Effects of adriamycin on cell differentiation and proliferation in rat testis.

Although adriamycin (ADR) is used to treat many cancers, it can be toxic to healthy organs including the testis. We investigated the effects of ADR on pluripotency in rat testis. Testicular damage was induced by either cumulative or single dose single dose administration of ADR in Wistar albino rats. Rats were divided randomly into three groups: untreated control, cumulative dose ADR group (2 mg/kg ADR every three days for 30 days) and single dose ADR group (15 mg/kg, single dose ADR). Testicular damage was evaluated and seminiferous tubule diameters were measured using light microscopy. Expression levels of Oct4, Sox2, Klf4, c-Myc, Utf1 and Dazl were assessed by immunohistochemistry and real time PCR. Serum testosterone levels were measured using ELISA assay. Histopathologic scores were lower and mean seminiferous tubule diameters were less compared to the ADR groups. Oct4, Sox2, Klf4 and Utf1 expressions were decreased significantly in spermatogenic cells of both cumulative and single dose ADR groups compared to the control group. We found that c-Myc expression in spermatogenic and Leydig cells were increased significantly in both ADR groups compared to the control group. Dazl expression was decreased in the cumulative adriamycin group compared to the control group, but increased in the single dose ADR group compared to both the control and cumulative ADR groups. Serum testosterone levels were decreased in both ADR groups compared to the control group. Our findings suggest that ADR is detrimental to regulation and maintenance of pluripotency in rat testis.

Physiological impacts of chronic and experimental Plasmodium infection on breeding-condition male songbirds.

While Plasmodium parasitism is common in songbirds, its impact on avian reproduction is unclear owing to conflicting reports in the existing literature. Particularly understudied is the impact of phase of infection on variation in host reproductive physiology in wild, breeding-condition birds. However, assessing the full impact of Plasmodium on reproductive success in the wild can be difficult because individuals experiencing severe effects of parasitism may not enter the breeding population and may be less likely to be captured during field studies. To address these factors, we quantified metrics of health and reproductive physiology in wild-caught, breeding-condition male dark-eyed juncos (Junco hyemalis hyemalis) before and after experimental Plasmodium inoculation in a captive setting. Metrics of health and reproductive physiology included activity rate, hematocrit, scaled body mass, testosterone and sperm production. Individuals already infected at capture (i.e., chronically infected) had higher levels of hematocrit than males without chronic infections. Experimentally infected males showed a larger reduction in hematocrit and activity rate as compared to controls. However, chronic infection status did not influence the extent of metric decline. Testosterone production did not vary by treatment and most birds produced sperm following inoculation. Broadly, our results suggest that male juncos exposed to Plasmodium during the breeding season likely experience declines in general health, but Plasmodium infections do not negatively impact reproductive physiology. We conclude that physiological tradeoffs in males may favor maintenance of reproductive function despite infection.

Sex differences in song syntax and syllable diversity in testosterone-induced songs of adult male and female canaries.

BACKGROUND: Behavioral sex differences are widespread in the animal world. These differences can be qualitative (i.e., behavior present in one sex but not the other, a true sex dimorphism) or quantitative (behavior is present at a higher rate or quality in one sex compared to the other). Singing in oscine songbirds is associated with both types of differences. In canaries, female rarely sing spontaneously but they can be induced to do so by treatments with steroids. Song in these females is, however, not fully masculinized and exhibits relatively subtle differences in quality as compared with male song. We analyzed here sex differences in syllable content and syllable use between singing male and female canaries. METHODS: Songs were recorded from three groups of castrated male and three groups of photoregressed female canaries that had received Silastic™ implants filled with testosterone (T), with T plus estradiol (E2), or left empty (control). After 6 weeks of hormone treatment, 30 songs were recorded from each of the 47 subjects. Songs were segmented and each syllable was annotated. Various metrics of syllable diversity were extracted and network analysis was employed to characterize syllable sequences. RESULTS: Male and female songs were characterized by marked sex differences related to syllable use. Compared to females, males had a larger syllable-type repertoire and their songs contained more syllable types. Network analysis of syllable sequences showed that males follow more fixed patterns of syllable transitions than females. Both sexes, however, produced song of the same duration containing the same number of syllables produced at similar rates (numbers per second). CONCLUSIONS: Under the influence of T, canaries of both sexes are able to produce generally similar vocalizations that nevertheless differ in specific ways. The development of song during ontogeny appears to be a very sophisticated process that is presumably based on genetic and endocrine mechanisms but also on specific learning processes. These data highlight the importance of detailed behavioral analyses to identify the many dimensions of a behavior that can differ between males and females.

