Lipoprotein (a) and lipid-lowering treatment from the perspective of a cardiac surgeon. An impact on the prognosis in patients with aortic valve replacement and after heart transplantation.

Lipoprotein(a) is a recognized risk factor for ASCVD. There is still no targeted therapy for Lp(a), however, drugs such as pelacarsen, olpasiran, zerlasiran, lepodisiran and muvalaplin are in clinical trials and have been shown to be effective in significantly reducing Lp(a) levels. Moreover, elevated Lp(a) levels significantly affect the prognosis of patients after aortic valve replacement (AVR) and heart transplantation (HTx). Therefore, the assessment of Lp(a) concentration in these patients will allow for a more accurate stratification of their cardiovascular risk, and the possibility of lowering Lp(a) will allow for the optimization of this risk. In this article, we summarized the most important information regarding the role of Lp(a) and lipid-lowering treatment in patients after AVR and HTx.

Influence of Dulaglutide on Serum Biomarkers of Atherosclerotic Plaque Instability: An Interventional Analysis of Cytokine Profiles in Diabetic Subjects-A Pilot Study.

Background and Objectives: The rise in global diabetes cases, reaching a staggering 529 million in 2021 from 108 million in 1980, underscores the urgency of addressing its complications, notably macrovascular ones like coronary artery, cerebrovascular, and peripheral artery diseases, which contribute to over 50% of diabetes mortality. Atherosclerosis, linked to hyperglycemia-induced endothelial dysfunction, is pivotal in cardiovascular disease development. Cytokines, including pentraxin 3 (PTX3), copeptin, lipoprotein(a) [Lp(a)], and matrix metalloproteinase-9 (MMP-9), influence atherosclerosis progression and plaque vulnerability. Inhibiting atherosclerosis progression is crucial, especially in diabetic individuals. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), increasingly used for type 2 diabetes, show promise in reducing the cardiovascular risk, sparking interest in their effects on atherogenesis. This study sought to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on biomarkers that indicate the instability of atherosclerotic plaques. These biomarkers include pentraxin 3 (PTX3), copeptin (CPC), matrix metalloproteinase-9 (MMP-9), and lipoprotein(a) [Lp(a)]. Materials and Methods: A total of 34 participants, ranging in age from 41 to 81 years (with an average age of 61), who had been diagnosed with type 2 diabetes mellitus (with a median HbA1c level of 8.8%), dyslipidemia, and verified atherosclerosis using B-mode ultrasonography, were included in the study. All subjects were eligible to initiate treatment with a GLP-1 RA-dulaglutide. Results: Significant reductions in anthropometric parameters, blood pressure, fasting glucose levels, and HbA1c levels were observed posttreatment. Moreover, a notable decrease in biochemical markers associated with atherosclerotic plaque instability, particularly PTX3 and MMP-9 (p < 0.001), as well as Lp(a) (p < 0.05), was evident following the GLP-1 RA intervention. Conclusions: These findings underscore the potential of GLP-1 RAs in mitigating atherosclerosis progression and plaque vulnerability, thus enhancing cardiovascular outcomes in individuals with type 2 diabetes mellitus.

Effect of GLP-1RA Treatment on Adhesion Molecules and Monocyte Chemoattractant Protein-1 in Diabetic Patients with Atherosclerosis.

Cardiovascular disease (CVD) remains a prominent cause of global mortality, primarily driven by atherosclerosis. Diabetes mellitus, as a modifiable risk factor, significantly contributes to atherogenesis. Monocyte recruitment to the intima is a critical step in atherosclerotic plaque formation, involving chemokines and adhesion molecules such as selectins, ICAM-1, and MCP-1. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are a promising group of drugs for reducing cardiovascular risk in diabetic patients, prompting investigation into their mechanisms of action. This interventional study enrolled 50 diabetes patients with atherosclerotic plaque, administering GLP-1RA for 180 days. Serum concentrations of MCP-1, ICAM-1, and L-selectin were measured before and after treatment. Anthropometric and biochemical parameters were also assessed. GLP-1RA treatment resulted in significant improvements in anthropometric parameters, glycemic control, blood pressure, and biochemical markers of liver steatosis. Biomarker laboratory analysis revealed higher baseline levels of MCP-1, ICAM-1, and L-selectin in diabetic patients with atherosclerotic plaque compared to healthy controls. Following treatment, MCP-1 and L-selectin levels decreased significantly (p < 0.001), while ICAM-1 levels increased (p < 0.001). GLP-1RA treatment in diabetic patients with atherosclerotic plaque leads to favorable changes in serum molecule levels associated with monocyte recruitment to the endothelium. The observed reduction in MCP-1 and L-selectin suggests a potential mechanism underlying GLP-1RA-mediated cardiovascular risk reduction. Further research is warranted to elucidate the precise mechanisms and clinical implications of these findings in diabetic patients with atherosclerosis.

