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The androgen signal pathways. The steroidal androgens, testosterone and DHT, mediate their biological effects predominantly through genomic pathway by binding to the AR and translocation into the nucleus, thereby facilitating the ability of AR to bind to its cognate response element, and recruiting coregulators to regulate the expression of target genes (left side). The nongenomic stimulation of second messenger cascades by androgens exerts biological effects through modulation of the transcriptional activity of AR or other transcription factors (right side). AR: androgen receptor; ARA: androgen receptor activator; ARE: androgen response element; cAMP: cyclic adenosine monophosphate; DHT: dihydrotestosterone; GPCR: G-protein coupled receptor; HSP: heat shock protein; MAPKs: mitogen-activated protein kinases; PKA: protein kinase A; PKC: protein kinase C; SHBG: steroid hormone binding globulin; SHBGR: SHBG receptor; Src: tyrosine kinase C; SHC: Src homology 2 domain-containing.
Source publication
The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration...
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Citations
... In cardiovascular diseases (CVD), sex differences are relevant to diagnosis, pathophysiology, and treatment efficiency [5,6] There are data showing the role of androgen hormones on the functionality of EPCs [7][8][9]. However, there are several conflicting reports that do not support this notion [10,11]. ...
Endothelial progenitor cells (EPCs) play a critical role in cardiovascular regeneration. Enhancement of their native properties would be highly beneficial to ensuring the proper functioning of the cardiovascular system. As androgens have a positive effect on the cardiovascular system, we hypothesized that dihydrotestosterone (DHT) could also influence EPC-mediated repair processes. To evaluate this hypothesis, we investigated the effects of DHT on cultured human EPCs' proliferation, viability, morphology, migration, angiogenesis, gene and protein expression, and ability to integrate into cardiac tissue. The results showed that DHT at different concentrations had no cytotoxic effect on EPCs, significantly enhanced the cell proliferation and viability and induces fast, androgen-receptor-dependent formation of capillary-like structures. DHT treatment of EPCs regulated gene expression of androgen receptors and the genes and proteins involved in cell migration and angiogenesis. Importantly, DHT stimulation promoted EPC migration and the cells' ability to adhere and integrate into murine cardiac slices, suggesting it has a role in promoting tissue regeneration. Mass spectrometry analysis further highlighted the impact of DHT on EPCs' functioning. In conclusion, DHT increases the proliferation, migration, and androgen-receptor-dependent angiogenesis of EPCs; enhances the cells' secretion of key factors involved in angiogenesis; and significantly potentiates cellular integration into heart tissue. The data offer support for potential therapeutic applications of DHT in cardiovascular regeneration and repair processes.
... Accelerated aging, which is mechanistically linked to decrements in vascular health and increased CVD risk, occurs when biological age exceeds chronological age [76][77][78][79]. Two critical parameters of vascular aging, vascular stiffness, and endothelial dysfunction are accelerated by ADT [80][81][82][83]. Inflammaging is a term coined explicitly in 2018 by Ferrucci et al., characterized by elevated inflammatory cytokines [84,85]. ...
Purpose of review
The primary objective of this review article is to dissect the intricate relationship between disparities, aging, diabetes, and their collective influence on cardiovascular disease (CVD) risk in prostate cancer (PC) patients. We sought to answer how these determinants interact with each other and contribute to the varying CVD outcomes observed in different subsets of PC patients.
Recent findings
It has become evident that social determinants of health (SDOH) significantly impact PC outcomes. Particularly, cardiovascular outcomes in non-Hispanic Black (NHB) patients, those from lower socioeconomic backgrounds, and residing in rural areas are notably worse. Diabetes, a growing concern worldwide, has been linked to increased PC-specific and all-cause mortality. Interestingly, recent studies highlight the potential of metformin therapy in enhancing survival rates, especially pivotal for those undergoing androgen deprivation therapy (ADT). Furthermore, the implications of age on PC are profound. The age-driven alterations in factors like allostatic load, responses to ADT, and vascular health play a crucial role in influencing CVD outcomes.
Summary
Our article highlights the multifaceted factors influencing cardiovascular risk in PC patients. Social disparities, aging, and diabetes mellitus significantly shape CVD outcomes. A holistic approach that targets both systemic and individual concerns, focusing on bridging healthcare access gaps and devising effective diabetes management strategies, is imperative. Metformin therapy emerges as a beacon of hope, especially for those patients on ADT. To improve cardiovascular outcomes in PC patients, there is an urgent need to target modifiable risk factors, emphasizing special attention to vulnerable populations. Further research is still needed to develop targeted interventions to mitigate the risk of disparities while improving cardiovascular outcomes, especially in vulnerable populations.
