Correlation between allopregnanolone levels and depressive symptoms during late menopausal transition and early postmenopause.

OBJECTIVES: This observational, cross-sectional study included 140 women with climacteric symptoms. The aim of the study was to evaluate the correlation between the presence and severity of depressive symptoms and allopregnanolone levels in women during late menopausal transition and early postmenopause. METHODS: The study group was divided into two groups: 45 women in late menopausal transition and 95 early postmenopausal women. We evaluated Kupperman index, Hamilton scale and serum follicle-stimulating hormone, luteinizing hormone, 17ß-estradiol, prolactin, total testosterone, dehydroepiandrosterone sulfate and allopregnanolone levels. RESULTS: We found that serum allopregnanolone concentration was lower in early postmenopausal women compared to women in late menopausal transition; that there was a correlation between serum allopregnanolone levels in early postmenopausal women and time since last menstruation, intensity of climacteric symptoms, and intensity of depression symptoms and that there was a correlation between serum allopregnanolone levels and several depression symptoms presence (shallow sleep and symptoms of the digestive tract in women during late menopause transition; feelings of guilt, sleep disorders and general somatic symptoms in early postmenopausal women). CONCLUSION: We concluded that reproductive aging is characterized by a reduction of allopregnanolone circulating levels that correlate to Hamilton depression index in early postmenopause and presence of specific depressive symptoms during late menopausal transition and early postmenopause.

Brain-derived neurotrophic factor plasma levels in patients with Turner syndrome.

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.

Decreased plasma concentrations of brain-derived neurotrophic factor (BDNF) in patients with functional hypothalamic amenorrhea.

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.

Anxiolytic properties of a 2-phenylindolglyoxylamide TSPO ligand: Stimulation of in vitro neurosteroid production affecting GABAA receptor activity.

A number of neurosteroids have been demonstrated to exert anxiolytic properties by means of a positive modulation of inhibitory GABAergic neurotransmission. The observation that neurosteroid synthesis can be pharmacologically regulated by ligands to the mitochondrial translocator protein (TSPO) has prompted the search for new, more selective TSPO ligands able to stimulate steroidogenesis with great efficacy. In the present study, the potential anxiolytic activity of a selective TSPO ligand, N,N-di-n-propyl-2-(4-methylphenyl)indol-3-ylglyoxylamide (MPIGA), was tested by means of the elevated plus maze paradigm. Moreover, the in vitro effects on synaptoneurosomal GABA(A) receptor (GABA(A)R) activity exerted by the conditioned salt medium from MPIGA-treated ADF human glial cells were investigated. MPIGA (30mg/kg) was found to affect rats' performance in the elevated plus maze test significantly, leading to an increase in both entries and time spent in the open arms. This same dose of MPIGA had no effect on rats' spontaneous exploratory activity. The conditioned salt medium from MPIGA-treated ADF cells potentiated the (36)Cl(-) uptake into cerebral cortical synaptoneurosomes. The exposure of ADF cells to MPIGA stimulated the production of pregnelonone derivatives including allopregnanolone, one of the major positive GABA(A)R allosteric modulator. In conclusion, the TSPO ligand MPIGA is a promising anxiolytic drug. The mechanism of action by which MPIGA exerts its anxiolytic activity was identified in the stimulation of endogenous neurosteroid production, which in turn determined a positive modulation of GABA(A)R activity, thus opening the way to the potential use of this TSPO ligand in anxiety and depressive disorders.

Metformin administration restores allopregnanolone response to adrenocorticotropic hormone (ACTH) stimulation in overweight hyperinsulinemic patients with PCOS.

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.

Paroxetine increases brain-derived neurotrophic factor in postmenopausal women.

