Influence of gonadectomy on muscle health in micro- and partial-gravity environments in rats.

Gonadal hormones, such as testosterone and estradiol, modulate muscle size and strength in males and females. However, the influence of sex hormones on muscle strength in micro- and partial-gravity environments (e.g., the Moon or Mars) is not fully understood. The purpose of this study was to determine the influence of gonadectomy (castration/ovariectomy) on progression of muscle atrophy in both micro- and partial-gravity environments in male and female rats. Male and female Fischer rats (n = 120) underwent castration/ovariectomy (CAST/OVX) or sham surgery (SHAM) at 11 wk of age. After 2 wk of recovery, rats were exposed to hindlimb unloading (0 g), partial weight bearing at 40% of normal loading (0.4 g, Martian gravity), or normal loading (1.0 g) for 28 days. In males, CAST did not exacerbate body weight loss or other metrics of musculoskeletal health. In females, OVX animals tended to have greater body weight loss and greater gastrocnemius loss. Within 7 days of exposure to either microgravity or partial gravity, females had detectable changes to estrous cycle, with greater time spent in low-estradiol phases diestrus and metestrus (∼47% in 1 g vs. 58% in 0 g and 72% in 0.4 g animals, P = 0.005). We conclude that in males testosterone deficiency at the initiation of unloading has little effect on the trajectory of muscle loss. In females, initial low estradiol status may result in greater musculoskeletal losses.NEW & NOTEWORTHY We find that removal of gonadal hormones does not exacerbate muscle loss in males or females during exposure to either simulated microgravity or partial-gravity environments. However, simulated micro- and partial gravity did affect females' estrous cycles, with more time spent in low-estrogen phases. Our findings provide important data on the influence of gonadal hormones on the trajectory of muscle loss during unloading and will help inform NASA for future crewed missions to space and other planets.

AMH Regulation by Steroids in the Mammalian Testis: Underlying Mechanisms and Clinical Implications.

Anti-Müllerian hormone (AMH) is a distinctive biomarker of the immature Sertoli cell. AMH expression, triggered by specific transcription factors upon fetal Sertoli cells differentiation independently of gonadotropins or sex steroids, drives Müllerian duct regression in the male, preventing the development of the uterus and Fallopian tubes. AMH continues to be highly expressed by Sertoli until the onset of puberty, when it is downregulated to low adult levels. FSH increases testicular AMH output by promoting immature Sertoli cell proliferation and individual cell expression. AMH secretion also showcases a differential regulation exerted by intratesticular levels of androgens and estrogens. In the fetus and the newborn, Sertoli cells do not express the androgen receptor, and the high androgen concentrations do not affect AMH expression. Conversely, estrogens can stimulate AMH production because estrogen receptors are present in Sertoli cells and aromatase is stimulated by FSH. During childhood, sex steroids levels are very low and do not play a physiological role on AMH production. However, hyperestrogenic states upregulate AMH expression. During puberty, testosterone inhibition of AMH expression overrides stimulation by estrogens and FSH. The direct effects of sex steroids on AMH transcription are mediated by androgen receptor and estrogen receptor α action on AMH promoter sequences. A modest estrogen action is also mediated by the membrane G-coupled estrogen receptor GPER. The understanding of these complex regulatory mechanisms helps in the interpretation of serum AMH levels found in physiological or pathological conditions, which underscores the importance of serum AMH as a biomarker of intratesticular steroid concentrations.

Age-associated reductions in cardiovagal baroreflex sensitivity are exaggerated in middle-aged and older men with low testosterone.

