Testicular Testosterone Production Research Articles

Biomarkers of Iron Are Associated with Anterior-Pituitary-Produced Reproductive Hormones in Men with Infertility.

Approximately 16% of North American couples are affected by infertility, with 30% of cases being attributable to male factor infertility. The regulation of reproductive hormones via the hypothalamic-pituitary-gonadal axis is important for spermatogenesis and subsequently male fertility. Maintaining iron homeostasis is critical to normal reproductive physiological function. This cross-sectional study's objective was to determine the association between serum biomarkers of iron and reproductive hormones. Men experiencing infertility (n = 303) were recruited from Mount Sinai Hospital, Toronto. Serum was analyzed for iron and ferritin as biomarkers of iron status and reproductive hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, and prolactin), which were the primary outcome. Associations were determined using non-parametric Spearman's rank correlation coefficient, linear regressions, and logistic regressions. A significant independent monotonic inverse relationship between serum iron and prolactin (p = 0.0002) was found. In linear regression analyses, iron was inversely associated with luteinizing hormone (unadjusted p = 0.03, adjusted p = 0.03) and prolactin (unadjusted p = 0.001 and adjusted p = 0.003). Serum ferritin was inversely associated with both gonadotropins, follicle-stimulating hormone (adjusted p = 0.03), and luteinizing hormone (adjusted p = 0.02). These findings suggest that biomarkers of iron are associated with pituitary-produced reproductive hormones, which play a role in the hypothalamic-pituitary-gonadal signaling pathway involved in spermatogenesis, testicular testosterone production, and male fertility.

Cell-Cell Interactions in the Testis that Support Male Fertility

The testis has two important functions: the production of sperm for fertility and the synthesis and release of androgens, such as testosterone, that maintain sperm production, sexual function, health, and wellbeing. Sperm production takes place within the seminiferous tubules, supported by the somatic Sertoli cells, and is stimulated by gonadotrophins produced by the pituitary and androgens produced by the Leydig cells in the interstitium. Spermatogenesis is a highly complex and co-ordinated process regulated via cell-cell interactions between multiple cell types. Sertoli cells produce many factors, in a cyclic manner, that are required for germ cell development and, in turn, they receive signals from developing germ cells to maintain their function. Regulation of the spermatogenic cycle involves different cell types co-operating to produce a “pulse” of retinoic acid that stimulates immature germ cells to become committed to differentiation. Research in the past decade has shown that Sertoli cells do much more than regulate germ cell development; they maintain the development and function of peritubular myoid cells, the testicular vasculature and the Leydig cells. Sertoli cells send signals to interstitial immune cells to maintain an immunosuppressive environment and deposit thousands of proteins into the interstitium, including spermatid-specific proteins that likely help to promote peripheral immune tolerance. Leydig cells produce testosterone that acts on receptors in Sertoli cells to initiate and maintain spermatogenesis, and in peritubular myoid cells to support germ cell development. Leydig cells exist in a niche with specialised macrophages that can regulate Leydig cell function and steroidogenesis, highlighting that cross-talk between testis cells and the immune system is important for testis function. Defining the specific signals that operate between the different cell types that regulate key testis functions will help to uncover new therapies to support male fertility and testicular testosterone production over the life course.

Reproductive toxicity following in utero and lactational exposure to a human-relevant phthalate mixture in rats.

