Molecular Regulation of the CNS by Vitamin D.

Vitamin D is a lipid-soluble vitamin that can be found in some foods. It is also produced endogenously (in the presence of ultraviolet light), transported through the blood to the targets organs and this is the reason to consider vitamin D as a hormone. It is known that vitamin D has genomic and non-genomic effects. This review is focused mainly on the vitamin D receptors, the importance of vitamin D as a neuromodulator, the role of vitamin D in the pathophysiology of devastating neurological disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and the benefit of vitamin D and its derivates in alleviating these disorders.

Vitamin D, a steroid hormone, from theory to practice.

Recently deceased professor Luboslav Stárka was a world-renowned doctor who devoted his whole life to the study and therapeutic use of steroids, and was particularly interested in vitamin D. He knew from his own experience and from deep knowledge that this vitamin, one of the oldest steroids in development, must have a number of effects in addition to the undeniably positive effects on bones. He commissioned our task force to address the issues surrounding vitamin D, leading to years of studies with robust results made possible by the use of chromatography coupled with mass spectrometry (LC-MS), a so-called gold standard of measurement that is a cornerstone of recent scientific studies. This led to a whole series of scientific publications, the aim of which was to point out the possibility of using the abilities of vitamin D and thus also the gift that nature has given us.

Endocrine risk factors for COVID-19 in context of aging.

Aged people are the most susceptible group to COVID-19 infection. Immunosenescence characterized by impairment of immune function with inflamm-aging contributes to pathophysiological alterations, among which endocrine and metabolic diseases are not exception. Diabetes, obesity along with impairment of disorders of thyroid functions are the most frequent ones, the common feature of which is failure of immune system including autoimmune processes. In the minireview we discussed how COVID-19 and aging impact innate and adaptive immunity, diabetes and selected neuroendocrine processes. Mentioned is also beneficial effect of vitamin D for attenuation of these diseases and related epigenetic issues. Particular attention is devoted to the role of ACE2 protein in the light of its intimate link with renin-angiotensin regulating system.

Aging, hormones and receptors.

Ageing is accompanied by deterioration in physical condition and a number of physiological processes and thus a higher risk of a range of diseases and disorders. In particular, we focused on the changes associated with aging, especially the role of small molecules, their role in physiological and pathophysiological processes and potential treatment options. Our previously published results and data from other authors lead to the conclusion that these unwanted changes are mainly linked to the hypothalamic-pituitary-adrenal axis can be slowed down, stopped, or in some cases even reversed by an appropriate treatment, but especially by a life-management adjustment.

Vitamin D in autistic children and healthy controls.

Insufficient levels of vitamin D have been demonstrated by many authors as a risk factor for autistic patients, however, the causality has not been reliably elucidated. In the present study, levels of calcidiol were determined in group of autistic children and compared with age matched healthy children as controls. Suboptimal levels of calcidiol in more than 60 % of both autistic patients as well as of control group were found. No significant differences in vitamin D between autistic children and healthy controls were observed.

Impaired vitamin D sensitivity.

Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor.

Physiological changes after spa treatment - a focus on endocrinology.

The paper presents the results of our effort to reveal objective parameters for evaluation of the spa treatment for patients with anxiety-depressive disorders. The study was based on our previous experience with neuroactive steroids and neurosteroids, which play a crucial role in the psychological well-being of patients by maintaining balance of the organism. A total number of 94 steroids were determinated in a group of 70 female patients diagnosed with anxiety-depressive disorders. Patients underwent a month spa treatment while maintaining unchanged medication dosing with SSRI (selective serotonin reuptake inhibitors). The other investigated factors contributing to improving the health of treated subjects were amino-acid homocysteine and serotonin. The blood samples were collected at the beginning and the end of the spa treatment. Serotonin in all patients increased by a relative 23 % (results given as relative differences in percent), while homocysteine decreased by 17.1 %. Statistically significant increases were found in 21 steroids, which indicate activation of the adrenal cortex. It can be assumed, that the overall improvement in the mental condition of patients, which was proved by questionnaire from Knobloch and Hausner, the increase in immune suppressive substances and anti-autoimmune responses, will maintain for a longer time after the spa treatment.

Vitamin D, neurosteroids and autism.

Vitamin D had been for a long time investigated for its effects on bone metabolism. Recently has been observed that the incidence of some neurodevelopmental disorders (including autism) increases hand in hand with vitamin D deficiency. Indeed, vitamin D was reported to modulate the biosynthesis of neurotransmitters and neurotrophic factors; moreover, its receptor was found in the central nervous system. Vitamin D deficiency was therefore assessed as a risk factor for autism, however the biological mechanism has not yet been revealed. In our review we focused on potential connections among vitamin D, steroids and autism. Potential mechanisms of vitamin D action are also discussed.

