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It is a known fact that abnormal seminal liquid specimens contain abnormal amounts of oxygen free radicals and reactive oxygen species (ROS), and that the use of antioxidant molecules bothin vivoandin vitroleads to improvement of semen quality in terms of motility, reduction in DNA damage, with obvious consequences on the fertilization potential. Myo-inositol has been observed to have anti-oxidant properties and be present in much greater concentrations specifically in seminal liquid than in the blood. Moreover, there seems to be a direct relationship between myo-inositol and mitochondrial membrane potential (MMP) and sperm motility. Studies performedin vivohave demonstrated that a dietary supplementation with myo-inositol in men undergoing assisted reproduction techniques may improve sperm quality and motility in oligoasthenospermia (OAT) patients. In the following study we utilized myo-inositolin vitroto verify its effect on semen quality in both normal and OAT patients undergoingin vitrofertilization (IVF) with respect to standard sperm medium.In vitroincubation of seminal liquid carried out using myo-inositol (Andrositol-Lab, Lo.Li. Pharma-Roma, Italy) at a concentration of 15 μl/ml improved progressive motility in both normospermia and OAT subjects. In our opinion, myo-inositol may prove to be a useful strategy to improve sperm preparation for clinical use in IVF. [ABSTRACT FROM PUBLISHER]

The steroidogenic endocrine glands and local synthesis both contribute to the pool of steroids present in the central nervous system and peripheral nervous system. Although the synthesis of neurosteroids in the nervous system is now well established, the spectrum of respective functions in regulating neuronal and glial functions remains to be fully elucidated. From the concept of neurosteroids derives another treatment strategy: the use of pharmaceutical agents that increase the synthesis of endogenous neurosteroids within the nervous system. This approach has so far been hampered by lack of knowledge concerning the regulation of the biosynthetic pathways of neurosteroids and their relationship with sex steroids produced by the peripheral gland or with exogenous steroids. The present review summarizes some of the available clinical and experimental findings supporting the critical role of neurosteroids during fertile life and reproductive aging and their relationship with endogenous and exogenous sex steroids. The brain metabolism of synthetic progestins and the implications of DHEA treatment in postmenopausal women will also be discussed. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome is one of the most common endocrine disorders in women of reproductive age. Features of PCOS are hyperandrogenism, chronic anovulation and polycystic ovaries on ultrasonography. Follicle development is a complex and carefully orchestrated phenomenon, involving gonadotropins and a rapidly expanding list of other intraovarian regulators, such as brain-derived neurotrophic factor (BDNF). The aim of this study is to evaluate BDNF in plasma and in follicular fluid in women affected by PCOS and in normal menstruating women. In PCOS patients the BDNF levels in plasma and in follicular fluid are higher than values obtained in healthy controls. Therefore we can hypothsize that high levels of luteinizing hormone, probably increase the secretion of BDNF in PCOS patients. [ABSTRACT FROM AUTHOR]