Male canaries normally sing complex songs at high rate while females only rarely sing very simple songs. Testosterone induces active singing in both male and female canaries, but female song is still not fully masculinized by these treatments even if song duration does not differ between the sexes. We analyzed the syllable repertoire and the sequence of use for different syllables in canaries of both sexes treated with testosterone or testosterone supplemented with estradiol. Compared to females, males had a larger syllable-type repertoire and their songs contained more syllable types. Syllable transitions were also more fixed in males. Sex differences in adult singing of canaries are thus a complex mixture of differences that result from the different endocrine condition of males and females (and are thus partially reversed by administration of exogenous testosterone) and of more stable differences that presumably develop during the ontogenetic process under the influence of endocrine and genetic differences and of differential learning processes. Canary song thus represents an outstanding model system to analyze the interaction between nature and nurture in the acquisition of a sophisticated learned behavior as well as the mechanisms controlling sex differences in vocal learning and production.

Nonestrogen Therapies for Treatment of Genitourinary Syndrome of Menopause: A Systematic Review.

OBJECTIVE: To systematically review the literature and provide clinical practice guidelines regarding various nonestrogen therapies for treatment of genitourinary syndrome of menopause (GSM). DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov , and Cochrane databases were searched from inception to July 2021. We included comparative and noncomparative studies. Interventions and comparators were limited to seven products that are commercially available and currently in use (vaginal dehydroepiandrosterone [DHEA], ospemifene, laser or energy-based therapies, polycarbophil-based vaginal moisturizer, Tibolone, vaginal hyaluronic acid, testosterone). Topical estrogen, placebo, other nonestrogen products, as well as no treatment were considered as comparators. METHODS OF STUDY SELECTION: We double-screened 9,131 abstracts and identified 136 studies that met our criteria. Studies were assessed for quality and strength of evidence by the systematic review group. TABULATION, INTEGRATION, AND RESULTS: Information regarding the participants, details on the intervention and comparator and outcomes were extracted from the eligible studies. Alternative therapies were similar or superior to estrogen or placebo with minimal increase in adverse events. Dose response was noted with vaginal DHEA and testosterone. Vaginal DHEA, ospemifene, erbium and fractional carbon dioxide (CO 2 ) laser, polycarbophil-based vaginal moisturizer, tibolone, hyaluronic acid, and testosterone all improved subjective and objective signs of atrophy. Vaginal DHEA, ospemifene, tibolone, fractional CO 2 laser, polycarbophil-based vaginal moisturizer, and testosterone improved sexual function. CONCLUSION: Most nonestrogen therapies are effective treatments for the various symptoms of GSM. There are insufficient data to compare nonestrogen options to each other.

Effects of transplantation of umbilical cord blood mononuclear cells into the scrotum on sexual function in elderly mice.

Aim: This study investigated the effect of allografting umbilical cord blood mononuclear cells (UCBMCs) into the scrotum on sexual function in male elderly mice. Methods: UCBMCs were injected once into the scrotal sheath cavity of elderly mice. Results: The transplanted UCBMCs survived in the scrotal sheath cavity for 1 month. The mice had significantly increased blood testosterone concentrations, cyclic guanosine monophosphate (cGMP) levels and total nitric oxide synthase (T-NOS) activity in the corpus cavernosum and an increase in the number of mouse matings within 30 min (all p = 0.000). Conclusion: Scrotum-implanted UCBMCs improve the sexual function of male elderly mice through testosterone production and the NOS/cGMP pathway, which may provide an innovative transplantation approach for the treatment of erectile dysfunction.

Ovarian Histology of Removed Ovaries After Gender-Affirming Testosterone Therapy.