This rodent (Wistar rats) study examined reproductive effects of in utero/lactational exposure to a mixture of 6 antiandrogenic phthalates (PMix): diisobutyl phthalate, di-n-butyl phthalate, diisopentyl phthalate, butylbenzyl phthalate, di-2-ethylhexyl phthalate, and diisononyl phthalate. The PMix was defined based on exposure data from pregnant women in Brazil. Experimental groups were established by extrapolating the estimated human dose to rats (0.1 mg/kg/day), followed by up to 3 additional doses corresponding to 5, 1000, and 5000 times the starting rat dose: 0 (control), 0.1, 0.5, 100, and 500 mg/kg/day. The fetal experiment assessed gestational exposure effects on fetal gonads, whereas the postnatal experiment evaluated reproductive parameters in males and females after in utero and lactational exposure. Prenatal exposure decreased fetal testicular testosterone production at 0.5 and 500 mg/kg/day. PMix 500 also reduced mRNA expression of steroidogenesis-related genes, upregulated transcript expression of the retinoic acid-degrading enzyme Cyp26b1, and increased multinucleated gonocytes incidence in fetal testes. Postnatal assessment revealed antiandrogenic effects at the highest dose, including reduced anogenital distance, nipple retention, and decreased weight of reproductive organs. Early puberty onset (preputial separation) was observed at the lowest dose in males. In contrast, females did not show significant changes in fetal and adult endpoints. Overall, the PMix recapitulated early and late male rat phthalate syndrome phenotypes at the highest dose, but also induced some subtle changes at lower doses, which warrant confirmation and mechanistic assessments. Our data support the use of epidemiologically defined mixtures for exposure risk assessments over traditional toxicological approaches.

Impaired Testicular Function without Altering Testosterone Concentration Using an Anti-Follicular-Stimulating Hormone Receptor (Anti-FSHr) Single-Chain Variable Fragment (scFv) in Long-Tailed Macaques (Macaca fascicularis).

FSHr antibodies have been shown to inhibit the differentiation of spermatogonia to primary spermatocytes, resulting in infertility without a pathological effect on reproductive organs. The aim of this study was to develop single-chain variable fragments (scFvs) against the follicular-stimulating hormone receptor (anti-FSHr) using phage-display technology and to evaluate the effects of intratesticular administration of the anti-FSHr scFv on testicular function and testosterone production. A phage clone against the extracellular domain of FSHr selected from a scFv phagemid library was analyzed for binding kinetics by surface plasmon resonance. Using ultrasound guidance, three adult macaques (M. fascicularis) were administered with 1 mL of 0.4 mg/mL anti-FSHr scFv (treatment) and 1 mL sterile phosphate buffer solution (control) into the left and right rete testis, respectively. Testicular appearance and volume, ejaculate quality, and serum testosterone levels were recorded on day 0 (before injection) and on days 7, 28, and 56 (after injection). Testicular tissue biopsies were performed on day 7 and day 56 to quantify the mRNA expressions of androgen binding protein (ABP), inhibin subunit beta B (IHBB), and vascular endothelial growth factor A (VEGFA). The results demonstrated that the anti-FSHr scFv molecule was calculated as 27 kDa with a dissociation constant (KD) of 1.03 µM. The volume of the anti-FSHr scFv-injected testicle was reduced on days 28 and 56 compared with day 0 (p < 0.05). Total sperm number was reduced from day 0 (36.4 × 106 cells) to day 56 (1.6 × 106 cells) (p < 0.05). The percentage of sperm motility decreased from day 0 (81.7 ± 1.0%) to day 7 (23.3 ± 1.9%), day 28 (41.7 ± 53.4%), and day 56 (8.3 ± 1.9%) (p < 0.05). Sperm viability on day 0 was 86.8 ± 0.5%, which reduced to 64.2 ± 1.5%, 67.1 ± 2.2%, and 9.3 ± 1.1% on days 7, 28, and 56, respectively (p < 0.05). The expression of ABP and VEGFA on days 7 (14.2- and 3.2-fold) and 56 (5.6- and 5.5-fold) was less in the scFv-treated testicle compared with the controls (p < 0.05). On day 56, the expression of IHBB was less (p < 0.05) in the treated testis (1.3-fold) compared with the controls. Serum testosterone levels were unchanged throughout the study period (p > 0.05). This study characterized the anti-FSHr scFv and demonstrated that treatment with anti-FSHr ameliorates testicular function without altering testosterone levels, offering a potential alternative contraceptive for the long-tailed macaques.

Effect of the GnRH stimulation test on Canine Prostatic-Specific Esterase (CPSE).