Background Sexual desire is affected by endocrine and psychosocial factors. Menopausal hormonal changes are relevant to the causes of sexual dysfunction during reproductive aging. Aim To evaluate the effects of different types of hormonal replacement therapy (HRT) on sexual function, frequency of sexual intercourse, and quality of relationship in early postmenopausal women. We recruited 48 healthy postmenopausal women aged 50-60 years (mean age 54.5 ± 3.3 years). Women with climacteric symptoms were uniformly randomized into three groups receiving either dehydroepiandrosterone (DHEA 10 mg) daily, or daily oral estradiol (1 mg) plus dihydrogesterone (5 mg), or daily oral tibolone (2.5 mg) for 12 months. Women who refused hormonal therapy were treated with oral vitamin D (400 IU). Efficacy was evaluated using the McCoy Female Sexuality Questionnaire before treatment and after 12 months. We evaluated the hormonal profile before treatment and after 3, 6 and 12 months. Results The groups receiving DHEA or HRT reported a significant improvement in sexual function compared to baseline ( p < 0.001 and p < 0.01, respectively) using the McCoy total score. The quality of relationship was similar at baseline and after 3, 6 and 12 months of treatment. There were significant increases in the numbers of episodes of sexual intercourse in the previous 4 weeks in women treated with DHEA, HRT and tibolone in comparison with the baseline value ( p < 0.01, p < 0.05, p < 0.01, respectively). No changes in the McCoy score occurred in women receiving vitamin D. Conclusions Daily oral DHEA therapy at the dose of 10 mg, HRT and tibolone all provided a significant improvement in comparison with vitamin D in sexual function and in frequency of sexual intercourse in early postmenopausal women. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate, in healthy postmenopausal women, the impact of tibolone (2.5 mg), transdermal estradiol (50 mg) (TE) and different oral estrogen-progestin regimens, conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (5 mg) (CEE+MPA) and estradiol (2 mg) plus norethisterone acetate (1 mg) (E2 + NETA) on circulating estradiol, progesterone, allopregnanolone, cortisol and dehydroepiandrosterone (DHEA) levels. Blood samples were collected before and after 1, 3, 6 and 9 months of treatment in 85 postmenopausal women. Estradiol levels increased (p < 0.001) in the TE, CEE+MPA and E2 +NETA groups after 1 month of therapy, but did not change in the tibolone group during the entire follow-up period. Both E2+NETA and tibolone treatments induced an increase in progesterone levels (p < 0.05) after 1 year of therapy. Allopregnanolone levels showed an increase in all estrogenbased groups, being significant after 3 months of treatment (p<0.01). Patients receiving tibolone showed a significant increase in allopregnanolone levels at 3 months (p<0.05), but lower than in the other groups. Cortisol levels decreased significantly in the TE and CEE+MPA groups after 6 months and 12 months of treatment, respectively. Neither tibolone nor E2+NETA treatments modified circulating cortisol levels. DHEA levels significantly (p<0.05) decreased after 6 months of TE or estrogen-progestin therapies independently of the presence or the type of progestin used. In contrast, DHEA remained stable throughout the 12 months of treatment with tibolone. The increase of allopregnanolone, a steroid with sedative and anxiolytic properties, in response to these different treatments could underlie, at least in part, the central effects that hormone replacement therapy and tibolone have on anxiety, mood and behavior. Unlike estrogen-based therapy, tibolone treatment did not reduce the DHEA milieu in the menopause, and thus did not enhance the androgen deficiency syndrome in postmenopausal women. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether a virtual reality workstation (Fetouch system) offering three-dimensional (3D)fetal visual and kinesthetic interaction may affect maternal stress.Methods: Maternal-fetal visual and kinesthetic interaction was obtained through a haptic interface based on 3D reconstruction of sequencial bi-dimensional ultrasound images of the fetus. Maternal stress was assessed before and after visual/kinesthetic interaction with the fetus: 1) by using the State Trait Anxiety Inventory-Form Y (STAI) test, and 2) by measuring salivary cortisol levels. Statistical analysis was performed by paired t test and analysis of variance for repeated measures.Results: After the fetal visual and kinesthetic experiences, a significant reduction was observed in anxiety (low state anxiety group, P < .0034; high state anxiety group, P < .0108), as well as in salivary cortisol concentration (P < .0004).Conclusion: Physical interaction with thefetus through a 3D model may reduce maternal stress. [ABSTRACT FROM PUBLISHER]

Several studies have been performed during recent years to investigate the existence of a possible endocrine cause for premenstrual syndrome (PMS); the results reported are often discordant, Great interest has been raised around allopregnanolone, which could be involved in the determination of mood disorders reported by PMS patients. During the luteal phase, lower levels of this hormone have been detected in PMS patients. The aim of our study was to evaluate estradiol, progesterone dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS). androstenedione, total and free testosterone, cortisol, pregnenolone and allopregnanolone levels in 20 patients suffering from PMS and to compare them with those found in 20fertile healthy women in the follicular and the luteal phases. Adrenocorticotropic hormone (ACTH) tests after dexamethasone suppression were per-formed in 10 patients of each group during the follicular and the luteal phases. In the PMS group, significantly lower allopregnanolone levels were found in the luteal phase, while progesterone was lower in the PMS group in both phases. In the PMS group, higher free testosterone level were found during the luteal phase and higher DHEA levels in both the follicular and the luteal phases. The present data confirm reduced allopregnanolone levels in the luteal phase in PMS patients, together with higher levels of DHEA and free testosterone. It is possible to conclude that, in addition to the previously described reduced literal secretion of allo-pregnanolone, the adrenal gland production of this steroid in PMS sufferers is also impaired in the luteal phase. Considering the specific actions of these hormones on the control of mood and behavior, this specific hormonal milieu may contribute to the cyclic occurrence of anxiety, aggressiveness and irritability reported by PMS patients. [ABSTRACT FROM AUTHOR]