Vitamin D in anxiety and affective disorders.

Reduced levels of vitamin or its metabolites have been reported in various psychiatric disorders. Insufficient levels of vitamin D in depressive patients have been confirmed by many authors, but there have been conflicting results in subjects with anxiety disorders. In the present cross-sectional study, levels of calcidiol were determined in groups of depressive men and women and in men and women with anxiety disorders and compared with age matched controls. Significantly lower levels of calcidiol were found in men and women with depression as well as in age matched patients with anxiety disorders.

Steroid hormones related to 11beta-hydroxysteroid dehydrogenase type 1 in treated obesity.

The local concentration of glucocorticoids is intensively regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1). Human 11beta-HSD 1 also reversibly catalyzes the inter-conversion of 7alpha-hydroxy- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) into 7-oxo-DHEA. The cohort of 282 obese adolescents, 154 girls (median age 15.31 years, range 14.17-16.68 years) and 128 boys (median age 14.95 years, range 13.87-16.16 years), BMI (Body Mass Index) >90th percentile was examined. In samples collected before and after one month of reductive diet therapy, circulating levels of steroids were analyzed by liquid chromatography-tandem mass spectrometry and radioimmunoassay methods. The model of the treatment efficacy prediction was calculated. A significant reduction in circulating levels of cortisone, E2 and increased levels of 7beta-hydroxy-DHEA after the reductive treatment was observed. Levels of cortisol, DHEA, DHT sustained without any significant change. The predictive Orthogonal Projections to Latent Structures (OPLS) model explained 20.1 % of variability of BMI, z-score change by the basal levels of 7alpha-hydroxy-DHEA, DHEA, cortisol and E2 as the strongest predictors. Reduced levels of circulating cortisone and reduced ratios of oxygenated/reduced metabolites reflect increased reductase activity of 11beta-HSD 1 with reduced BMI, z-score. We hypothesize whether these changes can be attributed to the altered activity of 11beta-HSD 1 in the liver.

Steroid hormones and homocysteine in the outcome of patients with normal pressure hydrocephalus.

Normal pressure hydrocephalus (NPH) is one of a few treatable conditions of cognitive decline affecting predominately elderly people. Treatment, commonly based on the ventriculoperitoneal shunt insertion, leads to a partial or complete correction of patient's state, although its effect does not unfortunately always last. The aim of our study was to observe the changes of homocysteine and selected steroids and neurosteroids and follow-up the patients with respect to the duration of the NPH-related dementia improvement. The cerebrospinal fluid and plasma levels of cortisol, cortisone, dehydroepiandrosterone (DHEA), 7alpha-hydroxy-DHEA, 7beta-hydroxy-DHEA, 7-oxo-DHEA, 16alpha-hydroxy-DHEA (all LC-MS/MS), DHEA-sulphate (DHEAS) (radioimmunoassay) and homocysteine (gas chromatography) were determined in NPH-diagnosed subjects before, during and 6, 12 and 24 months after shunt insertion. The cognitive functions ameliorated after shunt insertion and remain improved within 2 years. Changes in cerebrospinal fluid DHEAS, DHEA and its ratio, cortisone/cortisol and 16alpha-hydroxy-DHEA and plasma DHEAS, 7beta-hydroxy-DHEA, cortisone/cortisol and homocysteine were found. Mentioned changes may contribute to the clarification of NPH pathogenesis. Altered neurosteroids levels are possible indicators to be utilized in the follow-up of NPH subjects. Moreover, plasma homocysteine may serve as an early indicator of NPH-related dementia.

How hormones influence composition and physiological function of the brain-blood barrier.

Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

The steroid metabolome in men with mood and anxiety disorders.

The mood and behavior of individuals result from an orchestra of many factors. Among them steroids play an important role; however, only several common hormones have been investigated in this respect. It has been demonstrated that some steroid metabolites long considered merely the products of steroid hormone metabolism in fact possess considerable activity in the CNS. For this reason we studied the steroid metabolome including 50 analytes in 20 men with depression, 20 men with anxiety and 30 healthy controls. Significant differences were found not only between controls and men with either depression or anxiety, but also between men with depression and anxiety. Particularly striking were those steroids until now not generally associated with depression or anxiety, namely conjugated steroid forms, especially sulfates.

Differences in bisphenol A and estrogen levels in the plasma and seminal plasma of men with different degrees of infertility.

