Negative Feedback Mechanism Research Articles

Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis.

Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior-posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, β, or γ) and retinoid X receptors (RXRα, β, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation. Mutations in DHRS3 can result in embryonic lethality and congenital defects. This study shows that mouse Dhrs3 expression is responsive to vitamin A status and is directly regulated by the RAR/RXR complex through cis-regulatory elements. This highlights a negative feedback mechanism that ensures retinoic acid homeostasis.

Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α–HO–1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.

A brief discussion on the coupling principle of positive and negative feedback in the economic system

This study clarifies the concepts of “feedback”, “positive feedback”, and “negative feedback” and explains the philosophy of the coupling principle of positive and negative feedback. The evolution process of the system is the organic coupling of positive and negative feedback, and only the reciprocating cycle of positive and negative feedback can ensure the occurrence and existence of heterogeneous new things. In the economic system, the law of increasing returns corresponds to the positive feedback mechanism, whereas the law of diminishing returns corresponds to the negative feedback mechanism. This study briefly expounds on the differences in understanding between the law of increasing returns and diminishing returns, and the equilibrium and disequilibrium of economic operation in the economics circle, based on the histories of economic thoughts and social and economic forms. This study emphasizes that instead of dividing and opposing each other, the idea of static partial equilibrium and dynamic general nonequilibrium in epistemology can be united to solve this difference. Finally, this paper explains the essential relationship and compatibility between the law of diminishing returns and increasing returns from the characteristics, nature, and proportional changes of tangible and intangible factors of production. Applying the positive and negative feedback coupling principle can clarify the essential relationship between the law of diminishing returns and increasing returns. From the philosophical level and epistemological significance, it can bridge the fundamental differences between equilibrium and nonequilibrium theories, which in turn, can help realize the creative synthesis of economic theory.

MicroRNAs provide negative feedback and stability in gene regulatory network models of cell-state transitions

The development of multicellular organisms occurs through a series of cell state transitions controlled by gene regulatory networks. Central to these networks are transcription factors (TFs) which bind enhancers and activate the expression of other genes, some of which are also TFs. Gene regulatory networks (GRN) connect TFs and enhancers in a nonlinear circuit capable of producing complex behavior such as bifurcations between stable cell states. Our dynamic network modelling of the Embryonic Stem Cell (ESC) to Definitive Endoderm (DE) transition requires an as yet unknown negative feedback mechanism for stability. Here, we show that cell state specific microRNAs (miRNAs) can provide this negative feedback by inactivating other cell lineage determining TFs (ESC or DE) during the transition. Our model provides a mechanism to maintain stable cell states without requiring a large set of cell-type-specific repressive TFs, of which there are fewer known examples than activators. In support of this model, we use computational models and analyze gene and miRNA expression and chromatin accessibility data from human cell lines to detect enhancers activating the miRNAs consistent with our network model. Our analysis highlights the interplay between TFs and miRNAs during ESC to DE transition and proposes a novel model for gene regulation.

Impact of serum IL-10 level on the clinical outcome of COVID-19 patients and the development of post-COVID pulmonary fibrosis

A characteristic feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of serum interleukin 10 (IL-10). This may be a negative feedback mechanism to suppress inflammation. However, this IL-10 elevation may contribute to COVID-19 severity. In our study, we aimed to evaluate the effect of serum IL-10 level on patients' clinical outcome and the incidence of post-COVID19 pulmonary fibrosis. This was a prospective observational study, included 100 patients, confirmed to have COVID-19, Of these, 50 patients had COVID-19 without evidence of pneumonia in computed tomography (CT) scans (group I) and the other 50 patients had COVID-19 pneumonia (group II). Our results showed a significant increase in serum ferritin level in patients with COVID pneumonia. However, no difference was found in serum C-reactive protein (CRP) nor D-Dimer between both groups. There was a statistically significant increase in serum IL-10 in patients with COVID pneumonia compared with COVID patients without pneumonia (p<0.001). Fibrosis was developed in 35 patients (70%) with COVID pneumonia after 3 months and 4 of them died, however, all patients without pneumonia survived. Among age, serum IL-10, aspartate aminotransferase (AST), alanine transaminase (ALT), elevated serum IL-10 was found to be an independent predictor of pneumonia (p=0.32). However, there was no significant effect for IL-10 on patients’ clinical outcome. There was a statistically significant correlation between serum IL-10 levels and oxygen (O2) demand, CRP and D-Dimer (p= 0.015, p=0.034 and p=0.042, respectively). The higher the level of IL-10 the less fibrosis detected in follow up CT scans (p=0.038). In conclusion, even though IL-10 was significantly associated with disease severity (higher in pneumonia), elevated serum Il-10 has an independent role in decreasing the incidence of post-COVID-19 pulmonary fibrosis.

