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Annals of Internal Medicine Jun 2024Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. (Meta-Analysis)
Meta-Analysis Review
Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.
BACKGROUND
Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial.
PURPOSE
To clarify associations of sex hormones with these outcomes.
DATA SOURCES
Systematic literature review to July 2019, with bridge searches to March 2024.
STUDY SELECTION
Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up.
DATA EXTRACTION
Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use.
DATA SYNTHESIS
Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates ( = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events.
LIMITATIONS
Observational study design, heterogeneity among studies, and imputation of missing data.
CONCLUSION
Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality.
PRIMARY FUNDING SOURCE
Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
Topics: Humans; Male; Cardiovascular Diseases; Testosterone; Sex Hormone-Binding Globulin; Estradiol; Cause of Death; Luteinizing Hormone; Dihydrotestosterone; Incidence; Risk Factors; Aged; Middle Aged
PubMed: 38739921
DOI: 10.7326/M23-2781 -
Clinical Medicine Insights.... 2023Our study aimed to compare the efficacy of transdermal dihydrotestosterone and testosterone enanthate in treating idiopathic micropenis.
OBJECTIVES
Our study aimed to compare the efficacy of transdermal dihydrotestosterone and testosterone enanthate in treating idiopathic micropenis.
PATIENTS AND METHODS
It's a comparative randomized study of 49 patients with idiopathic micropenis who are followed up in the Endocrinology-Diabetology and Nutrition Department of Mohammed VI University Hospital Center of Oujda, Morocco. The study was conducted from December 2019 to April 2021. All patients received a clinical examination including measurement of penis size before and after hormonal treatment. The patients were divided into two random groups, each group received a different drug, the first arm was treated with transdermal dihydrotestosterone (27 patients) and the second arm was treated with testosterone enanthate (22 patients). The Trial registration number was researchregistry7745.
RESULTS
The majority of the patients were children. The mean age was 9.7 ± 4.4 years. In the first arm, the mean penile size increased from -2.42 SD to -0.7 SD with a gain of 2.37 cm on average. In the second arm, the mean size increased from -2.48 SD to -0.69 SD, with a gain of 1.82 cm on average. The increase in penile size in the first arm was significantly greater than in the second arm ( = .008). No side effects were detected in both arms.
DISCUSSION AND CONCLUSION
In the present study, we demonstrated the superiority of transdermal DHT compared to injectable exogenous testosterone in the treatment of idiopathic micropenis. According to the age subgroups, there was no significant difference between the 2 treatments in each age group.
PubMed: 37920173
DOI: 10.1177/11795514231208328 -
The Journal of Clinical Endocrinology... Oct 2023There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be...
CONTEXT
There is no early, first-trimester risk estimation available to predict later (gestational week 24-28) gestational diabetes mellitus (GDM); however, it would be beneficial to start an early treatment to prevent the development of complications.
OBJECTIVE
We aimed to identify early, first-trimester prediction markers for GDM.
METHODS
The present case-control study is based on the study cohort of a Hungarian biobank containing biological samples and follow-up data from 2545 pregnant women. Oxidative-nitrative stress-related parameters, steroid hormone, and metabolite levels were measured in the serum/plasma samples collected at the end of the first trimester from 55 randomly selected control and 55 women who developed GDM later.
RESULTS
Pregnant women who developed GDM later during the pregnancy were older and had higher body mass index. The following parameters showed higher concentration in their serum/plasma samples: fructosamine, total antioxidant capacity, testosterone, cortisone, 21-deoxycortisol; soluble urokinase plasminogen activator receptor, dehydroepiandrosterone sulfate, dihydrotestosterone, cortisol, and 11-deoxycorticosterone levels were lower. Analyzing these variables using a forward stepwise multivariate logistic regression model, we established a GDM prediction model with a specificity of 96.6% and sensitivity of 97.5% (included variables: fructosamine, cortisol, cortisone, 11-deoxycorticosterone, SuPAR).
CONCLUSION
Based on these measurements, we accurately predict the development of later-onset GDM (24th-28th weeks of pregnancy). Early risk estimation provides the opportunity for targeted prevention and the timely treatment of GDM. Prevention and slowing the progression of GDM result in a lower lifelong metabolic risk for both mother and offspring.
Topics: Female; Humans; Pregnancy; Cortisone; Desoxycorticosterone; Diabetes, Gestational; Fructosamine; Hydrocortisone; Pregnancy Trimester, First; Case-Control Studies
PubMed: 37247379
DOI: 10.1210/clinem/dgad301 -
Proceedings of the National Academy of... Oct 2023Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this...
Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.
Topics: Adult; Humans; Male; Female; Sex Differentiation; Septal Nuclei; Androgens; Gonadal Hormones; Puberty
PubMed: 37847733
DOI: 10.1073/pnas.2306475120 -
Sexual Medicine Aug 2023Endothelial dysfunction caused by low androgen levels in penile tissue can lead to erectile dysfunction. The exact mechanism of endothelial dysfunction has not been...
BACKGROUND
Endothelial dysfunction caused by low androgen levels in penile tissue can lead to erectile dysfunction. The exact mechanism of endothelial dysfunction has not been thoroughly studied.