Objective: Animal data suggest that neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3a,5a-THP), dehydroepiandrosterone (DHEA), and its sulfated metabolite (DHEA-S), are involved in the modulation of eating behavior, aggressiveness, mood, and anxiety. Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders characterized by abnormal eating patterns, depressive and anxious symptoms, enhanced aggressiveness, and endocrine alterations. Previous studies reported decreased blood levels of DHEA and DHEA-S in small samples of anorexic patients, whereas no study has been performed to evaluate the secretion of these neuroactive steroids in BN as well as the production of 3alpha,5alpha-THP in both AN and BN. Therefore, we measured plasma levels of DHEA, DHEA-S, 3alpha,5alpha-THP and other hormones in patients with AN or BN and explored possible relationships between neuroactive steroids and psychopathology.Method: Ninety-two women participated in the study. There were 30 drug-free AN patients, 32 drug-free BN patients, and 30 age-matched, healthy control subjects. Blood samples were collected in the morning for determination of hormone levels. Eating-related psychopathology, depressive symptoms, and aggressiveness were rated by using specific psychopathological scales.Results: Compared with healthy women, both AN and BN patients exhibited increased plasma levels of 3alpha,5alpha-THP, DHEA, DHEA-S, and cortisol but reduced concentrations of 17beta-estradiol. Plasma testosterone levels were decreased in anorexic women but not in bulimic women. Plasma levels of neuroactive steroids were not correlated with any clinical or demographic variable.Conclusions: These findings demonstrate increased morning plasma levels of peripheral neuroactive steroids in anorexic and bulimic patients. The relevance of such hormonal alterations to the pathophysiology of eating disorders remains to be elucidated. [ABSTRACT FROM AUTHOR]

Oestrogen, progestagens and androgens are able to modulate several brain functions. Receptors for gonadal steroids have been identified in several brain areas: amygdala, hippocampus, cortex, basal forebrain, cerebellum, locus coeruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypothalamus and central grey matter. The mechanism of action of sex steroids at this level is similar to that observed in the peripheral target organs, including both genomic and non-genomic effects. The increased use of sex steroid hormone derivative therapies has lead to study of the biochemical and metabolic properties of the different progestin molecules available in hormonal therapies. In particular, experimental and clinical studies focused the attention of researchers on interactions between oestrogens and progestins in the neuroendocrine control of the brain functions and its clinical implications. Moreover, steroids are also synthesized de novo in the brain or may be derived from the conversion of blood-borne precursors, suggesting that the brain is also a source of steroids, named neurosteroids. Neurosteroids exert non-classical rapid actions as allosteric agonists of γ-aminobutyric acid receptor A (GABAA) and also modulate classic neurotransmitters in the brain. In addition, progesterone derivatives, e.g. pregnanolone, and 3α 5α-OH THP (allopregnanolone) are synthesized de novo by astrocytes and oligodendrocites starting from cholesterol. Physiological or pathological modifications of the synthesis and release of neurosteroids play a relevant role in the control of brain function. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate whether a virtual reality workstation (Fetouch system) offering three-dimensional (3D) fetal visual and kinesthetic interaction may affect maternal stress. Methods: Maternal-fetal visual and kinesthetic interaction was obtained through a haptic interface based on 3D reconstruction of sequencial bi-dimensional ultrasound images of the fetus. Maternal stress was assessed before and after visual/kinesthetic interaction with the fetus: 1) by using the State Trait Anxiety Inventory-Form Y (STAI) test, and 2) by measuring salivary cortisol levels. Statistical analysis was performed by paired t test and analysis of variance for repeated measures. Results: After the fetal visual and kinesthetic experiences, a significant reduction was observed in anxiety (low state anxiety group, P < .0034; high state anxiety group, P < .0108), as well as in salivary cortisol concentration (P < .0004). Conclusion: Physical interaction with the fetus through a 3D model may reduce maternal stress. [Copyright &y& Elsevier]