The general population is potentially exposed to many chemicals that can affect the endocrine system. These substances are called endocrine disruptors (EDs), and among them bisphenol A (BPA) is one of the most widely used and well studied. Nonetheless, there are still no data on simultaneous measurements of various EDs along with steroids directly in the seminal fluid, where deleterious effects of EDs on spermatogenesis and steroidogenesis are assumed. We determined levels of BPA and 3 estrogens using LC-MS/MS in the plasma and seminal plasma of 174 men with different degrees of infertility. These men were divided according their spermiogram values into 4 groups: (1) healthy men, and (2) slightly, (3) moderate, and (4) severely infertile men. Estradiol levels differed across the groups and body fluids. Slightly infertile men have significantly higher BPA plasma and seminal plasma levels in comparison with healthy men (p<0.05 and p<0.01, respectively). Furthermore, seminal BPA, but not plasma BPA, was negatively associated with sperm concentration and total sperm count (-0.27; p<0.001 and -0.24; p<0.01, respectively). These findings point to the importance of seminal plasma in BPA research. Overall, a disruption of estrogen metabolism was observed together with a weak but significant impact of BPA on sperm count and concentration.

Are there any differences between stress hormone levels in non-stress conditions and in potentional stress overload (heart catheterisation) in sows?

In order to study a possible effect of mini-invasive heart intervention on a response of hypothalamo-pituitary-adrenal stress axis, we analyzed four stress markers (cortisol, cortisone, DHEA and DHEAS) in 25 sows using minimally invasive heart catheterisation as the stress factor. The marker levels were assessed in four periods of the experiment, (1) the baseline level on the day before intervention, (2) after the introduction of anesthesia, (3) after conducting tissue stimulation or ablation, and (4) after the end of the catheterisation. For statistical analyses we used the non-parametric Friedman test for four dependent samples (including all four stages of the operation) or three dependent samples (influence of operation only, baseline level was excluded). Statistically significant differences in both Friedman tests were found for cortisol and for cortisone. Significant differences for DHEA as well as for DHEAS were found for all tested stages but not for the effect of operation itself. We have concluded that cortisol levels are blunted by the influence of anesthesia after its administration, and therefore decrease back to the baseline at the end of the operation. The other markers (cortisone, DHEA and DHEAS) acted as balanced systems against the injurious stress effect.

Determination of homocysteine in cerebrospinal fluid as an indicator for surgery treatment in patients with hydrocefalus.

Increased homocysteine levels in serum are typical features of neurodegenerative brain diseases including hydrocephalus. The most frequent therapeutic approach consists of the insertion of a shunt, connecting the brain ventricles to an alternative drainage site. To decide whether the patient should undergo this, the lumbar drainage test is usually carried out to distinguish patients who can benefit from the shunt insertion. In searching for other potential biochemical markers for shunt indication we determined homocysteine levels in CSF during the lumbar drainage test. Homocysteine in CSF was measured during the 5-day lumbar drainage test in 27 patients with normal-pressure hydrocephalus (NPH) and in 25 patients with excluded hydrocephalus. A novelized gas chromatography method with flame ionization detection (GC-FID) was developed and evaluated. During the first two days of lumbar drainage, the levels of CSF homocysteine in NPH patients were significantly higher compared to the controls, while on the fifth day, the homocysteine levels in patients with hydrocephalus reached the level of controls. Determination of CSF homocysteine in patients with confirmed or suspected hydrocephalus may serve as an independent marker for deciding on their further treatment strategy.

Reduced levels of circulating 7alpha-hydroxy-dehydroepiandrosterone in treated adolescent obese patients.

Elevated levels of glucocorticoids lead to the development of obesity and metabolic syndrome. Local glucocorticoid levels are regulated through the enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD 1), an enzyme that regenerates active cortisol from inert cortisone. Increased expression of 11beta-HSD 1 in adipose tissue promotes higher body mass index (BMI), insulin resistance, hypertension, and dyslipidemia. Human 11beta-HSD 1 is also responsible for inter-conversion of 7-hydroxylate metabolites of dehydroepiandrosterone (7-OH-DHEA) to their 7-oxo-form. To better understanding the mechanism of the action, we focused on 7-OH- and 7-oxo-DHEA, and their circulating levels during the reductive treatment in adolescent obese patients. We determined plasma levels of 7alpha-OH-DHEA, 7beta-OH-DHEA, and 7-oxo-DHEA in 55 adolescent patients aged 13.04-15.67 years, BMI greater than 90th percentile. Samples were collected before and after one month of reductive therapy. Circulating levels of 7alpha-OH-DHEA decreased during the reductive therapy from 1.727 (1.614; 1.854, transformed mean with 95 % confidence interval) to 1.530 nmol/l (1.435; 1.637, p<0.05) in girls and from 1.704 (1.583; 1.842) to 1.540 nmol/l (1.435; 1.659, p<0.05) in boys. With regard to the level of 7-oxo-DHEA, a significant reduction from 1.132 (1.044; 1.231) to 0.918 nmol/l (0.844; 1.000, p<0.05) was found after the treatment, but only in boys. No significant difference in 7beta-OH-DHEA levels was observed. In conclusions, diminished levels of 7alpha-OH-DHEA indicate its possible effect on activity of 11beta-HSD 1. Further studies are necessary to clarify whether competitive substrates for 11beta-HSD 1 such as 7alpha-OH-DHEA could inhibit production of glucocorticoids and may be involved in metabolic processes leading to reduction of obesity.