The gonadotropin-releasing hormone (GnRH) stimulation test is used to investigate testicular production of testosterone (T) when performing a breeding soundness examination. In male dogs with fertility problems, the prostate should also be investigated as prostatic conditions may frequently lower semen quality. Serum concentrations of canine prostatic-specific esterase (CPSE) increase in dogs with benign prostatic hyperplasia (BPH). When performing a breeding soundness examination in a male dog, GnRH administration is frequently done at the beginning of the process and then both T and CPSE are assayed on the same serum sample collected 1 h following the GnRH injection. The aim of this study was to assess whether or not the administration of GnRH may alter CPSE concentrations in dogs with a healthy prostate. Twenty-eight client-owned intact adult male dogs were included in the study. Following a 7-day sexual rest all male dogs underwent a clinical examination and an ultrasonographic examination of the prostatic gland. Prostatic size and parenchyma of every tested dog were evaluated by ultrasonography to assess prostatic conditions. Two different GnRH stimulation protocols were used, A = gonadorelin 50μg/dog SC (n = 15) and B = buserelin 0.12 μg/kg IV (n = 13). T and CPSE concentrations were measured before and 1 h after GnRH administration by a laser-induced fluorescence analysis. Buserelin and gonadorelin were equally effective in causing a significant increase in serum T concentrations in the post GnRH sample. When considering the 28 dogs together, CPSE concentrations did not change following the stimulation test with either GnRH compound; however, in 4/28 cases, the post GnRH value was markedly increased to values compatible with a diagnosis of BPH. There was no difference in the action of buserelin or gonadorelin in causing an increase in serum T concentrations. CPSE secretion was increased in approximately 15% of dogs treated with either buserelin or gonadorelin. Therefore, whenever performing diagnostic testing in intact male dogs, CPSE should not be assayed on a post-GnRH serum sample.

Steroidogenic enzyme gene expression and testosterone production are developmentally modulated by bone morphogenetic protein receptor-1B in mouse testis.

Bone morphogenetic proteins (BMPs) and receptors (BMPR-1A, BMPR-1B, BMPR-2) have been shown to be vital for female reproduction, while their roles in males are poorly described. Our study was undertaken to specify the function of BMPR-1B in steroidogenic enzyme gene expression, testosterone production and reproductive development in male mice, given that Bmpr1b mRNA is expressed in mouse testis and Bmpr1b knockout results in compromised fertility. Male mice were passively immunized for 6 days with anti-BMPR-1B in the presence or absence of exogenous gonadotrophins. We then measured the effects of anti-BMPR-1B on testicular hydroxysteroid dehydrogenase isoforms (Hsd3b1, Hsd3b6, and Hsd17b3) and aromatase (Cyp19) mRNA expression, testicular and serum testosterone levels, and testis and seminal vesicle weight. In vitro testosterone production in response to anti-BMPR-1B was determined using testicular culture, and Leydig cell culture in the presence or absence of gonadotrophins. In Leydig cell culture the contribution of seminiferous tubules and Leydig cells were examined by preconditioning the media with these testicular constituents. In adult mice, anti-BMPR-1B increased testosterone and Hsd3b1 but decreased Hsd3b6 and Cyp19 mRNA. In adult testicular culture and seminiferous tubule conditioned Leydig cell culture, anti-BMPR-1B reduced testosterone, while in normal and Leydig cell conditioned Leydig cell culture it increased testosterone levels. In pubertal mice, anti-BMPR-1B reduced gonadotrophin stimulated seminal vesicle growth. In conclusion, BMPR-1B has specific developmental functions in the autocrine and paracrine regulation of testicular steroidogenic enzyme gene expression and testosterone production in adults and in the development of seminal vesicles during puberty.