Melatonin inhibits voltage-gated potassium KV4.2 channels and negatively regulates melatonin secretion in rat pineal glands.

Melatonin is synthesized in and secreted from the pineal glands and regulates circadian rhythms. Although melatonin has been reported to modulate the activity of ion channels in several tissues, its effects on pineal ion channels remain unclear. In the present study, the effects of melatonin on voltage-gated K+ (KV) channels, which play a role in regulating the resting membrane potential, were examined in rat pinealocytes. The application of melatonin reduced pineal KV currents in a concentration-dependent manner (IC50 = 309 µM). An expression analysis revealed that KV4.2 channels were highly expressed in rat pineal glands. Melatonin-sensitive currents were abolished by the small interfering RNA knockdown of KV4.2 channels in rat pinealocytes. In human embryonic kidney 293 (HEK293) cells expressing KV4.2 channels, melatonin decreased outward currents (IC50 = 479 µM). Inhibitory effects were mediated by a shift in the voltage dependence of steady-state inactivation in a hyperpolarizing direction. This inhibition was observed even in the presence of 100 nM luzindole, an antagonist of melatonin receptors. Melatonin also blocked the activity of KV4.3, KV1.1, and KV1.5 channels in reconstituted HEK293 cells. The application of 1 mM melatonin caused membrane depolarization in rat pinealocytes. Furthermore, KV4.2 channel inhibition by 5 mM 4-aminopyridine attenuated melatonin secretion induced by 1 µM noradrenaline in rat pineal glands. These results strongly suggest that melatonin directly inhibited KV4.2 channels and caused membrane depolarization in pinealocytes, resulting in a decrease in melatonin secretion through parasympathetic signaling pathway. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands. NEW & NOTEWORTHY Melatonin is a hormone that is synthesized in and secreted from the pineal glands, which regulates circadian rhythms. However, the effects of melatonin on pineal ion channels remain unclear. The present study demonstrated that melatonin directly inhibited voltage-gated potassium KV4.2 channels, which are highly expressed in rat pinealocytes, and induced membrane depolarization, resulting in a decrease in melatonin secretion. This mechanism may function as a negative-feedback mechanism of melatonin secretion in pineal glands.

The logic of ambitious legislators in fluid party systems

AbstractClassic theories of political ambition assume relatively stable and programmatic party systems. However, in many parts of the world, ‘fluid’ or ‘inchoate’ party systems do not provide ambitious legislators with the electoral benefits associated with stable party brands. In this paper, we examine ambition in fluid party systems: What is the frequency of party switching for legislators who seek re‐election, and what are their characteristics? What incentives do parties create to push away or retain legislators? And which parties do ambitious legislators seek out? Using a systems approach, we argue that in fluid party systems, legislators' office‐seeking behavior is driven by their attitudes towards parties and their constituents, their prospective evaluation of party performance, and ideology. Incentives for politicians to switch parties act as negative feedback mechanisms which keep the party system stuck in a fluid state. We test the determinants of party switching using two data sources from Ecuador: a public records dataset of every legislator who earned re‐election from 1979 to 2021, and the Parliamentary Elites in Latin America (PELA) surveys of all legislators from 1994 to 2017. Both sources distinguish between switchers and non‐switchers. The results support the conclusion that ambitious legislators in fluid party systems are strategic actors that seek or keep parties to maximize their probability of re‐election—and thereby further exacerbate the party system's fluidity.

Non-linear stress-softening of the bacterial cell wall confers cell shape homeostasis.