OBJECTIVE: Menopause is marked by a decline in ovarian function resulting in one or more climacteric symptoms. In the last few years, attention has been focused on the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of vasomotor symptoms associated with the menopausal transition. Thanks to the recent findings on the interaction between the serotoninergic system and neurotrophins, it has been suggested that brain-derived neurotrophic factor (BDNF) could contribute to the activity of SSRIs. Moreover, because endogenous gonadal hormones modulate both BDNF expression and serotonin biosynthesis and bioavailability and regulate brain functions like affective and cognitive functions, we proposed to evaluate the effects of a treatment with paroxetine, an SSRI, in a group of postmenopausal women and to clarify the possible relationship between paroxetine, plasma BDNF levels, and climacteric symptoms. METHODS: A total of 119 postmenopausal women (age, 46-60 y; menopause age, 1-20 y) were included; 89 took paroxetine 10 mg/day for 6 months and 30 took estrogen + progestogen therapy (EPT) for 6 months. Blood samples were taken before the beginning of the therapy and at 3 and 6 months. The Green Climacteric Scale questionnaire was used to follow up women's clinical conditions. RESULTS: Plasma BDNF levels significantly increased after 3 and 6 months of therapy (P < 0.001), although a negative correlation between plasma BDNF level and both age and menopause age persisted throughout the treatment. Moreover, a significant reduction in the Greene Climacteric Scale score was observed. In the EPT group, the plasma BDNF level significantly increased after 6 months of therapy. The plasma BDNF levels after 6 months of paroxetine were significantly lower than those after 6 months of EPT. CONCLUSIONS: The present data suggest that a low dose of paroxetine is effective in enhancing plasma BDNF levels, and this increase might have a role in improving climacteric symptoms, highlighting the possible role of BDNF in endocrinological and cognitive functions.

Selective effect of chlormadinone acetate on brain allopregnanolone and opioids content.

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.

Sex differences in brain and plasma beta-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 (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.

Brain-region responsiveness to DT56a (Femarelle) administration on allopregnanolone and opioid content in ovariectomized rats.

OBJECTIVE: The natural selective estrogen receptor modulator DT56a (Femarelle), derived from soybean, has been shown to relieve menopausal vasomotor symptoms with no effect on sex steroid hormone levels or endometrial thickness.The purpose of the present study was to evaluate the neuroendocrine effect of DT56a administration through the evaluation of brain content of allopregnanolone (AP), an endogenous neurosteroid gamma-aminobutyric acid agonist with anxiolytic properties, and through the assessment of beta-endorphin (beta-END), the endogenous opioid implicated in pain mechanism, emotional state, and autonomic control. METHODS: Five groups of Wistar ovariectomized (OVX) rats received one of the following treatments: oral DT56a administration at doses of 6, 12, 60, and 120 mg kg(-1) day(-1) or estradiol valerate (E2V) at a dose of 0.05 mg kg(-1) day(-1) for 14 days. One group of fertile and one group of OVX rats receiving placebo were used as controls. The concentration of AP was assessed in the frontal and parietal cortex, hippocampus, hypothalamus, anterior pituitary, and serum, whereas the content of beta-END was evaluated in the frontal and parietal cortex, hippocampus, hypothalamus, neurointermediate lobe, anterior pituitary, and plasma. RESULTS: DT56a increased AP levels in all brain areas analyzed and in serum, with a classical dose-related curve in comparison with OVX rats. In some brain areas, such as the frontal cortex, the parietal cortex, and the anterior pituitary, positive results were found even with the administration of a lower DT56a dose of 60 mg kg(-1) day(-1), attaining AP levels in the range of those in animals treated with E2V. Similarly, beta-END levels were enhanced in selected brain areas such as the hippocampus, the hypothalamus, the neurointermediate lobe, and the anterior pituitary in comparison with those in OVX rats, in which the increase of the opioid was dose related and in the range of those in rats treated with E2V. CONCLUSIONS: This study demonstrated that DT56a positively affects brain neurosteroidogenesis and the opiatergic system: DT56a exerts an estrogen-like effect on selective areas related to mood, cognition, and homeostasis control, presenting a specific pattern of interaction with the brain function. These findings may, in part, explain the clinical effect of DT56a on menopausal symptoms.