... Age-related decline of serum testosterone levels in males can result from age-related illnesses or senescence-related decreases in secretion [3]. Androgens confer a protective influence on the cardiovascular system [4,5]. ...
Hypogonadism is associated with an increased risk of coronary artery disease. This study sought to describe the histomorphology of the left coronary arteries of the adult male rabbit following orchiectomy and subsequent testosterone administration. We included 20 adult male rabbits, divided into a baseline group (n=2), an interventional group subjected to castration only (n=6), an intervention group subjected to castration followed by testosterone injection (n=6), and a control group (n=6). Key variables under investigation were serum testosterone levels, the intima-media thickness of coronary arteries, smooth muscle cell density, and adventitial collagen fiber density. The mean coronary arteries' intimal medial thickness was significantly higher in the castrated group than in controls (0.488 mm and 0.388 mm, respectively), while the testosterone-injected group had a mean of 0.440 mm. Mean smooth muscle cell density was significantly lower in the castrated rabbits versus controls (26.96% and 47.80%, respectively), this observation being reversed with testosterone injection (47.53%). Mean adventitial collagen fiber density was significantly higher in the castrated group than in controls (66.6% and 36.1%, respectively), with a marginal difference after testosterone injection (65.2%). This study demonstrates that castration-induced hypogonadism causes morphological changes in the coronary arteries that are partly reversible using testosterone injections. These findings provide a morphological basis for understanding the role of testosterone in coronary arteries.
... Prior studies have shown forms of estrogen to prevent endothelial dysfunction, vascular inflammation, and atherosclerosis as well as to promote vasodilatory modulators like nitric oxide, whereas androgens have been shown to be both beneficial and disruptive to vasculature function. [51][52][53] Additionally, there is increased risk of vascular disease such as stroke in post-versus premenopausal women and increased DR progression during pregnancy, supporting the potential influence of sex hormones on vascular disease. 54,55 However, sex hormones are likely not solely responsible for the disproportionate microvascular disease seen in male patients with diabetes, as men continue to have elevated vascular risks even compared to women of post-menopausal age. 5 Others have proposed that an additional component of DR is metabolic dysregulation and glial cell activation leading to an inflammatory state. ...
Purpose
Epidemiologically, men have a higher incidence, severity, and progression of diabetic retinopathy (DR) than women. We investigated microvascular differences between men and women with diabetes on optical coherence tomography angiography (OCTA).
Methods
Three × 3 mm OCTA macula scans of non-diabetic and patients with diabetes were obtained. Vascular parameters included parafoveal vessel density (VD), vessel length density (VLD), and flow index (FI) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) as well as foveal avascular zone (FAZ) area and perimeter. Multivariable linear regression was used for statistical analysis.
Results
There were 1809 patients with diabetes and 217 non-diabetic participants that were included in this study. Diabetic individuals included those with no DR (n = 1356), mild non-proliferative DR (NPDR; n = 286), moderate NPDR (n = 126), and severe NPDR/proliferative DR (PDR; n = 41). Male sex was significantly associated with smaller FAZ area/perimeter and lower DCP VLD in both non-diabetic subjects and patients with diabetes. Male sex in the diabetic group was additionally associated with lower SCP VD/VLD and DCP VD. Addition of an interaction between male sex and diabetes status in the interaction analysis showed that being male and diabetic conferred increased reduction in DCP VD and VLD compared to sex-based changes in non-diabetics. Larger FAZ perimeter, lower SCP VD/VLD, and lower DCP VLD were associated with poorer visual acuity in diabetics.
Conclusions
On OCTA, male patients with diabetes may have more severe microvascular disease especially in the DCP compared to women.
Translational Evidence
Sex-based alterations in diabetic microvascular disease has the potential to influence future basic and clinical studies as well as the implementation of OCTA disease markers.
... Androgens also modulate endothelin signaling, a pathway that regulates vascular tone, and contribute to regulating smooth muscle tone in blood vessels. By promoting vasodilation, androgens help maintain optimal vascular function and regulate blood pressure [42,43]. ...
Menopause represents a critical life stage in women, characterized by hormonal changes that significantly impact cardiovascular health. While the decline in estrogen levels has long been recognized as a major contributor to cardiovascular aging in menopausal women, the role of androgens, particularly testosterone, has gained increasing attention in recent years. This comprehensive review aims to provide a thorough understanding of the impact of menopause on cardiovascular aging, with a specific focus on the influences of androgens.
A literature search was conducted to gather relevant studies and clinical evidence exploring the relationship between menopause, androgens, and cardiovascular health. The review integrates findings from various studies to present a holistic view of the topic.