The bacillus - or rod - is a pervasive cellular morphology among bacteria. Rod-shaped cells elongate without widening by reinforcing their cell wall anisotropically to prevent turgor pressure from inflating cell width. Here, we demonstrate that a constrictive force is also essential for avoiding pressure-driven widening in Gram-positive bacteria. Specifically, super-resolution measurements of the nonlinear mechanical properties of the cell wall revealed that across a range of turgor pressure cell elongation directly causes width constriction, similar to a "finger trap" toy. As predicted by theory, this property depends on cell-wall anisotropy and is precisely correlated with the cell's ability to maintain a rod shape. Furthermore, the acute non-linearities in the dependence between cell length and width deformation result in a negative-feedback mechanism that confers cell-width homeostasis. That is, the Gram-positive cell wall is a "smart material" whose exotic mechanical properties are exquisitely adapted to execute cellular morphogenesis.

Abstract MP17: Angiotensin II Inhibits Renin Secretion Directly By Eliciting Robust Calcium Oscillations In Juxtaglomerular Cells

Background: Renin secretion from the juxtaglomerular (JG) cells controls circulating Angiotensin II (AngII), a critical blood pressure determinant. AngII is believed to suppress renin release from JG cells to prevent excessive blood pressure elevation. However, a direct negative feedback mechanism has yet to be established in JG cells. In JG cells, Ca 2+ is a crucial second messenger that governs renin secretion by suppressing cAMP, a potent renin secretion stimulator. Thus, in contrast to most secretory cells, renin secretion from JG cells is inversely related to the intracellular Ca 2+ level. However, the role of AngII in modulating JG cell Ca 2+ dynamics remains unclear. Objective: Define intracellular Ca 2+ responses to AngII and identify the critical channels to suppress renin secretion in JG cells. Methods: Kidney slices from mice expressing JG-specific GCaMP6f, a genetically encoded Ca 2+ indicator under the control of the Ren1 c promoter, were imaged ex vivo on a widefield fluorescent microscope for 30 min per experiment (n = 5). In each experiment, slices were continuously perfused with buffer containing variable Ca 2+ and AngII concentrations, ± specific Ca 2+ channel inhibitors. Images were captured at 10 Hz and analyzed using Mesmerize Ca 2+ imaging software to identify and plot fluorescent intensity over time for each JG cell. Additional kidney slices were incubated in 24-well plates with buffer containing vehicle or AngII ± Ca 2+ channel inhibitors for 30 min. ELISA determined renin concentration. Results: 1) AngII dose-dependently evoked robust and periodic Ca 2+ -oscillations (Ca 2+ spikes) in JG cells (mean spikes/min; 50 pM: 5.4, 300 pM: 7.7, 3 nM: 13.2, and 300 nM: 17.6). 2) AngII-elicited Ca 2+ activity was markedly reduced with “Ca 2+ -free” buffer. 3) L-type voltage-dependent Ca 2+ channel (VDCC) blocker nifedipine moderately decreased AngII-elicited Ca 2+ spikes, while T-type VDCC blocker TTA-P2 did not. 4) Blocking endoplasmic reticulum (ER) Ca 2+ -release drastically reduced Ca 2+ activity. 5) AngII dose-dependently decreased renin secretion in kidney slices, congruent with the AngII-elicited Ca 2+ activity in imaging studies. Conclusion: AngII dose-dependently and directly elicited large, periodic Ca 2+ -oscillations in JG cells that suppressed renin release. Both extracellular Ca 2+ influx and intracellular Ca 2+ release from ER stores are required for sustained Ca 2+ activity. L-type, but not T-type, Ca 2+ channels participate in JG cell Ca 2+ -oscillations.

Transcriptome Analysis of Ethylene-Related Genes in Chlorine Dioxide-Treated Fresh-Cut Cauliflower.

Chlorine dioxide (ClO2) is widely used for the quality preservation of postharvest horticultural plants. However, the molecular mechanism of how ClO2 works is not clear. The purpose of this study was to understand ethylene-related molecular signaling in ClO2-treated fresh-cut cauliflower florets. Transcriptome analysis was used to investigate ethylene-related gene regulation. A total of 182.83 Gb clean data were acquired, and the reads of each sample to the unique mapped position of the reference genome could reach more than 85.51%. A sum of 2875, 3500, 4582 and 1906 differential expressed genes (DEGs) were identified at 0 d, 4 d, 8 d and 16 d between the control group and ClO2-treated group, respectively. DEGs were enriched in functions such as 'response to oxygen-containing compounds' and 'phosphorylation', as well as MAPK signaling pathway, plant hormone transduction pathway and so on. Genes, including OXI1, MPK3, WRKY22 and ERF1, which are located at the junction of wounding, pathogen attack, pathogen infection or ethylene signal transduction pathways, were up-regulated in response to stress. ETR and CTR1 (both up-regulated), as well as three down-regulated genes, including BolC5t34953H (a probable NAC), BolC1t05767H (a probable NAC) and BolC2t06548H (a probable ERF13), might work as negative regulators for ethylene signal transduction. In conclusion, ethylene-related genes and pathways are involved in ClO2 treatment, which might enhance stress resistance and have a negative feedback mechanism.

