BACKGROUND Plasma brain-derived neurotrophic factor (BDNF) levels are associated with the hormonal status of women. Moreover, the suprachiasmatic nucleus appears to be implicated in the modulation of ...BDNF central levels. We aimed to investigate whether BDNF circadian rhythms exist in women and if there is a relationship with cortisol circadian rhythmicity. Moreover, we aimed to establish whether the hormonal status influences BDNF diurnal variations. METHODS A total of 30 women were studied: 10 fertile ovulatory women, 10 women undergoing oral contraceptive (OC) therapy and 10 post-menopausal women. Basal BDNF and estradiol levels were assayed in blood samples collected after overnight fasting at regular intervals (08:00, 12:00, 16:00, 20:00, 24:00). BDNF and cortisol levels were measured in samples collected during the follicular and luteal phases in ovulatory women and once a month in OC and post-menopausal women. RESULTS Luteal BDNF levels were significantly higher than follicular levels in fertile women (P < 0.001). In OC women, BDNF levels were similar to the follicular BDNF levels, whereas in post-menopausal women, they were significantly lower (P < 0.001). BDNF showed a diurnal rhythm in the follicular phase and in women undergoing OC, although the diurnal rhythm was blunted in the luteal phase. In post-menopausal women, BDNF and cortisol levels significantly decreased during the day. CONCLUSIONS BDNF has a diurnal variation in women that is somewhat analogous to cortisol variation; however, the amplitude of the variation in BDNF levels appears to be influenced by ovarian function. Interactions between BDNF, the hypothalamus–pituitary–adrenal axis and sex steroids might play a critical role in the human homeostasis and adaptation.
Steroid hormone receptors have been traditionally considered to act via the regulation of transcriptional processes, involving nuclear translocation and binding to specific response elements, and ...ultimately leading to regulation of gene expression. However, novel non-transcriptional mechanisms of signal transduction through steroid hormone receptors have been identified. These so-called 'non-genomic' effects do not depend on gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Several relevant biological actions of steroids have been associated with this kind of signaling. Ubiquitous regulatory cascades such as mitogen-activated protein kinases, the phosphatidylinositol 3-OH kinase and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptor modulation of cell membrane-associated molecules such as ion channels and G-protein-coupled receptors has been shown. TIssues traditionally considered as 'non-targets' for classical steroid actions are instead found to be vividly regulated by non-genomic mechanisms. To this aim, the cardiovascular and the central nervous system provide excellent examples, where steroid hormones induce rapid vasodilatation and neuronal survival via non-genomic mechanisms, leading to relevant pathophysiological consequences. The evidence collected in the past Years indicates that target cells and organs are regulated by a complex interplay of genomic and non-genomic signaling mechanisms of steroid hormones, and the integrated action of these machineries has important functional roles in a variety of pathophysiological processes. The understanding of the molecular basis of the rapid effects of steroids is therefore important, and may in the future turn out to be of relevance for clinical purposes.
We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. ...Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (< 10 years) become menopausal, who have menopausal symptoms and who are less than 60 years old, with a low baseline risk for adverse events. MHT should be considered as an option for the maintenance of skeletal health in women, specifically as an additional benefit in the context of treatment of menopausal symptoms, when commenced at the menopause, or shortly thereafter, in the context of a personalized benefit-risk evaluation.
•DHEA and DHEAS are the most abundant steroids in humans.•DHEA and DHEAS are synthesized and metabolized in the brain.•DHEA and DHEAS have presynaptic and postsynaptic effects.•DHEAS levels are ...associated with mood/anxiety disorder, sexual function and cognitive impairment.•Clinical efficacy of DHEA therapy is still conflicting across studies.
Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the most abundant steroid hormones in the humans. However, their physiological significance, their mechanisms of action and their possible roles as treatment are not fully clarified.