Semen samples are known to contain abnormal amounts of reactive oxygen species (ROS) and oxygen free radicals; therefore, the identification of antioxidant molecules able to counteract the oxidative damage caused by ROS is foresight. Indeed, improving semen quality in terms of motility and reduction in DNA damage, can significantly improve the fertilization potential of sperm in vitro. To this regard, myo-inositol, based on its antioxidant properties, has been reported to be effective in improving sperm quality and motility in oligoasthenozoospermic patients undergoing assisted reproduction techniques when used as a dietary supplementation. Moreover, in vitro treatment demonstrated a direct relationship between myo-inositol, mitochondrial membrane potential and sperm motility. This experimental study aimed to evaluate the effects of myo-inositol (Andrositol-lab) in vitro treatment on sperm motility, capacitation, mitochondrial oxidative phosphorylation and DNA damage. Our results demonstrate that myo-inositol induces a significant increase in sperm motility and in oxygen consumption, the main index of oxidative phosphorylation efficiency and ATP production, both in basal and in in vitro capacitated samples. Moreover, we provide evidence for a significant protective role of myo-inositol against oxidative damage to DNA, thus supporting the in vitro use of myo-inositol in assisted reproductive techniques. Even if further studies are needed to clarify the mechanisms underlying the antioxidant properties of myo-inositol, the present findings significantly extend our knowledge on human male fertility and pave the way to the definition of evidence-based guidelines, aiming to improve the in vitro procedure currently used in ART laboratory for sperm selection.

Controlled ovarian stimulation (COH) in PCOS is a challenge for fertility expert both ovarian hyperstimulation syndrome (OHSS) and oocytes immaturity are the two major complication. Ovarian response to COH vary widely among POCS patients and while some patients are more likely to show resistance to COH, other experienced an exaggerated response. The aim of our study is to investigate a possible correlation between PCOS phenotypes and the variety of ovarian response to COH and ART outcomes in patients with different PCOS phenotypes. We retrospectively analyzed a total of 71 cycles performed in 44 PCOS infertile patients attending ART at Centre of Infertility and Assisted Reproduction of Pisa University between January 2013 and January 2016. Patientsundergoing IVF with GnRH-antagonist protocol and 150-225 UI/days of recombinant FSH; triggering was carried out using 250 mg of recombinant hCG or a GnRH analogous on the basis of the risk to OHSS. We observed that Phenotype B had a tendency to have a greater doses of gonadotropins used respect to all phenotypes. Phenotype A group showed a greater serum estrogen levels compared to all phenotypes groups, a greater number of follicles of diameter between 8-12 mm found by ultrasound on the day of triggering and a greater mean number of freeze embryo. Additionally serum AMH and antral follicles count (AFC) follow the same trend in the different phenotypes ad they were significantly higher in phenotype A and in phenotype D. In conclusion this study shows that the features of PCOS phenotypes reflect the variety of ovarian response to COH as well as the risks to develop OHSS. Serum AMH and AFC are related to the degree of ovulatory dysfunction making these 'added values' in identifying the different PCOS phenotypes. Phenotype A seems to be the phenotype with the higher risk to develop OHSS and the use of GnRH as a trigger seems to improve oocyte quality. To classify PCOS phenotype at diagnosis might help clinicians to identify patients at greater risk of OHSS, customize therapy and subsequently plan the trigger agent.

Introduction: Polycystic ovary syndrome (PCOS) is a common cause of female infertility affecting multiple aspects of a women's health., Areas Covered: The aim of this review is to summarize the existing evidence on the treatment of PCOS patients and to examine the actual available therapies to overcome the problem of infertility and improve the outcome of pregnancy. We analyse different treatment strategies such as lifestyle modification, bariatric surgery, insulin sensitizing agents, inositol, clomiphene citrate (CC), aromatase inhibitors, gonadotrophins, laparoscopic ovarian drilling, and assisted reproductive techniques (ART)., Expert Commentary: Lifestyle modification is the best initial management for obese PCOS patients seeking pregnancy and insulin sensitizing agents seem to have an important role in treating insulin resistance. Up to now, CC maintains a central role in the induction of ovulation and it has been confirmed as the first-line treatment; the use of gonadotrophins is considered the second-line in CC resistant patients; laparoscopic ovarian drilling is an alternative to gonadotrophins in patients who need laparoscopy for another reason. However, in anovulatory patients, ART represents the only possible alternative to obtain pregnancy. Larger and well-designed studies are needed to clarify the best way to improve the outcome of pregnancy in PCOS women.