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.

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.

Androgens and the brain.

Steroids arriving from the gonads via the circulation modulate brain function, affecting gender differentiation and sexually differentiated behavioral responses, but also the ability of the brain to process, store and retrieve sensory information. Androgens play a pivotal neuroactive role during the "organizational/developmental" phase, mainly in the fetal-neonatal period, when participated to the formation of neuronal circuits, as well as during the aging process when it has been demonstrated to directly affect hippocampal spine synapse density, suggesting a physiopathological role for androgen in the modulation cognitive function and development of neurodegenerative disease. The present short review will focus on the neuroactive effect of androgen with particular regard to the Delta4 and Delta5 androgen replacement therapy.

Drospirenone increases central and peripheral beta-endorphin in ovariectomized female rats.

OBJECTIVE: Drospirenone is the unique progestin derived from 17-spironolactone used for contraception and hormone therapy. Few data are available concerning the effects of drospirenone on the central nervous system and neuroendocrine milieu. The opioid beta-endorphin and the neurosteroid allopregnanolone are considered markers of neuroendocrine functions, and their synthesis and activity are regulated by gonadal steroids. The aim of the present study was to evaluate the effect of a 2-week oral treatment with drospirenone, estradiol valerate, and combined therapy of drospirenone + estradiol valerate on central and peripheral beta-endorphin and allopregnanolone levels in ovariectomized female rats. DESIGN: Seven groups of Wistar ovariectomized rats received oral drospirenone (0.1, 0.5, and 1.0 mg/kg per day), estradiol valerate (0.05 mg/kg per day), or drospirenone (0.1, 0.5, and 1.0 mg/kg per day) + estradiol valerate (0.05 mg/kg per day). One group of fertile and one group of ovariectomized rats were used as controls. beta-endorphin levels were measured in frontal and parietal lobes, hippocampus, hypothalamus, anterior and neurointermediate pituitary, and plasma, and allopregnanolone content was assessed in frontal and parietal lobes, hippocampus, hypothalamus, anterior pituitary, adrenal glands, and serum. RESULTS: Ovariectomy induced a significant decrease in beta-endorphin and allopregnanolone content in all brain areas analyzed and in circulating levels, whereas it increased allopregnanolone content in the adrenal gland. Estradiol valerate replacement increased beta-endorphin and allopregnanolone levels in all brain areas analyzed and in plasma/serum. Drospirenone treatment significantly increased beta-endorphin levels in all brain areas analyzed (with the only exception being the parietal lobe), whereas it produced no effect on allopregnanolone levels. The addition of drospirenone to estradiol valerate did not modify the effects of estradiol valerate on beta-endorphin or allopregnanolone levels. Drospirenone showed an additive and synergistic effect with estradiol in the neurointermediate lobe on beta-endorphin synthesis. CONCLUSIONS: Drospirenone significantly increases central and circulating beta-endorphin levels and does not seem to interfere with allopregnanolone production.

Estrogen, cognition and female ageing.