Aging is associated with reductions in cardiovagal baroreflex sensitivity (cBRS), which increases cardiovascular disease risk. Preclinical data indicate that low testosterone reduces cBRS. We determined whether low testosterone is associated with greater age-associated reductions in cBRS in healthy men. Twenty-six men categorized as young (N = 6; age = 31 ± 4 yr; testosterone = 535 ± 60 ng/dL), middle-aged/older with normal (N = 10; aged 56 ± 3 yr; testosterone = 493 ± 85 ng/dL) or low (N = 10; age = 57 ± 6 yr; testosterone = 262 ± 31 ng/dL) testosterone underwent recordings of beat-by-beat blood pressure and R-R interval during rest and two Valsalva maneuvers, and measures of carotid artery compliance. IL-6, C-reactive protein (CRP), oxidized LDL cholesterol, and total antioxidant status (TAS) were also measured in blood. Middle-aged/older men had lower cBRS compared with young men (17.0 ± 6.5 ms/mmHg; P = 0.028); middle-age/older men with low testosterone had lower cBRS (5.5 ± 3.2 ms/mmHg; P = 0.039) compared with age-matched men with normal testosterone (10.7 ± 4.0 ms/mmHg). No differences existed between groups during Phase II of the Valsalva maneuver; middle-aged/older men with low testosterone had reduced cBRS (4.7 ± 2.6 ms/mmHg) compared with both young (12.8 ± 2.8 ms/mmHg; P < 0.001) and middle-aged/older men with normal testosterone (8.6 ± 4.4 ms/mmHg; P = 0.046). There were no differences in oxidized LDL (P = 0.882) or TAS across groups (P = 0.633). IL-6 was significantly higher in middle-aged/older men with low testosterone compared with the other groups (P < 0.05 for all) and inversely correlated with cBRS (r = -0.594, P = 0.007). Middle-aged/older men had reduced carotid artery compliance compared with young, regardless of testosterone status (P < 0.001). These observations indicate that low testosterone in middle-aged/older men may contribute to reductions in cBRS. These data suggest that increased inflammation may contribute to reductions in cBRS.NEW & NOTEWORTHY Middle-aged/older men with low testosterone have accelerated reductions in cardiovagal BRS compared with middle-aged/older men with normal testosterone. Increased concentrations of the proinflammatory cytokine IL-6 appear to contribute to the reductions in cardiovagal BRS in men with low testosterone.

Androgen synthesis inhibition increases behavioural flexibility and mPFC tyrosine hydroxylase in gonadectomized male rats.

Behavioural flexibility is essential to adapt to a changing environment and depends on the medial prefrontal cortex (mPFC). Testosterone administration decreases behavioural flexibility. It is well known that testosterone is produced in the gonads, but testosterone is also produced in the brain, including the mPFC and other nodes of the mesocorticolimbic system. It is unclear how testosterone produced in the brain versus the gonads influences behavioural flexibility. Here, in adult male rats, we assessed the effects of the androgen synthesis inhibitor abiraterone acetate (ABI) and long-term gonadectomy (GDX) on behavioural flexibility in two paradigms. In Experiment 1, ABI but not GDX reduced the number of errors to criterion and perseverative errors in a strategy set-shifting task. In Experiment 2, with a separate cohort of rats, ABI but not GDX reduced perseverative errors in a reversal learning task. In Experiment 1, we also examined tyrosine hydroxylase immunoreactivity (TH-ir), and ABI but not GDX increased TH-ir in the mPFC. Our findings suggest that neurally-produced androgens modulate behavioural flexibility via modification of dopamine signalling in the mesocorticolimbic system. These results indicate that neurosteroids regulate executive functions and that ABI treatment for prostate cancer might affect cognition.

Treatment with androgens plus estrogens cannot reverse sex differences in song and the song control nuclei in adult canaries.