Understanding negative feedback: Changes in high-molecular-weight adrenocorticotropic hormone in adrenocorticotropic hormone-independent Cushing's syndrome.

Cushing's syndrome is characterized by chronic glucocorticoid oversecretion and diverse clinical manifestations. Distinguishing between adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent forms is crucial for determining treatment options. Plasma ACTH levels aid in the differential diagnosis, with undetectable or low levels suggesting ACTH-independent hypercortisolemia. ACTH is derived from pro-opiomelanocortin, and its processing involves prohormone convertase 1/3. High-molecular-weight ACTH is generally found in ACTH-producing pituitary tumors and ectopic ACTH syndrome. The mechanism of negative feedback and the process of high-molecular-weight ACTH alternation during ACTH-independent Cushing's syndrome remain unclear. A 40-year-old woman with hypertension and multiple fractures developed symptoms suggestive of Cushing's syndrome. Computed tomography revealed a left adrenocortical tumor along with atrophy of the right adrenal gland. ACTH levels were undetectable at the previous clinic, indicating ACTH-independent Cushing's syndrome. However, subsequent measurements at our hospital revealed non-suppressed ACTH (18.1 pg/mL), prompting further investigation. Gel exclusion chromatography confirmed the presence of high-molecular-weight ACTH. Metyrapone treatment decreased the cortisol levels. In this situation, in which ACTH levels should be elevated, a decrease in high-molecular-weight ACTH levels was observed. Histological findings revealed cortisol-producing adenoma without ACTH expression. This case highlights the importance of assay differences in evaluating ACTH concentrations and introduces a novel finding of circulating high-molecular-weight ACTH. The observed decline in high-molecular-weight ACTH levels suggests a potential time lag in the negative feedback within the hypothalamic-pituitary-adrenal axis exhibited by glucocorticoids. This temporal aspect of the regulation of ACTH-related molecules warrants further exploration to enhance our understanding of the hypothalamic-pituitary-adrenal axis feedback mechanism.

Fine-tuned protein-lipid interactions in biological membranes: exploration and implications of the ORMDL-ceramide negative feedback loop in the endoplasmic reticulum.

Biological membranes consist of a lipid bilayer in which integral membrane proteins are embedded. Based on the compositional complexity of the lipid species found in membranes, and on their specific and selective interactions with membrane proteins, we recently suggested that membrane bilayers can be best described as "finely-tuned molecular machines." We now discuss one such set of lipid-protein interactions by describing a negative feedback mechanism operating in the de novo sphingolipid biosynthetic pathway, which occurs in the membrane of the endoplasmic reticulum, and describe the atomic interactions between the first enzyme in the pathway, namely serine palmitoyl transferase, and the product of the fourth enzyme in the pathway, ceramide. We explore how hydrogen-bonding and hydrophobic interactions formed between Asn13 and Phe63 in the serine palmitoyl transferase complex and ceramide can influence the ceramide content of the endoplasmic reticulum. This example of finely-tuned biochemical interactions raises intriguing mechanistic questions about how sphingolipids and their biosynthetic enzymes could have evolved, particularly in light of their metabolic co-dependence.

The role of uncertainty and negative feedback loops in the evolution of induced immune defenses.