Biological actions of DHEA(S) in the brain involve neuroprotection, neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-inflammatory and antiglucocorticoid effects. In addition, DHEA affects neurosteroidogenis and endorphin synthesis/release. We also demonstrated in a model of ovariectomized rats that DHEA therapy increases proceptive behaviors, already after 1 week of treatment, affecting central function of sexual drive. In women, the analyses of clinical outcomes are far from being conclusive and many issues should still be addressed. Although DHEA preparations have been available in the market since the 1990s, there are very few definitive reports on the biological functions of this steroid. We demonstrate that 1 year DHEA administration at the dose of 10mg provided a significant improvement in comparison with vitamin D in sexual function and in frequency of sexual intercourse in early postmenopausal women. Among symptomatic women, the spectrum of symptoms responding to DHEA requires further investigation, to define the type of sexual symptoms (e.g. decreased sexual function or hypoactive sexual desire disorder) and the degree of mood/cognitive symptoms that could be responsive to hormonal treatment. In this regard, our findings are promising, although they need further exploration with a larger and more representative sample size.
This article is part of a Special Issue entitled: Essential role of DHEA.
Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65-75% of symptoms connected with postmenopausal period are vasomotor ...symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS.
围绝经期的妇女会出现一系列症状, 这些症状会干扰身体, 性生活和社交。绝经期间约65-75％的症状是血管舒缩症状（VMS）, 如潮热和盗汗。潮热是与皮肤血管舒张和核心温度下降相关的主观热感。VMS被怀疑与促性腺激素释放激素（GnRH）脉冲式释放过多和随后的黄体生成素（LH）分泌密切相关。同时研究显示, 卵巢中合成的类固醇激素缺乏负反馈导致位于漏斗核中的肥大Kisspeptin /神经激肽B /强啡肽（KNDy）神经元过度活化。 Kisspeptin（KISS1）和神经激肽B（NKB）的过度分泌以及强啡肽的下调在GnRH脉冲的产生中起主导作用, 反之导致VMS的发生。给予NK3受体特异性激动剂, 高效选择性NK3R激动剂导致绝经后妇女血清LH浓度增加, 诱导VMS发生, 心率增加和皮肤温度升高。这些发现表明, 对KNDy神经元的调节可能成为治疗VMS的新方法。
Estetrol (E4), a naturally occurring estrogen only produced by the human fetal liver, is being evaluated in human studies for potential use in contraception and menopausal care. The present study was ...designed to profile E4 in the central nervous system, to assess the in vivo effects of E4 administration on allopregnanolone (AP) synthesis in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated AP synthesis.
Intact female adult rats received different doses of E4, and ovariectomized OVX rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of AP were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, anterior pituitary, and serum.
E4 did not alter AP in intact animals in any region. E4 at a dosage of 5mg/kg/day increased AP levels in different brain areas and in the serum of OVX animals. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect on the brain and serum levels of AP.
E4 increases the CNS and peripheral levels of AP, behaving as a weak estrogen-agonist in OVX rats. The antagonistic effect observed with E2V co-administration further profile E4 as a natural SERM.
Progestogens and brain: An update Pluchino, N; Cubeddu, A; Giannini, A ...
Maturitas,
04/2009, Letnik:
62, Številka:
4
Journal Article, Conference Proceeding
Recenzirano
Abstract Each synthetic progestins has its own specific activities on different tissues, which can vary significantly between progestins of different classes and even within the same class. Indeed, ...different progestins may support or oppose the effects of estrogen depending on the tissue, thereby supporting the concept that the clinical selection of progestins for HRT is critical in determining potential positive or detrimental effects. These actions might be particularly relevant in the central nervous system (CNS) where progesterone (P) has pivotal roles besides reproduction and sexual behavior, going from neuropsychological effects to neuroprotective functions. Growing evidence supports the idea that synthetic progestins differ significantly in their brain effects, and clinical studies indicate that these differences also occur in women. Molecular and cellular characterization of the signaling properties of synthetic progestins in brain cells is therefore required and is hoped will lead to a better clinical utilization of the available compounds, as well as to new concepts in the engineering of new molecules. The aim of the present paper is to briefly review and compare neuroendocrine effects of progestogens with special reference to P metabolism into neuroactive steroids and the opioids system.
ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese ...women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone DHEA (50 mg/day) in early postmenopausal women (50-55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60-65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.
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