Adult treatments with testosterone (T) do not activate singing behavior nor promote growth of song control nuclei to the same extent in male and female canaries (Serinus canaria). Because T acts in part via aromatization into an estrogen and brain aromatase activity is lower in females than in males in many vertebrates, we hypothesized that this enzymatic difference might explain the sex differences seen even after exposure to the same amount of T. Three groups of castrated males and 3 groups of photoregressed females (i.e., with quiescent ovaries following exposure to short days) received either 2 empty 10 mm silastic implants, one empty implant and one implant filled with T or one implant filled with T plus one with estradiol (E2). Songs were recorded for 3 h each week for 6 weeks before brains were collected and song control nuclei volumes were measured in Nissl-stained sections. Multiple measures of song were still different in males and females following treatment with T. Co-administration of E2 did not improve these measures and even tended to inhibit some measures such as song rate and song duration. The volume of forebrain song control nuclei (HVC, RA, Area X) and the rate of neurogenesis in HVC was increased by the two steroid treatments, but remained significantly smaller in females than in males irrespective of the endocrine condition. These sex differences are thus not caused by a lower aromatization of the steroid; sex differences in canaries are probably organized either by early steroid action or by sex-specific gene regulation directly in the brain.

Arginine vasopressin in the medial amygdala causes greater post-stress recruitment of hypothalamic vasopressin neurons.

Arginine vasopressin (AVP) is expressed in both hypothalamic and extra-hypothalamic neurons. The expression and role of AVP exhibit remarkable divergence between these two neuronal populations. Polysynaptic pathways enable these neuronal groups to regulate each other. AVP neurons in the paraventricular nucleus of the hypothalamus increase the production of adrenal stress hormones by stimulating the hypothalamic-pituitary-adrenal axis. Outside the hypothalamus, the medial amygdala also contains robust amounts of AVP. Contrary to the hypothalamic counterpart, the expression of extra-hypothalamic medial amygdala AVP is sexually dimorphic, in that it is preferentially transcribed in males in response to the continual presence of testosterone. Male gonadal hormones typically generate a negative feedback on the neuroendocrine stress axis. Here, we investigated whether testosterone-responsive medial amygdala AVP neurons provide negative feedback to hypothalamic AVP, thereby providing a feedback loop to suppress stress endocrine response during periods of high testosterone secretion. Contrary to our expectation, we found that AVP overexpression within the posterodorsal medial amygdala increased the recruitment of hypothalamic AVP neurons during stress, without affecting the total number of AVP neurons or the number of recently activated neurons following stress. These observations suggest that the effects of testosterone on extra-hypothalamic AVP facilitate stress responsiveness through permissive influence on the recruitment of hypothalamic AVP neurons.

Comparative transcriptome analysis reveals potential testosterone function-related regulatory genes/pathways of Leydig cells in immature and mature buffalo (Bubalus bubalis) testes.

Leydig cells (LCs) are testosterone-generating endocrine cells that are located outside the seminiferous tubules in the testis, and testosterone is fundamental for retaining spermatogenesis and male fertility. In buffalo, adult Leydig cells (ALCs) are developed by immature Leydig cells (ILCs) in the postnatal testes. However, the genes/pathways associated to the regulation of testosterone secretion function during the development of postnatal LCs remains comprehensively unidentified. The present study comparatively analyzed the transcriptome profiles of ILC and ALC in buffalo with significant differences in testosterone secretion. Differentially expressed genes (DEGs) analysis identified 972 and 1,091 annotated genes that were significantly up- and down-regulated in buffalo ALC. Functional enrichment analysis showed that cAMP signaling being the most significantly enriched pathway, and testosterone synthesis and lipid transport-related genes/pathways were upregulated in ALC. Furthermore, gene set enrichment analysis (GSEA) shows that cAMP signaling and steroid hormone biosynthesis were activated in ALC, demonstrating that cAMP signaling may serve as a positive regulatory pathway in the maintenance of testosterone function during postnatal development of LCs. Protein-protein interaction (PPI) networks analysis highlighted that ADCY8, ADCY2, POMC, CHRM2, SST, PTGER3, SSTR2, SSTR1, NPY1R, and HTR1D as hub genes in the cAMP signaling pathway. In conclusion, this study identified key genes and pathways associated in the regulation of testosterone secretion function during the ILC-ALC transition in buffalo based on bioinformatics analysis, and these key genes might be deeply involved in cAMP generation to influencing testosterone levels in LCs. The results suggest that ALCs might increase testosterone levels by enhancing cAMP production than ILCs. Our data will enhance the understanding of developmental mechanism studies related to testosterone function and provide preliminary evidence for molecular mechanisms of LCs regulating spermatogenesis.