Introduction. Assigned female at birth transgender people go through a gender-affirming hormone therapy using testosterone. We aimed to define the histological changes in the removed ovaries of these patients and investigate the correlation of these changes to factors like chronological age and duration of hormone therapy. Methods. The ovaries of 84 patients who had at least 6 months of testosterone therapy before surgery were examined. Tunica albuginea thickness, cortical thickness, and number of different stages of follicles were recorded. Results. The mean age was 27.2 ± 4.9 years. Testosterone duration 25.8 ± 13.1 months. The mean tunica albuginea thickness was 356.4 ± 152.6 µm. The mean cortical thickness was 799.6 ± 245.6 µm. The number of primordial (C1) follicles was 18.03 ± 13.6 and antral (C3) follicles was 3.1 ± 1.9 per cm². When grouped as using therapy under or over 2 years the groups did not have differences in histological findings. Hormone duration did not correlate with histological findings except for a positive correlation with atretic follicle number. However, age was negatively correlated with number of follicles at all stages except atretic follicles and positively correlated with cortical thickness (P < .05). Conclusion. Testosterone therapy induces multifollicularity, stromal hyperplasia, and luteinization in some patients. Hormone duration did not correlate with ovarian histology whereas chronological age did suggesting an effect of age on ovarian reserve rather than duration of hormone therapy.

Effects of testosterone treatment on anal sphincter damage repair in ovariectomized rats.

BACKGROUND: Fecal incontinence (FI) generally occurs with anal sphincter damage caused by vaginal delivery in women, obvious FI can develop in the postmenopausal stage. This pelvic floor dysfunction has no rational medical therapeutic options. We investigated the effect of testosterone treatment on the anal sphincter structure, serum thiol/disulfide levels, uterine tissue, and body composition in female rats in an experimental menopause-FI model. METHODS: The animal experiments were performed between September and November 2020 at Experimental Animal Application and Research Center, Afyon Kocatepe University, Afyonkarahisar, Turkey. Thirty-two female rats were divided into four groups: sham, saline, 10 mg/kg testosterone undecanoate, 100 mg/kg testosterone undecanoate. Except for the sham group, all the other groups underwent ovariectomy (OVE) to create a menopause model. Two weeks after this procedure, the FI model was created under general anesthesia in all rat groups. At the end of the experiment, the rats were placed under general anesthesia, weighed, and euthanized after recording the data. The anal sphincter region and uterine tissue samples were collected for histopathological examinations, and blood samples were collected for total testosterone and thiol/disulfide homeostasis analyses. RESULTS: An increase in anal sphincter muscles and connective tissue thickness was observed in the testosterone-administered groups (p = 0.001). No difference was detected between the groups in the total thiol, native thiol, and disulfide balance (p = 0.087, p = 0.604, p = 0.092). The testosterone-treated groups did not have severe uterine epithelial degradation, hyperemia, or increased endometrial thickness (p = 0.186, p = 0.222, p = 0.630). The body weight of all rats increased (p < 0.05), but the omental weight did not increase (p = 0.061). DISCUSSION: Testosterone treatment increased the anal sphincter muscle and connective tissue thickness without causing any oxidative stress and did not result in a pathological change in the uterine tissue and body fat composition.

Morin mitigates cadmium-induced testicular impairment by stimulating testosterone secretion and germ cell proliferation in mice.

Cadmium (Cd) is one of the heavy metal pollutants present in the environment due to human intervention. It is well known that Cd causes toxicological effects on various organs, including the testes. Morin hydrate is a plant-derived bioflavonoid with antioxidant, anti-inflammatory, and anti-stress properties. Thus, the question can be raised as to whether Morin has an effect on Cd-intoxication-induced testicular impairment. Therefore, the aim of this study was to investigate the role of Morin on Cd-mediated disruption of testicular activity. Mice were divided into three groups: group 1 served as the control group, group 2 was given Cd (10 mg/kg) orally for 35 days, and group 3 was given Cd and Morin hydrate (100 mg/kg) for 35 days. To validate the in vivo findings, an in vitro study on testicular explants was also performed. The results of the in vivo study showed that Cd-intoxicated mice had testicular disorganization, reduced circulating testosterone levels, decreased sperm density, and elevated oxidative stress and sperm abnormality. The expression of the germ cell proliferation marker, germ cell nuclear acidic protein (GCNA), and adipocytokine visfatin were also downregulated. It was observed that Morin hydrate upregulated testicular visfatin and GCNA expression in Cd-intoxicated mice, along with improvement in circulating testosterone, testicular histology, and sperm parameters. Furthermore, the in vitro study showed that Cd-mediated downregulation of testicular visfatin and GCNA expression, along with the suppressed secretion of testosterone from testicular explants, was normalized by Morin treatment, whereas visfatin expression was not. Overall, these data indicate that environmental cadmium exposure impairs testicular activity through downregulation of visfatin and GCNA expression, and Morin might play a protective role against Cd-induced testicular toxicity.