Reproductive hormones influence breast cancer development and progression. While the actions of sex steroids in this setting are established, tentative evidence suggests that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may also play a role, yet this remains elusive. We here identify that T-47D breast cancer cells express functional receptors for FSH and LH, and that these hormones regulate breast cancer cell motility and invasion through the control of the actin cytoskeleton and the formation of cortical actin aggregates and focal adhesion complexes. Such actions are mediated by the cytoskeletal controllers Moesin and focal adhesion kinase (FAK). Moesin is recruited rapidly by FSH and LH through a signaling cascade requiring the G protein Gα 13 and the Rho-associated kinase, ROCK-2. FSH and LH activate FAK via a Gα i /β and c-Src-dependent signaling cascade. Both cascades involve signaling to phosphatidylinositol-3 kinase and Akt. FSH and LH receptors and the related signaling intermediates are necessary for the actions of gonadotrophins on breast cancer cell cytoskeletal rearrangement, migration and invasion. These findings provide original information on the actions of gonadotrophins on breast cancer cells and may have clinical implications for the use of drugs that modulate gonadotrophins in breast cancer patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To analyze the results obtain in cancer patients who receive the same controlled ovarian stimulation protocol, started in two different moments of the menstrual cycle, follicular or luteal phase. The stimulation is performed before cancer treatment in order to preserve fertility through oocytes cryopreservation., Study Design: The study is a retrospective analysis about 25 cancer patients at our centre, Department of Reproductive Medicine of University of Pisa, in order to preserve their fertility before cancer treatment. Patients are divided into two groups depending on the menstrual cycle phase, follicular or luteal phase, at the moment of first examination. Standard stimulation protocol with gonadotropins is administered in the follicular group, whereas in the second group we use GnRH (gonadotropin-releasing hormone) antagonist before gonadotropins administration in order to have a rapid luteolysis. The outcome measures are the number of days needed before starting procedure, duration of stimulation, cumulative dosage of gonadotropins number of oocyte retrieved and percentage of mature oocytes., Results: Any difference showed between two groups based on days of stimulation, total amount of gonadotropins administered and the number of good mature quality oocytes was retrieved. The real difference is the number of days needed to start the procedure, lesser in the luteal group., Conclusions: This study suggests that oocytes can be obtained before cancer treatment, irrespective of menstrual cycle phase without compromising the efficacy of procedure. Moreover, starting ovarian stimulation anytime during menstrual cycle allows the patients to not postpone the beginning of cancer treatment. Different stimulation protocols, according to different kinds of disease, are available in order to obtain the maximum results without any complication for patients.

Background: Brain-derived neurotrophic factor (BDNF) is strongly related to hormonal networks and is modulated by hypothalamic activity., Objective: To evaluate plasma BDNF concentration in patients with functional hypothalamic amenorrhea (FHA), with reference to the BDNF circadian rhythm and its relation with the cortisol (F) rhythm, and to assess whether the duration of amenorrhea might influence the BDNF:F ratio in FHA., Design: This was an observational study evaluating 36 amenorrheic and 30 eumenorrheic women., Setting: Basal values of BDNF and hormones were examined in blood samples collected from 7:00 to 9:00 h in all the women. Basal BDNF and F levels were determined in blood samples collected in 12 subjects from each group at 8:00, 12:00, 16:00, 20:00, and 24:00 h., Results: BDNF plasma levels are significantly lower in amenorrheic women (p < 0.001) than in the follicular phase of eumenorrheic women. There are no correlations between BDNF values (p > 0.05), sex steroids, and F in FHA. Low plasma BDNF levels in FHA are not significantly correlated with duration of amenorrhea. The 24-hour variation of BDNF in amenorrheic women is significantly lower when compared to the control group, and normal daily variations of BDNF disappeared in FHA patients. F preserved its circadian rhythm in both groups., Conclusions: Interactions between BDNF, the hypothalamus-pituitary-adrenal axis, and sex steroids might be critical in clinical conditions of modified homeostasis/adaptation, such as FHA., (© 2015 S. Karger AG, Basel.)

