ArticleLiterature Review

Vitamin D: A steroid hormone with progesterone-like activity

Authors:
  • A.G.Un.Co. · Obstetrics & Gynecology center
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Abstract

Objective: This review is aimed at demonstrating the progesterone-like activity exerted by the active form of vitamin D, or calcitriol (1,25(OH)2D). To achieve this outcome, we compared the effects in vivo and in vitro exerted by progesterone and vitamin D, with a special focus on the female reproductive system and pregnancy. Materials and methods: This is a literature review of the most important articles published in English on vitamin D as a hormone, mainly found by MEDLINE. Furthermore, a section of our review contains some unpublished data, concerning the analysis in silico of the similarities between the steric structure of progesterone and calcitriol, based on the availability of the experimental structures of progesterone and vitamin D3 receptors in complex with their physiological ligands in the RCSB Protein Data Bank. Results: Vitamin D was shown to exert many physiological activities during the very early stages of gestation in perfect synchrony with progesterone. Both the molecules mutually help and reinforce the activity exerted by each one. A little bit later than progesterone is released, vitamin D secretion rises, but only if pregnancy occurs. Calcitriol contributes to prepare the endometrium to be receptive. Moreover, it supports the implantation process and the course of pregnancy through different but similar pathways to those used by progesterone, giving rise to a significant synergy of action. It is increasingly evident that vitamin D gives an essential support from the luteal phase onwards. Conclusions: Based on the evidence displayed in this review we may define appropriately vitamin D as a steroid hormone with progesterone-like activity.

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... The progesterone-like activity of vitamin D during the luteal phase may provide a possible explanation for the exhibited beneficial effects and resulting positive reproductive outcomes (Monastra et al., 2018). With structural and functional similarities, vitamin D and progesterone work synergistically to support the luteal phase onwards through immune-modulating actions and by inducing anti-inflammatory pathways (Monastra et al., 2018). ...
... The progesterone-like activity of vitamin D during the luteal phase may provide a possible explanation for the exhibited beneficial effects and resulting positive reproductive outcomes (Monastra et al., 2018). With structural and functional similarities, vitamin D and progesterone work synergistically to support the luteal phase onwards through immune-modulating actions and by inducing anti-inflammatory pathways (Monastra et al., 2018). Progesterone has been found to reinforce the anti-inflammatory effect of vitamin D and vice versa, whereby both promote either the synthesis of beneficial molecules or the suppression of harmful molecules (e.g. ...
... Progesterone has been found to reinforce the anti-inflammatory effect of vitamin D and vice versa, whereby both promote either the synthesis of beneficial molecules or the suppression of harmful molecules (e.g. corticotropin-releasing factor (CRF) and Th1 cells, respectively) between the luteal phase and 12th week of pregnancy (Monastra et al., 2018). ...
Article
Around one billion people worldwide are understood to have sub-optimal levels of vitamin D. Polycystic ovary syndrome (PCOS) is reportedly a primary reason for female infertility. The main objective of this research was to understand the mechanistic role of vitamin D in the pathogenesis of female infertility in PCOS, specifically in relation to ovarian follicle development. In addition, the impact of vitamin D deficiency on oxidative stress and hormone production central to folliculogenesis was explored. The efficacy of vitamin D supplementation as an intervention to ameliorate ovulatory dysfunction in individuals with PCOS was evaluated. The systematic search strategy included three stages of search with a critical appraisal of the accepted papers: 1) other review papers; 2) primary mechanistic animal, in vitro and human studies; 3) primary intervention studies. In total, 80 papers were examined in detail and results analysed and evaluated. Mechanistic evidence indicated an association between vitamin D deficiency and impaired ovulatory function. Sub-optimal vitamin D levels were implicated in disrupted reproductive hormone balance, including overproduction of anti-mullerian hormone (AMH); accumulation of pro-inflammatory Advanced Glycation End Products (AGEs) and formation of Reactive Oxygen Species (ROS) in ovarian tissue, leading to abnormal folliculogenesis. Human intervention studies demonstrated the capability of vitamin D supplementation for restoring sufficient serum calcidiol (25(OH)D) levels in deficient individuals. Furthermore, the anti-inflammatory benefit of vitamin D was illustrated in studies examining the impact on oxidative stress. Co-supplementation with calcium was shown to benefit follicle growth; oxidative stress reduced with calcium, omega-3 fatty acid or probiotic co-supplementation.
... It as well interacts with nuclear receptors. Apart from its interaction with steroid receptors: androgen receptors (ARs), estrogen receptors (ERs), progesterone receptors (PRs), glucocorticoid receptors (CRs) (Larriba et al., 2014;Nasiri Ansani et al., 2015;Monastra et al., 2018), it also interacts with nuclear factors: SP-1, AP-1, CREB, p53, FOXO3a, FOXO4, PPAR alpha, PPAR beta/delta, PPAR gamma, HNF4 alpha, PIT-1, RAR, etc., and many of those nuclear receptors are involved in steroidogenesis and reproduction (Larriba et al., 2014). Therefore, all these interactions of vitamin D could be a direct link of its influence on reproduction. ...
... The impact of vitamin D on progesterone production goes along with the similarity in the structure of vitamin D and progesterone, and possible inter-reactions with their receptors (Monastra et al., 2018), and similarity in the effect of vitamin D and progesterone on endometrial development, implantation, pregnancy protection -endometrial inflammatory response (production of pro-inflammatory and anti-inflammatory cytokines, activity of T-helper cells, T regulatory cells and natural killer cells) and blockade of embryo rejection, their positive effects on placenta development and function, and protection from early pregnancy loses, from pre-eclampsia, fetal growth retardation, fetal death and premature delivery, as well glucocorticoid fetal overload (Voulgaris et al., 2017;Monastra et al., 2018). Lower vitamin D concentrations have been often found not only in infertile women (Pagliardini et al., 2015), but also in women with recurrent pregnancy losses and repeated implantation failures (Kwak-Kim et al., 2016). ...
... The impact of vitamin D on progesterone production goes along with the similarity in the structure of vitamin D and progesterone, and possible inter-reactions with their receptors (Monastra et al., 2018), and similarity in the effect of vitamin D and progesterone on endometrial development, implantation, pregnancy protection -endometrial inflammatory response (production of pro-inflammatory and anti-inflammatory cytokines, activity of T-helper cells, T regulatory cells and natural killer cells) and blockade of embryo rejection, their positive effects on placenta development and function, and protection from early pregnancy loses, from pre-eclampsia, fetal growth retardation, fetal death and premature delivery, as well glucocorticoid fetal overload (Voulgaris et al., 2017;Monastra et al., 2018). Lower vitamin D concentrations have been often found not only in infertile women (Pagliardini et al., 2015), but also in women with recurrent pregnancy losses and repeated implantation failures (Kwak-Kim et al., 2016). ...
Chapter
Abstract Obesity and metabolic syndrome (MetS) are related to numerous reproductive abnormalities, both in men and in women, through multiple pathways. In addition, obesity and MetS are also related to the decreased vitamin D levels. Low vitamin D levels can negatively influence reproductive function, in both genders. The purpose of this article is to describe the association of obesity, MetS and low vitamin D levels with the development of reproductive abnormalities in men and women, and to explore the mechanisms for this association. Keywords Infertility Men Metabolic syndrome Obesity Reproductive Vitamin D Women
... Moreover, Vitamin D exerts various and distinct physiological activities during gestation along with progesterone; in some cases, it may act also as its substitute, or they may strengthen reciprocally. Like progesterone, Vitamin D seems extremely functional during the luteal phase onwards [7]. Therefore, adequate levels of Vitamin D are recommended in the periconceptional and first trimester periods to avoid infertility and recurrent miscarriage [8]. ...
... Vitamin D and its metabolites are chemically like glucocorticoids, testosterone, progesterone, estrogens, chorionic gonadotropin [7]. The structural similarities between vitamin D and sexual hormones are confirmed by their actions, in particular progesterone and vitamin D play synergistic pivotal functions in female reproductive system. ...
... More in details, they simultaneously act in different phases of the menstrual cycle. In this scenario, vitamin D plays the role of second main actor, it modulates the innate and adaptive immune system, controls cell proliferation and functions, as a regulator of various and important metabolic processes, with effects on the implant increasing the endometrial proliferation [17], stimulates the production of cytokines and the immune response to infections, acting as a progesterone-like-hormone [7]. ...
Article
Background This study proposes a review of nutraceuticals used in the treatment of typical symptoms of Polycystic Ovary Syndrome (PCOS).The aim is to provide a classification of the most widely used nutraceutical supplements identifying the most effective nutraceuticals on glucose and insulin metabolism, the androgenic hormone profile, fertility, ovulatory capacity, inflammation, and oxidative stress.Material and Methods We included randomized controlled trials on PCOS patients undergoing administration of nutraceuticals, in particular vitamin D, vitamin E, probiotics, and inositols. These administrations are variable in terms of dosage, single supplementation, or combined with other compounds, dosage, and duration of the intervention.ResultsThe supplementation of inositols, at the physiologic ratio of 40: 1 of myo- and D-chiro-inositols, resulted to be the most effective in improving the glucose homeostasis and fertility, with a restoration of ovulatory capacity and menstrual regularity. Other nutraceuticals are particularly effective in reducing hyperandrogenism, with promising results demonstrated by the combinations of vitamin D and probiotics, vitamin E and coenzyme Q10, and the enrichment of inositol therapy with group B vitamins. An improvement in the inflammatory status and antioxidant capacity is obtained with the co-supplementation of probiotics and selenium or with vitamin E combined with omega 3.Conclusions Inositol supplementation is effective in the treatment of insulin resistance and fertility. Probiotics reduced hyperandrogenism, inflammatory and oxidative conditions, and resulted more effective when combined with selenium. Although these results proved to be satisfactory, further studies are needed with larger samples and a more homogeneous analysis of the outcomes.
... CYP24A1 catalyses the hydroxylation and degradation of calcitriol. Calcitriol has progesterone-like activity in the early stages of gestation in humans, acting on endometrial receptivity and implantation [100]. Circulating concentrations of calcitriol are increased during pregnancy [101] and are suggested to also increase CYP24A1 expression in a negative feedback system to prevent over activation of the calcitriol system in pregnancy [100]. ...
... Calcitriol has progesterone-like activity in the early stages of gestation in humans, acting on endometrial receptivity and implantation [100]. Circulating concentrations of calcitriol are increased during pregnancy [101] and are suggested to also increase CYP24A1 expression in a negative feedback system to prevent over activation of the calcitriol system in pregnancy [100]. Thus, in the present study, sPIF had effects on steroid biosynthesis that would be expected in pregnant endometrium. ...