Effect of pentoxifylline on the testicular hemodynamic, volume, testosterone, nitric oxide levels and semen quality in Ossimi rams during non breeding-season.

During the non-breeding season, Ossimi rams have testicular regression, including reductions in blood flow, size and spermatogenesis. The objective was to determine the effect of pentoxifylline (PTX) on Ossimi rams during the non-breeding season. Fifteen sexually mature Ossimi rams were allotted to three groups: (1) G0 (n = 5) control group (basic diet, no PTX); (2) G1 (n = 5) 10 mg/kg BW PTX; and (3) G2 (n = 5) 20 mg/kg BW PTX. The PTX was given orally once daily for 7 weeks (wk1 to wk7), whereas ultrasonographic assessment of testes, and collection of semen and blood started 1 week before PTX and were done weekly for 8 weeks (wk0 to wk7). In G2, there was a decrease(P < 0.05) in both Doppler indices (resistive index, pulsatility index) in G2 from wk2 to wk4 and an increase(P < 0.05) in ultrasonographic testicular coloration from wk2 to wk7. Moreover, G2 had the highest (P < 0.05) testicular volume (wk5 to wk7), individual motility, sperm viability and acrosome integrity (wk4 to wk7) and sperm cell concentration (wk6 and wk7). Blood concentrations of testosterone and nitric oxide were increased (P < 0.05) concurrent with decreased Doppler indices. In conclusion, PTX enhanced testicular blood flow and volume, semen quality, and concentrations of testosterone and nitric oxide potential in Ossimi rams during the non-breeding season, with potential to ameliorate deleterious effects of heat stress and perhaps enhance ram fertility.

Testosterone administration modulates inequality aversion in healthy males: evidence from computational modeling.

Fairness concerns play a prominent role in promoting cooperation in human societies. Social preferences involving fairness concern have been associated with individual testosterone levels. However, the causal effects of testosterone administration on fairness-related decision making remain to be elucidated. Here, we used a randomized, double-blind, between-participant design and administered testosterone or placebo gel to 120 healthy young men. Three hours after administration, participants performed a modified Dictator Game from behavioral economics, in which they were asked to choose one of two monetary allocations between themselves and anonymous partners. Participants were either in a position of advantageous inequality (i.e., endowed with more than others) or disadvantageous inequality (i.e., endowed with less than others). Computational modeling showed that inequality-related preferences explained behavior better than competing models. Importantly, compared with the placebo group, the testosterone group showed significantly reduced aversion to advantageous inequality but enhanced aversion to disadvantageous inequality. These findings suggest that testosterone facilitates decisions that prioritize selfish economic motives over fairness concerns, which in turn may boost status-enhancing behaviors.

Treatment of osteoporosis using a selective androgen receptor modulator ostarine in an orchiectomized rat model.

PURPOSE: The selective androgen receptor modulator ostarine has been shown to have advantageous effects on skeletal tissue properties, reducing muscle wasting and improving physical function in males. However, data on effects in male osteoporosis remain limited. In this study, the effects of ostarine on osteoporotic bone were evaluated in a rat model of male osteoporosis and compared with those of testosterone treatments. METHODS: Eight-month-old male Sprague-Dawley rats were either non-orchiectomized to serve as a healthy control (Non-Orx, Group 1) or orchiectomized (Orx, Groups 2-6) and then grouped (n = 15/group): (1) Non-Orx, (2) Orx, (3) Ostarine Therapy, (4) Testosterone Therapy, (5) Ostarine Prophylaxis and (6) Testosterone Prophylaxis. Prophylaxis treatments started directly after orchiectomy and continued for 18 weeks, whereas Therapy treatments were initiated 12 weeks after Orx. Ostarine and Testosterone were applied orally at daily doses of 0.4 and 50 mg/kg body weight, respectively. The lumbar vertebral bodies and femora were analyzed using biomechanical, micro-CT, ashing, and gene expression analyses. RESULTS: Ostarine Prophylaxis showed positive effects in preventing osteoporotic changes in cortical and trabecular bone (femoral trabecular density: 26.01 ± 9.1% vs. 20.75 ± 1.2% in Orx and in L4: 16.3 ± 7.3% vs 11.8 ± 2.9% in Orx); biomechanical parameters were not affected; prostate weight was increased (0.62 ± 0.13 g vs 0.18 ± 0.07 g in Orx). Ostarine Therapy increased solely the cortical density of the femur (1.25 ± 0.03 g/cm3 vs. 1.18 ± 0.04 g/cm3 in Orx); other bone parameters remained unaffected. Testosteron Prophylaxis positively influenced cortical density in femur (1.24 ± 0.05 g/cm3 vs. 1.18 ± 0.04 g/cm3 in Orx); Test. Therapy did not change any bony parameters. CONCLUSION: Ostarine Prophylaxis could be further investigated as a preventative treatment for male osteoporosis, but an androgenic effect on the prostate should be taken into consideration, and combination therapies with other anti-osteoporosis agents could be considered.