Starting from fetal life, estrogens are crucial in determining central gender dimorphism, and an estrogen-induced synaptic plasticity is well evident during puberty and seasonal changes as well as during the ovarian cycle. Estrogens act on the central nervous system (CNS) both through genomic mechanisms, modulating synthesis, release and metabolism of neurotransmitters, neuropeptides and neurosteroids, and through non-genomic mechanisms, influencing electrical excitability, synaptic function and morphological features. Therefore, estrogen's neuroactive effects are multifaceted and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protecting against a wide range of neurotoxic insults. Clinical evidences show that, during the climacteric period, estrogen withdrawal in the limbic system gives rise to modifications in mood, behaviour and cognition and that estrogen administration is able to improve mood and cognitive efficiency in post-menopause. Many biological mechanisms support the hypothesis that estrogens might protect against Alzheimer's disease (AD) by influencing neurotransmission, increasing cerebral blood flow, modulating growth proteins associated with axonal elongation and blunting the neurotoxic effects of beta-amyloid. On the contrary, clinical studies of estrogen replacement therapy (ERT) and cognitive function have reported controversial results, indicating a lack of efficacy of estrogens on cognition in post-menopausal women aged >or=65 years. These findings suggest the presence of a critical period for HRT-related neuroprotection and underlie the potential importance of early initiation of therapy for cognitive benefit. In this review, we shall first describe the multiple effects of steroids in the nervous system, which may be significant in the ageing process. A critical update of HRT use in women and a discussion of possible prospectives for steroid use are subsequently proposed.

Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women.

OBJECTIVE: The aging process is associated with a decline in the circulating Delta5-androgen dehydroepiandrosterone (DHEA) and its sulfate ester, dehydroepiandrosterone sulfate (DHEAS). The present study aimed to evaluate the effects of a long-term (12 months) oral DHEA administration (25 mg/day) on adrenal function, before and after 3, 6 and 12 months of treatment. METHOD: Postmenopausal women belonging to two age groups, 50-55 years (n = 10) and 60-65 years (n = 10), were studied. Adrenal function was assessed in basal conditions, after suppression with dexamethasone (DXM) and following a stimulation test with adrenocorticotropic hormone (ACTH) (10 microg bolus). Serum levels of DHEA, DHEAS, androstenedione (Delta4-A), allopregnanolone, 17-hydroxyprogesterone (17-OHP) and cortisol were measured and the effects of DHEA supplementation on specific adrenal enzymatic pathways were evaluated by calculating precursor/product ratios (17-OHP/cortisol, 17-OHP/Delta4-A, DHEA/Delta4-A and DHEA/DHEAS). RESULTS: DHEA supplementation annulled the age-related differences in DHEA and DHEAS levels and induced a marked increase in all steroids, except for cortisol, after 3-6 months of treatment. Serum cortisol levels decreased from the 3rd month, both in younger and older subjects. DHEA supplementation did not affect DXM-induced suppression of adrenal steroidogenesis. During the treatment period all adrenal androgens and progestins showed a significant increase in their response to ACTH, while the cortisol response decreased significantly. The results suggest a significant DHEA-induced change in adrenal enzymatic activities, as also evidenced by the change in precursor/product ratios during therapy. CONCLUSION: Chronic DHEA administration is capable of modifying circulating levels of androgens and progestins in both early and late postmenopausal women by modulating the age-related changes in adrenal function.

Progesterone and medroxyprogesterone acetate effects on central and peripheral allopregnanolone and beta-endorphin levels.