Article
Full-text available
Preimplantation factor (PIF) is an embryo derived peptide which exerts an immune modulatory effect on human endometrium, promoting immune tolerance to the embryo whilst maintaining the immune response to invading pathogens. While bovine embryos secrete PIF, the effect on the bovine endometrium is unknown. Maternal recognition of pregnancy is driven by an embryo-maternal cross talk, however the process differs between humans and cattle. As many embryos are lost during the early part of pregnancy in cattle, a greater knowledge of factors affecting the embryo-maternal crosstalk, such as PIF, is needed to improve fertility. Therefore, for the first time, we demonstrate the effect of synthetic PIF (sPIF) on the bovine transcriptome in an ex vivo bovine endometrial tissue culture model. Explants were cultured for 30h with sPIF (100nM) or in control media. Total RNA was analysed via RNA-sequencing. As a result of sPIF treatment, 102 genes were differentially expressed compared to the control ( P adj<0.1), although none by more than 2-fold. The majority of genes (78) were downregulated. Pathway analysis revealed targeting of several immune based pathways. Genes for the TNF, NF-κB, IL-17, MAPK and TLR signalling pathways were down-regulated by sPIF. However, some immune genes were demonstrated to be upregulated following sPIF treatment, including C3 . Steroid biosynthesis was the only over-represented pathway with all genes upregulated. We demonstrate that sPIF can modulate the bovine endometrial transcriptome in an immune modulatory manner, like that in the human endometrium, however, the regulation of genes was much weaker than in previous human work.
... Combinational treatments of vitamin D and probiotics also showed a significant response when it comes to androgen level reduction [149]. Although this suggests that probiotics might be more efficient on managing hirsutism when combined with vitamin D, other researchers have not shown any significant effect of the vitamin alone to the referred condition [158][159][160][161], despite its significant anti-inflammatory and insulin sensitivity effect [162][163][164]. Therefore, it is possible that the effects of the combinational treatment are due to the improvement of IR from vitamin D, along with the probiotics effect [149]. ...
Article
Full-text available
Probiotics and synbiotics are known to have beneficial effects on human health and disease. Hirsutism, a disorder that is characterised by the presence of coarse terminal hairs in a male-like pattern, is usually caused by elevated androgen levels in blood plasma. This disorder is usually observed in PCOS women and it is linked to insulin resistance (IR). Although idiopathic hirsutism (IH) is not shown to have excess androgen production from the ovarian and adrenal glands, increased 5α-reductase in peripheral tissues and insulin resistance are common observations. The effect of probiotics and synbiotics have been recently studied on PCOS women; androgens were also included in the hormonal groups that were investigated. Only a few studies focus on hirsutism and the potential effect of the beneficial microbes mentioned, whereas the increasing interest on insulin resistance and synbiotics indicate a potential beneficial effect on hirsutism through the management of insulin resistance.
... Several studies have found that progesterone suppresses the inflammatory response in many animal models 13 . Interestingly, vitamin D was also shown to exert many physiological activities during the very early stages of gestation in perfect synchrony with progesterone, including an anti-inflammatory role during pregnancy 14,15 . Other studies have also shown that maternal obesity is associated with low first trimester serum progesterone, suggesting maternal obesity as a risk factor for low progesterone during pregnancy 16,17 . ...
Article
Full-text available
Progesterone plays a protective role in preventing inflammation and preterm delivery during pregnancy. However, the mechanism involved is unknown. Microbial product translocation from a permeable mucosa is demonstrated as a driver of inflammation. To study the mechanism of the protective role of progesterone during pregnancy, we investigated the effect of physiologic concentrations of progesterone on tight junction protein occludin expression and human gut permeability in vitro and systemic microbial translocation in pregnant women in vivo. Plasma bacterial lipopolysaccharide (LPS), a representative marker of in vivo systemic microbial translocation was measured. We found that plasma LPS levels were significantly decreased during 24 to 28 weeks of gestation compared to 8 to 12 weeks of gestation. Moreover, plasma LPS levels were negatively correlated with plasma progesterone levels but positively correlated with plasma tumor necrosis factor-alpha (TNF-α) levels at 8 to 12 weeks of gestation but not at 24 to 28 weeks of gestation. Progesterone treatment increased intestinal trans-epithelial electrical resistance (TEER) in primary human colon tissues and Caco-2 cells in vitro through upregulating tight junction protein occludin expression. Furthermore, progesterone exhibited an inhibitory effect on nuclear factor kappa B (NF-κB) activation following LPS stimulation in Caco-2 cells. These results reveal a novel mechanism that progesterone may play an important role in decreasing mucosal permeability, systemic microbial translocation, and inflammation during pregnancy.
... In addition, vitamin D acts as a steroid hormone, in some cases, as it helps regulate the manifestation of numerous genes in reproductive tissues. Vitamin D is associated with modulation of the human reproductive process [2,3]. ...
Article
Full-text available
Background: Molecular analyses of vitamin D in a typical cycling endometrium has received minimal research attention in the reproductive field. This study was designed to assess how expression of the endometrial vitamin D receptor (VDR) and CYP27B1, a vitamin D metabolizing enzyme, change during the menstrual cycle in women of reproductive age. In addition, this study explores the association between expression of vitamin D-VDR system and endometrial receptivity during the implantation window. Methods: Sixteen patients underwent standardized in vitro fertilization (IVF) treatment and freeze-all techniques. Before embryo transfer, total serum 25(OH) D levels were determined through blood samples and VDR, CYP27B1, HOXA10, and CYP19 expression were determined through endometrial samples. Endometrial receptivity was also assessed using an electron microscope. Results: We found that VDR protein expression was significantly lower throughout the endometrial secretory phase compared to the proliferative phase, while CYP27B1 expression remained constant during the menstrual cycle. During the implantation window, ultrastructural evaluation showed that higher serum vitamin D levels were associated with more mature pinopodes; VDR and HOXA10 protein expression were substantially elevated in pregnant women compared to non-pregnant women; and VDR protein levels were positively correlated with HOXA10 levels. In addition, serum vitamin D levels were positively correlated with VDR and HOXA10 protein levels in the endometrium. Conclusions: Women with increased VDR expression in the endometrium, especially during the implantation window of the menstrual cycle, were significantly more likely to be pregnant than women with decreased expression. Our results support the hypothesis that the Vitamin D-VDR system performs a role during the development of endometrial receptivity.
... erefore, the addition of macro-and microelements, several vitamins, and other molecules, despite being possibly useful in some cases, International Journal of Endocrinology basically appears to be a pure marketing maneuver and could even impair inositol absorption. In our discussion of vitamins, we focus our attention on vitamin D since it can offer valuable adjunctive therapy for pregnancy if correctly administered [56] during the luteal phase (and not in the follicular phase) of the menstrual cycle. ...
Article
Full-text available
The aim of this paper is to critically analyze the composition of many inositol-based products currently used to treat Polycystic Ovary Syndrome (PCOS). Several different combinations of myo-inositol and D-chiro-inositol, with and without additional compounds such as micro- and macroelements, vitamins, and alpha-lipoic acid, have been formulated over the years. Such therapeutic proposals do not take various features of inositol stereoisomers into consideration. As an example, it is important to know that D-chiro-inositol treatment may be beneficial when administered in low doses, yet the progressive increase of its dosage results in the loss of its advantageous effects on the reproductive performance of women and a deterioration in the quality of blastocysts created via in vitro fertilization (IVF). In addition, we have to consider that the intestinal absorption of myo-inositol is reduced by the simultaneous administration of D-chiro-inositol since the two stereoisomers compete with each other for the same transporter that has similar affinity for each of them. A decrease in myo-inositol absorption is also found when it is coadministered with inhibitors of sugar intestinal absorption and/or types of sugars such as sorbitol, maltodextrin, and sucralose. The combination of these may require higher amounts of myo-inositol in order to reach a therapeutic dosage compared to inositol administration alone, a particularly important fact when physicians strive to obtain a specific plasma level of the stereoisomer. Finally, we must point out that D-chiro-inositol was found to be an aromatase inhibitor which increases androgens and may have harmful consequences for women. Therefore, the inositol supplements used in PCOS treatment must be carefully defined. Clinical evidence has demonstrated that the 40 : 1 ratio between myo-inositol and D-chiro-inositol is the optimal combination to restore ovulation in PCOS women. Therefore, it is quite surprising to find that inositol-based treatments for PCOS seem to be randomly chosen and are often combined with useless or even counterproductive molecules, all of which can weaken myo-inositol’s efficacy. Such treatments clearly lack therapeutic rationale. 1. Introduction This review aims to evaluate the composition of many inositol-based products currently used for treating Polycystic Ovary Syndrome (PCOS). Those product compositions were examined in light of the scientific evidence thus far available, and we focused our analysis on the therapeutic rationale for utilizing such compounds. A careful MEDLINE search was conducted to identify the most significant studies on inositols used to treat women with PCOS. Furthermore, an examination of the dietary supplement market was targeted towards identifying the different products containing myo-inositol (MI) and D-chiro-inositol (DCI) alone vs. MI plus DCI along with other significant molecules used in said PCOS patients. Important organs such as the brain need high MI concentrations (10- to 15-fold the values detected in peripheral blood) [1]. Also, the ovary uses high levels of MI to efficiently carry out its physiological activities [2]. MI can be transformed into DCI by a specific NAD/NADH-dependent epimerase, which is unidirectional and is stimulated by insulin [3, 4]. Endogenous production of both inositol isomers varies depending on the needs of the specific target tissue [5]; as an example, in normal women, the plasma ratio of MI to DCI is 40 : 1 [6], while in ovarian follicular fluid the ratio is close to 100 : 1 [7]. 