OBJECTIVE
The study sought to verify whether low androgen levels induce ferroptosis of endothelial cells in rat penile tissue.
METHODS
Rat penile cavernous endothelial cells (CP-R133) were divided into a no-androgen group (Dihydrotestosterone (DHT): 0 nmol/L), very low-androgen group (DHT: 0.1 nmol/L), low-androgen group (DHT: 1 nmol/L), DHT = 10 nmol/L group, DHT (0 nmol/L) + ferrostatin-1 (Fer-1) group, DHT (0.1 nmol/L) + Fer-1 group, DHT (1 nmol/L) + Fer-1 group, DHT (10 nmol/L) + Fer-1 group. Cell viability, intracellular ferrous ion (Fe), malondialdehyde (MDA), GSH into oxidized glutathione (GSSG), reactive oxygen species (ROS), nitric oxide (NO), transferrin receptor 1 protein (TfR1), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), endothelial nitric oxide synthase (eNOS), and phospho-eNOS (p-eNOS) were detected.
OUTCOMES
Low androgen levels could induce ferroptosis of rat penile cavernous endothelial cells in vivo by upregulating the expressions of TfR1 and ACSL4 and downregulating the expressions of SLC7A11 and GPX4.
RESULTS
Cell viability, the levels of glutathione (GSH), NO, SLC7A11, GPX4, and p-eNOS/eNOS in the DHT = 0 nmol/L group were lower than those in the other groups ( < .05). The levels of Fe, ROS, MDA, GSSG, TfR1, and ACSL4 in the DHT = 0 nmol/L group were higher than those in the other groups ( < .05). Cell viability and the levels of GSH, NO, SLC7A11, GPX4, and p-eNOS/eNOS in the DHT = 1 nmol/L group were lower than those in the DHT (1 nmol/L) + Fer-1 group, DHT = 10 nmol/L group, and DHT (10 nmol/L) + Fer-1 group ( < .05). The levels of Fe, ROS, MDA, GSSG, TfR1, and ACSL4 in the DHT = 1 nmol/L group were higher than those in the DHT (1 nmol/L) + Fer-1 group, DHT = 10 nmol/L group, and DHT (10 nmol/L) + Fer-1 group ( < .05).
CLINICAL IMPLICATIONS
A ferroptosis inhibitor might be a novel drug for treating erectile dysfunction caused by low androgen level.
STRENGTHS AND LIMITATIONS
The results of this study need to be further confirmed in in vitro and in human studies. Meanwhile, further investigation is needed to clarify whether low androgen levels affect ferroptosis of rat penile cavernous smooth muscle and nerve cells.
CONCLUSION
Low androgen levels can induce ferroptosis of endothelial cells in rat penile tissue. Inhibition of ferroptosis can reverse endothelial dysfunction caused by low androgen levels.
PubMed: 37547873
DOI: 10.1093/sexmed/qfad043 -
Brain, Behavior, and Immunity Nov 2023Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19...
BACKGROUND
Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients.
METHODS
A cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome.
RESULTS
There were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings.
CONCLUSIONS
These original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.
PubMed: 37648004
DOI: 10.1016/j.bbi.2023.08.026 -
Bioactive Materials Jun 2024Androgenic alopecia (AGA) is a highly prevalent form of non-scarring alopecia but lacks effective treatments. Stem cell exosomes have similar repair effects to stem...
Androgenic alopecia (AGA) is a highly prevalent form of non-scarring alopecia but lacks effective treatments. Stem cell exosomes have similar repair effects to stem cells, suffer from the drawbacks of high cost and low yield yet. Cell-derived nanovesicles acquired through mechanical extrusion exhibit favorable biomimetic properties similar to exosomes, enabling them to efficiently encapsulate substantial quantities of therapeutic proteins. In this study, we observed that JAM-A, an adhesion protein, resulted in a significantly increased the adhesion and resilience of dermal papilla cells to form snap structures against damage caused by dihydrotestosterone and macrophages, thereby facilitating the process of hair regrowth in cases of AGA. Consequently, adipose-derived stem cells were modified to overexpress JAM-A to produce engineered JAM-A overexpressing nanovesicles (JAM-A@NV). The incorporation of JAM-A@NV into a thermosensitive hydrogel matrix (JAM-A@NV Gel) to effectively addresses the limitations associated with the short half-life of JAM-A@NV, and resulted in the achievement of a sustained-release profile for JAM-A@NV. The physicochemical characteristics of the JAM-A@NV Gel were analyzed and assessed for its efficacy in promoting hair regrowth in vivo and vitro. The JAM-A@NV Gel, thus, presents a novel therapeutic approach and theoretical framework for promoting the treatment of low cell adhesion diseases similar to AGA.