Enokitake Mushroom and Its Active Component, Adenosine, Which Restores Testosterone Production in Impaired and Fatigued Mouse Models

Several studies have reported the effects of the consumption of various mushroom species on the testes in animal experimental models. Mushrooms, including enokitake mushrooms (Flammulina velutipes), and vegetables contain adenosine may affect testosterone production. Here, we aimed to elucidate the effects of enokitake and its active component, adenosine, on testosterone production in primary cultures of testicular cells in vivo using mice models and in vitro. The administration of enokitake ethanolic extract increased testosterone production in the cisplatin-impaired mouse model. The direct effect of mushroom extracts on testicular cells was examined and liquid chromatography–mass spectrometry analysis confirmed that the mushroom- and vegetable-induced increase in testosterone production mainly involved adenosine. Additionally, the administration of enokitake extract or adenosine to wet floor fatigue model mice promoted testicular testosterone production and enhanced Leydig cell function through insulin-like peptide three level upregulation. Structurally related compounds, including cordycepin, showed lower bioactivity than adenosine. This study showed that the ingestion of adenosine-containing mushrooms and vegetables may effectively increase testicular testosterone production. We conclude that mushrooms with a relatively high adenosine content, such as enokitake, may be useful against aging and fatigue.

The Acute Exposure of Human Adult Testis Tissue to Cannabinoids THC and CBD Does Not Impact Testosterone Production Nor Germ Cell Lineage.

While an increased risk of developing germ cell tumors has been established in regular cannabis consumers, there is conflicting evidence about an association between cannabis use and testosterone levels in those regular consumers. In this context, we aimed to determine whether Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two major and best-studied cannabinoids present in cannabis, also the most used for therapeutic applications, can directly impact the steroidogenic function and germ cell lineage of the human adult testis. We used our well-characterized organotypic culture of human testis, in which adult testis explants were exposed to CBD, THC, or CBD/THC [ratio 1:1] from 10-9 to 10-5 M for up to either 48 hours or 9 days of culture. The testes were obtained from multi-organ donors (n=13; mean age: 55.15±5.62 y). The testosterone production and the spatial distribution of Leydig cells did not change upon CBD and/or THC exposure versus controls after 48 hours or 9 days. The overall tissue morphology of the cannabinoids-exposed testis explants was similar to their control upon 24 hours or 9 days of exposure, a finding confirmed by morphometric analyses on short-term cultures. In line, the number of apoptotic cells was not affected by either 48 hours or 9 days of cannabinoids treatment versus mock. Cannabinoids had no impact on the number of proliferating cells nor on mRNA expression of genes encoding proteins involved in germ cell differentiation, meiosis, or Sertoli and Leydig functions after 24 hours exposure. Altogether, these findings show an absence of acute direct effects of exposure to cannabis-derived cannabinoids THC and CBD on testicular testosterone production and germ cells ex vivo. Further studies are warranted to explore an indirect impact of cannabinoids on testis functions through the hypothalamic-pituitary-testis axis, as well as the potential effects of long-term exposures.

SEMEN ANALYSIS FINDINGS FROM LARGE COHORT OF ADOLESCENTS WITH KLINEFELTER SYNDROME

INTRODUCTION: Klinefelter Syndrome (KS) is the most common genetic condition cause of non-obstructive azoospermia (NOA). KS also often results in decreased testicular growth and testosterone production. Because of this, exogenous testosterone therapy is commonly prescribed for KS patients to treat hypogonadism, but this may have additional impacts to future fertility potential. Current clinical practice is to have KS adolescent patients provide frequent semen samples in an effort to identify potential sperm for early cryopreservation.

Coenzyme Q10 Supplementation enhances testicular volume and hemodynamics, reproductive hormones, sperm quality, and seminal antioxidant capacity in goat bucks under summer hot humid conditions