2. Inositols and the Therapeutic Target of PCOS The research world demands a rationale for the necessary justification to carry out any scientific study, and the therapeutic rationale underlying the use of inositols in PCOS derives from their activities as insulin sensitizing molecules and their beneficial effects on metabolism [5, 8–10]. We highlight herein the two specific inositol stereoisomers, MI and DCI, as they both function as insulin second messengers and mediate different actions of insulin. MI is converted to an inositolphosphoglycan (IPG) insulin second messenger (MI-IPG) involved in cellular glucose uptake, whereas DCI is converted to an IPG insulin second messenger (DCI-IPG) involved in glycogen synthesis [11]. At the ovarian level, however, it has been shown that an MI-based second messenger is involved in both glucose uptake and FSH signaling, whereas a DCI-based second messenger is devoted to insulin-mediated androgen production. Previous studies performed by Cheang and his team [12] provided evidence that the impairment in insulin signaling in PCOS could be the result of a defect in the IPG insulin second messenger pathway, consistent with the insulinomimetic role of IPGs in activating enzymes that control glucose metabolism. In women with PCOS, a deficiency of IPGs in tissues, or altered metabolism of inositols to IPG mediators, could play a role in inducing insulin resistance [13]. The first controlled clinical trial of inositols in PCOS was published in 1999. In that study, 1200 mg of DCI vs. placebo, given orally once a day for 6–8 weeks to 44 obese PCOS women, improved insulin sensitivity and decreased circulating free testosterone levels, whereas there was no effect of placebo. DCI administration also resulted in ovulation in 19 of 22 women (86%), whereas only 6 of 22 women (27%) ovulated in the placebo group [14]. In 1998, before the study publication, Insmed Pharmaceuticals had obtained a US patent claiming the effectiveness of DCI in the treatment of PCOS and, in 2002, a follow-up study was performed by the same group in lean women with PCOS [15]. Again, and in agreement with the earlier study [14], the administration of DCI was associated with improved insulin sensitivity, a reduction in circulating free testosterone, and increased frequency of ovulation [15]. Insmed Pharmaceuticals subsequently embarked on a large multicenter placebo-controlled trial of DCI in women with PCOS using a dose of DCI twice as high as ever previously used (i.e., 2400 mg). However, the results were never published and were very surprising and disappointing. The higher dose of DCI failed to reproduce the outcomes of the two previous studies [14, 15] in terms of improving ovulatory frequency. The lack of efficacy in the latter trial was attributed to the higher dose of DCI administered. Consequently, the company gave up proceeding with the use of DCI in clinical trials on PCOS. Previous studies had highlighted the pivotal role of MI administration for enhancing the success of in vitro human fertilization (IVF) [16]. It was also reported that follicular fluid (FF) volume and its content of MI were significantly higher in follicles containing mature and subsequently fertilized oocytes compared with follicles with immature and oocytes retrieved but unfertilized. Furthermore, the levels of MI in FF were positively correlated with embryo quality [17]. In 2007, a randomized controlled trial (RCT) was carried out with MI in 30 PCOS women undergoing ICSI; patients were administered 4 g MI daily starting from the day of Gonadotropin Releasing Hormone (GnRH) administration. Treated patients, compared with controls, obtained an increased frequency of spontaneous menstrual cycles, and this finding suggested that MI may be useful in the treatment of infertility in PCOS [18]. Several follow-up studies supported these findings and the idea that MI exerts beneficial effects on ovulation and oocyte quality [19–22]. Of note, MI administration to women with PCOS undergoing IVF was associated with a reduction in the total quantity of recombinant FSH (rFSH) administered and the number of days of stimulation [23]. These evidences demonstrate that MI improves FSH sensitivity, lending further support to the idea that MI administration beneficially affects ovarian function and oocyte development. Unfer and coworkers conducted a comparative study of the effects of administration of MI versus DCI on oocyte quality in PCOS patients. They reported that the number of mature oocytes was significantly higher, with a parallel diminution in the number of immature oocytes, in the MI group compared to the DCI group, even though the total number of oocytes retrieved did not differ between the two treatment groups [24]. A potential explanation for this phenomenon is the tissue-specific nature of insulin resistance in women with PCOS. Indeed, although muscle and liver are insulin resistant in women with PCOS, the ovaries retain normal insulin sensitivity, highlighting the tissue-specificity of insulin resistance in PCOS. This is the so-called “DCI paradox” in the ovary [25], proposed by Unfer and coworkers. In fact, the epimerase enzyme converts MI to DCI in the ovary, and ovarian epimerase is stimulated by insulin. Unfer et al. suggested that, in women with PCOS, hyperinsulinemia likely stimulates epimerase activity in the ovary, resulting in an overproduction of DCI and a concomitant depletion of MI. The authors postulated that the resulting deficiency of MI could be responsible for the poor oocyte quality and the impairment of the FSH signaling. Clearly, DCI supplementation would be ineffective (if not harmful) in such women as they already have high levels of this molecule in the ovary. 3. A Long Clinical Experience of MI/DCI Ratio in the Treatment of PCOS During the past several years, starting from the finding that the plasma MI/DCI ratio in normal women is approximately 40 : 1, several clinical studies tested this ratio and found that it obtains the best effect to induce ovulation in PCOS patients. The authors found that although MI allows us to achieve satisfactory results, the 40 : 1 ratio improves this performance. It was suggested that the cooperation between the two stereoisomers can induce two important effects: (1) a DCI-mediated improvement of insulin sensitivity in liver and muscle with a consequent reduction in circulating insulin and (2) the reestablishment of MI levels in the ovary, resulting in the restoration of FSH sensitivity and in a better oocyte quality. A recent meta-analysis [26] evaluated the efficacy of treatments with MI, alone or combined with DCI (40 : 1 ratio of MI : DCI) for 12–24 weeks, in nine RCTs comprising 247 cases and 249 controls [19, 20, 22, 27–32]. The authors took into consideration fasting insulin concentrations as a primary outcome, with HOMA index, testosterone, androstenedione, and sex hormone-binding globulin (SHBG) plasma levels as secondary. Significant reductions in fasting insulin (standardized mean difference = −1.021 μU/mL, 95% CI: −1.791 to −0.251, ) and HOMA index (standardized mean difference = −0.585, 95% CI: −1.145 to −0.025, ) were found after inositol supplementation. The meta-analysis clearly demonstrated the efficacy of the therapy. In particular, a slight trend toward testosterone decrease was observed with respect to controls, whereas androstenedione levels remained unchanged. Finally, MI was able to significantly increase SHBG levels only after at least 24 weeks of administration (standardized mean difference = 0.425 nmol/L, 95% CI: 0.050–0.801, ). This evidence strongly suggests that the findings on the primary outcome are conclusive. Concerning the androgenic hormones, the different effects obtained on androstenedione and testosterone levels should be investigated more in depth by dedicated studies. The authors recommended avoiding exclusive DCI supplementation for three reasons: (a) high doses of DCI/day are detrimental for ovaries and oocyte maturation (see additional data below); (b) epimerase works in a unidirectional fashion; consequently, DCI cannot be reconverted into MI and therefore the action of the latter is lost; (c) MI and MI-IPG deficiencies are correlated with many insulin resistance conditions. In conclusion, the meta-analysis gave new and strong support to the supplementation of MI to improve the metabolic profile of PCOS patients. Another systematic review and meta-analysis [33] confirmed the efficacy of myo-inositol alone or in combination with DCI in PCOS women. Those authors highlighted that various studies demonstrated the role of DCI at low dosage to increase insulin sensitivity and ovulation regularity and to reduce the levels of lipid biomarkers and serum androgen. 4. Latest Studies Some recent preclinical and clinical studies have allowed a more complete picture concerning the different efficacies of the various ratios between MI and DCI in PCOS women. A preclinical study [34] was recently carried out in a PCOS animal model. Female mice, subjected to continuous light for 10 weeks, developed an androgenic‐like phenotype of their ovaries as we find in PCOS women. The study provided the first experimental evidence that the efficacy exerted by various MI/DCI ratios (5 : 1, 20 : 1, 40 : 1, and 80 : 1) changes, supporting the metabolic link between the two stereoisomers, specifically for PCOS. The daily treatment of mice with 420 mg/kg MI/DCI in a 40 : 1 molar ratio allowed investigators to obtain a rapid and almost full recovery from PCOS signs and symptoms. Since theca cell layer hypertrophy is a hallmark of PCOS and is strongly associated with an increased production of androgens [35], it is noteworthy that the ovaries from treated mice recovered normal histological features with a reduced ratio between theca and granulosa cell layer thickness (TGR). This means that the androgenic phenotype was efficaciously reversed. The other MI/DCI ratios were less effective or even exerted negative effects on the clinical pathological conditions (obviously, the total amount of inositols administered was the same). In particular, the formulation with high DCI content demonstrated to be unfavorable with worsening PCOS features. Moreover, a 2019 published clinical trial [36] was performed to directly compare the efficacy of seven different ratios between MI and DCI in PCOS therapy. Fifty-six patients (8 for each group) were treated orally using the following formulations: DCI alone and in 1 : 3.5, 2.5 : 1, 5 : 1, 20 : 1, 40 : 1, and 80 : 1 MI/DCI ratios. They received 2 g of inositols twice a day for 3 months. The primary outcome was ovulation, and the secondary outcomes included the improvement of FSH, LH, sex hormone-binding globulin (SHBG), 17-beta-estradiol (E2), free testosterone, and basal and postprandial insulin levels, as well as HOMA index, BMI, and menses. The authors found that the 40 : 1 MI/DCI ratio was the best for PCOS therapy directed at restoring ovulation and normalizing important parameters (progesterone, LH, SHBG, estradiol, and testosterone) in those patients. These results were significant. The other formulations were less effective. In particular, a decreased activity was observed when the 40 : 1 ratio was modified in favor of DCI. Clearly, these findings completely agree with the preclinical study of PCOS mice. 5. Two Explanations The concerning decrease in efficacy found in PCOS treatment when patients were administered high doses of DCI may be explained by examining some biological mechanisms. Here, we discuss two key points for the reader, both useful in understanding this phenomenon. The first one concerns the biological local effect of DCI on blastocyst quality, while the second is related to the pharmacokinetics of MI administered alone vs. being with DCI vs. being with other substances. 