The increased use of hormonal therapies has led to the study of the properties of different progestin molecules and their effects on the central nervous system. The central and peripheral levels of neurosteroid allopregnanolone and the opioid peptide beta-endorphin (beta-END) are regulated by estrogens. The aim of the present study was to investigate the effects of a 2-week oral treatment with micronized progesterone or medroxyprogesterone acetate (MPA) alone or in addition to estradiol valerate (E2V) on central and peripheral allopregnanolone and beta-END levels in ovariectomized (OVX) female rats. Thirteen groups of Wistar OVX rats received one of the following treatments: oral progesterone (2, 4 or 8 mg/kg/day); oral MPA (0.05, 0.1 or 0.2 mg/kg/day); E2V (0.05 mg/kg/day); E2V + progesterone (0.05 mg/kg/day + 2, 4 or 8 mg/kg/day), or E2V + MPA (0.05 mg/kg/day + 0.05, 0.1 or 0.2 mg/kg/day) for 14 days. One group of fertile and one group of OVX rats were used as controls. The concentration of allopregnanolone was assessed in the frontal and parietal lobes, hypothalamus, hippocampus, anterior pituitary, adrenals and serum, while the beta-END content was assessed in the frontal and parietal lobes, hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma. E2V administration reverted the ovariectomy-induced reduction in allopregnanolone and beta-END. Progesterone and MPA increased allopregnanolone levels in all tissues except in the adrenal gland. The combined administration of progesterone or MPA and E2V determined a further increase in allopregnanolone levels with respect to E2V alone except in the adrenal gland and hippocampus only after MPA treatment. Progesterone did not affect beta-END levels in the frontal and parietal lobes, hippocampus and anterior pituitary, while it caused an increase plasma, hypothalamic and neurointermediate pituitary beta-END levels. MPA only affected beta-END levels in the hippocampus and in the neurointermediate lobe. The combined administration of progesterone or MPA and E2V did not alter the effect of estradiol or it determined a further dose-dependent increase in beta-END levels. In conclusion, this study demonstrates that progesterone and MPA have a similar but not identical effect on central and peripheral allopregnanolone and beta-END levels. Their association with an estrogenic compound does not interfere with the positive effects produced by estrogen on allopregnanolone and beta-END brain content.

Clinical evaluation of patients with weight loss-related amenorrhea: neuropeptide Y and luteinizing hormone pulsatility.

AIM: To characterize patients with weight loss-related amenorrhea and controls with respect to the pulsatility of neuropeptide Y (NPY) and luteinizing hormone (LH). SUBJECTS: Nine young women (aged 20.23+/-2.11 years) diagnosed with weight loss-related amenorrhea (body mass index (BMI) 17.52+/-2.43 kg/m2) and five age-matched (age 21.88+/-3.12 years) normally menstruating (every 28-33 days) controls with normal BMI (23.62+/-3.11 kg/m2) (mean value+/-standard deviation). METHODS: Basal hormonal evaluation included serum follicle-stimulating hormone (FSH), LH, estradiol (E2) and NPY. A pulsatility study investigated NPY and LH episodic release. Patients from control the group were studied during the mid-follicular phase (days 6-8) of the menstrual cycle. RESULTS: Patients with weight loss-related amenorrhea had lower FSH, LH and E2 levels than controls (p < 0.01). Basal serum NPY levels were lower in amenorrheic patients than in menstruating women (p < 0.01). The numbers of NPY and LH peaks were higher in patients with weigh loss-related amenorrhea than in controls (p < 0.01 and p < 0.05, respectively). CONCLUSION: Increased NPY pulsatility may have pathophysiological significance in weight loss-related hypothalamic amenorrhea.

Effect of tibolone administration on central and peripheral levels of allopregnanolone and beta-endorphin in female rats.

OBJECTIVE: We evaluated the effects of tibolone oral administration on neuroendocrine function by investigating the modulation exerted by tibolone administration on allopregnanolone and central and peripheral beta-endorphin (beta-EP) levels in ovariectomized rats. DESIGN: Female Wistar rats (N = 64) were included: 48 rats were ovariectomized, 8 cycling rats were included as controls, and 8 cycling rats were treated with placebo. The ovariectomized animals were divided into six groups: untreated rats and those that received 14-day oral treatment with either placebo, estradiol valerate (E2V) 0.05 mg/kg/d, or tibolone (0.1, 0.5, or 2 mg/kg/d. beta-EP levels were assessed in the frontal lobe, parietal lobe, hippocampus, hypothalamus, anterior pituitary, neurointermediate pituitary, and plasma, whereas allopregnanolone levels were measured in the frontal lobe, parietal lobe, hippocampus, hypothalamus, anterior pituitary, adrenal glands, and serum. RESULTS: The administration of tibolone (0.5 and 2 mg/kg/d) in ovariectomized rats induces a significant increase of allopregnanolone in the frontal lobe, parietal lobe, hippocampus, hypothalamus, whereas in serum a significant increase of allopregnanolone occurs only with the dose of 2 mg/kg/d, a significant decrease in allopregnanolone levels occurs in the adrenal glands. No changes occurred in the anterior pituitary. Tibolone doses of 0.5 and 2 mg/kg/d induced a significant increase in beta-EP content in the frontal lobe, hypothalamus, and neurointermediate lobe; and, at doses of 2 mg/kg/d, in the parietal lobe, anterior pituitary, and plasma, without changes in the hippocampus. Compared with E2V, 0.5 mg/kg/d tibolone showed a similar effect on allopregnanolone and beta-EP in most brain regions. CONCLUSIONS: Tibolone administration affects beta-EP and allopregnanolone levels, playing a role as a neuroendocrine modulator.