Oxidative stress (OS) is brought on by heat stress (HS), which weakens antioxidant defense and initiates OS. Since mitochondria are the primary source of reactive oxygen species (ROS), HS-mediated OS may be lessened by targeting mitochondria with particular antioxidants. The purpose of this study was to investigate the effect of oral coenzyme Q10 (CoQ10) supplementation on the reproductive performance of goat bucks under HS conditions. Ten mature bucks were randomly separated into two groups and housed in an environment with a high-temperature humidity index (THI: 88.3 to 94.8; summer season). The first group (n = 5) got the baseline diet while the second group (n = 5) received supplemental oral CoQ10 (3 mg/kg BW; CoQ10 group) daily for six weeks. Testicular blood flow parameters (TBF), testicular volume (TV) and echogenicity (TE), nitric oxide (NO), seminal alanine aminotransferase (ALT) and catalase (CAT) activities, total antioxidant capacity (TAC), malondialdehyde (MDA) content, and semen quality traits were all measured. The examinations started a week before (W-1), on the first supplementation day (W0), and weekly for eight consecutive weeks (W1-W8). There were marked (P < 0.05) increases in TBF (W3-W6) and TV, and a decrease in TE (W3-W5) in the CoQ10 group compared to the CON group. Similarly, testosterone (T) and NO levels (W3-W5) in the CoQ10 group were higher (P < 0.05) than those of the control group. The CoQ10 group demonstrated significant (P < 0.05) increases in seminal CAT (W4-W8) and TAC (W2-W6) activities and decreases in ALT (W4-W7) activity and MDA (W5-W8) concentration as compared to the control group. The CoQ10 group showed improvements (P < 0.05) at W3-W6 for sperm progressive motility, viability, and normal morphology and at W6-W8 for sperm concentration. In conclusion, oral CoQ10 supplementation improved testicular hemodynamics, testosterone production, semen quality, and antioxidant capacity in goat bucks during summer heat stress conditions.

Relugolix in the management of prostate cancer

ABSTRACT Introduction Relugolix is the first oral gonadotrophin-releasing hormone (GnRH) receptor antagonist. Based on the phase III HERO trial results, relugolix received Food and Drug Administration approval for adult patients with advanced prostate cancer (PCa). Areas covered We provide an overview of the preclinical and clinical development of relugolix and its role in the current treatment landscape of PCa. Expert opinion Relugolix leads to rapid inhibition of testicular production of testosterone and its rapid recovery upon discontinuation. In the HERO trial, relugolix was associated with a superior cardiovascular safety profile compared to GnRH agonists. These attributes make relugolix a promising therapy for patients with preexisting cardiovascular comorbidities, those pursuing intermittent androgen deprivation therapy, and those who desire rapid testosterone recovery during ‘off-treatment’ periods. In the HERO trial, very few patients received concomitant enzalutamide (n = 17, 2.7%) or docetaxel (n < 10, 1.3%). Safety of relugolix has not been established in combination with many androgen-receptor-axis targeted therapies (e.g. abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan, which precludes its use in combination with these agents. In addition, being an oral drug, relugolix may also be associated with challenges of affordability, adherence, and compliance in this predominantly elderly population.

Hormonal Male Contraception: Getting to Market.

Rates of unplanned pregnancies are high and stagnant globally, burdening women, families and the environment. Local limitations placed upon contraceptive access and abortion services exacerbate global disparities for women. Despite survey data suggesting men and their partners are eager for expanded male contraceptive options, efforts to develop such agents have been stymied by a paucity of monetary investment. Modern male hormonal contraception, like female hormonal methods, relies upon exogenous progestins to suppress the hypothalamic-pituitary-gonadal axis, in turn suppressing testicular testosterone production and sperm maturation. Addition of an androgen augments gonadotropin suppression, more effectively suppressing spermatogenesis in men, and provides androgenic support for male physiology. Previous contraceptive efficacy studies in couples have shown that hormonal male methods are effective and reversible. Recent efforts have been directed at addressing potential user and regulatory concerns by utilizing novel steroids and varied routes of hormone delivery. Provision of effective contraceptive options for men and women is an urgent public health need. Recognizing and addressing the gaps in our contraceptive options and engaging men in family planning will help reduce rates of unplanned pregnancies in the coming decades.