Sex hormones regulate NHE1 functional expression and brain endothelial proteome to control paracellular integrity of the blood endothelial barrier.

BACKGROUND: Sex hormones have been implicated in pH regulation of numerous physiological systems. One consistent factor of these studies is the sodium-hydrogen exchanger 1 (NHE1). NHE1 has been associated with pH homeostasis at epithelial barriers. Hormone fluctuations have been implicated in protection and risk for breaches in blood brain barrier (BBB)/blood endothelial barrier (BEB) integrity. Few studies, however, have investigated BBB/BEB integrity in neurological disorders in the context of sex-hormone regulation of pH homeostasis. METHODS//RESULTS: Physiologically relevant concentrations of 17-ß-estradiol (E2, 294 pM), progesterone (P, 100 nM), and testosterone (T,3.12 nM) were independently applied to cultured immortalized bEnd.3 brain endothelial cells to study the BEB. Individual gonadal hormones showed preferential effects on extracellular pH (E2), 14C-sucrose uptake (T), stimulated paracellular breaches (P) with dependence on functional NHE1 expression without impacting transendothelial resistance (TEER) or total protein expression. While total NHE1 expression was not changed as determined via whole cell lysate and subcellular fractionation experiment, biotinylation of NHE1 for surface membrane expression showed E2 reduced functional expression. Quantitative proteomic analysis revealed divergent effects of 17-ß-estradiol and testosterone on changes in protein abundance in bEnd.3 endothelial cells as compared to untreated controls. CONCLUSIONS: These data suggest that circulating levels of sex hormones may independently control BEB integrity by 1) regulating pH homeostasis through NHE1 functional expression and 2) modifying the endothelial proteome.

Association between sex hormones and kidney stones: analysis of the National Health and Nutrition Examination Survey.

PURPOSE: Increasing age, male gender, and metabolic syndrome are associated with kidney stone formation. As sex hormones change with age, gender, and metabolic syndrome, we hypothesized that sex hormones may underlie the physiologic changes affecting stone formation. METHODS: We analyzed the relationships between testosterone, estradiol, and history of kidney stones using data from 10,193 participants in the Continuous National Health and Nutrition Examination Survey (NHANES) database from 2013-2016. We performed logistic regression analysis to analyze the predictive value of low testosterone and low estradiol on the history of kidney stones in both males and females. Self-reported history of kidney stone diagnosis was the outcome. RESULTS: After adjusting for risk factors known to be associated with nephrolithiasis such as age, race, BMI, and medical comorbidities including: gout, angina, coronary disease, stroke, asthma, hypertension, and diabetes, multiple regression analysis demonstrated that there is no independent association between sex hormones (testosterone and estradiol) and history of kidney stones in either males or females. CONCLUSIONS: There appears to be no association between sex hormones and history of kidney stones. Whether there is a more complex interaction of sex hormone levels and the shared association with factors such as metabolic syndrome requires additional investigation. Further studies matching menopausal status for women are necessary to further investigate the potential relationship between estrogen and kidney stones.

Understanding the opposite effects of sex hormones in mediating renal injury.