Does the syrinx, a peripheral structure, constrain effects of sex steroids on behavioral sex reversal in adult canaries?

We previously confirmed that effects of testosterone (T) on singing activity and on the volume of brain song control nuclei are sexually differentiated in adult canaries: females are limited in their ability to respond to T as males do. Here we expand on these results by focusing on sex differences in the production and performance of trills, i.e., rapid repetitions of song elements. We analyzed >42,000 trills recorded over a period of 6 weeks from 3 groups of castrated males and 3 groups of photoregressed females that received Silastic™ implants filled with T, T plus estradiol or left empty as control. Effects of T on the number of trills, trill duration and percent of time spent trilling were all stronger in males than females. Irrespective of endocrine treatment, trill performance assessed by vocal deviations from the trill rate versus trill bandwidth trade-off was also higher in males than in females. Finally, inter-individual differences in syrinx mass were positively correlated with specific features of trills in males but not in females. Given that T increases syrinx mass and syrinx fiber diameter in males but not in females, these data indicate that sex differences in trilling behavior are related to sex differences in syrinx mass and syrinx muscle fiber diameter that cannot be fully suppressed by sex steroids in adulthood. Sexual differentiation of behavior thus reflects organization not only of the brain but also of peripheral structures.

Chronic testosterone deficiency increases late inward sodium current and promotes triggered activity in ventricular myocytes from aging male mice.

Clinical studies suggest low testosterone levels are associated with cardiac arrhythmias, especially in later life. We investigated whether chronic exposure to low circulating testosterone promoted maladaptive electrical remodeling in ventricular myocytes from aging male mice and determined the role of late inward sodium current (INa,L) in this remodeling. C57BL/6 mice had a gonadectomy (GDX) or sham surgery (1 mo) and were aged to 22-28 mo. Ventricular myocytes were isolated; transmembrane voltage and currents were recorded (37°C). Action potential duration at 70 and 90% repolarization (APD70 and APD90) was prolonged in GDX compared with sham myocytes (APD90, 96.9 ± 3.2 vs. 55.4 ± 2.0 ms; P < 0.001). INa,L was also larger in GDX than sham (-2.4 ± 0.4 vs. -1.2 ± 0.2 pA/pF; P = 0.002). When cells were exposed to the INa,L antagonist ranolazine (10 µM), INa,L declined in GDX cells (-1.9 ± 0.5 vs. -0.4 ± 0.2 pA/pF; P < 0.001) and APD90 was reduced (96.3 ± 14.8 vs. 49.2 ± 9.4 ms; P = 0.001). GDX cells had more triggered activity (early/delayed afterdepolarizations, EADs/DADs) and spontaneous activity than sham. EADs were inhibited by ranolazine in GDX cells. The selective NaV1.8 blocker A-803467 (30 nM) also reduced INa,L, decreased APD and abolished triggered activity in GDX cells. Scn5a (NaV1.5) and Scn10a (NaV1.8) mRNA was increased in GDX ventricles, but only NaV1.8 protein abundance was increased in GDX compared with sham. In vivo studies showed QT prolongation and more arrhythmias in GDX mice. Thus, triggered activity in ventricular myocytes from aging male mice with long-term testosterone deficiency arises from APD prolongation mediated by larger NaV1.8- and NaV1.5-associated currents, which may explain the increase in arrhythmias.NEW & NOTEWORTHY Older men with low testosterone levels are at increased risk of developing cardiac arrhythmias. We found aged mice chronically exposed to low testosterone had more arrhythmias and ventricular myocytes had prolonged repolarization, abnormal electrical activity, larger late sodium currents, and increased expression of NaV1.8 sodium channels. Drugs that inhibit late sodium current or NaV1.8 channels abolished abnormal electrical activity and shortened repolarization. This suggests the late sodium current may be a novel target to treat arrhythmias in older testosterone-deficient men.