The review outlines the changes in hormone levels during menopause and discusses the cardiovascular risk factors associated with this transition. Furthermore, it explores the impact of menopause on cardiovascular structure and function, elucidating the underlying mechanisms that contribute to cardiovascular aging. Androgens' significance in maintaining cardiovascular homeostasis is discussed, followed by exploring the effects of androgen decline during menopause on lipid profiles, insulin sensitivity, vascular function, and other cardiovascular parameters. The review delves into the mechanisms of androgen action on the cardiovascular system, emphasizing the role of androgen receptors and the intricate interplay between androgens, estrogens, and other hormones. Clinical evidence supporting the effects of androgens on cardiovascular aging is presented, including studies investigating the association between androgen levels and cardiovascular outcomes. Additionally, the impact of androgen replacement therapy (ART) on cardiovascular risk markers and events in menopausal women is examined, along with controversies and conflicting findings surrounding the use of androgen therapy in cardiovascular aging.
This structured review provides a comprehensive understanding of the impact of menopause on cardiovascular aging, with a specific focus on the role of androgens. By highlighting the significance of androgens in cardiovascular health during menopause, this review aims to create an initial impression and interest among readers, inviting potential citations in the future. The findings underscore the need for further research and offer insights into managing cardiovascular aging in menopausal women, including lifestyle interventions, pharmacological approaches, and the potential role of personalized medicine and precision therapies.
... The primary endogenous androgens, such as testosterone and dihydrotestosterone (DHT), perform their function as ligands and exert their effects through complex interactions with the androgen receptor. The AR functions as a ligand-inducible transcription factor that mediates the expression of target genes [15,18]. As well as the welldocumented AR genomic signaling pathway, the AR can also undergo a non-genomic signaling cascade [18,19]. ...
... The AR functions as a ligand-inducible transcription factor that mediates the expression of target genes [15,18]. As well as the welldocumented AR genomic signaling pathway, the AR can also undergo a non-genomic signaling cascade [18,19]. These two mechanisms of AR action are further explained in Sections 2.3 and 2.4, respectively. ...
... Additionally, genetic polymorphisms may affect the risk of androgen-related CVDs. Genetic polymorphisms of AR gene have been demonstrated to alter the efficacy of androgens and may also affect disposition and efficacy of androgens [18]. These polymorphisms have been recognized with endogenous androgens (such as T) to affect not only the efficacy of the AR and related genes, but also genes related to T disposition, such as SHBG and PDE7B [18], which may affect the removal of androgens, since expression of these genes is seemingly upregulated under supra-physiological concentrations of androgenic drugs [76]. ...
The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological function through complex interactions with the AR. It has been speculated that overexertion of AR signaling cascades as a result of SARM abuse can be a risk factor for the development of various cardiovascular diseases. The present literature review explores the implications of the interaction between SARMs and the AR on cardiovascular health by focusing on the AR structure, function, and mechanisms of action, as well as the current clinical literature on various SARMs. It is shown that SARMs may increase the risk of cardiovascular diseases through implications on the renin–angiotensin system, smooth muscle cells, sympathetic nervous system, lipid profile, inflammation, platelet activity, and various other factors. More research on this topic is necessary as SARM abuse is becoming increasingly common. There is a noticeable lack of clinical trials and literature on the relationship between SARMs, cardiovascular diseases, and the AR. Future in vivo and in vitro studies within this field are vital to understand the mechanisms that underpin these complex interactions and risk factors.
... increase in DHEA levels may reduce the process of atherosclerosis and coronary artery stenosis [17]. Some findings also demonstrate that DHEA and androgens, through genomic and/or nongenomic pathways, have a significant effect on endothelial cell proliferation and migration, vascular contractility, and endothelial pathological processes, such as inflammation, atherosclerosis, and clot formation [38]. Moreover, DHEA has been reported to reduce body fat, without significant changes in the diet. ...
Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in primates, which is predominantly synthesized in the adrenal cortex. A characteristic curve of growth and decline of its synthesis during life was observed, together with the corresponding formation of its sulphate ester (DHEAS). High levels of plasma circulating DHEA are suggested as a marker of human longevity, and various pathophysiological conditions lead to a decreased DHEA level, including adrenal insufficiency, severe systemic diseases, acute stress, and anorexia. More recent studies have established importance of DHEA in the central nervous system (CNS). A specific intranuclear receptor for DHEA has not yet been identified; however, highly specific membrane receptors have been detected in endothelial cells, the heart, kidney, liver, and the brain. Research shows that DHEA and DHEAS, as well as their metabolites, have a wide range of effects on numerous organs and organ systems, which places them in the group of potential pharmacological agents useful in various clinical entities. Their action as neurosteroids is especially interesting, due to potential neuroprotective, pro-cognitive, anxiolytic, and antidepressant effects. Evidence from clinical studies supports the use of DHEA in hypoadrenal individuals, as well as in the treatment of depression and associated cognitive disorders. However, there is also an increasing trend of recreational DHEA misuse in healthy people, as it is classified as a dietary supplement in some countries. This article aims to provide a critical review regarding the biological and pharmacological effects of DHEA, its mechanism of action, and potential therapeutic use, especially in CNS disorders.