Effect of tofacitinib on the phenotype and activity of Caco­2 cells in a model of inflammatory bowel disease.

Reports have indicated that autoimmune bowel disorders affect an increasing number of people on every continent; therefore, it is important to better understand inflammatory bowel disease (IBD) and to explore new treatment options for patients suffering from it. Research has indicated the important role of enterocytes in IBD. Understanding the role of the intestinal epithelium in the pathogenesis of IBD may contribute to a better understanding of the inflammatory processes and aid in the identification of potential therapeutic treatments. The present study aimed to evaluate the effects of tofacitinib on Caco-2 cells cultured in an inflammatory environment induced using cytokines naturally found in patients with ulcerative colitis. Tofacitinib is an orally administered inhibitor of Janus kinases (JAKs) which, by modifying the JAK/STAT signaling pathway, reduces the effect of inflammatory cytokines in the gut. Caco-2 cells were used to model the intestinal epithelium and the culture conditions included the proinflammatory cytokine TNFα and tofacitinib. At the end of the culture period, enzymes involved in oxidative stress (superoxide dismutase 1, catalase, nicotinamide adenine dinucleotide phosphate), a marker of apoptosis (Bcl-2) and a key player in intracellular inflammatory signaling (nuclear factor κB) were assessed by quantitative PCR and western blotting. The in vitro phenotype of Caco-2 cells exposed to an inflammatory environment was observed to be similar to that observed in ulcerative colitis. Notably, tofacitinib was able to improve TNFα-induced changes in an in vitro model of ulcerative colitis, and a reduction in the activity of enzymes associated with oxidative stress was observed. In addition, tofacitinib-induced upregulation of Bcl-2 and claudin-1 may contribute to the beneficial effects of tofacitinib on the intestinal epithelium. Tofacitinib appears to have a protective effect on Caco-2 cells. Notably, in the present study, exposure to TNFα stimulated oxidative stress and apoptotic effects, and disrupted intercellular connectivity. The addition of tofacitinib decreased the activity of the examined parameters of oxidative and apoptotic stress, while increasing the activity of the parameter examined to evaluate the degree of intercellular connections. In conclusion, the inhibitory effects of tofacitinib on oxidative stress, as well as its anti-apoptotic and regenerative effects, provide important information regarding the positive effect of tofacitinib on Caco-2 cells, and therefore constitute potential information about the beneficial effect of the evaluated drug in UC.

Impact of Glucagon-Like Peptide 1 Receptor Agonists on Biochemical Markers of the Initiation of Atherosclerotic Process.

Atherosclerosis stands out as one of the leading causes of global mortality. The inflammatory response against vascular wall components plays a pivotal role in the atherogenic process. The initiation of this process is notably driven by oxidized low-density lipoprotein (oxLDL) and a range of pro-inflammatory cytokines, with interleukin-1ß (Il-1ß) and tumor necrosis factor α (TNFα) emerging as particularly significant in the early stages of atherosclerotic plaque formation. In recent years, researchers worldwide have been diligently exploring innovative therapeutic approaches for metabolic diseases, recognizing their impact on the atherogenesis process. Our study aimed to investigate the influence of glucagon-like peptide 1 receptor agonists (GLP-1RA) on cytokine concentrations associated with the initiation of atherosclerotic plaque formation in a group of patients with type 2 diabetes and dyslipidemia. The study encompassed 50 subjects aged 41-81 (mean: 60.7), all diagnosed with type 2 diabetes, dyslipidemia and confirmed atherosclerosis based on B-mode ultrasound. Following a 180-day treatment with dulaglutide or semaglutide, we observed a statistically significant reduction in biochemical markers (oxLDL, TNFα and Il-1ß) associated with the initiation of the atherosclerotic process (p < 0.001) within our study group. In addition to the already acknowledged positive effects of GLP-1RA on the metabolic parameters of treated patients, these drugs demonstrated a notable reduction in proinflammatory cytokine concentrations and may constitute an important element of therapy aimed at reducing cardiovascular risk.