Introduction: Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and synaptic plasticity. BDNF is known to circulate in plasma and its levels are strictly linked to the sex hormones., Aim: The aim of this study was to assess the plasma BDNF concentration in patients with Turner syndrome (TS). This is a first of such study in TS women., Methods: 31 TS patients were enrolled to the study and compared with a control group (10 healthy, ovulatory women). We collected blood for measurement of BDNF plasma concentration, estradiol (E2) and gonadotrophins serum levels. The blood was taken after overnight fasting, in menstruating women in follicular phase., Results: We found that BDNF plasma concentration was significantly higher in the group of TS patients compared to the control group (mean 768.5 ± 194.9 pg/ml versus 407.2 ± 25.7 pg/ml; p < 0.0001). What is more, the BDNF levels in TS were not correlated to E2 levels, whereas in the control group, positive and strong correlation with E2 was found (r = 0.92; p < 0.0001). The testosterone concentration correlated strongly with BDNF levels in TS patients., Conclusions: In this study, we showed for the first time that TS patients has a higher BDNF levels than healthy ones and BDNF is not correlated with E2 concentration but tend to be related to testosterone. This study brings interesting insights to BDNF physiology.

Introduction: Functional hypothalamic amenorrhea (FHA) is a non organic, secondary amenorrhea related to gonadotropin-releasing hormone pulsatile secretion impairment. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of survival-promoting molecules, plays an important role in the growth, development, maintenance and function of several neuronal systems., Aim of the Study: The aim of the study was the evaluation of plasma BDNF concentrations in patients with the diagnosis of FHA., Material and Methods: We studied 85 subjects diagnosed with FHA who were compared with 10 healthy, eumenorrheic controls with normal body mass index. Plasma BDNF and serum luteinizing hormone, follicle-stimulating hormone and estradiol (E2) concentrations were measured by immunoenzymatic method (enzyme-linked immunosorbent assay)., Results: Significantly lower concentration of plasma BDNF was found in FHA patients (196.31 ± 35.26 pg/ml) in comparison to healthy controls (407.20 ± 25.71 pg/ml; p < 0.0001). In the control group, there was a strong positive correlation between plasma BDNF and serum E2 concentrations (r = 0.92, p = 0.0001) but in FHA group it was not found., Conclusions: Role of BDNF in FHA is not yet fully understood. There could be found studies concerning plasma BDNF concentrations in humans and animals in the literature. However, our study is one of the first projects which describes decreased plasma BDNF concentration in patients with diagnosed FHA. Therefore, further studies on BDNF in FHA should clarify the role of this peptide.

Background: Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system., Methods: Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12)., Results: Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring., Conclusion: Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life.

Problem: The aim of this study was to verify whether anti-thyroid antibodies are present in the follicular milieu of euthyroid infertile women with thyroid autoimmunity undergoing in vitro fertilization (IVF) and whether IVF outcome is different in affected women with respect to negative controls. A secondary endpoint was to check whether there are changes in thyroid hormone levels during the IVF cycle., Method of Study: Anti-thyroglobulin and anti-thyroperoxidase levels were measured in both follicular fluid and serum on the day of oocyte retrieval in women with thyroid autoimmunity. Serum TSH, FT3, and FT4 levels were measured in all patients before treatment initiation, on the day of oocyte retrieval and of pregnancy test. IVF outcome parameters were recorded in all women., Results: Oocyte fertilization, grade A embryos, and pregnancy rates were lower in women with thyroid autoimmunity than in negative controls, while early miscarriage rate was higher. Anti-thyroid antibodies were measurable in follicular fluid in all affected women and were strongly correlated with serum levels. No significant changes in thyroid hormone levels were recorded in any women., Conclusion: The presence of anti-thyroid antibodies in ovarian follicles, as demonstrated for the first time in this study, may play a critical role in female infertility related to thyroid autoimmunity., (© 2011 John Wiley & Sons A/S.)

Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms that begin during the late luteal phase of the menstrual cycle and disappear after the onset of menses. Since PMS might be caused by an alteration in the cyclical hormonal modifications and ovarian steroids are directly involved in the regulation of mood, affective and cognitive functions and influence neurotrophins expression, in particular the brain-derived neurotrophic factor (BDNF), we aimed to evaluate whether plasma BDNF levels in women with PMS differ from those of normally menstruating women without PMS. Sixty-two women were divided into two groups: one group of women (n=35) with PMS and one group (n=27) composed by normally menstruating women. Plasma samples were collected at day 7 (follicular phase) and day 21 (luteal phase) of the menstrual cycle. Plasma BDNF of the control group significantly increased (p<0.001) from the follicular phase (402.90±74.41pg/ml) to the luteal phase (1098.79±146.49pg/ml). On the other hand, in the PMS group plasma BDNF levels significantly decreased (p<0.001) from the follicular phase (412.45±78.35pg/ml) to the luteal phase (233.03±75.46pg/ml) Luteal BDNF levels of the PMS women were significantly lower than those of the control group (p<0.001). In women with PMS, plasma BDNF followed a decreasing trend during the ovarian cycle, in opposition to the increasing trend observed in women without PMS. The lower luteal BDNF levels of the PMS women might be a consequence of an altered hormonal response and might play a role in the onset of the symptoms PMS related., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Weight gain is a well-known unwanted effect of valproic acid (VPA) therapy. Studies on VPA-associated changes of homeostatic hormones remain limited and controversial. Allopregnanolone (AP) is a circulating neuroactive steroid involved in modulation of behavioral activities whose serum levels are increased in obese children. The aim of the present study was to determine whether VPA therapy affects leptin and AP circulating levels in prepubertal girls with epilepsy. One-hundred and one patients were divided into four groups: epileptic patients with VPA-associated obesity (n = 21); lean epileptic patients under VPA therapy (n = 35); healthy obese children (n = 23), and healthy lean children (n = 22). Patients with VPA-associated obesity had significantly enhanced blood concentrations of AP (p = 0.001) and leptin (p = 0.007) than lean subjects. There were no differences in leptin and AP plasma levels between patients with VPA-associated obesity and obese controls (p = 0.45 and p = 0.10, respectively), as there were no differences between lean patients under VPA therapy and lean healthy controls (p = 0.06). In patients under VPA therapy, both plasma leptin and AP levels were significantly correlated with BMI (r = 0.074, p = 0.02, and r = 0.084, p = 0.01, respectively). Plasma leptin concentrations were not correlated with AP levels (r = 0.023, p = 0.13). In conclusion, a correlation between obesity and neuroactive steroids was shown. It remains to be established whether the increased circulating level of AP is a secondary effect of anxiolytic-sedative processes occurring in subjects with obesity-related emotional and behavioral anomalies, or plays a central role in determining abnormal eating behaviors., (Copyright © 2010 S. Karger AG, Basel.)

Objective: To investigate the adrenal response in terms of allopregnanolone secretion in a group of hyperinsulinemic patients with polycystic ovary syndrome (PCOS)., Design: Controlled clinical study., Setting: Patients with PCOS in a clinical research environment., Patients: Twenty-two overweight patients with PCOS with hyperinsulinism were enrolled after informed consent., Interventions: All patients underwent hormonal evaluations, oral glucose tolerance test (OGTT) and adrenocorticotropic hormone (ACTH) test before and after 4 months of metformin administration (500 mg p.o. bi-daily). Ultrasound examinations and Ferriman-Gallway score were also performed. Main outcome measures. plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol, 17-hydroxy-progesterone (17OHP), androstenedione (A), testosterone (T), allopregnanolone, glucose, insulin, C peptide concentrations, body mass index (BMI)., Results: Metformin administration reduced significantly LH, A, T, insulin and BMI, while allopregnanolone was significantly increased with no change in progesterone plasma levels. Insulin response to OGTT decreased and allopregnanolone response to ACTH stimulation before while this was restored after the treatment interval. The Ferriman-Gallway score as well as the ovarian volume was significantly decreased after 4 months of metformin therapy., Conclusions: In overweight patients with PCOS with hyperinsulinism, allopregnanolone secretion is impaired and metformin administration restored normal allopregnanolone concentrations modulating both steroid syntheses from the ovaries and from adrenal gland.