Utility of evaluating semen samples from adolescents with Klinefelter Syndrome for cryopreservation: A multi-institution evaluation

Klinefelter Syndrome (KS) is the most common genetic condition cause of non-obstructive azoospermia (NOA). KS also often results in decreased testicular growth and testosterone production. Because of this, exogenous testosterone therapy is commonly prescribed for KS patients to treat hypogonadism, but this may have additional impacts to future fertility potential. KS adolescent patients may be asked to provide multiple semen samples to identify potential sperm for early cryopreservation. To develop a multi-institutional database to evaluate the prevalence of sperm in the ejaculate of adolescent KS patients. A retrospective study was performed of all adolescent KS patients seen at two high-volume tertiary male infertility clinics between 2015 and 2020. Adolescence was defined as individuals aged 12-19 years, as per the World Health Organization. Demographic information data including weight, height, medical comorbidities, and concurrent medications were collected. Serum hormone levelsincluding FSH, LH, and testosterone were collected, as well as any available semen analysis data. A total of 116 patients were identified and included in the database. A total of 100 (86.2%) had hormone data available and 48 (41.3%) had semen analysis data. Of the 48 patients with semen analyses, only 4 (8.3%) patients had rare sperm in the ejaculate while the remaining had azoospermia (91.7%). None of the specimens were suitable for cryopreservation. The average serum total testosterone level of adolescent KS patients was 181±216ng/dL. FSH levels were 14.3±18.8 IU/L (normal 0.3-10.0 IU/L) and LH levels were 7.8±12.4 IU/L (normal 1.2-7.8 IU/L). A total of 17 patients repeated a semen analysis, and in no instance did this result in sperm where there was none previously. The findings from a large multicenter retrospective cohort of adolescent KS patients suggest that a single semen analysis is sufficient for attempted cryopreservation purposes, and that multiple semen analyses is not needed.

Maternal Paracetamol Intake During Pregnancy-Impacts on Offspring Reproductive Development.

Paracetamol (acetaminophen) is the preferred antipyretic/analgesic for pregnant women as it is believed there are no adverse fetal effects at the recommended dose. However, emerging evidence suggests that intrauterine paracetamol exposure may be associated with certain urogenital/reproductive disorders in the offspring. In this mini-review, we describe human fetal sex development and possible pharmacological mechanisms by which paracetamol may disrupt this process, including reduced testicular production of testosterone and/or insulin-like peptide 3. We then review the available epidemiological literature on associations between maternal paracetamol exposure and offspring sexual development. Three epidemiological studies have reported associations between maternal paracetamol intake and increased risk of cryptorchidism, although five others have not. None have found associations with hypospadias or penile length. Two out of three studies have reported a shorter anogenital distance (a marker of androgen action during the masculinisation programming window, ∼8–14 weeks of gestation) in male infants antenatally exposed to paracetamol. One study has described a dose-dependent relationship between maternal paracetamol consumption and earlier female (but not male) attainment of puberty. Such epidemiological analyses are complicated by various factors, including method of paracetamol exposure assessment (usually retrospective self-report), variation in diagnostic accuracy, selection bias, confounding by clinical indication, and demographic/genetic differences between geographically separated populations. There is an urgent need for stronger evidence in this area, from both relevant experimental studies and large, carefully-designed prospective studies. In the meantime, a precautionary attitude to gestational paracetamol usage should be considered as the evidence for clinically significant reproductive effects in humans is limited.

Rethinking our chemical legacy and reclaiming our planet

Rethinking our chemical legacy and reclaiming our planet

Effects of melatonin administration on testicular hemodynamics, echotexture, steroids production, and semen parameters during the non-breeding season in Ossimi rams