Metformin administration modulates neurosteroids secretion in non-obese amenorrhoic patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disease that is observed frequently to be related to increased insulin resistance. The use of insulin-sensitizer compounds, such as metformin, permits great improvement of such metabolic abnormality and the restoration of normal ovarian function. Metformin administration reduces insulin resistance and androgen production both from the ovary and adrenal gland. AIM: On this basis we aimed to evaluate a group of non-obese amenorrheic PCOS patients before and after 6 months of metformin administration (500 mg per os twice daily) to better understand what changes might be induced by metformin on adrenal and ovarian function and in terms of temporal coupling of the pulsatile profiles of luteinizing hormone (LH), cortisol and allopregnanolone, the latter representative of the neurosteroid family. METHOD: A group of non-obese PCOS patients (n = 8) was enrolled after informed consent and underwent to a pulsatility study for LH, cortisol and allopregnanolone, and an oral glucose tolerance test before and on day 7 of the first menstrual cycle occurring after the 5th month of treatment. RESULTS: Plasma androgen levels were decreased significantly by metformin treatment, as were plasma LH and allopregnanolone levels and insulin resistance. Metformin administration decreased LH pulse amplitude but not pulse frequency. On the contrary, cortisol and allopregnanolone showed a significant change in pulse frequency. When temporal coupling was tested between pulsatile profiles of LH or cortisol with allopregnanolone, cortisol pulses were temporally coupled to allopreganolone peaks both before and under metformin administration while LH pulses were temporally coupled to allopreganolone secretory peaks only under metformin treatment. CONCLUSIONS: Our data demonstrate that metformin administration modulates LH secretion as well as cortisol and allopregnanolone pulsatile release. In addition, the results demonstrate that adrenal and ovarian steroidogenic activity is greatly modulated by any change in insulin sensitivity.

Impaired reduction of enhanced levels of dehydroepiandrosterone by oral dexamethasone in anorexia nervosa.

Allopregnanolone and dehydroepiendrosterone (DHEA) have been supposed to be involved in some psychiatric disorders including anorexia nervosa (AN). The secretion of DHEA and allopregnanolone occurs in both the brain and the adrenal gland, where it is under the control of the corticotrophin-releasing factor (CRF)/adrenocorticotrophin hormone (ACTH) system, and, according to the increased CRF/ACTH drive found in AN, we previously reported enhanced morning levels of both DHEA and allopregnanolone in underweight anorexic patients. To further characterize the physiology of these neurosteroids in AN, we measured plasma levels of cortisol, DHEA and allopregnanolone after the oral administration of 1 mg dexamethasone at 800h in six underweight AN women and ten age-matched healthy females. We found that, before dexamethasone administration, both cortisol and DHEA plasma concentrations were significantly increased in anorexic patients as compared to controls, whereas plasma allopregnanolone levels although increased in the former did not reach a statistical significance. Moreover, while cortisol levels after dexamethasone administration were suppressed in AN to values similar to normal controls, DHEA concentrations, although significantly decreased, remained higher than in normal controls. These data support the view that in AN, the increased production of DHEA may be linked to mechanisms other than the enhanced CRF/ACTH drive.