5.1. Blastocyst Quality A published study successfully related the concentrations of MI and DCI in follicular fluid (FF) to the quality of blastocysts. That was the first time that the concentrations of MI and DCI in FF were directly correlated with blastocyst quality. It demonstrated that DCI concentrations above the MI/DCI limit ratio of 70 : 1 in follicular fluid decreased blastocyst quality [37]. The oocytes were taken from strictly healthy young women (egg donors) who were subjected to ovarian stimulation, whereas the sperm used for fertilization was given by the male partner of each couple undergoing IVF (all men were normospermic). Good quality blastocysts, classified by grades 4 and 3, were correlated with higher percentages of MI/DCI found in FF and with more satisfactory results in IVF compared to blastocysts assessed to be of poor quality, classified by grades 2 and 1. FF specimens were allocated into two groups correlated with grades 4 + 3 and grades 2 + 1 blastocysts, respectively. Data analysis determined that the good quality threshold related to the ratio between MI and DCI in FF is basically very close to or higher than 70 : 1 (and up to 100 : 1). The reduction of the ratio under this value was shown to exert negative consequences on blastocyst quality, assessed as grades 2 and 1 blastocysts. In conclusion, a higher MI/DCI ratio in FF correlated positively with good quality blastocysts, therefore constituting a promising parameter for the success of embryo implantation and pregnancy in IVF patients undergoing intracytoplasmic sperm injection (ICSI). This event is explainable since the DCI-IPG second messenger serves as the signal transduction system for the stimulation—due to insulin—of human testosterone biosynthesis in theca cells [38]. This condition agrees with the higher amounts of testosterone that may be found in PCOS women in comparison with healthy subjects. As pointed out by Harwood and coworkers [39], in contrast to healthy women in whom androgens are produced equally from both the adrenal glands and the ovaries [40], in women with PCOS the ovaries are usually the major source of androgens [41]. Increased androgen levels decrease the liver production of sex hormone-binding globulin (SHBG) [42], the major circulating protein that binds testosterone, thus increasing free (biologically active) testosterone levels. These hormonal abnormalities might be related in part to obesity [43]. Recent evidence regarding DCI effects on aromatase is of great importance and adds a new piece to the mosaic of our knowledge. Sacchi and coworkers [44] stimulated primary cultures of human granulosa cells (hGCs) by insulin and tested the aromatase CYP19A1 gene expression by Real-Time PCR to find out whether DCI, after 24 h incubation, inhibited the insulin effect. They used four concentrations of DCI, namely, 1, 5, 10, and 20 nM: the first one was totally ineffective, 5 nM exerted a barely visible inhibitory activity, whereas 10 and 20 nM achieved a significant inhibitory effect that became greater with increasing DCI concentrations (slightly more than 50% reduction with 20 nM DCI). Therefore, DCI seems to decrease aromatase gene (CYP19A1) expression in a dose-dependent manner [44]. Aromatase is an enzyme involved in the transformation of androgens to estrogens; hence the inhibition of its activity ends up causing an increase in the levels of testosterone and other androgens. These observations induce one to think that DCI excess in the ovary stimulates ovarian androgen production and can help to explain the worsening of oocyte and blastocyst quality observed with high DCI levels [37]. 5.2. MI and DCI Pharmacokinetics A very recent study [45] evaluated the changes in the PK profile of MI absorption in humans when administered combined with DCI or with glucose transporter inhibitors, as compared to MI alone. Fasting 18 healthy volunteers received a single oral dose of MI (6 g); after seven days, the same subjects were administered MI (6 g) and DCI (1 g) together, and they were treated again after one week with MI (6 g) plus 25.5 mg phlorizin, 1.7 mg quercetin, 46.7 mg chlorogenic acid, 1193.1 mg sorbitol, 260.7 mg maltodextrin, and 42.7 mg sucralose. This study demonstrated that the absorption of MI decreases when administered with DCI, showing a reduction of the AUC 0–540 of 19.1% and a reduction of 22.3% of the Cmax. Although the absorption of MI can occur by a diffusion process at high MI concentrations, the uptake of inositols by cells is primarily carried out by a complex system of transporters (SMIT1, SMIT2, and HMIT) which mediate an active transport of inositols [46]. These MI transporters have different tissue distributions within the human body. So far only SMIT2 was identified in the small intestine [47]; therefore it is reputed to be the only one involved in MI intestinal absorption. Based on the data analysis of their study, the authors speculated about an inhibitory effect of DCI on MI absorption in humans. SMIT2 transports MI with an average Km of 120–150 μM (spanning between 67 and 283 μM), which is consistent with MI human plasma concentration having a mean value of 32.5 ± 1.5 μM, with a range of 26.8–43.0 μM [48]. Conversely, although DCI is transported with an average Km of 110–130 μM (similar to that of MI), the average plasma level of DCI is less than 100 nM [46]. Therefore, DCI transport usually represents a minor physiological activity of SMIT2 due to the low concentration of DCI as compared to MI. Nevertheless, when DCI is administered at a high dosage and achieves higher concentrations it is able to compete with MI. This mechanism may explain the reason why administration of DCI in high dosage seems to be able to interfere with and inhibit the intestinal transport of MI as reported in this study [45], and this fact should be carefully considered when it becomes necessary to achieve the correct dietary supplementation of inositols. An even greater effect in decreasing MI intestinal absorption was found when the healthy volunteers took MI plus phlorizin with the other compounds. The likely main effect was due to phlorizin, an inhibitor of glucose transport that acts as a nontransported competitive inhibitor of sodium-coupled sugar cotransporters. For this reason, it is used in the treatment of diabetes and obesity because of its induction of renal glycosuria and the blockage of intestinal glucose absorption [49]. Phlorizin provides hypoglycemic activity in humans and improves glucose metabolism. Like SGLT1, the glucose transporter of the small intestine, SMIT2, is sensitive to phlorizin, which acts as a potent inhibitor at an average Ki of 15 ± 6 μM [46]. These data may explain in part the decrease of MI absorption (AUC 0–540 is 31.8% less and Cmax 41.1%). In addition, we can conjecture that the additional presence of nonnegligible amounts of sorbitol, maltodextrin, and sucralose acts as inhibitors, albeit weak, for the passage through SMIT2 (which is much more specific for inositols). In this way, the reduction of MI absorption due to phlorizin is further increased, resulting in an even lower plasma concentration in contrast to the administration of MI alone. These findings provide important information for PCOS therapy and are a warning to avoid the concomitant administration of MI with sugar absorption inhibitors and with sugars, since all of these compounds negatively alter MI pharmacokinetics in the human body. At the end of this paragraph, we would like to briefly mention two studies with alpha-lactalbumin and MI. This formulation was tested since alpha-lactalbumin increases the intestinal absorption of molecules such as MI. In addition, it exerts an anti-inflammatory activity that is beneficial in PCOS. The first study demonstrated, both in vivo and in vitro, that alpha-lactalbumin significantly improves MI intestinal absorption and bioavailability [50]. In the second study, PCOS women, who were nonresponsive (inositol-resistant patients) to MI alone, were given 2 g MI plus 50 mg alpha-lactalbumin, twice a day for three months [51]. Ovulation was the primary outcome, whereas some important laboratory parameters were secondary outcomes. At the end of the treatment, 86% patients ovulated, showing an increase of plasmatic MI levels and a significant improvement of total cholesterol, triglycerides, testosterone, free testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG). Also, androstenedione decreased, although it was nonsignificant. Therefore, these studies provide meaningful results to sustain the use of alpha-lactalbumin in combination with MI. 6. The Situation of the Current Inositol Market for PCOS Given this overview of the scientific evidence thus far available regarding inositol pharmacokinetics and pharmacodynamics, we were astonished when we analyzed the current inositol market for the treatment of PCOS as we find a high number of combinations between MI and DCI, often in combination with other molecules (Tables 1 and 2). In most of these cases, no therapeutic rationale or therapeutic target seems to have been taken into consideration. Aside from the 40 : 1 ratio, the other ratios are very imaginative and seem to have been randomly chosen. They are without scientific and therapeutic bases. Furthermore, the ratios with high concentrations of DCI strongly conflict with all of the unfavorable data demonstrated from the use of high therapeutic doses of DCI, and these data are well known. As previously shown, the 40 : 1 combination is well supported by many preclinical and clinical studies, while preclinical trials for the other ratios and combinations are either lacking or completely absent. MI/DCI ratio 1 0.4 : 1 2 0.8 : 1 3 3.6 : 1 4 5 : 1 5 7 : 1 6 8 : 1 7 9.5 : 1 8 10 : 1 9 19.4 : 1 10 40 : 1 11 66 : 1 12 92 : 1 13 104 : 1
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Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by chronic ovulation dysfunction and hyperandrogenism. It is considered the most common endocrinological disorder, affecting up to 25% of women of reproductive age, and associated with long-term metabolic abnormalities predisposing to cardiovascular risk, such as insulin resistance (IR), dyslipidemia, endothelial dysfunction, and systemic inflammation. PCOS is also characterized by elevated serum levels of luteinizing hormone (LH), causing a condition of hyperandrogenism and a consequent altered ratio between LH and the follicle stimulating hormone (FSH). Over the years, several different approaches have been proposed to alleviate PCOS symptoms. Supplementation with natural molecules such as inositols, resveratrol, flavonoids and flavones, vitamin C, vitamin E and vitamin D, and omega-3 fatty acids may contribute to overcoming PCOS pathological features, including the presence of immature oocyte, IR, hyperandrogenism, oxidative stress and inflammation. This review provides a comprehensive overview of the current knowledge about the efficacy of natural molecule supplementation in the management of PCOS.
... Vitamin D deficiency has been associated with the most prevalent phenomena in PCOS, such as hyperandrogenism [158], insulin resistance [101], adiposity indices [159], systemic proinflammatory indices, and ovulatory dysfunction [160,161]. Moreover, vitamin D is a steroid hormone with progesterone-like activity [162]. However, the mechanisms underlying the association between vitamin D and PCOS are not fully understood. ...
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Recent evidence has revealed anti-inflammatory properties of vitamin D as well as extra-skeletal activity. In this context, vitamin D seems to be involved in infections, autoimmune diseases, cardiometabolic diseases, and cancer development. In recent years, the relationship between vitamin D and insulin resistance has been a topic of growing interest. Low 25-hydroxyvitamin D (25(OH)D) levels appear to be associated with most of the insulin resistance disorders described to date. In fact, vitamin D deficiency may be one of the factors accelerating the development of insulin resistance. Vitamin D deficiency is a common problem in the population and may be associated with the pathogenesis of diseases related to insulin resistance, such as obesity, diabetes, metabolic syndrome (MS) and polycystic ovary syndrome (PCOS). An important question is the identification of 25(OH)D levels capable of generating an effect on insulin resistance, glucose metabolism and to decrease the risk of developing insulin resistance related disorders. The benefits of 25(OH)D supplementation/repletion on bone health are well known, and although there is a biological plausibility linking the status of vitamin D and insulin resistance supported by basic and clinical research findings, well-designed randomized clinical trials as well as basic research are necessary to know the molecular pathways involved in this association.