This study was conducted to determine the influence of a single subcutaneous (SC) injection of melatonin (18 and 36 mg) on testicular hemodynamics, echotexture, plasma testosterone concentration, and sperm quality characteristics during the non-breeding season in Ossimi rams. Eighteen sexually mature, Ossimi rams were randomly allocated into two treated groups that received either 18 mg (Mel 18 group; n = 6) or 36 mg (Mel 36 group; n = 6) of melatonin powder dissolved in 1 ml corn oil (SC) and a control group (n = 6) that received 1 ml corn oil only. Blood collection and ultrasonographic assessment of the testes and supratesticular arteries were conducted immediately before treatment (W0) and once weekly for 8 successive weeks after melatonin injection (W1–W8). Resistive index (RI) and pulsatility index (PI) values were markedly decreased (P ˂ 0.05) within Mel 36 (at W4–W8) and e Mel 18 (at W8) groups, which was not observed within the control group (P ˃ 0.05). Testicular echogenicity was severely reduced (P ˂ 0.05) in Mel 36 (at W4–W5) and Mel 18 (at W8) groups, which was not occurred in the control one (P ˃ 0.05). The concentration of plasma testosterone was increased (P ˂ 0.05) in Mel 36 (at W3–W8) and Mel 18 (at W8) groups, which was not clear for the control rams (P ˃ 0.05). The percentage of progressively motile sperm cells was higher (P ˂ 0.05) in Mel 36 group (at W5–W8), which was not recorded within the Mel 18 or control groups (P ˃ 0.05).The percentages of sperm cells viability and normal morphology were higher (P ˂ 0.05) within Mel 36 (at W6–W8) and Mel 18 (at W7–W8) groups, which was not detected within the control group (P ˃ 0.05).In conclusion, the administration of melatonin ameliorates the testicular function via enhancing the testicular vascular irrigation, testosterone production, and sperm cells’ quality parameters in Ossimi rams. So, we recommend administration of a single SC dose of melatonin (36 mg) at least one month before using rams for breeding especially out of the reproductive season.

Cadmium induces testosterone synthesis disorder by testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to reduced sexual behavior in piglets

Cadmium (Cd) is a highly toxic metal pollutant that can endanger the life and health of animals. Toll-like receptor 4 (TLR4) can result in testicular cell damage by positively regulating mitogen-activated protein kinase (MAPK)/nuclear factor-kappaB (NF-κB) signaling pathway. Meanwhile, Testosterone (T) synthesis disorder can affect sexual behavior. However, the harmful influence of Cd on animal sexual behavior during its growth and development and the role of TLR4/MAPK/NF-κB signaling pathway in testicular cell damage and testosterone production remained poorly understood. Forty-two-day-old male piglets were fed with diets that contained CdCl2 (20 mg Cd/kg) for 40 days to explore the toxic effects of Cd on sexual behavior. The results showed that Cd activated TLR4, promoted MAPK (p-ERK, p-JNK, and p-p38)/NF-κB expression, induced apoptosis (Caspase-3, Cleaved Caspase3, Bax, Cyt-c, and Caspase-9 expression increased, but Bcl-2 expression decreased) and necroptosis (MLKL, RIPK1, and RIPK3 expression increased) in piglet testis. In addition, Cd exposure decreased mRNA expression of STAR, CYP11A1, 3β-HSD, CYP17A1, and 17β-HSD of testis and the concentrations of T and thyroid-stimulating hormone (TSH). Both the mRNA and protein expression levels of the major genes in TLR4/MAPK/NF-κB signaling pathway, apoptosis signaling pathway, and necroptosis signaling pathway increased significantly and the expression levels of testosterone decreased gradually in pig Leydig cells cultured in vitro after being treated with different concentrations of Cd. Moreover, Cd reduced sexual behavior (the parameters of sniffing, chin resting, and mounting decreased) in piglets. In conclusion, Cd induced testicular cell damage via TLR4/MAPK/NF-κB signaling pathway leading to testosterone synthesis disorder and sexual behavior reduction in piglets.

Melatonin improves testicular haemodynamics, echotexture and testosterone production in Ossimi rams during the breeding season.