PubMed: 38440324
DOI: 10.1016/j.bioactmat.2024.02.023 -
Frontiers in Endocrinology 2023Polycystic ovary syndrome (PCOS) is a common disorder resulting in irregular menstruation and infertility due to improper follicular development and ovulation. PCOS...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common disorder resulting in irregular menstruation and infertility due to improper follicular development and ovulation. PCOS pathogenesis is mediated by downregulated follicle-stimulating hormone receptor (FSHR) expression in granulosa cells (GCs); however, the underlying mechanism remains elusive. Unkeito (UKT) is a traditional Japanese medicine used to treat irregular menstruation in patients with PCOS. In this study, we aimed to confirm the effectiveness of UKT in PCOS by focusing on follicle-stimulating hormone (FSH) responsiveness.
METHODS
A rat model of PCOS was generated by prenatal treatment with 5α-dihydrotestosterone. Female offspring (3-week-old) rats were fed a UKT mixed diet or a normal diet daily. To compare the PCOS phenotype in rats, the estrous cycle, hormone profiles, and ovarian morphology were evaluated. To further examine the role of FSH, molecular, genetic, and immunohistological analyses were performed using ovarian tissues and primary cultured GCs from normal and PCOS model rats.
RESULTS
UKT increased the number of antral and preovulatory follicles and restored the irregular estrous cycle in PCOS rats. The gene expression levels of FSHR and bone morphogenetic protein (BMP)-2 and BMP-6 were significantly decreased in the ovarian GCs of PCOS rats compared to those in normal rats. UKT treatment increased FSHR staining in the small antral follicles and upregulated and expression in the ovary and GCs of PCOS rats. There was no change in serum gonadotropin levels. In primary cultured GCs stimulated by FSH, UKT enhanced estradiol production, accompanied by increased intracellular cyclic adenosine monophosphate levels, and upregulated the expression of genes encoding the enzymes involved in local estradiol synthesis, namely and . Furthermore, UKT elevated the expression of and , involved in progesterone production in cultured GCs in the presence of FSH.
CONCLUSIONS
UKT stimulates ovarian follicle development by potentiating FSH responsiveness by upregulating BMP-2 and BMP-6 expression, resulting in the recovery of estrous cycle abnormalities in PCOS rats. Restoring the FSHR dysfunction in the small antral follicles may alleviate the PCOS phenotype.
Topics: Humans; Pregnancy; Female; Rats; Animals; Polycystic Ovary Syndrome; Follicle Stimulating Hormone; Bone Morphogenetic Protein 6; Estradiol; Follicle Stimulating Hormone, Human; Menstruation Disturbances
PubMed: 37790609
DOI: 10.3389/fendo.2023.1228088 -
EMBO Reports Dec 2023Aging is accompanied by a decreased DNA repair capacity, which might contribute to age-associated functional decline in multiple tissues. Disruption in hormone...
Aging is accompanied by a decreased DNA repair capacity, which might contribute to age-associated functional decline in multiple tissues. Disruption in hormone signaling, associated with reproductive organ dysfunction, is an early event of age-related tissue degeneration, but whether it impacts DNA repair in nonreproductive organs remains elusive. Using skin fibroblasts derived from healthy donors with a broad age range, we show here that the downregulation of expression of XRCC4, a factor involved in nonhomologous end-joining (NHEJ) repair, which is the dominant pathway to repair somatic double-strand breaks, is mediated through transcriptional mechanisms. We show that the androgen receptor (AR), whose expression is also reduced during aging, directly binds to and enhances the activity of the XRCC4 promoter, facilitating XRCC4 transcription and thus stabilizing the genome. We also demonstrate that dihydrotestosterone (DHT), a powerful AR agonist, restores XRCC4 expression and stabilizes the genome in different models of cellular aging. Moreover, DHT treatment reverses senescence-associated phenotypes, opening a potential avenue to aging interventions in the future.
Topics: Androgens; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Signal Transduction; Humans
PubMed: 37955230
DOI: 10.15252/embr.202356984 -
Molecules (Basel, Switzerland) Feb 2024β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease...
β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease therapeutic, due to its medicinal properties. The effects of NMN on the growth of mouse hair were observed after hair removal. The results indicated that NMN can reverse the state of hair follicle atrophy, hair thinning, and hair sparsity induced by dihydrotestosterone (DHT), compared to that of minoxidil. In addition, the action mechanisms of NMN promoting hair growth in cultured human dermal papilla cells (HDPCs) treated with DHT were investigated in detail. The incubation of HDPCs with DHT led to a decrease in cell viability and the release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1Beta (IL-1β) and tumor necrosis factor Alpha (TNF-α). It was found that NMN can significantly lower the release of inflammatory factors induced by DHT in HDPCs. HDPCs cells are protected from oxidative stress damage by NMN, which inhibits the NF-κB p65 inflammatory signaling pathway. Moreover, the levels of androgen receptor (AR), dickkopf-1 (DKK-1), and β-catenin in the HDPCs were assessed using PCR, indicating that NMN can significantly enhance the expression of VEGF, reduced IL-6 levels and suppress the expression of AR and DKK-1, and notably increase β-catenin expression in DHT-induced HDPCs.
Topics: Animals; Mice; Humans; beta Catenin; Nicotinamide Mononucleotide; Interleukin-6; Hair; Hair Follicle; Dihydrotestosterone; Cell Proliferation; Oxidative Stress
PubMed: 38398550
DOI: 10.3390/molecules29040798