Testosterone and estradiol modify the expression of adhesins and biofilm formation in Actinobacillus seminis.

Actinobacillus seminis is the causal agent of epididymitis and has other effects on the reproductive tracts of small ruminants and bovines. This bacterium causes infection when luteinizing (LH) or follicle-stimulating hormones increase, and hosts reach sexual maturity. LH induces female ovulation and male testosterone production, suggesting that these hormones affect A. seminis pathogenicity. In the present study, we evaluated the effect of testosterone (1-5 ng/ml) or estradiol (5-25 pg/ml) added to culture medium on the in vitro growth, biofilm production, and adhesin expression of A. seminis. Estradiol does not promote the growth of this bacterium, whereas testosterone increased A. seminis planktonic growth 2-fold. Both hormones induced the expression of the elongation factor thermo unstable (EF-Tu) and phosphoglycerate mutase (PGM), proteins that A. seminis uses as adhesins. Estradiol (5 or 10 pg/ml) decreased biofilm formation by 32%, whereas testosterone, even at 5 ng/ml, showed no effect. Both hormones modified the concentrations of carbohydrates and eDNA in biofilms by 50%. Amyloid proteins are characterized by their capacity to bind Congo red (CR) dye. Actinobacillus seminis binds CR dye, and this binding increases in the presence of 5-20 pg/ml estradiol or 4 ng/ml testosterone. The A. seminis EF-Tu protein was identified as amyloid-like protein (ALP). The effect of sexual hormones on the growth and expression of virulence factors of A. seminis seems to be relevant for its colonization and permanence in the host.

Effect of 12-months testosterone replacement therapy on bone mineral density and markers of bone turnover in testicular cancer survivors - results from a randomized double-blind trial.

BACKGROUND: Testicular cancer survivors (TCS) are at risk of Leydig cell insufficiency, which is a condition characterized by elevated luteinising hormone (LH) in combination with low levels of testosterone. It has been suggested that this condition is associated with impaired metabolic profile and low bone mineral density (BMD). The primary aim of the randomized double-blind trial NCT02991209 was to evaluate metabolic profile after 12-months testosterone replacement therapy (TRT) in TCS with mild Leydig cell insufficiency. Here we present the secondary outcomes of changes in BMD and markers of bone turnover. METHODOLOGY: In total, 69 TCS with mild Leydig cell insufficiency were randomized 1:1 to 12 months TRT (n = 35) (Tostran, gel, 2%, applied transdermally, with a maximum daily dose of 40 mg) or placebo (n = 34). BMD and markers of bone turnover were evaluated at baseline, after 6- and 12-months TRT, and 3-months post-treatment. Linear mixed effects models were used to analyse changes in BMD, N-terminal propeptide of type 1 procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX). RESULTS: After 12 months treatment, TRT was not associated with a statistically significant difference in BMD compared to placebo; total body BMD: 0.01 g/cm2 (95% confidence interval (CI): -0.01 - 0.02), BMD of the lumbar spine: 0.01 g/cm2, (95% CI: -0.01-0.03), BMD of the left femoral neck: 0.00, (95% CI: -0.01-0.02). TRT was associated with a small but statistically significant increase in P1NP: 11.65 µg/L (95% CI: 3.96, 19.35), while there was no difference in CTX. CONCLUSION: 12 months of TRT did not change BMD, while there was as small and clinically irrelevant increase in P1NP compared to placebo in TCS with mild Leydig cell insufficiency. The findings need validation in a larger cohort.

Effects of Exercise on Testosterone and Implications of Drug Abuse: A Review.