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Currently, there is abundant scientific evidence showing that the vitamin D endocrine system (VDES) is a highly complex endocrine system with multiple actions in different regions of the body. The unequivocal presence of vitamin D receptors in different tissues related to fertility, and to specific aspects of women’s health such as pregnancy, undoubtedly implies functions of this steroid hormone in both male and female fertility and establishes relationships with different outcomes of human gestation. In order to review the role of the VDES in human fertility, we evaluated the relationships established between 25-hydroxyvitamin D (calcifediol) deficiency and in vitro fertilization, as well as aspects related to ovarian reserve and fertility, and commonly diagnosed endocrinopathies such as polycystic ovary disease. Likewise, we briefly reviewed the relationships between calcifediol deficiency and uterine fibroids, as well as the role that treatment may have in improving human fertility. Finally, the best scientific evidence available on the consequences of calcifediol deficiency during pregnancy is reviewed in relation to those aspects that have accumulated the most scientific literature to date, such as the relationship with the weight of the newborn at the time of delivery, the appearance of preeclampsia, and the risk of developing gestational diabetes and its final consequences for the pregnancy. To date, there is no definitive consensus on the necessary dose for treatment of calcifediol deficiency in the therapeutic management of infertility or during pregnancy. Large prospective clinical intervention studies are needed to clarify the benefits associated with this supplementation and the optimal dose to use in each situation. Although most intervention studies to date have been conducted with cholecalciferol, due to its much longer history of use in daily care, the use of calcifediol to alleviate 25-hydroxyvitamin D deficiency seems safe, even during pregnancy. The unequivocal presence of vitamin D receptors in very different tissues related to human fertility, both male and female, as well as in structures typical of pregnancy, allows us to investigate the crucial role that this steroid hormone has in specific aspects of women’s health, such as pregnancy and the ability to conceive. Well-designed clinical studies are needed to elucidate the necessary dose and the best form of treatment to resolve the very common calcifediol deficiency in women of reproductive age.
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The incidence of preterm birth (PTB), delivery before 37 completed weeks of gestation, is rising in most countries. Several recent small clinical trials of myo -inositol supplementation in pregnancy, which were primarily aimed at preventing gestational diabetes, have suggested an effect on reducing the incidence of PTB as a secondary outcome, highlighting the potential role of myo -inositol as a preventive agent. However, the underlying molecular mechanisms by which myo -inositol might be able to do so remain unknown; these may occur through directly influencing the onset and progress of labour, or by suppressing stimuli that trigger or promote labour. This paper presents hypotheses outlining the potential role of uteroplacental myo -inositol in human parturition and explains possible underlying molecular mechanisms by which myo -inositol might modulate the uteroplacental environment and inhibit preterm labour-onset. We suggest that a physiological decline in uteroplacental inositol levels to a critical threshold with advancing gestation, in concert with an increasingly pro-inflammatory uteroplacental environment, permits spontaneous membrane rupture and labour-onset. A higher uteroplacental inositol level, potentially promoted by maternal myo -inositol supplementation, might affect lipid metabolism, eicosanoid production, and secretion of pro-inflammatory chemocytokines, that overall dampen the pro-labour uteroplacental environment responsible for labour-onset and progress, thus, reducing the risk of PTB. Understanding how and when inositol may act to reduce PTB risk would facilitate the design of future clinical trials of maternal myo -inositol supplementation and definitively address the efficacy of myo -inositol prophylaxis against PTB.
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To assess whether oral supplementation of vitamin D3, myo-inositol, folic acid and melatonin affects IVF outcomes. One hundred and twenty consecutive infertile women attending IVF treatment were 1:1 randomly distributed in two groups. Women in group A (control) were assigned to receive myo-inositol, alpha-lactalbumin and folic acid in the morning, and myo-inositol, folic acid and melatonin in the evening. Women in group B (treated) were assigned to receive analogous treatment, with the addition of cholecalciferol (vitamin D3) in the evening from the early beginning of the luteal phase. 50 patients in group A and 50 in group B underwent blastocyst transfer and were considered in the statistical analysis. Vitamin D3 levels significantly increased after 45 days of treatment: 33.2 ng/ml in group B Vs. 24.3 ng/ml in group A (p < .0001). The implantation rate increased as well: 37.1% in group B Vs. 19.2% in group A (p < .0151). Overall, the results indicate that increased vitamin D3 levels positively correlate with the implantation rate in IVF. Because of the low number of participants, these findings need to be confirmed with larger cohorts of patients.
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Review article is devoted to one of the most common polygenic endocrinopathies in women of reproductive age, polycystic ovarian syndrome (PCOS). We review the current criteria used to make a correct diagnosis based on four phenotypes of PCOS: Frank (phenotype A) – biochemical and/or clinical hyperandrogenism, oligo-/anovulation, polycystic ovarian morphology according to ultrasound; anovulatory (phenotype B) – oligo-/anovulation, biochemical and/or clinical hyperandrogenism; ovulatory (phenotype C) – biochemical and/or clinical hyperandrogenism, polycystic ovarian morphology according to ultrasound; non-androgenic (phenotype D) – oligo-/anovulation, polycystic ovarian morphology according to ultrasound. This article presents the main theories of PCOS pathogenesis: peripheral, central, insulin, genetic, and also considers epigenetic factors. PCOS is a multifactorial disease in which genes are responsible for the mechanisms of the process, and environmental factors through epigenetics affect the genetic material. PCOS phenotypes play an important role in clinical practice, as they allow an individualised approach to the selection of therapy in each case, taking into account the pathogenesis of the disease and predicting its course in the future. The main therapeutic options for treating patients with PCOS, taking into account the multifactorial nature of the disease and the patient's interest in pregnancy, are reviewed. The article presents modern methods for the correction of hyperandrogenism and anovulation, with special emphasis on the need for progesterone therapy.
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Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder characterized by oligo-anovulation, hyperandrogenism, and insulin resistance, this latter with a key role in the pathogenesis of this syndrome. Considering the heterogeneity of this condition, various therapeutic approaches have been attempted in PCOS women, besides the classical treatments such as metformin or pioglitazone. Emerging data support the use of natural compounds such as inositols, myo- and D-chiro-inositol, alone or in combination. Moreover, vitamins and dietary factors such as vitamin D, alpha-lipoic acid, omega 3, melatonin and probiotics may be efficient in PCOS treatment counteracting its endocrine and metabolic aspects, as well as their secondary complications. The present chapter addresses the current knowledge about the efficacy of these nutrients in the treatment of PCOS, in view of experimental and clinical studies.
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Cerebral cavernous malformations (CCMs), one of the most common vascular malformations, are characterized by abnormally dilated intracranial microvascular capillaries resulting in increased susceptibility to hemorrhagic stroke. As an autosomal dominant disorder with incomplete penetrance, the majority of CCMs gene mutation carriers are largely asymptomatic but when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage, while the molecular "trigger" initiating the occurrence of CCM pathology remain elusive. Currently, the invasive neurosurgery removal of CCM lesions is the only option for the treatment, despite the recurrence of the worse symptoms frequently occurring after surgery. Therefore, there is a grave need for identification of molecular targets for therapeutic treatment and biomarkers as risk predictors for hemorrhagic stroke prevention. Based on reported various perturbed angiogenic signaling cascades mediated by the CCM signaling complex (CSC), there have been many proposed candidate drugs, targeting potentially angiogenic-relevant signaling pathways dysregulated by loss of function of one of the CCM proteins, which might not be enough to correct the pathological phenotype, hemorrhagic CCMs. In this review, we describe a new paradigm for the mechanism of hemorrhagic CCM lesions, and propose a new concept for the assurance of the CSC-stability to prevent the devastating outcome of hemorrhagic CCMs.
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Objective: Vitamin D3 and progesterone (P4) both belong to steroid hormones. These hormones have effects on the function of each other in different ways. The immunomodulatory activity of vitamin D3 and P4 and their role in inducing maternal tolerance for fetus have been shown in various studies. The purpose of this study was to evaluate the effect of vitamin D3 on the expression of membrane progesterone receptors (mPRs) on CD4+ T cells. Materials and methods: Naive CD4+ T cells were isolated from peripheral blood of 38 healthy women of childbearing age. After stimulating by anti-CD3 and anti-CD28 monoclonal antibodies (mAb), these cells were exposed to either various concentrations of vitamin D3 or no exposure at all in a culture medium at 37 °C for 3 days. In the final stage, the mean fluorescence intensity (MFI) of mPRα and mPRβ were evaluated using polyclonal and monoclonal antibodies and several gating strategies on CD4+ T cells. Results: Vitamin D3 significantly increased the expression of mPR α and mPR β on the surface of CD4+ T cells (p ≤ 0.05). Conclusion: The present study demonstrated the potential effect of vitamin D3 on increasing the expression of P4 receptors on CD4+ T cells. This study shows a new aspect of correlation between vitamin D3 and P4 that may influence P4 performance. Therefore, our findings suggest that the appropriate level of this vitamin may affect the optimum P4 immunomodulatory activity during pregnancy.
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Background Chest pain is a serious symptom that is routinely investigated as a sign of coronary artery disease. Non-cardiac chest pain (NCCP) is indistinguishable from ischemic chest pain and both are considered serious and receive similar medical investigations. Although NCCP is not associated with cardiovascular diseases (CVDs), patients with NCCP may become anxious and frightened from developing coronary events. So, it will be valuable to improve modifiable cardiovascular risk factors in such subjects to reduce fear from CVDs. Because vitamin D deficiency was considered as a possible modifiable cardiovascular risk factor, our aim was to investigate association between serum vitamin D and cardiovascular risk variables in subjects with NCCP. Methods A cross-sectional study involved 104 subjects who underwent cardiac catheterization that did not reveal any cardiac origin for their chest pain. 25-hydroxyvitamin D was measured by electrochemiluminescence immunoassay, glucose was measured by hexokinase method, hemoglobin A1c (HbA1c) was measured by turbidimetric inhibition immunoassay and lipid profile was measured by enzymatic colorimetric assays. Results High density lipoprotein cholesterol (HDL-C) was significantly higher in subjects with sufficient vitamin D compared to those with insufficient or deficient vitamin D (p-value< 0.01). 25-hydroxyvitamin D was positively associated with HDL-C (p-value< 0.01) and inversely associated with HbA1c (p-value = 0.02). 25-hydroxyvitamin D was not significantly correlated with other cardiovascular biomarkers including blood pressure, glucose, and other components of lipid profile (p-values> 0.05). Conclusions low serum vitamin D could be involved in reducing HDL-C and increasing HbA1c and thus it may increase cardiovascular risk in subjects with NCCP.