According to epidemiological studies, chronic kidney disease (CKD) affects more women than men, but the incidence of end-stage renal disease is higher in men than in women. However, most of these studies have not considered the incidence of CKD in women of reproductive or post-menopausal age, and even fewer with hormone replacement therapy. Some meta-analyses have reported an exacerbated progression of CKD in men compared with women. Consequently, in most of the experimental models of renal injury, men of reproductive age exhibit more abnormalities in renal function and structure that lead to greater progression to CKD than women, which suggests that these differences are mediated by sex hormones rather than by other factors. This review intends to show the mechanisms regulated by oestrogen or testosterone that may explain the different risks and evolution of renal diseases between men and women. Regardless of the initial cause of kidney disease, sex hormones have been implicated in modulating vascular tone, oxidative stress, inflammation and apoptosis. Finally, our previous study highlights the mechanisms by which the transition from acute kidney injury to CKD does not occur in female rats as commonly as it does in male rats. This review not only identifies sex differences in several kidney diseases but also supports potential therapeutic opportunities to reduce or prevent the progression of CKD and highlights the importance of considering sex differences in the design of any clinical study.

Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19).

Given the rapid spread of the coronavirus disease 2019 (COVID-19) pandemic and its overwhelming effect on health care systems and the global economy, innovative therapeutic strategies are urgently needed. The proposed primary culprit of COVID-19 is the intense inflammatory response-an augmented immune response and cytokine storm-severely damaging the lung tissue and rendering some patients' conditions severe enough to require assisted ventilation. Sex differences in the response to inflammation have been documented and can be attributed, at least in part, to sex steroid hormones. Moreover, age-associated decreases in sex steroid hormones, namely, estrogen and testosterone, may mediate proinflammatory increases in older adults that could increase their risk of COVID-19 adverse outcomes. Sex hormones can mitigate the inflammation response and might provide promising therapeutic potential for patients with COVID-19. In this article, we explore the possible anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone, with particular attention to the potential therapeutic role of hormone replacement therapy in older men and women with COVID-19.

Modeling Temperature-Dependent Sex Determination in Oviparous Species Using a Dynamical Systems Approach.

In many oviparous species, the incubation temperature of the egg determines the sex of the offspring. This is known as temperature-dependent sex determination (TSD). The probability of the hatched offspring being male or female varies across the incubation temperature range. This leads to the appearance of different TSD patterns in species such as FM pattern where females are predominately born at lower temperature and males at higher temperature, FMF pattern where the probability of female being born is higher at extreme temperatures and of the male being born is high at intermediate temperatures. We analyze an enzymatic reaction system proposed in the literature involving sex hormones with positive feedback effect to understand the emergence of different TSD patterns. The nonlinearity in the model is accounted through temperature sensitivity of the reaction rates affecting the catalytic mechanism in the reaction system. We employ a dynamical systems approach of singularity theory and bifurcation analysis to divide the parameter plane of temperature sensitivities into different regions where different TSD patterns are observed. Bifurcation analysis in association with the delineation of the parameter space for different TSD pattern has led to the identification of a subspace where all the TSD patterns observed in nature can be realized. We also show how modulation of the sex hormone in the species can be used to change the probability of occurrence of a specific sex, thereby preventing the extinction of endangered species.

Evaluation of neoadjuvant gonadotropin administration with downregulation by testosterone prior to second time microsurgical testicular sperm extraction: A prospective case-control study.

PURPOSE: The aim of this prospective study was to determine whether there is a beneficial role of combining gonadotropin administration with testosterone downregulation in non-obstructive azoospermia patients prior to a second time microsurgical testicular sperm extraction after a negative one. METHODS: A total of 40 non-obstructive azoospermia men were recruited from a specialized IVF center from 2014 to 2016. Participants were divided equally into two groups: Group A was subjected to testosterone downregulation alone for 1 month and then combined with gonadotropin administration for 3 months prior to second time testicular sperm extraction; Group B (controls) underwent second time microsurgical testicular sperm extraction without prior hormonal therapy. RESULTS: Mean baseline follicle-stimulating hormone levels of the controls and the cases were 26.9 ± 11.8 and 25.4 ± 8.7, respectively. One month after testosterone downregulation, follicle-stimulating hormone level of the cases was normalized and became 2.4 ± 1.2. There was no statistically significant difference between baseline follicle-stimulating hormone levels of the controls and cases (p = 0.946). Remarkably, two cases were positive after downregulation (10%) and no controls were positive at second testicular sperm extraction (0%). There was no statistically significant difference between sperm retrieval after the second microsurgical testicular sperm extraction in the controls and the cases (p = 0.072). CONCLUSION: Patients who underwent first time testicular sperm extraction with unfavorable outcome due to different techniques may benefit from testosterone downregulation combined with neoadjuvant gonadotropin administration as it had shown positive sperms retrieval in 2 out of the 20 cases, especially those with hypergonadotropic azoospermia.