OBJECTIVE: Research points to exercise having a positive effect in fighting relapse and use of drugs of abuse. Through conducting this research, differences have been observed in the effects of exercise on drug abuse between sexes. Many of the studies found that exercise tends to cause a more profound effect in blocking drug relapse or reinstatement in males when compared with females. METHODS: Our hypothesis is that these differences in response to drugs of abuse after an exercise regimen could in part be attributed to variations in testosterone levels between males and females. RESULTS: Testosterone has been shown to have a modulatory impact on the dopaminergic activity in the brain, causing an effect on the brain's response to drugs of abuse. Exercise has demonstrated a causal effect on increasing testosterone levels in males, whereas drugs of abuse decrease testosterone levels in males. CONCLUSIONS: Thus, exercise raising testosterone levels in males helps to decrease the dopaminergic response in the brain to drugs of abuse causing attenuation to drugs. To find sex-specific exercise treatments for drugs of abuse, it is important to continue researching exercise's efficacy against drugs of abuse.

Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness.

Background: Although estrogen (ERα/ERß), progesterone (PGR), and androgen (AR) receptors are pathologically altered in colorectal cancer (CRC), their simultaneous expression within the same cohort of patients was not previously measured. Methods: ERα/ERß/PGR/AR proteins were measured in archived paired normal and malignant colon specimens (n =120 patients) by immunohistochemistry, and results were analyzed by gender, age (≤50 vs. ≥60 years), clinical stages (early-stage I/II vs. late-stage III/IV), and anatomical location (right; RSCs vs. left; LSCs). Effects of 17ß-estradiol (E2), progesterone (P4), and testosterone alone or combined with the specific blockers of ERα (MPP dihydrochloride), ERß (PHTPP), PGR (mifepristone), and AR (bicalutamide) on cell cycle and apoptosis were also measured in the SW480 male and HT29 female CRC cell lines. Results: ERα and AR proteins increased, whilst ERß and PGR declined markedly in malignant specimens. Moreover, male neoplastic tissues showed highest AR expression, whilst ERß and PGR weakest alongside ERα strongest expression was seen in cancerous tissues from women aged ≥60 years. Late-stage neoplasms also revealed maximal alterations in the expression of sex steroid receptors. By tumor location, LSCs disclosed significant elevations in ERα with marked declines in PGR compared with RSCs, and ERα strongest alongside PGR weakest expression was detected in advanced LSCs from women aged ≥60 years. Late-stage LSCs from females aged ≥60 years also showed weakest ERß and strongest AR expression. In contrast, male RSC and LSC tissues exhibited equal ERß and AR expression in all clinical stages. ERα and AR proteins also correlated positively, whereas ERß and PGR inversely, with tumor characteristics. Concomitantly, E2 and P4 monotherapies triggered cell cycle arrest and apoptosis in the SW480 and HT29 cells, and while pre-treatment with ERα-blocker enhanced the effects of E2, ERß-blocker and PGR-blocker suppressed the E2 and P4 anti-cancer actions, respectively. In contrast, treatment with the AR-blocker induced apoptosis, whilst co-treatment with testosterone hindered the effects. Conclusions: This study advocates that protein expression of sex steroid receptors in malignant tissues could represent prognostic markers, as well as hormonal therapy could provide an alternative strategy against CRC, and their efficacies could be dependent on gender, clinical stage, and tumor location.

[Mechanisms mediating the inhibitory effects of quercetin against phthalates-induced testicular oxidative damage in rats].

OBJECTIVE: To explore the mechanism underlying the inhibitory effect of quercetin against testicular oxidative damage induced by a mixture of 3 commonly used phthalates (MPEs) in rats. METHODS: Forty male Sprague-Dawley rats were randomly divided into control group, MPEs exposure group, and MPEs with low-, median- and high-dose quercetin treatment groups. For MPEs exposure, the rats were subjected to intragastric administration of MPEs at the daily dose of 900 mg/kg for 30 consecutive days; Quercetin treatments were administered in the same manner at the daily dose of 10, 30, and 90 mg/kg. After the treatments, serum levels of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testicular malondialdeyhde (MDA), catalase (CAT) and superoxide dismutase (SOD) were detected, and testicular pathologies of the rats were observed with HE staining. The expressions of nuclear factor-E2-related factor 2 (Nrf2), Kelch-like ECH2 associated protein 1 (Keap1) and heme oxygenase 1 (HO-1) in the testis were detected using immunofluorescence assay and Western blotting. RESULTS: Compared with the control group, the rats with MPEs exposure showed significant reductions of the anogenital distance, weight of the testis and epididymis, and the coefficients of the testis and epididymis with lowered serum testosterone, LH and FSH levels (P < 0.05). Testicular histological examination revealed atrophy of the seminiferous tubules, spermatogenic arrest, and hyperplasia of the Leydig cells in MPEs-exposed rats. MPEs exposure also caused significant increments of testicular Nrf2, MDA, SOD, CAT and HO-1 expressions and lowered testicular Keap1 expression (P < 0.05). Treatment with quercetin at the median and high doses significantly ameliorated the pathological changes induced by MPEs exposure (P < 0.05). CONCLUSION: Quercetin treatment inhibits MPEs-induced oxidative testicular damage in rats possibly by direct scavenging of free radicals to lower testicular oxidative stress and restore the regulation of the Nrf2 signaling pathway.