The objective was to determine effects of a single parenteral dose of melatonin on testicular blood flow indices, testicular echogenicity and plasma testosterone concentrations in rams during the physiological breeding season. We hypothesized that melatonin enhances testicular blood flow, echogenicity and plasma testosterone concentrations during the breeding season in rams. During the breeding season, 12 sexually mature Ossimi rams were randomly allocated to either a melatonin group (n=8) that received 18mg of melatonin in 1ml of corn oil (injected SC) or a control group (n=4) that received 1ml corn oil only. Blood collection and ultrasonographic assessment of the testes and supratesticular arteries were conducted immediately before treatment (W0) and once weekly for 6weeks after melatonin injection (W1-W6). Mean plasma testosterone concentrations were greater (p<.05; at least 1ng/ml) in the melatonin-treated group compared to the control group from W4 to W6 after treatment. A decrease (p<.05) in both resistive index (RI) and pulsatility index (PI) began 1week after melatonin injection (W1) and persisted until the end of the experiment, with mean RI and PI values in the melatonin group lower (p<.05) than those in the control group on W3 and W4. Furthermore, plasma testosterone concentrations in melatonin-treated rams were inversely correlated to both RI and PI (r=-.7 and -.6, respectively, p<.01). Testicular echogenicity decreased (p<.05) 1week after melatonin injection (W1) and remained lower (p<.05) in the melatonin-treated group compared to the control group until the end of the study (W6). In conclusion, melatonin administration significantly altered testicular blood flow and echogenicity and increased plasma testosterone concentrations in Ossimi rams during the breeding season.

A MULTI-INSTITUTION EVALUATION OF ADOLESCENTS WITH KLINEFELTER SYNDROME AND ASSESSING THE UTILITY OF EVALUATING SEMEN SAMPLES FOR CRYOPRESERVATION

Klinefelter Syndrome (KS) is the most common genetic condition cause of non-obstructive azoospermia (NOA). KS can often result in decreased testicular growth and testosterone production. Exogenous testosterone therapy is commonly prescribed for KS patients to treat hypogonadism, though the exogenous testosterone therapy may have additional impacts to future fertility potential. Current clinical practice is to have KS adolescent patients provide frequent semen samples to identify potential sperm for early cryopreservation.

Zoledronic acid does not affect insulin resistance in men receiving androgen deprivation therapy: a prespecified secondary analysis of a randomised controlled trial.

Background:Animal studies suggest that undercarboxylated osteocalcin may improve insulin sensitivity via its effect on testicular testosterone production. Human studies have been conflicting. Men undergoing androgen deprivation therapy (ADT) for prostate cancer experience profound hypogonadism resulting in increased insulin resistance. In a randomised controlled trial (RCT) of zoledronic acid versus placebo in men commencing extended-duration ADT, we aimed to examine the effects on fat mass and glucose metabolism. We hypothesised that zoledronic acid, which reduces osteocalcin concentrations, would worsen ADT-induced insulin resistance.Methods:This was a prespecified secondary analysis of an RCT designed to evaluate the effects of zoledronic acid on bone microarchitecture in 76 men with non-metastatic prostate cancer undergoing curative radiotherapy combined with adjuvant ADT (n = 39 randomised to a single dose of zoledronic acid 5 mg, n = 37 randomised to matching placebo). Oral glucose tolerance tests to determine Matsuda Index were performed at 0, 3, 12 and 24 months. Using a mixed model, mean adjusted differences [MAD (95% confidence interval)] between the groups over time are reported.Results:Over 24 months of ADT, fat mass increased and lean mass decreased for both groups, with no significant between group difference [MAD 401 g (−1307; 2103), p = 0.23 and −184 g (−1325; 955), p = 0.36 respectively]. Bone remodelling markers C-telopeptide [MAD −176 ng/l (−275; −76), p < 0.001 and P1NP −18 mg/l (−32; −5), p < 0.001] as a surrogate for osteocalcin, remained significantly lower in the zoledronic acid group, compared with placebo. There was no mean adjusted between-group difference for homeostatic model assessment 2 insulin resistance (HOMA2-IR) [−0.2 (−0.6; 0.2), p = 0.45], HbA1c [−0.1% (−0.3; 0.1), p = 0.64] or Matsuda Index [0.8 (−1.1; 2.7), p = 0.38]. The Matsuda Index decreased in both groups consistent with worsening insulin resistance with ADT.Conclusion:A single dose of zoledronic acid does not appear to influence glucose metabolism in men newly commencing ADT. Further study to evaluate the endocrine relationship between bisphosphonates, bone and glucose metabolism is required.Trial Registration Number:[ClinicalTrials.gov identifier: NCT01006395].