The Application of Peptide Nucleic Acids (PNA) in the Inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Gene Expression in a Cell-Free Transcription/Translation System.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a protein that plays a key role in the metabolism of low-density lipoprotein (LDL) cholesterol. The gain-of-function mutations of the PCSK9 gene lead to a reduced number of surface LDL receptors by binding to them, eventually leading to endosomal degradation. This, in turn, is the culprit of hypercholesterolemia, resulting in accelerated atherogenesis. The modern treatment for hypercholesterolemia encompasses the use of biological drugs against PCSK9, like monoclonal antibodies and gene expression modulators such as inclisiran-a short, interfering RNA (siRNA). Peptide nucleic acid (PNA) is a synthetic analog of nucleic acid that possesses a synthetic peptide skeleton instead of a phosphate-sugar one. This different structure determines the unique properties of PNA (e.g., neutral charge, enzymatic resistance, and an enormously high affinity with complementary DNA and RNA). Therefore, it might be possible to use PNA against PCSK9 in the treatment of hypercholesterolemia. We sought to explore the impact of three selected PNA oligomers on PCSK9 gene expression. Using a cell-free transcription/translation system, we showed that one of the tested PNA strands was able to reduce the PCSK9 gene expression down to 74%, 64%, and 68%, as measured by RT-real-time PCR, Western blot, and HPLC, respectively. This preliminary study shows the high applicability of a cell-free enzymatic environment as an efficient tool in the initial evaluation of biologically active PNA molecules in the field of hypercholesterolemia research. This cell-free approach allows for the omission of the hurdles associated with transmembrane PNA transportation at the early stage of PNA selection.

The impact of wound-healing assay, phorbol myristate acetate (PMA) stimulation and siRNA-mediated FURIN gene silencing on endogenous retroviral ERVW-1 expression level in U87-MG astrocytoma cells.

PURPOSE: Human endogenous retroviruses (HERVs) are ubiquitous genomic sequences. Normally dormant HERVs, undergo reactivation by environmental factors. This deregulation of HERVs' transcriptional equilibrium correlates with medical conditions such as multiple sclerosis (MS). Here we sought to explore whether exposing the U-87 MG astrocytoma cells to traumatic injury deregulates the expression of HERV-W family member ERVW-1 encoding syncytin-1. We also examined the expression of FURIN gene that is crucial in syncytin-1 synthesis. MATERIAL AND METHODS: Scratch assay was used as a model of cells injury in U-87 MG cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot (WB) and migration assay using Boyden chamber were used. Phorbol 12-myristate 13-acetate (PMA) and small interfering RNA (siRNA) were used for cell stimulation and gene expression inhibition, respectively. RESULTS: Results revealed reduced ERVW-1 expression in cells exposed to injury (p â€‹< â€‹0.05) while GFAP gene - a marker of active astrocytes, was upregulated (p â€‹< â€‹0.01). These findings were confirmed by both WB and RT-qPCR. Expression of FURIN gene was not altered after injury, but cell stimulation by PMA strongly increased FURIN expression, simultaneously downregulating ERVW-1 (p â€‹< â€‹0.01). SiRNA-mediated expression inhibition of ERVW-1 and FURIN influenced the mRNA level for SLC1A5 (ASCT2) - primary syncytin-1 receptor, that was significantly lower. FURIN inhibition by siRNA caused strong upregulation of ERVW-1 expression (p â€‹< â€‹0.01). CONCLUSION: Results showed that mechanical impact affects the expression of endogenous retroviruses in U-87 MG astrocytoma cells by scratch assay. Regulation of FURIN, a crucial enzyme in ERVW-1 turnover may support the therapy of some neurological conditions.