Organisms use constitutive or induced defenses against pathogens and other external threats. Constitutive defenses are constantly on, whereas induced defenses are activated when needed. Each of these strategies has costs and benefits, which can affect the type of defense that evolves in response to pathogens. In addition, induced defenses are usually regulated by multiple negative feedback mechanisms that prevent overactivation of the immune response. However, it is unclear how negative feedback affects the costs, benefits, and evolution of induced responses. To address this gap, we developed a mechanistic model of the well-characterized Drosophila melanogaster immune signaling network that includes 3 separate mechanisms of negative feedback as a representative of the widespread phenomenon of multilevel regulation of induced responses. We show that, under stochastic fly-bacteria encounters, an induced defense is favored when bacterial encounters are rare or uncertain, but in ways that depend on the bacterial proliferation rate. Our model also predicts that the specific negative regulators that optimize the induced response depend on the bacterial proliferation rate, linking negative feedback mechanisms to the factors that favor induction.

Th1 cells reduce the osteoblast-like phenotype in valvular interstitial cells by inhibiting NLRP3 inflammasome activation in macrophages

Background and aimsInflammation is initiates the propagation phase of aortic valve calcification. The activation of NLRP3 signaling in macrophages plays a crucial role in the progression of calcific aortic valve stenosis (CAVS). IFN-γ regulates NLRP3 activity in macrophages. This study aimed to explore the mechanism of IFN-γ regulation and its impact on CAVS progression and valve interstitial cell transdifferentiation.Methods and resultsThe number of Th1 cells and the expression of IFN-γ and STAT1 in the aortic valve, spleen and peripheral blood increased significantly as CAVS progressed. To explore the mechanisms underlying the roles of Th1 cells and IFN-γ, we treated CAVS mice with IFN-γ-AAV9 or an anti-IFN-γ neutralizing antibody. While IFN-γ promoted aortic valve calcification and dysfunction, it significantly decreased NLRP3 signaling in splenic macrophages and Ly6C+ monocytes. In vitro coculture showed that Th1 cells inhibited NLPR3 activation in ox-LDL-treated macrophages through the IFN-γR1/IFN-γR2-STAT1 pathway. Compared with untreated medium, conditioned medium from Th1-treated bone marrow–derived macrophages reduced the osteogenic calcification of valvular interstitial cells.ConclusionInhibition of the NLRP3 inflammasome by Th1 cells protects against valvular interstitial cell calcification as a negative feedback mechanism of adaptive immunity toward innate immunity. This study provides a precision medicine strategy for CAVS based on the targeting of anti-inflammatory mechanisms.Graphical

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

Very long-chain fatty acids control peroxisome dynamics via a feedback loop in intestinal stem cells during gut regeneration.

Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.

Reporting Only the Good News but Not the Bad? Mechanism of Negative Performance Feedback

Reporting Only the Good News but Not the Bad? Mechanism of Negative Performance Feedback

Hepatocyte-derived extracellular vesicles regulate liver regeneration after partial hepatectomy.

While significant progress has been made in understanding different aspects of liver regeneration, the molecular mechanisms responsible for the initiation and termination of cell proliferation in the liver after massive loss or injury of liver tissue remain unknown. The loss of liver mass affects tissue-specific mitogenic inhibitors in the blood, which in turn regulate the proliferation of remaining hepatocytes and liver regeneration. Although well described in a number of publications, which inhibitory substances or "sensor molecules" control the regeneration mechanisms to properly maintain liver size remain unknown. Extracellular vesicles (EVs) are nano-sized, membrane-limited structures secreted by cells into the extracellular space. Their proposed role is stable intercellular carriers of proteins and RNAs, mostly micro-RNA, from secreted to recipient cells. Taken up by the recipient cells, EVs can significantly modulate their biological functions. In the present study, using in vivo and in vitro models, we demonstrate that hepatocyte proliferation and liver regeneration are regulated by EVs secreted by hepatocytes into the bloodstream. This regulation is carried out through a negative feedback mechanism, which explains the very precise regeneration of liver tissue after massive damage. We also demonstrate that an essential component of this mechanism is RNA carried by hepatocyte-derived EVs. These findings open up a new and unexplored area of biology regarding the mechanisms involved in the homeostasis regulation of various constantly renewing tissues by maintaining the optimal size and correct ratio between differentiating and proliferating cells.

Физиологическая роль и клиническое значение глобулина, связывающего половые гормоны, у мужчин.