7-oxygenated derivatives of dehydroepiandrosterone and obesity.

7-hydroxy/oxo derivatives of dehydroepiandrosterone are potential regulators of the local cortisol activity due to their competition in the cortisolcortisone balance mediated by 11ß-hydroxysteroid dehydrogenase. 7-hydroxy-dehydroepiandrosterone is marketed as anti-obesity medication, though no clinical study aimed at the benefit of administering 7-oxygenated derivatives of dehydroepiandrosterone has appeared until now. We tried to show whether there exist differences in levels of circulating 7-hydroxy/oxo-dehydroepiandrosterone derivatives between lean and obese boys and girls. From a cohort of adolescents investigated within the frame of anti-obesity programme 10 obese boys and 10 obese girls were compared with age-matched lean boys and girls in their anthropometric data, and concentrations of both epimers of 7-hydroxy-dehydroepiandrosterone and 7-oxo-dehydroepiandrosterone were determined by the RIA method. The basal levels of 7α-hydroxy-dehydroepiandrosterone were significantly higher in obese boys than in lean boys but not in girls. The association was found for anthropometric parameters and 7α-hydroxy-dehydroepiandrosterone, however again only in boys and not in girls. Higher levels of 7α-hydroxy-dehydroepiandrosterone its positive association with anthropometric data in obese boys may serve as a sign that, at least in boys, 7-oxygenated 5-ene-steroids may take part in regulating the hormonal signal for fat formation or distribution.

[Phytoestrogenes in menopause: working mechanisms and clinical results in 28 patients]. / Fytoestrogeny v menopauze: mechanismus úcinku a výsledky lécby v sestave 28 pacientek.

OBJECTIVE: Comparison of phytoestrogen treatment efficacy in menopausal women with and without ability to metabolise phytoestrogens. DESIGN: Clinical trial. SETTING: Department of Obstetrics and Gynaecology, Regional Hospital, Mlada Boleslav. METHODS: 28 menopausal women were treated with phytoestrogens in dose 80 mg daily. Before start and after finishing of treatment urinary concentrations of active metabolite S-equol were measured using ELISA method. Similarly before and after treatment Kupperman's index was measured. Patients with urinary concentrations of S-equol above 1 ng/ml were considered as S-equol producers, remaining patients formed control group. RESULTS: 16 out of 28 women were considered as S-equol producers, remainig 12 as a non-producers. Initial urinary concentrations of S-equol were 0.34 +/- 0.37 ng/ml in producers group and 0.29 +/- 0.30 ng/ml in non-producers. After finishing of therapy urinary concentration of S-equol increased to 10.67 +/- 11.57 ng/ml (p = 0.002) in producers group and 0.34 +/- 0.30 ng/ml (p = 0.701) in non-producers. Kupperman's index values were 23.44 +/- 11.57 in producers group and 17.25 +/- 7.78 in non-producers. After therapy value of Kupperman's index decreased to 14.44 +/- 9.97 (p = 0.003) in producers and to 12.00 +/- 7.18 (p = 0.100) in non-producers. No correlation between improvement in Kupperman's index and urinary concentration of S-equol after therapy was found similarly as between urinary concentration of S-equol before and after therapy in producents group. CONCLUSION: Significant phytoestrogen treatment effect in menopausal women producing S-equol was proven. Testing method for S-equol production introduced by our team togehter with suggested threshold urine concentration level of 1 ng/ml allows precise distinction of producers and non-producers of S-equol and subsequently to predict better treatment effect of phytoestrogens.

Might cardiac catheterization influence diurnal rhythm of the steroid stress hormones secretion?

Glucocorticoids (GCs) are steroid hormones produced by the adrenal cortex in reaction to stress stimuli. GCs production is not stable over a 24-hour period; the plasma concentration peaks in the morning (approximately upon awakening) and then the plasma levels decrease, reaching the nadir in the evening. In our experiments, the levels of cortisol, cortisone, DHEA and DHEAS were tested in young female pigs (n=23) during heart catheterization at two different day times (in the morning and in the afternoon). The non-parametric Mann-Whitney test for statistical analysis was used. We found only minimal statistical differences in studied markers between the morning and afternoon group (p>0.05). The absence of circadian variation in GCs levels could originate either at an early age of our experimental pigs, or in stressful conditions on the experiment day, or most likely the day before (e.g. social isolation, fasting, transport, and catheterization), respectively. We can conclude there is no difference in the stress load between morning and afternoon experiments, and therefore we can assume the stress load is not a limiting factor for the timing when catheterization should be preferably performed.