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Objective The aim of this study was to determine the effect of vitamin D and probiotic co-administration on mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome (PCOS). Methods This randomized, double-blinded, placebo-controlled clinical trial was carried out on 60 subjects, aged 18–40 years old. Subjects were randomly allocated to take either 50,000 IU vitamin D every 2 weeks plus 8 × 10⁹ CFU/day probiotic (n = 30) or placebo (n = 30) for 12 weeks. Results Vitamin D and probiotic co-supplementation, compared with the placebo, significantly improved beck depression inventory [β (difference in the mean of outcomes measures between treatment groups) − 0.58; 95% CI, − 1.15, − 0.02; P = 0.04], general health questionnaire scores (β − 0.93; 95% CI, − 1.78, − 0.08; P = 0.03) and depression, anxiety and stress scale scores (β − 0.90; 95% CI, − 1.67, − 0.13; P = 0.02). Vitamin D and probiotic co-supplementation was associated with a significant reduction in total testosterone (β − 0.19 ng/mL; 95% CI, − 0.28, − 0.10; P < 0.001), hirsutism (β − 0.95; 95% CI, − 1.39, − 0.51; P < 0.001), high-sensitivity C-reactive protein (hs-CRP) (β − 0.67 mg/L; 95% CI, − 0.97, − 0.38; P < 0.001) and malondialdehyde (MDA) levels (β − 0.25 μmol/L; 95% CI, − 0.40, − 0.10; P = 0.001), and a significant increase in total antioxidant capacity (TAC) (β 82.81 mmol/L; 95% CI, 42.86, 122.75; P < 0.001) and total glutathione (GSH) levels (β 40.42 μmol/L; 95% CI, 4.69, 76.19; P = 0.02), compared with the placebo. Conclusions Overall, the co-administration of vitamin D and probiotic for 12 weeks to women with PCOS had beneficial effects on mental health parameters, serum total testosterone, hirsutism, hs-CRP, plasma TAC, GSH and MDA levels. Trial Registration This study was retrospectively registered in the Iranian website (www.irct.ir) for registration of clinical trials (IRCT20170513033941N37).
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Study question: Is serum vitamin D associated with live birth rates in women undergoing ART? Summary answer: Women undergoing ART who are replete in vitamin D have a higher live birth rate than women who are vitamin D deficient or insufficient. What is known already: Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation as well as obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on conception and early pregnancy outcomes in couples undergoing ART is poorly understood. Study design, size, duration: A systematic review and meta-analysis of 11 published cohort studies (including 2700 women) investigating the association between vitamin D and ART outcomes. Participants/materials, settings, methods: Literature searches were conducted to retrieve studies which reported on the association between vitamin D and ART outcomes. Databases searched included MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL. Eleven studies matched the inclusion criteria. Main results and the role of chance: Live birth was reported in seven of the included studies (including 2026 patients). Live birth was found to be more likely in women replete in vitamin D when compared to women with deficient or insufficient vitamin D status (OR 1.33 [1.08-1.65]). Five studies (including 1700 patients) found that women replete in vitamin D were more likely to achieve a positive pregnancy test than women deficient or insufficient in vitamin D (OR 1.34 ([1.04-1.73]). All 11 of the included studies (including 2700 patients) reported clinical pregnancy as an outcome. Clinical pregnancy was found to be more likely in women replete in vitamin D (OR 1.46 [1.05-2.02]). Six studies (including 1635 patients) reported miscarriage by vitamin D concentrations. There was no association found between miscarriage and vitamin D concentrations (OR 1.12 [0.81-1.54]. The included studies scored well on the Newcastle-Ottawa quality assessment scale. Limitations reasons for caution: Although strict inclusion criteria were used in the conduct of the systematic review, the included studies are heterogeneous in population characteristics and fertility treatment protocols. Wider implications of the findings: The findings of this systematic review show that there is an association between vitamin D status and reproductive treatment outcomes achieved in women undergoing ART. Our results show that vitamin D deficiency and insufficiency could be important conditions to treat in women considering ARTs. A randomized controlled trial to investigate the benefits of vitamin D deficiency treatment should be considered to test this hypothesis. Study funding/competing interests: No external funding was either sought or obtained for this study. The authors have no competing interests to declare. Registration number: N/A.
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Skin inflammatory responses in individuals with allergic dermatitis may be suppressed by dietary vitamin D through induction and upregulation of the suppressive activity of regulatory T ( T R e g ) cells. Vitamin D may also promote T R e g cell tropism to dermal sites. In the current study, we examined the capacity of dietary vitamin D 3 to modulate skin inflammation and the numbers and activity of T R e g cells in skin and other sites including lungs, spleen, and blood. In female BALB/c mice, dietary vitamin D 3 suppressed the effector phase of a biphasic ear swelling response induced by dinitrofluorobenzene in comparison vitamin D 3 -deficient female BALB/c mice. Vitamin D 3 increased the percentage of T R e g (CD3+CD4+CD25+Foxp3+) cells in the skin-draining lymph nodes (SDLN). The suppressive activity of T R e g cells in the SDLN, mesenteric lymph nodes, spleen, and blood was upregulated by vitamin D 3 . However, there was no difference in the expression of the naturally occurring T R e g cell marker, neuropilin, nor the expression of CCR4 or CCR10 (skin-tropic chemokine receptors) on T R e g cells in skin, SDLN, lungs, and airway-draining lymph nodes. These data suggest that dietary vitamin D 3 increased the percentages and suppressive activity of T R e g cells in the SDLN, which are poised to suppress dermal inflammation.
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The endocrinology of human pregnancy involves endocrine and metabolic changes that result from physiological alterations at the boundary between mother and fetus. Progesterone and oestrogen have a great role along with other hormones. The controversies of use of progestogen and others are discussed in this chapter. Progesterone has been shown to stimulate the secretion of Th2 and reduces the secretion of Th1 cytokines which maintains pregnancy. Supportive care in early pregnancy is associated with a significant beneficial effect on pregnancy outcome. Prophylactic hormonal supplementation can be recommended for all assisted reproduction techniques cycles. Preterm labor can be prevented by the use of progestogen. The route of administration plays an important role in the drug's safety and efficacy profile in different trimesters of pregnancy. Thyroid disorders have a great impact on pregnancy outcome and needs to be monitored and treated accordingly. Method of locating review: Pubmed, scopus.
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Vitamin D has a pivotal role in regulating immune responses by promoting Th2 immune responses and suppressing Th1 responses. Propensities to a Th1 immune response and increased NK-cell levels and cytotoxicity have been reported in women with recurrent pregnancy losses (RPL). In women with RPL, vitamin D deficiency is prevalent; however, the effect of vitamin D on NK cells is largely unknown. In this study, we demonstrated that CD69(+) activating receptor expression on NK cells was significantly decreased by incubation with 1,25(OH)2 D3 in a dose dependent manner, while CD158a and CD158b inhibitory receptor expression was up-regulated. The degranulation marker CD107a was significantly down-regulated on NK cells following incubation with 1,25(OH)2 D3 . NK-cell conjugation with K562 target cells was not affected by 1,25(OH)2 D3 ; however, depolarization of perforin granules in conjugated NK cells was significantly increased. TLR4 expression on NK cells was significantly decreased and TNF-α and IFN-γ production was significantly reduced by 1,25(OH)2 D3 through interference with nuclear factor-κB (NF-κB). Our results suggest 1,25(OH)2 D3 has immune regulatory effects on NK cell cytotoxicity, cytokine secretion and degranulation process as well as TLR4 expression. Potential therapeutic application of 1,25(OH)2 D3 for dysregulated NK-cell immunity should be explored in the future. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Progesterone production from the corpus luteum is critical for natural reproduction. Progesterone supplementation seems to be an important aspect of any assisted reproductive technology treatment. Luteal phase deficiency in natural cycles is a plausible cause of infertility and pregnancy loss, though there is no adequate diagnostic test. This article describes the normal luteal phase of the menstrual cycle, investigates the controversy surrounding luteal phase deficiency, and presents the current literature for progesterone supplementation during assisted reproductive technologies. Copyright © 2015 Elsevier Inc. All rights reserved.
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Steroid hormones are produced throughout the phylogenetic tree, from plants to mammals. In the past 40 years, steroid receptors localized to the nucleus have been recognized as being important to mediating steroid action in many organs. This action mainly arises from the regulation of key genes that are important for organ development and function. These include but are not limited to genes influencing the reproductive tract, mammary glands, bone, brain, fat differentiation, pituitary hormone regulation, and metabolic effects in many organs. Unfortunately, steroids also promote the development of hormone-responsive cancers, including breast, uterus, and prostate cancer. It has also been shown that steroid receptors exist outside the nucleus in many organs and cells, with unclear impact for normal development, health, and disease. This review describes the evidence from many laboratories that these receptors exist and function with nuclear receptors to provide the full impact of all steroid hormones.
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The development of the human corpus luteum (yellow body) is dictated by a strictly controlled system of mutually communicating cells, the luteal steroid hormone-producing cells and endothelial cells. This cell-to-cell communication facilitates control of neoangiogenesis which is a prerequisite for the development of the corpus luteum and its function, the rapid release of large amounts of progesterone into the blood-vascular system. Preconditions for this process are the hormonal regulation of endothelial cell proliferation as well as of vascular permeability through LH and hCG. The morphological correlates of endothelial permeability are cell-to-cell adhesion molecules such as adherens junctions (AJ) and tight junctions (TJ) that open and close the gaps between mutually interacting, neighbouring endothelial cells like a "zip fastener". Various types of cell adhesion molecules have been detected in the corpus luteum such as occludin, claudin 1 and claudin 5 as well as VE-cadherin. It may be assumed that the regulation of AJ and TJ proteins is of particular importance for the permeability and thus for the function of the corpus luteum in early pregnancy since hCG treatment leads to a down-regulation of cell adhesion molecules in the luteal vessels. This effect is apparently mediated by VEGF. From a functional point of view, the hCG-dependent and VEGF-mediated down-regulation of cell adhesion molecules leads to a reduced transmissibility of cell-to-cell contacts and thus to an increased endothelial permeability. In this process the various cell adhesion molecules are not only directly regulated by VEGF but they also mutually interact and thus influence one another.