Androgens During Infancy, Childhood, and Adolescence: Physiology and Use in Clinical Practice.

We provide an in-depth review of the role of androgens in male maturation and development, from the fetal stage through adolescence into emerging adulthood, and discuss the treatment of disorders of androgen production throughout these time periods. Testosterone, the primary androgen produced by males, has both anabolic and androgenic effects. Androgen exposure induces virilization and anabolic body composition changes during fetal development, influences growth and virilization during infancy, and stimulates development of secondary sexual characteristics, growth acceleration, bone mass accrual, and alterations of body composition during puberty. Disorders of androgen production may be subdivided into hypo- or hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism may be either congenital or acquired (resulting from cranial radiation, trauma, or less common causes). Hypergonadotropic hypogonadism occurs in males with Klinefelter syndrome and may occur in response to pelvic radiation, certain chemotherapeutic agents, and less common causes. These disorders all require testosterone replacement therapy during pubertal maturation and many require lifelong replacement. Androgen (or gonadotropin) therapy is clearly beneficial in those with persistent hypogonadism and self-limited delayed puberty and is now widely used in transgender male adolescents. With more widespread use and newer formulations approved for adults, data from long-term randomized placebo-controlled trials are needed to enable pediatricians to identify the optimal age of initiation, route of administration, and dosing frequency to address the unique needs of their patients.

Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome.

The mechanisms underlying metabolic and reproductive dysfunction caused by arrhythmic circadian clock and their involvement in polycystic ovary syndrome (PCOS) are not understood. Here, we addressed this issue using rats with constant light or darkness exposure for 8 weeks and human leukocytes and serum of PCOS and non-PCOS patients. Additionally, we utilized HepG2 cells and KGN cells to verify the molecular mechanisms. The arrhythmic expressions of circadian clock genes due to constant darkness induced the metabolic and reproductive hallmarks of PCOS in rats. After exposure to constant darkness, decreased brain and muscle ARNT-like protein 1 (BMAL1) promoted insulin resistance via glucose transporter 4 (GLUT4), and decreased period (PER) 1 and PER2 promoted androgen excess via insulin-like growth factor-binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) in the liver. Hyperinsulinemia and hyperandrogenism shared a bidirectional link promoting aberrant expression of circadian genes and inducing apoptosis of ovarian granulosa cells. Notably, the altered expressions of circadian clock genes in darkness-treated rats matched those of PCOS patients. Furthermore, melatonin treatment relieved the hyperinsulinemia and hyperandrogenism of darkness-treated rats via BMAL1, PER1, and PER2. Restoring normal light/dark exposure for 2 weeks reversed these conditions via BMAL1. In conclusion, our findings elucidated the critical function of circadian clock genes, especially BMAL1, PER1, and PER2 in PCOS, which might aid the development of feasible preventive and therapeutic strategies for PCOS in women with biorhythm disorder.

A Transient Hermaphroditic Stage in Early Male Gonadal Development in Little Yellow Croaker, Larimichthys polyactis.

