCX) induced a significant decrease in AP in all brain areas analyzed, as well as in serum. In OVX rats, T replacement, as well as E2V, significantly increased AP content in all brain areas and in plasma. In OCX, T and E2V did not actively result in influencing AP concentration in frontal and parietal lobe, while it produced a significant rise in AP levels in the hippocampus, hypothalamus, anterior pituitary, and serum. Conversely, DHT replacement had no affect on AP levels anywhere or at any administered dose, either in males or in female rats. CONCLUSIONS Gender difference and T therapy affect brain AP synthesis/release during the reproductive aging. This effect becomes particularly evident in the brain of ovariectomized animals, where the content of this specific neurosteroid is much more responsive than male animals to testosterone replacement.