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Context: Vitamin D deficiency is common among reproductive-aged women and has a role in female reproduction. Objective: This study evaluated the role of 1,25-dihydroxyvitamin D3 (vit D3) in ovarian follicular development and steroidogenesis by using a human granulosa cell (GC) model. Design, setting, and participants: Fifty-four women who underwent in vitro fertilization were enrolled. Intervention: Follicular fluid (FF) and mural and cumulus GCs were collected from small and large follicles. In separate experiments, primary cumulus GCs were cultured with or without vit D3 followed by RT-PCR for mRNA expression levels. The effect of recombinant anti-Mullerian hormone (AMH) on nuclear localization of phospho-Smad 1/5/8 was evaluated in the presence or absence of vit D3 by using immunofluorescence. 25-Hydroxyvitamin D levels in FF as well as cell culture media AMH, progesterone, and estradiol (E2) concentrations were determined by ELISA and RIA. Main outcome measures: The following were measured: 1) mRNA expression levels; 2) 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme activity; 3) FSH-induced aromatase mRNA and E2 production; and 4) nuclear localization of phospho-Smad 1/5/8. Results: In a multivariate analysis, 25 OH-D levels in FF negatively correlated with AMH and AMH receptor (AMHR)-II mRNA levels in cumulus GCs of small follicles. Compared with women with replete 25-hydroxyvitamin D levels in FF, those with insufficient/deficient levels had a 2-fold increase in AMHR-II mRNA levels in cumulus GCs of small follicles (P = .02). Treatment with vit D3 caused a decrease in AMHR-II and FSH receptor mRNA but an increase in 3-βHSD mRNA levels compared with control (P < .05). Vit D3 enhanced 3-βHSD enzyme activity as assessed by increasing progesterone release; however, vit D3 did not affect FSH-induced aromatase mRNA and E2 production, but it decreased the phosphorylation of Smad 1/5/8 and its nuclear localization. Conclusion: These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation.
Article
In healthy bones mineralization has to be tightly controlled to avoid pathological phenotypes. In this study we investigated interactions between 1α,25(OH)2 D3 (1,25D3) and activin A in the regulation of osteoblast induced mineralization. In human osteoblast cultures we demonstrated that besides stimulation of mineralization, 1,25D3 also induced activin A, a strong inhibitor of mineralization. Simultaneously, follistatin (FST), the natural antagonist of activin A, was down-regulated by1,25D3. This resulted in an increase in activin A activity during 1,25D3 treatment. We also showed that in 1,25D3-treated osteoblasts, mineralization can be further increased when activin A activity was abrogated by adding exogenous FST. This observation implies that, besides stimulation of mineralization, 1,25D3 also controls activin A-mediated inhibition of mineralization. Besides activin A, 1,25D3 also induces osteocalcin (BGLAP), another inhibitor of mineralization. Warfarin, which has been shown to inactivate osteocalcin, increased 1,25D3-induced mineralization. Interaction between these two systems became evident from the synergistic increase in BGLAP expression upon blocking activin activity in 1,25D3-treated cultures. In conclusion, we demonstrate that 1,25D3 stimulation of mineralization by human osteoblasts is suppressed by concomitant induction of inhibitors of mineralization. Mineralization induction by 1,25D3 may actually be controlled via interplay with activin A and osteocalcin. Finally, this complex regulation of mineralization substantiates the significance of tight control of mineralization to prevent excessive mineralization and consequently reduction in bone quality and strength. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
Article
Background: Vitamin D (vD) deficiency in pregnancy is a global health problem and the amount of vD supplementation to prevent vD deficiency is controversial. Objective: The objective of the study was to determine effectiveness and safety of prenatal 2000 IU and 4000 IU/d compared with 400 IU/d vD3 supplementation in a randomized controlled trial in population in which vD deficiency is endemic. Design/methods: Arab women were randomized at 12-16 weeks of gestation to 400, 2000, and 4000 IU/d vD3, which were continued to delivery. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured during pregnancy and at delivery. The primary outcome was the maternal and cord blood 25(OH)D, and the secondary outcomes were the achievement of sufficient serum 25(OH)D of 32 ng/mL or greater (≥80 nmol/L) at delivery. Setting: The locations were primary care and tertiary perinatal care centers. Results: Of 192 enrolled, 162 (84%) continued to delivery. Mean serum 25(OH)D of 8.2 ng/mL (20.5 nmol/L) at enrollment was low. Mean serum 25(OH)D concentrations at delivery and in cord blood were significantly higher in the 2000 and 4000 IU than the 400 IU/d group (P < .001) and was highest in the 4000 IU/d group. The percent who achieved 25(OH)D greater than 32 ng/mL and greater than 20 ng/mL concentrations in mothers and infants was highest in 4000 IU/d group. Safety measurements were similar by group and no adverse event related to vD supplementation. Conclusions: Vitamin D supplementation of 2000 and 4000 IU/d appeared safe in pregnancy, and 4000 IU/d was most effective in optimizing serum 25(OH)D concentrations in mothers and their infants. These findings could apply to other populations in which vD deficiency is endemic.
Article
An examination of the alterations in Fibroblast Growth Factor-1 (FGF-1) expression in a group of repeated implantation failure after in vitro fertilization (IVF) patients, when compared to fertile patients. Study group consisted of 24 patients with repeated implantation failure and 29 fertile control patients. Endometrial samples received at the luteal phase were exposed to immunohistochemical staining for the fibroblast growth factor-1 (FGF-1) with antibodies. In the study group all patients have primary infertility (n = 24), and the average duration of infertility was 3.9 ± 1.3 years. The average recurrent IVF failure was 2.6 ± 0.6 attemps. There were no significant differences in the histological data according to the Noyes classification (p = 0.226) and age (p = 0.231) between the patients in the study and control groups (n=29). The control group was found to have more severe expression of FGF-1 (< 0.001) than the study group when endometrial glandular epithelial cells, stromal cells and vascular endothelial cells were evaluated. Endometrial glandular epithelial cells, stromal cells and vascular endothelial cells of the control and study group were evaluated and it was found that the control group displayed a stronger expression of the FGF-1 (< 0.001). The expression of FGF-1 in the IVF implantation failure group is less than in the fertile group, which suggests that growth factors such as FGF-1 are important maternal factors effecting implantation.
Article
T helper (Th) cells play a central role in immune responses and new Th1/Th2/Th17 and regulatory T (Treg)-cell paradigm in pregnancy has developed. Progesterone (P(4)) is essential for the maintenance of pregnancy; however the effect of P(4) on Th1/Th2/Th17 and Treg paradigm is unclear in cows. We evaluated the effect of P(4) on the expression of Th1/Th2/Th17 and Treg-related cytokines, transcription factors, and P(4) receptors in the peripheral blood mononuclear cells (PBMCs) from 8 pregnant (163.1 ± 16.9 days of gestation) and 8 non-pregnant luteal phase cows. PBMCs were stimulated with P(4) at 0, 0.1, 1 or 10 μg/ml, and the mRNA expression of Th1, Th2, Th17 and Treg-related cytokines (IFN-γ, IL-4, IL-17 and TGF-β), transcription factors (T-bet, GATA-3, RORC and Foxp3) and P(4) receptors (PGR, PGRMC1 and PGRMC2) were analyzed by real time RT-PCR. In both pregnant and non-pregnant cows, P(4) significantly inhibited the expression of IFN-γ and IL-17 dose-dependently, whereas P(4) did not affect the expression of TGF-β and Foxp3. In addition, P(4) significantly decreased the expression of T-bet and RORC, and enhanced the expression of IL-4 in the pregnant cows, but this reaction was not found in the non-pregnant cows. P(4) tended to increase PGRMC1 in the pregnant cows but not in the non-pregnant cows, indicating that PGRMC1 may be involved in the regulation of the effect of P(4) during bovine pregnancy. These results indicate that P(4) is an important regulator of Th1/Th2/Th17 and Treg immunity, and higher Th2 immunity is characteristic in the pregnant cows.
Article
Mounting evidence suggests that vitamin D deficiency could be linked to several chronic diseases, including cardiovascular disease and cancer. The purpose of this study was to examine the prevalence of vitamin D deficiency and its correlates to test the hypothesis that vitamin D deficiency was common in the US population, especially in certain minority groups. The National Health and Nutrition Examination Survey 2005 to 2006 data were analyzed for vitamin D levels in adult participants (N = 4495). Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D concentrations ≤20 ng/mL (50 nmol/L). The overall prevalence rate of vitamin D deficiency was 41.6%, with the highest rate seen in blacks (82.1%), followed by Hispanics (69.2%). Vitamin D deficiency was significantly more common among those who had no college education, were obese, with a poor health status, hypertension, low high-density lipoprotein cholesterol level, or not consuming milk daily (all P < .001). Multivariate analyses showed that being from a non-white race, not college educated, obese, having low high-density lipoprotein cholesterol, poor health, and no daily milk consumption were all significantly, independently associated with vitamin D deficiency (all P < .05). In summary, vitamin D deficiency was common in the US population, especially among blacks and Hispanics. Given that vitamin D deficiency is linked to some of the important risk factors of leading causes of death in the United States, it is important that health professionals are aware of this connection and offer dietary and other intervention strategies to correct vitamin D deficiency, especially in minority groups.
Article
Vitamin D Receptor (VDR) is expressed in both animal and human ovarian tissue, however, the role of vitamin D in human ovarian steroidogenesis is unknown. Cultured human ovarian cells were incubated in tissue culture medium supplemented with appropriate substrates, with or without 50 pM-150 pM or 50 nM-150 nM of 1,25-(OH)2D3, and in the presence or absence of insulin. Progesterone, testosterone, estrone, estradiol, and IGFBP-1 concentrations in conditioned tissue culture medium were measured. Vitamin D receptor was present in human ovarian cells. 1,25-(OH)2D3 stimulated progesterone production by 13% (p<0.001), estradiol production by 9% (p<0.02), and estrone production by 21% (p<0.002). Insulin and 1,25-(OH)2D3 acted synergistically to increase estradiol production by 60% (p<0.005). 1,25-(OH)2D3 alone stimulated IGFBP-1 production by 24% (p<0.001), however, in the presence of insulin, 1,25-(OH)2D3 enhanced insulin-induced inhibition of IGFBP-1 production by 13% (p<0.009). Vitamin D stimulates ovarian steroidogenesis and IGFBP-1 production in human ovarian cells likely acting via vitamin D receptor. Insulin and vitamin D synergistically stimulate estradiol production. Vitamin D also enhances inhibitory effect of insulin on IGFBP-1 production.