... Such a mechanism is reported in the literature in circulatory and cardiovascular contexts. 4,5 The mechanism by which this phenomenon is transient, the nail finally reaching a uniform thickness, is assumed as follows: as a result of continued ART, the trough testosterone level had been elevated to a level at which no further improvement of peripheral circulation occurred. Unfortunately, the management of this case was based on subjective complaints of the patient, lacking objective blood tests and scorings. ...
Introduction:
A distinctive nail pattern in a patient undergoing androgen replacement therapy is presented hereby.
Case presentation:
A 47-year-old male patient noticed a peculiar "washboard-like" pattern on his fingernails. He had been undergoing androgen replacement therapy for late onset hypogonadism syndrome. The patient realized his nails were growing faster after his therapy was altered from a tri-weekly basis to a bi-weekly basis.
Conclusion:
This phenomenon is likely to be attributed to the androgen replacement therapy, as the spacing between the ridges were widening in concordance with the strengthening of the therapy.
... Conversely, low androgen levels have been associated with increased levels of inflammatory cytokines, risk of atherosclerosis, and CAD [37,38]. Androgen supports endothelial function by mediating a number of cellular processes such as cell proliferation, vasodilation, inflammatory response, and anticoagulant activity [39]. Androgen can also regulate gene expression by binding to the androgen receptor, which then acts a transcription factor to activate gene expression. ...
... Androgen can also regulate gene expression by binding to the androgen receptor, which then acts a transcription factor to activate gene expression. However, the downstream genes and molecular mechanism of androgen receptor-mediated transcriptional regulation are not well understood [39]. Since androgen has been shown to regulate ADTRP expression in endothelial cells, ADTRP may play a key role in androgen's actions on the endothelium by mediating important downstream pathways involved in maintaining endothelial function. ...
The first genome-wide association study on coronary artery disease (CAD) in the Han Chinese population identified C6orf105 as a susceptibility gene. The C6orf105 gene was later found to encode for a protein that regulates tissue factor pathway inhibitor (TFPI) expression in endothelial cells in an androgen-dependent manner, and the novel protein was thus termed androgen-dependent TFPI-regulating protein (ADTRP). Since the identification of ADTRP, there have been several studies associating genetic variants on the ADTRP gene with CAD risk, as well as research providing mechanistic insights on this novel protein and its functional role. ADTRP is a membrane protein, whose expression is upregulated by androgen, GATA-binding protein 2, oxidized low-density lipoprotein, peroxisome proliferator‐activated receptors, and low-density lipoprotein receptors. ADTRP regulates multiple downstream targets involved in coagulation, inflammation, endothelial function, and vascular integrity. In addition, ADTRP functions as a fatty acid esters of hydroxy fatty acid (FAHFA)-specific hydrolase that is involved in energy metabolism. Current evidence suggests that ADTRP may play a role in the pathogenesis of atherosclerosis, CAD, obesity, and metabolic disorders. This review summarizes the current literature on ADTRP, with a focus on the peripheral actions of ADTRP, including expression, genetic variations, signaling pathways, and function. The evidence linking ADTRP and cardiometabolic diseases will also be discussed.
... As cancer cells lost their ability to divide in a controlled manner, they require a dedicated blood supply to provide oxygen and nutrients for growth. Cancer cells can produce various growth factors including VEGF [260], to induce angiogenesis [261]. ...
Long noncoding RNAs (lncRNAs) are defined as noncoding RNA transcripts with a length greater than 200 nucleotides. Research over the last decade has made great strides in our understanding of lncRNAs, especially in the biology of their role in cancer. In this article, we will briefly discuss the biogenesis and characteristics of lncRNAs, then review their molecular and cellular functions in cancer by using prostate and breast cancer as examples. LncRNAs are abundant, diverse, and evolutionarily, less conserved than protein-coding genes. They are often expressed in a tumor and cell-specific manner. As a key epigenetic factor, lncRNAs can use a wide variety of molecular mechanisms to regulate gene expression at each step of the genetic information flow pathway. LncRNAs display widespread effects on cell behavior, tumor growth, and metastasis. They act intracellularly and extracellularly in an autocrine, paracrine and endocrine fashion. Increased understanding of lncRNA's role in cancer has facilitated the development of novel biomarkers for cancer diagnosis, led to greater understanding of cancer prognosis, enabled better prediction of therapeutic responses, and promoted identification of potential targets for cancer therapy.