The main physiological functions of globulin that binds sex hormones (SHBG) in the male body are the transport of sex steroids in hydrophilic blood and the creation of a buffer system that smooths out fluctuations in the concentration of free testosterone. In addition, sex hormone binding globulin can limit the biological activity of sex steroids by reducing the concentration of the free fraction of the hormone, but only when the hypothalamicpituitary-testicular axis is non-functioning or inadequately functioning. If the negative feedback mechanism works correctly, the concentration of SHBG will determine the level of total testosterone, but will not affect the free fraction and, accordingly, the biological activity of sex steroids. It is likely that SHBG has other functions, as indicated by the presence of SHBG receptors in some tissues and the mechanism of SHBG transport into the cell through endocytosis, but the physiological role of these processes is currently unclear and requires further study. From a practical point of view, determining the level of SHBG is necessary primarily to calculate the level of free testosterone, since accurate methods for directly measuring free testosterone are not available in clinical practice. Diagnosing hypogonadism based solely on total testosterone levels is associated with the risk of overdiagnosis, since the concentration of SHBG in the blood can have a significant effect on total testosterone levels without changing free testosterone levels. The use of SHBG as a biomarker for a number of diseases and pathological conditions seems promising. Lower SHBG concentrations are associated with an increased risk of diabetes mellitus, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), and higher SHBG concentrations are associated with an increased risk of osteoporosis and fractures in older men. At the same time, the question remains open whether SHBG is just a biomarker or is involved in the pathogenesis of the development of these diseases?

(124) GENITOURINARY SYNDROME OF LACTATION (GSL): A NEW PERSPECTIVE ON POSTPARTUM AND LACTATION-RELATED GENITOURINARY SYMPTOMS

Abstract Introduction Genitourinary syndrome of menopause (GSM) is a well-documented and researched condition characterized by a range of genitourinary symptoms in peri- and postmenopausal women. Similar to GSM, postpartum and lactating women experience significantly reduced estrogen and androgen levels. However, there is limited research on the occurrence and impact of similar symptoms during the postpartum and breastfeeding period, as well as possible treatment options. Objective The aim of this project was to review the available literature for genitourinary health in the postpartum breastfeeding population and summarize the key findings and potential treatment options. Methods We performed a comprehensive literature review utilizing several databases and the following keywords individually or in combination “physiology of postpartum” or “physiology of lactogenesis” or “vulvovaginal health” or “vaginal atrophy” or “vaginal dryness” or “dyspareunia” or “urinary incontinence” or “lactation” or “breastfeeding” or “vaginal estrogen.” Full text review of 75 articles was performed, and ultimately 50 articles were included in this review. Results During lactation, high levels of prolactin inhibit estrogen and androgen secretion via negative feedback mechanisms (1). These hormonal changes lead to an increased prevalence (of up to 50% higher) of vulvovaginal atrophy in lactating and breastfeeding women compared to non-breastfeeding women (2,3). The shift in hormones also contributes to increased rates (~30% higher) of dyspareunia (4–7), likely due to a lack of vaginal lubrication (up to 46%) among breastfeeding women (8). Decreased sexual desire is also common and reported to be experienced by up to 46% of postpartum women (8). Despite these highly prevalent and potentially devastating symptoms, there is a lack of consistent screening at postpartum visits and no treatment guidelines available to healthcare providers. Similar to GSM, vaginal lubricants can be used by breastfeeding women with vaginal dryness. However, for lactating women with refractory vaginal dryness or significant vulvovaginal changes, vaginal estrogen or DHEA therapy may be considered. Studies have shown minimal or no transfer of estrogen to breast milk even at high concentrations, and no reduction in breast milk supply (9–11), likely because vaginal estrogen is not a systemic dose. Studies on vaginal estrogen therapy in postpartum women are limited, but one randomized placebo-controlled trial showed excellent compliance and a subjective improvement in women utilizing vaginal estrogen (12). Conclusions Postpartum breastfeeding women experience similar physiology and symptoms to the postmenopausal phase, as seen in GSM. We propose the introduction of a novel term to describe the genitourinary changes seen in breastfeeding individuals: Genitourinary Syndrome of Lactation (GSL). The creation and diagnostic use of a syndrome, such as GSL, will equip healthcare providers with an all-encompassing term to bring awareness to the symptoms experienced by postpartum breastfeeding individuals. This awareness can lead to improved screening and treatment guidelines for the high numbers of breastfeeding individuals suffering from these genitourinary changes. Disclosure No.