Article
To determine whether 25OH-D levels in the follicular fluid (FF) of infertile women undergoing IVF demonstrate a relationship with IVF cycle parameters and outcome, hypothesizing that levels of 25OH-D in body fluids are reflective of vitamin repletion status. Prospective cohort study. Academic tertiary care center. Eighty-four infertile women undergoing IVF. Follicular fluid from follicles>or=14 mm; serum (n = 10) and FF levels of 25OH-D. Clinical pregnancy (CP), defined as evidence of intrauterine gestation sac on ultrasound, following IVF; IVF cycle parameters. Serum and FF levels of 25OH-D were highly correlated (r=0.94). In a predominantly Caucasian population (66%), significantly lower FF 25OH-D levels were noted in Black versus non-Black patients. Significant inverse correlations were seen between FF 25OH-D levels and body mass index (r=-0.25). Significantly higher CP and implantation rates were observed across tertiles of FF25OH-D; patients achieving CP following IVF (n=26) exhibited significantly higher FF levels of 25OH-D. Multivariable logistic regression analysis confirmed FF 25OH-D levels as an independent predictor to success of an IVF cycle; adjusting for age, body mass index, ethnicity, and number of embryos transferred, each ng/mL increase in FF 25OH-D increased the likelihood for achieving CP by 6%. Our findings that women with higher vitamin D level in their serum and FF are significantly more likely to achieve CP following IVF-embryo transfer are novel. A potential for benefit of vitamin D supplementation on treatment success in infertile patients undergoing IVF is suggested and merits further investigation.
Article
An increase in maternal serum levels of 1 alpha, 25-dihydroxycalciferol during pregnancy has been linked to enhancement of intestinal calcium absorption. Several sites of its synthesis have been proposed in different species, human decidua being one of them. Collagenase-dispersed decidual cells isolated from term placenta were fractionated on a Percoll gradient. The isolated cells were set in culture in the presence of 6 nM [3H]cholecalciferol. Two cell populations of similar morphology hydroxylated the substrate, yielding a compound that had a mass spectrum identical to and that comigrated with authentic 1 alpha, 25-dihydroxycholecalciferol in four chromatographic systems and bound to a specific rachitic chick receptor. These preparations, thus, provide a potential system by which the kinetics and regulation of the synthesis of the hormonal form of vitamin D by human placenta can be studied in vitro.
Article
The major polar metabolite of cholecalciferol (vitamin D3) present in chick intestinal mucosa has been chemically characterized by mass spectrometric analysis to have a molecular formula of C27H4403 and a structure of 1,25-dihydroxycholecalciferol. This compound, which is produced in the kidney from 25-hydroxycholecalciferol, has been previously shown to be from 4 to 13 times as active as cholecalciferol in stimulating intestinal calcium transport. 1,25-Dihydroxycholecalciferol (previously designated metabolite 4B in this (laboratory) probably represents the biologically active form of cholecalciferol in the intestine.
Article
Vitamin D (calciferol) has been postulated [A.W. Norman, , 184 1965] to mediate its physiological effects via an inductive process which produces new RNA and proteins. This was tested directly by studying the effect of the biologically active form of calciferol, 1,25-dihydroxycholecalciferol to stimulate the pulse labeling of intestinal mucosa by 3H uridine. The maximum stimulation of RNA labeling occurs 6 hours after the intracardial administration of 325 pmoles of 1,25-dihydroxy-cholecalciferol: the first effects were apparent within 3–4 hours. Also, actinomycin D was shown to block both 1,25-dihydroxy-cholecalciferol stimulated Ca2+ transport and RNA synthesis. The chronology of events occurring after administration of 1,25-dihydroxy-cholecalciferol suggest that the primary biochemical response of intestinal mucosa to 1,25-dihydroxy-cholecalciferol is probably the initiation of RNA and protein synthesis.
Article
Rat myometrial tissue and endometrial cells were incubated with labeled 25-hydroxyvitamin D3 ([3H-26,27] 25OHD3) for 70 min at 37 C, and the resulting metabolites were isolated by sequential Sephadex LH-20 chromatography and high performance liquid chromatography. Two peaks more polar than 25OHD3 were present on the Sephadex LH-20 chromatograms. One of these metabolites had an identical chromatographic behavior on three different HPLC systems and an identical sensitivity to periodate cleavage as biosynthetic [3H-26,27] 24,25-dihydroxyvitamin D3 ([3H-26,27]24,25-(OH)2D3]. The in vitro production of this putative 24,25-(OH)2D3 was significantly higher in castrated animals than in normal adult rats. Treatment of rats with 17 beta-estradiol and/or medroxyprogesterone acetate reversed the effect of ovariectomy on 25OHD3 conversion. The in vitro production of the putative 24,25-(OH)2D3 was low during the estrous cycle and the initial stage of pregnancy. A dramatic increase in its production was observed on days 12 and 14 of pregnancy. 25OHD3 conversion was higher in endometrium than in myometrium under every experimental condition tested. These results demonstrate the ability of rat uterine tissue to convert 25OHD3 into more polar derivatives in vitro, and show the influence of the hormonal status of the rat on this in vitro capacity.
Article
Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and an inducer of angiogenesis. VEGF is also known as a vascular permeability factor because it can stimulate vascular permeability. In the rodent, increased uterine vascular permeability occurs at the sites of blastocysts with the onset of the attachment reaction. This is followed by stromal decidualization and angiogenesis. We examined the temporal and spatial expression of VEGF and its receptors, Flk-1 and Flt-1, in the mouse uterus during the peri-implantation period (days 1–8) using Northern and in situ hybridization to assess the involvement of VEGF in the process of implantation. Primarily, a major (≈4·2 kb) transcript for VEGF mRNA was detected in uterine poly(A) samples, except for the presence of two other minor (≈3·7 and 2·5 kb) transcripts in decidual samples. The steady-state levels of these transcripts did not vary much during the peri-implantation period, except for an increase in day-8 decidual samples. Results of in situ hybridization experiments demonstrated accumulation of VEGF mRNA in the luminal epithelium on days 1 and 2. In contrast, stromal cells exhibited a modest level of signals on day 3. On day 4, luminal epithelial cells and those in the subepithelial stromal bed accumulated VEGF mRNA. On days 5–7, a clear cell type-specific accumulation of this mRNA was noted. On day 5 after the initial attachment reaction, luminal epithelial and stromal cells immediately surrounding the blastocyst exhibited accumulation of VEGF mRNA. On days 6–8, the accumulation occurred in cells in the decidual bed at both the mesometrial and antimesometrial poles. The embryo, especially the trophoblast giant cells, also accumulated VEGF mRNA on day 8. The expression of the VEGF receptors, Flk-1 and Flt-1, was also examined. A single transcript (≈6·5-7·0 kb) for Flk-1 mRNA and two transcripts (≈6·5 and 7·5 kb) for that of Flt-1 were detected in poly(A) ⁺ uterine RNA samples. In situ hybridization studies showed accumulation of Flk-1 mRNA in a subset of cells in the stromal bed on day 4, but not in any uterine cell types on day 1. On days 5–8, cells in both the mesometrial and antimesometrial decidual beds exhibited accumulation of Flk-1 and Flt-1 mRNAs. Lectin binding ( Dolichos biflorus agglutinin) was used to identify newly sprouting endothelial cells (angiogenesis), while an antibody to the von Willebrand factor (vWF) was employed to identify endothelial cells in general. The results suggest that vWF-positive stromal cells on day 4 and cells in the antimesometrial decidual bed on days 5–8 correlated with the expression of Flk-1 mRNA, as did the vWF- and lectin-positive cells in the mesometrial decidual bed. This implies that cells involved in angiogenesis at the mesometrial pole express the VEGF receptor mRNAs. In contrast, perhaps the endothelial cells of the existing blood vessels in the stromal bed on day 4 and those in the antimesometrial decidual bed on days 5–8 accumulated the receptor mRNAs, suggesting an involvement of VEGF in changes in vascular permeability. Flk-1 mRNA was also detected in embryonic tissues on day 8. Collectively, the results suggest that VEGF participates in increased vascular permeability and/or angiogenesis occurring in the uterine vascular bed during implantation. Further, the data suggest that VEGF is involved in trophoblast differentiation and invasion, as well as in decidualization and placentation. Journal of Endocrinology (1995) 147, 339–352
Article
The effect of progesterone (P) on the cytokine production profile of Ag-specific human CD4+ T cell lines and clones was investigated. T cell lines specific for purified protein derivative or streptokinase (SK) derived in the presence of P exhibited significant increased ability to produce IL-5 in comparison with T cell lines derived in the absence of P. Moreover, IL-4 was significantly increased in SK-specific T cell lines derived in the presence of P in comparison with SK-specific T cell lines derived in the absence of this hormone. In addition, SK-specific T cell lines generated in the presence of P developed into T cell clones showing a Th0-, instead of Th1-like, cytokine profile. Furthermore, SK-specific T cell clones with an established Th1 profile of cytokine secretion did express mRNA for, and produced detectable amounts of, IL-4 when stimulated with P in combination with insoluble anti-CD3 mAb. Combined stimulation with P and insoluble anti-CD3 mAb also enabled Th1 clones to express CD30 on their surface membrane. These results indicate that P can favor the development of Th cells producing Th2-type cytokines and is an inducer of both transient IL-4 production and CD30 expression in established Th1 cells. Thus, P production at the placental level may be responsible, at least in part, for increased production of Th2-type cytokines which have been implied in fetal allograft survival and maintenance of successful pregnancy.
Article
Human decidual cells are known to produce 1,25-(OH)2D3 at the end of pregnancy, the present study evaluates this capacity, and the part played by stromal decidual cells, in early pregnancy. Cells were obtained from nine human decidua by aspiration or curettage during early pregnancy (7-10 weeks), separated on Ficoll-Paque and plastic adherence, and incubated for 1 h with 25-(OH)D3. Incubation medium and cells were extracted and chromatographed on two successive HPLC systems. The cells examined were of both physiological and pathological (ectopic pregnancy) origin. Endometrial cells obtained in four non-pregnant situations (myomas) were also studied to determine whether the 1,25-(OH)2D3 synthesis by the uterus is associated with the appearance of decidual cells. Results show that human decidual cells from early pregnancy convert 25(OH)D3 (2.5 nM or 2.5 microM) into a metabolite with the physicochemical characteristics of synthetic 1,25-(OH)2D3. This ability is shared by cells isolated during early pregnancy, whether physiological or ectopic (tubal pregnancy). Non-adherent cells, which include mainly stromal decidual cells, are less able to produce 1,25-(OH)2D3 than are the adherent cells, suggesting that macrophages, granulocytes or as yet unidentified cell types are required for the 1,25-(OH)2D3 production by decidual tissue during early human pregnancy. In addition, one out of four experiments with non-pregnant endometrial cells could produce 1,25-(OH)2D3 suggesting that, although not the rule in the non-pregnant state, in vitro production of 1,25-(OH)2D3 by uterine cells can be found in the absence of decidual cells.