Animal taxa show remarkable variability in sexual reproduction, where separate sexes, or gonochorism, is thought to have evolved from hermaphroditism for most cases. Hermaphroditism accounts for 5% in animals, and sequential hermaphroditism has been found in teleost. In this study, we characterized a novel form of the transient hermaphroditic stage in little yellow croaker (Larimichthys polyactis) during early gonadal development. The ovary and testis were indistinguishable from 7 to 40 days post-hatching (dph). Morphological and histological examinations revealed an intersex stage of male gonads between 43 and 80 dph, which consist of germ cells, somatic cells, efferent duct, and early primary oocytes (EPOs). These EPOs in testis degenerate completely by 90 dph through apoptosis yet can be rescued by exogenous 17-ß-estradiol. Male germ cells enter the mitotic flourishing stage before meiosis is initiated at 180 dph, and they undergo normal spermatogenesis to produce functional sperms. This transient hermaphroditic stage is male-specific, and the ovary development appears to be normal in females. This developmental pattern is not found in the sister species Larimichthys crocea or any other closely related species. Further examinations of serum hormone levels indicate that the absence of 11-ketotestosterone and elevated levels of 17-ß-estradiol delineate the male intersex gonad stage, providing mechanistic insights on this unique phenomenon. Our research is the first report on male-specific transient hermaphroditism and will advance the current understanding of fish reproductive biology. This unique gonadal development pattern can serve as a useful model for studying the evolutionary relationship between hermaphroditism and gonochorism, as well as teleost sex determination and differentiation strategies.

The neuroendocrine integration of environmental information, the regulation and action of testosterone and the challenge hypothesis.

The authors of the original challenge hypothesis proposed influential hypotheses concerning the relationship between testosterone concentrations in the blood and aggressive social behaviors. Many of the key observations were made in avian species studied in the wild and in captivity. In this review we evaluate some remaining questions about the ideas discussed in the challenge hypothesis from a neuroendocrine perspective. For example, a rise in testosterone in response to a social aggressive stimulus might involve complex social information being processed by the brain and an appropriate signal sent to the gonadotrophin-releasing hormone (GnRH) neuronal system. Alternatively, social stimuli could more directly stimulate the testis and testosterone release via sympathetic innervation of the testis though such pathways have not been linked to a response to social behaviors. The social behavior decision network in the brain seems to play a key role in the regulation of aggressive behavior but how sensory information concerning aggressive behaviors is interpreted appropriately, processed by the social decision network and sent to the GnRH system is still not well understood. There are continuing questions about the extensive species variation in whether an increase in testosterone occurs in response to a territorial challenge, what its function might be and whether increases in testosterone are necessary to activate morphological changes, or the expression of sexual and aggressive behaviors associated with successful reproduction.

Sexual Dimorphism in Titi Monkeys' Digit (2D:4D) Ratio is Associated with Maternal Urinary Sex Hormones During Pregnancy.

The second-to-fourth digit (2D:4D) ratio is a sexually-dimorphic biomarker for prenatal sex hormone exposure. We investigated whether titi monkeys (Plecturocebus cupreus) exhibit sexually-dimorphic 2D:4D ratio, and whether variation in 2D:4D ratio correlates with maternal testosterone and estrogen levels during early pregnancy. Subjects were 61 adult titi monkeys (32 males, 29 females). For 26 subjects, maternal urine samples were collected approximately 15-20 weeks before birth and assayed for testosterone and estrone conjugate (E1 C). Titi monkeys exhibited a human-like pattern of sexual dimorphism in right-hand 2D:4D ratio, with females exhibiting higher 2D:4D ratio than males (ß = -0.29, p = 0.023). For left-hand 2D:4D ratio, high levels of maternal E1 C predicted low offspring 2D:4D ratio (ß = -0.48, p = 0.009). For right-hand 2D:4D ratio, high levels of testosterone (ß = -0.53, p = 0.005) and testosterone-to-E1 C ratio (ß = -0.41, p = 0.028) predicted low offspring 2D:4D ratio. For 2D:4D ratio asymmetry (right-hand - left-hand), high levels of testosterone (ß = -0.43, p = 0.03) and testosterone-to-E1 C ratio (ß = -0.53, p = 0.003) predicted low (right-biased) asymmetry. This is the first report of sexually-dimorphic 2D:4D ratio in New World monkeys, and the results support a growing literature suggesting prenatal sex hormones may modulate offspring 2D:4D ratio.