Background: Synthetic progestins may have different biological actions depending on the target tissue, the dose administered or the coadministration of an estrogen molecule. The purpose of the present study was to evaluate the neuroendocrine effect of chlormadinone acetate (CMA) administration, analyzing the brain content of allopregnanolone (ALLO), an endogenous neurosteroid gamma-aminobutyric acid agonist with anxiolytic properties, and the brain level of beta-endorphin (beta-END), an endogenous opioid implicated in pain mechanism, emotional state and autonomic control., Study Design: Seven groups of Wistar ovariectomized (OVX) rats received one of the following treatments: oral CMA at a dose of 0.1, 0.5 or 1 mg/kg per day; estradiol valerate (E(2)V) at a dose of 0.05 mg/kg per day; CMA plus E(2)V (CMA 0.1 or 0.5 or 1 mg/kg per day + E(2)V 0.05 mg/kg per day) for 14 days. One group of fertile rats and one group of OVX rats were used as controls., Results: CMA increased ALLO content in the hippocampus and, when it was administered with E(2)V, also in the hypothalamus and anterior pituitary, evidence of a synergic effect with estrogens only in selective brain areas. beta-END content increased in the neurointermediate lobe and anterior pituitary after CMA administration, and it did not antagonize the positive, estrogen-induced increase of beta-END level., Conclusion: CMA is effective in increasing ALLO and beta-END in selective brain areas showing a specific pattern of interaction with brain function, different compared to progesterone or to other synthetic progestins. In particular, CMA action on part of the limbic system (hippocampus and hypothalamus) and on the anterior pituitary support the hypothesis that this progestin might affect cognitive function, emotional state and autonomic control.

Aims: The present study aims at evaluating the effect of a 2-week treatment with testosterone (T), dihydrotestosterone (DHT) and estradiol valerate (E(2)V) on brain and plasma beta-endorphin (beta-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 microg/kg/day (female rats) or 1 and 5 mg/kg/day (male rats). Subcutaneous DHT was administered at the doses of 1, 10, 100 microg/kg/day (female rats) or 0.1, 1 and 5 mg/kg/day (male rats). E(2)V was administered subcutaneously at 0.05 mg/kg/day. beta-END levels were measured in different brain areas and plasma., Results: Ovariectomy (OVX) induced a significant decrease in beta-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 E(2)V significantly increased beta-END concentration in all brain areas and in plasma. In the OCX group, T and E(2)V did not influence beta-END concentrations in different hypothalamic areas. However, they produced a significant rise in beta-END levels in the hypothalamus, neurointermediate lobe, anterior pituitary and plasma. Conversely, DHT replacement did not affect beta-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., (Copyright 2009 S. Karger AG, Basel.)

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.

Objective: To investigate the effects of dydrogesterone (DYD), a synthetic progestin largely used in hormone therapy, on the central nervous system by studying two markers of the neuroendocrine function: the neurosteroid allopregnanolone and the opioid beta-endorphin., Design: Experimental study on animal model., Setting: Academic research environment., Animal(s): 72 Wistar female rats., Intervention(s): One group of fertile and one of ovariectomized rats (receiving placebo) were used as control. After ovariectomy, the rats underwent a 2-week oral treatment of DYD (0.2, 0.6, or 1.0 mg/kg per day), alone or with estradiol valerate (E2V; 0.05 mg/kg per day)., Main Outcome Measure(s): Allopregnanolone and beta-endorphin, assessed in different brain areas and in circulation., Result(s): Ovariectomy decreased allopregnanolone anywhere except in the adrenal gland and reduced beta-endorphin central levels; E2V reversed the effects of ovariectomy; and DYD (1 mg/kg per day) increased allopregnanolone levels in frontal lobe, hippocampus, and hypothalamus. Combined administration of DYD at 1 mg/kg per day plus E2V determined a further increase of allopregnanolone levels in frontal lobe, hippocampus, hypothalamus, and serum. Dydrogesterone did not modify the levels of beta-endorphin induced by E2V., Conclusion(s): Dydrogesterone interacts with allopregnanolone levels (less with beta-endorphin), and it can be considered important modulator of the neuroendocrine function.