The Current and Promising Oral Delivery Methods for Protein- and Peptide-Based Drugs.

Drugs based on peptides and proteins (PPs) have been widely used in medicine, beginning with insulin therapy in patients with diabetes mellitus over a century ago. Although the oral route of drug administration is the preferred one by the vast majority of patients and improves compliance, medications of this kind due to their specific chemical structure are typically delivered parenterally, which ensures optimal bioavailability. In order to overcome issues connected with oral absorption of PPs such as their instability depending on digestive enzymes and pH changes in the gastrointestinal (GI) system on the one hand, but also their limited permeability across physiological barriers (mucus and epithelium) on the other hand, scientists have been strenuously searching for novel delivery methods enabling peptide and protein drugs (PPDs) to be administered enterally. These include utilization of different nanoparticles, transport channels, substances enhancing permeation, chemical modifications, hydrogels, microneedles, microemulsion, proteolytic enzyme inhibitors, and cell-penetrating peptides, all of which are extensively discussed in this review. Furthermore, this article highlights oral PP therapeutics both previously used in therapy and currently available on the medical market.

Impact of metformin on hypothalamic-pituitary-thyroid axis activity in women with autoimmune and non-autoimmune subclinical hypothyroidism: a pilot study.

BACKGROUND: Metformin reduces plasma TSH levels if these levels are elevated. No study has investigated whether the hormonal effects of metformin are impacted by thyroid autoimmunity. The current study aimed to compare the effect of metformin on hypothalamic-pituitary-thyroid axis activity between subjects with mild hypothyroidism of different origins. METHODS: The study population consisted of two groups of women with prediabetes and mildly elevated TSH levels, matched by age, insulin sensitivity, TSH, and thyroid hormone levels. Group A included 26 women with autoimmune thyroiditis, while group B enrolled 26 individuals with hypothyroidism of non-autoimmune origin. Both groups were treated with metformin (2.55-3 g daily). Circulating levels of TSH, total and free thyroid hormones, glucose, insulin, prolactin, high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D, concentrations of thyroid antibodies, and structure parameters of thyroid homeostasis were assessed at baseline and 6 months later. RESULTS: All patients completed the study. At baseline, both groups differed in concentrations of thyroid peroxidase antibodies, thyroglobulin antibodies, hsCRP, and 25-hydroxyvitamin D. The drug reduced TSH and Jostel's index, with no difference between the study groups. The improvement in insulin sensitivity, observed in both groups, was more pronounced in group B than in group A. In women with autoimmune hypothyroidism, the drug increased SPINA-GT and decreased hsCRP levels. The remaining markers did not change throughout the study. CONCLUSIONS: The obtained results suggest that, despite differences in thyroid output, the impact of metformin on TSH levels is similar in hypothyroid women with and without thyroid autoimmunity.

Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease.

Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease.

Impaired Prolactin-Lowering Effects of Metformin in Women with Polycystic Ovary Syndrome.

The effect of metformin on prolactin concentration seems to be sex-dependent. The aim of this study was to determine whether the androgen status modulates the impact of metformin on plasma prolactin levels in women. This study included two matched groups of prediabetic women with hyperprolactinemia: 25 with PCOS and 25 control subjects with androgen levels within the reference range and with normal ovarian morphology. Glucose homeostasis markers, prolactin, the remaining anterior pituitary hormones, sex hormones, SHBG and IGF-1 were determined before and after six months of metformin treatment. At baseline, both groups differed in LH, LH/FSH ratio, testosterone, FAI, DHEA-S, androstenedione and estradiol. Although metformin improved insulin sensitivity and increased SHBG in both study groups, these effects were more pronounced in control subjects than in women with PCOS. In control subjects, the drug decreased total and monomeric prolactin and increased LH. In women with PCOS, metformin reduced LH, LH/FSH ratio, testosterone and FAI. In the control group, the impact on total and monomeric prolactin positively correlated with their baseline levels and with the degree of improvement in insulin sensitivity, as well as negatively correlated with testosterone and FAI. In women with PCOS, treatment-induced changes in testosterone and FAI positively correlated with the changes in LH and LH/FSH ratio. The obtained results suggest that the prolactin-lowering properties of metformin are less pronounced in women with coexisting PCOS than in women with elevated prolactin levels, probably owing to the increased production of endogenous testosterone.