Cavernous smooth muscles: innovative potential therapies are promising for an unrevealed clinical diagnosis.

While erectile dysfunction (ED) is highly prevalent worldwide, unrevealed cavernous smooth muscles (CSM) defects can confound the diagnosis of vascular ED and lead to failure of treatments. Currently, the first-line oral treatment for ED is phosphodiesterase type 5 inhibitors (PDE5Is). Patients with diabetes mellitus (DM), those who have undergone a radical prostatectomy (RP), and the elderly population are difficult to treat by the PDE5Is; unrevealed CSM defects can result in corporo veno-occlusive dysfunction (CVOD); and penile veno-ligation surgeries are currently abandoned due to high failure rates. It has been found that gene and stem cell therapies, among others, reduce cavernous tissue apoptosis and fibrosis and can specifically target CSM defects such as the nitric oxide (NO)-mediated signaling pathway, Rho-ROCK system, and transformation growth factor (TGF)-ß1/angiotensin II (Ang II) pathway, in several laboratory animals. Current data clarify the need of diagnostic techniques that can provide an initial assessment of CSM. This assessment should be essential before giving a diagnosis of vascular ED and before applying several tests searching for a specific CSM defect to guide the specific therapy. Moreover, while patients with corporal fibrosis would fail the current medical therapies, these patients can benefit from the stem cell-based therapies that induce the internal mechanisms of tissue repair. However, penile elastography can determine the stiffness of tissues and corpus cavernosum electromyography (CC-EMG) can assess the integrated activity of CSM bulk, further refinements are required for these techniques before being considered in the evaluation of patients with ED. In conclusion, on the basis of the current scientific research, it may be possible to formulate new therapies and achieve the appropriate selection of patients who can benefit from these therapies.

Testosterone antagonizes paraquat-induced cardiomyocyte senescence via the mIGF-1/SIRT1 signaling pathway

Testosterone has been demonstrated to antagonize doxorubicin-induced cardiomyocyte senescence. However, whether testosterone prevents the paraquat-induced cardiomyocyte senescence is largely unknown. The detection of SA-β-gal activity was performed using senescence β-gal staining kit and the reactive oxygen species levels were determined by reactive oxygen species assay kit. The plasmids for insulin-like growth factor 1 shRNA (sh-mIGF-1), sirtuin-1 shRNA (sh-SIRT1), scramble shRNA (sh-NC), overexpressing mIGF-1 (mIGF-1), overexpressing SIRT1 (SIRT1), and negative controls (NC) were obtained for this study. The expression of target genes was detected using quantitative real-time PCR, immunolabeling, and western blot. We found that testosterone significantly delayed the paraquat-induced HL-1 cardiomyocyte senescence as evidenced by decreasing senescence-associated β-galactosidase activity and reactive oxygen species generation, which were accompanied by the up-regulated expression of mIGF-1 and SIRT1. RNA interference to reduce mIGF-1 and SIRT1 expression showed that testosterone prevented paraquat-induced HL-1 senescence via the mIGF-1/SIRT1 signaling pathway. Furthermore, myocardial contraction was evaluated by expression of genes of the contractile proteins/enzymes, such as α-myosin heavy chain 6 (MHC6), α-myosin heavy chain 7 (MHC7), α-skeletal actin (ACTA-1), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA2). Testosterone adjusted the above four gene expressions and the adjustment was blocked by mIGF-1 or SIRT1 inhibition. Our findings suggested that the mIGF-1/SIRT1 signaling pathway mediated the protective function of testosterone against the HL-1 cardiomyocyte senescence by paraquat, which provided new clues for the mechanisms underlying the anti-aging role of testosterone in cardiomyocytes.