Protective effects of iodine on rat prostate inflammation induced by sex hormones and on the DU145 prostate cancer cell line treated with TNF.

Molecular iodine (I2) prevents oxidative stress and prostate hyperplasia induced by hyperandrogenism and reduces cell viability in prostate cancer cell lines. Here, we aimed to evaluate the protective effect of I2 and testosterone (T) on hyperestrogenism-induced prostate inflammation. Additionally, the effects of I2 and/or tumor necrosis factor (TNF) on cell viability and interleukin 6 (IL6) secretion were evaluated in a prostate cancer cell line (DU145). We also investigated whether the effects of I2 on viability are peroxisome proliferator-activated receptor gamma (PPARG)-dependent. Castrated (Cx) rats received pellets of either 17ß estradiol (E2) or E2 and T and were treated with I2 (0.05%) in the drinking water for four weeks. The experimental groups were sham, Cx, Cx + E2, Cx + E2+I2, Cx + E2+T, and Cx + E2+T + I2. As expected, inflammation was triggered in the Cx + E2 group (high inflammation score; increase in TNF and transcriptional activity of RELA [nuclear factor-kappa B p65 subunit]), and this effect was diminished in the Cx + E2+T group (medium inflammation score and decrease in TNF). The lowest inflammation score (decrease of TNF and RELA and increase of PPARG) was obtained in the Cx + E2+T + I2 group. In DU145 cells, I2 (400 µM) and TNF (10 ng/ml) additively reduced cell viability, and I2 reduced the production of TNF-stimulated IL6. The PPARG antagonist (GW9662) did not inhibit the effects of I2 on the loss of cell viability. In summary, our data suggest that I2 and T exert a synergistic anti-inflammatory action on the normal prostate, and the interrelationship between I2 and TNF leads to anti-proliferative effects in DU145 cells. PPARG does not seem to participate in the I2-induced cell viability loss in the prostate.

Orchiectomy sensitizes cortical bone in male mice to the harmful effects of kynurenine.

Kynurenine (Kyn) is a tryptophan metabolite that increases with age and promotes musculoskeletal dysfunction. We previously found a sexually dimorphic pattern in how Kyn affects bone, with harmful effects more prevalent in females than males. This raises the possibility that male sex steroids might exert a protective effect that blunts the effects of Kyn in males. To test this, orchiectomy (ORX) or sham surgeries were performed on 6-month-old C57BL/6 mice, after which mice received Kyn (10 mg/kg) or vehicle via intraperitoneal injection, once daily, 5×/week, for four weeks. Bone histomorphometry, DXA, microCT, and serum marker analyses were performed after sacrifice. In vitro studies were performed to specifically test the effect of testosterone on activation of aryl hydrocarbon receptor (AhR)-mediated signaling by Kyn in mesenchymal-lineage cells. Kyn treatment reduced cortical bone mass in ORX- but not sham-operated mice. Trabecular bone was unaffected. Kyn's effects on cortical bone in ORX mice were attributed primarily to enhanced endosteal bone resorption activity. Bone marrow adipose tissue was increased in Kyn-treated ORX animals but was unchanged by Kyn in sham-operated mice. ORX surgery increased mRNA expression of the aryl hydrocarbon receptor (AhR) and its target gene Cyp1a1 in the bone, suggesting a priming and/or amplification of AhR signaling pathways. Mechanistic in vitro studies revealed that testosterone blunted Kyn-stimulated AhR transcriptional activity and Cyp1a1 expression in mesenchymal-linage cells. These data suggest a protective role for male sex steroids in blunting the harmful effects of Kyn in cortical bone. Therefore, testosterone may play an important role in regulating Kyn/AhR signaling in musculoskeletal tissues, suggesting crosstalk between male sex steroids and Kyn signaling may influence age-associated musculoskeletal frailty.