Does Therapy with Glucagon-like Peptide 1 Receptor Agonists Have an Effect on Biochemical Markers of Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD)? Pleiotropic Metabolic Effect of Novel Antidiabetic Drugs in Patients with Diabetes-Interventional Study.

Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) is associated with the excessive collection of lipids in hepatocytes. Over 75% of diabetes patients typically have MASLD, and, at the same time, the presence of MASLD increases the risk of diabetes by more than two times. Type 2 diabetes and MASLD are independent cardiovascular disease (CVD) risk factors. New diabetes treatment should also take into account pleiotropic effects that reduce cardiovascular risk. The aim of our study is to investigate whether analogs of GLP1 receptors have a pleiotropic metabolic effect and global impact to decrease cardiovascular risk, and also reduce the risk of hepatic fibrosis in patients with MASLD. This study involved 41 patients with diabetes and dyslipidemia who also had atherosclerotic plaque and hepatic steatosis verified by ultrasonography and who were eligible to begin one of the GLP1 receptor agonists treatments. We observed a statistically significant decrease in: BMI (p < 0.001) waist and hip circumference (p < 0.001), glycated hemoglobin (p < 0.001) and creatinine (p < 0.05). Additionally, we obtained a decrease in FIB-4 (p < 0.001) and in the De Ritis (AST/ALT aminotransferase ratio) (p < 0.05). The positive correlation between the FIB-4 value and BMI, WHR, waist circumference and the De Ritis index was observed. In conclusion, semaglutide and dulaglutide had a beneficial effect on metabolic and cardiovascular risk factors in patients with type 2 diabetes. These medications had a positive effect on MASLD biochemical markers.

The Effect of PCSK9 Inhibition on the Stabilization of Atherosclerotic Plaque Determined by Biochemical and Diagnostic Imaging Methods.

Atherosclerosis is a multifactorial, progressive, chronic inflammatory disease. Ultrasound and magnetic resonance imaging are the most accurate predictors of atherosclerotic plaque instability (MRI). Cytokines such as osteopontin, osteoprotegerin, and metalloproteinase 9 could be used as the most recent markers to identify and track the efficacy of anti-atherosclerotic therapy. Patients with USG and MRI-verified unstable atherosclerotic plaque were included in the study. Biomarker concentrations were measured and compared before and after PCSK9 inhibitor therapy. Additionally, concentrations prior to treatment were correlated with MRI images of the carotid artery. After treatment with alirocumab, the concentrations of MMP-9 (p < 0.01) and OPN, OPG (p < 0.05) decreased significantly. Furthermore, the results of OPN, OPG, and MMP 9 varied significantly depending on the type of atherosclerotic plaque in the MRI assay. In stable atherosclerotic plaques, the concentrations of OPN and OPG were greater (p < 0.01), whereas the concentration of MMP9 correlated with the instability of the plaque (p < 0.05). We demonstrated, probably for the first time, that alirocumab therapy significantly decreased the serum concentration of atherosclerotic plaque markers. In addition, we demonstrated the relationship between the type of atherosclerotic plaque as determined by carotid MRI and the concentration of these markers.

The Impact of Atorvastatin on Cardiometabolic Risk Factors in Sisters of Women with Polycystic Ovary Syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a frequent endocrinopathy in young women with significantly increased cardiometabolic risk. Siblings of women with this disorder are at increased risk of insulin resistance and androgen excess. The current study was aimed at investigating cardiometabolic effects of atorvastatin in sisters of women with PCOS. METHODS: This prospective observational study compared two age-, body mass index-, blood pressure-, and plasma lipid-matched groups of women with hypercholesterolemia: sisters of PCOS probands (group A) and unrelated control subjects (group B), receiving atorvastatin (40 mg daily). Plasma lipids, glucose homeostasis markers, concentrations of sex hormones, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen and uric acid, and the urinary albumin-to-creatinine ratio (UACR) were measured before entering the study and 6 months later. RESULTS: Both groups differed in the degree of insulin resistance, testosterone, free androgen index (FAI), circulating levels of hsCRP and homocysteine, and UACR. There were no between-group differences in the impact of atorvastatin on plasma lipids. Despite reducing hsCRP and homocysteine in both groups of women, the effect on these biomarkers was stronger in group B than in group A. Only in group B, atorvastatin did reduce fibrinogen, uric acid, and UACR. Only in group A, atorvastatin did worsen insulin sensitivity and tended to reduce testosterone and FAI. The impact of atorvastatin on hsCRP, homocysteine, fibrinogen, uric acid, and UACR inversely correlated with testosterone and FAI. CONCLUSION: The obtained results suggest that sisters of women with PCOS may benefit to a lesser degree from atorvastatin treatment than other women.

Lethargic patient with hepatocirrhosis - more than meets the eye.

Not required for Clinical Vignette.

Impaired Gonadotropin-Lowering Effects of Metformin in Postmenopausal Women with Autoimmune Thyroiditis: A Pilot Study.

Metformin has been found to reduce elevated gonadotropin levels. Hashimoto's thyroiditis is the most common thyroid disorder in iodine-sufficient areas, and it often develops in postmenopausal women. The aim of this study was to investigate whether autoimmune thyroiditis determines the impact of metformin on gonadotrope secretory function. Two matched groups of postmenopausal women were studied: 35 with euthyroid Hashimoto's thyroiditis (group A) and 35 without thyroid disorders (group B). Throughout the study, all participants received oral metformin (2.55-3 g daily). Plasma glucose, insulin, gonadotropins, estradiol, progesterone, thyrotropin, free thyroid hormones, prolactin, adrenocorticotropic hormone, insulin-like growth factor-1, hsCRP, thyroid peroxidase, and thyroglobulin antibody titers were measured at the beginning of the study and six months later. At entry, both groups differed in thyroid peroxidase antibody titers, thyroglobulin antibody titers, and hsCRP levels. In group A, baseline antibody titers correlated positively with hsCRP and negatively with insulin sensitivity. Although metformin improved glucose homeostasis and reduced hsCRP levels in both study groups, these effects were more pronounced in group B than in group A. Only in group B did metformin decrease FSH levels and tend to reduce LH levels. Thyroid antibody titers and the levels of the remaining hormones did not change throughout the study. The impact of metformin on gonadotropin levels correlated with their baseline values and the degree of improvement in insulin sensitivity, as well as with the baseline and treatment-induced reduction in hsCRP. Moreover, the impact on gonadotropins and insulin sensitivity in group A depended on baseline antibody titers. The obtained results indicate that coexisting autoimmune thyroiditis impairs the gonadotropin-lowering effects of metformin in postmenopausal women.

Vitamin D Status Determines the Impact of Metformin on Gonadotropin Levels in Postmenopausal Women.

Metformin was found to decrease elevated levels of anterior pituitary hormones. Its impact on lactotrope secretory function was absent in women with vitamin D insufficiency. This study investigated whether vitamin D status determines metformin action on overactive gonadotropes. We compared the effect of six-month metformin treatment on the plasma levels of gonadotropins, TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, and 25-hydroxyvitamin D, as well as on glucose homeostasis markers between three matched groups of postmenopausal women at high risk for diabetes: untreated subjects with vitamin D insufficiency (group A), untreated women with normal vitamin D status (group B), and individuals receiving vitamin D supplementation with normal 25-hydroxyvitamin D levels (group C). Only in groups B and C did metformin reduce FSH levels and tend to decrease LH levels, and these effects correlated with baseline gonadotropin levels, baseline 25-hydroxyvitamin D levels, and the improvement in insulin sensitivity. Follow-up gonadotropin levels were higher in group A than in the other two groups. The drug did not affect circulating levels of TSH, prolactin, ACTH, estradiol, free thyroid hormones, IGF-1, or 25-hydroxyvitamin D. The obtained results suggest that the impact of metformin on gonadotropin secretion in women after menopause is determined by vitamin D status.

The Effect of Metformin on Plasma Prolactin Levels in Young Women with Autoimmune Thyroiditis.

Metformin decreases elevated prolactin levels, which are frequently found in patients with thyroid disorders. The aim of this study was to investigate whether thyroid autoimmunity modulates the impact of metformin on lactotrope secretory function. This study compared two matched groups of young women with prediabetes and mild-to-moderate prolactin excess: 28 subjects with coexisting euthyroid autoimmune thyroiditis (group 1) and 28 individuals without thyroid disorders (group 2), treated for six months with metformin (3 g daily). Thyroid antibody titers, glucose homeostasis markers, prolactin, thyrotropin, free thyroid hormones, FSH, LH, ACTH, IGF-1 and hsCRP were assessed at the beginning and at the end of the study. At entry, the study groups differed in antibody titers and hsCRP levels. Although the improvement in glucose homeostasis and the decrease in hsCRP levels were observed in both study groups, they were more pronounced in group 2. Only in group 2 did metformin reduce circulating prolactin levels (both total and monomeric). Prolactin-lowering properties of metformin positively correlated with baseline prolactin levels, baseline antibody titers (in group 1) and with the degree of reduction in hsCRP levels. The obtained results suggest that autoimmune thyroiditis may attenuate the impact of metformin on lactotrope secretory function.

Sexual Function and Depressive Symptoms in Young Women with Euthyroid Hashimoto's Thyroiditis Receiving Vitamin D, Selenomethionine and Myo-Inositol: A Pilot Study.

Thyroid autoimmunity is associated with an increased risk of sexual dysfunction. The aim of this study was to compare sexual functioning and depressive symptoms in women with Hashimoto's thyroiditis receiving different treatments. The study included euthyroid women with autoimmune thyroiditis, untreated or receiving vitamin D, selenomethionine, or myo-inositol. Apart from measuring antibody titers and hormone levels, all participants completed questionnaires evaluating female sexual function (FSFI) and depressive symptoms (BDI-II). In untreated women, the overall FSFI scores and domain scores for desire, arousal, lubrication, and sexual satisfaction were lower than in women receiving vitamin D, selenomethionine, and myo-inositol. In the vitamin D-treated women, the total FSFI scores and scores for desire and arousal were higher than in women receiving the remaining micronutrients. The BDI-II score was lowest in the vitamin D-treated women and highest in the untreated patients with thyroiditis. Vitamin D-treated women were also characterized by lower antibody titers and higher testosterone levels than the women receiving the remaining micronutrients. There were no differences in sexual functioning and depressive symptoms between the selenomethionine- and myo-inositol-treated women. The study results suggest that although all antibody-lowering treatments are associated with better sexual functioning and well-being in young women with euthyroid autoimmune thyroiditis, the greatest benefits are observed in patients receiving vitamin D.

Vitamin D Status Determines Cardiometabolic Effects of Cabergoline in Women with Elevated Prolactin Levels: A Pilot Study.

Both hyperprolactinemia and vitamin D deficiency appear to be associated with increased cardiometabolic risk. This study aimed to determine whether vitamin D status influences the cardiometabolic effects of cabergoline. The study included three matched groups of women with mild to moderate hyperprolactinemia: vitamin D-naive subjects with vitamin D insufficiency (group A), women with vitamin D deficiency/insufficiency successfully treated with vitamin D (group B), and vitamin D-naive individuals with normal vitamin D status (group C). Plasma prolactin, 25-hydroxyvitamin D, estradiol, glucose homeostasis markers, lipids, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and uric acid, as well as the urinary albumin-to-creatinine ratio (UACR), were measured at study entry and after four months of cabergoline treatment. Although cabergoline reduced prolactin levels and increased estradiol levels in all study groups, the effect on prolactin was more pronounced in groups B and C compared to group A. In groups B and C, the drug enhanced glucose homeostasis, increased HDL-cholesterol, and decreased triglycerides, hsCRP, fibrinogen, homocysteine, uric acid, and UACR. In group A, only insulin resistance, hsCRP, and homocysteine were reduced by cabergoline. The effects on insulin sensitivity, HDL-cholesterol, triglycerides, hsCRP, fibrinogen, homocysteine, uric acid, and UACR were proportional to the decrease in prolactin and baseline levels of 25-hydroxyvitamin D. The obtained results suggest that vitamin D status determines cabergoline's cardiometabolic effects.