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Nathan Goodyear

PLOS ONE: Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular ... - 0 views

  • Studies in both humans and rodents, however, suggest that low testosterone is due to age-related lesions in testes rather than irregular luteinizing hormone metabolism
  • Various dietary factors and diet-induced obesity have been shown to increase the risk for late onset male hypogonadism and low testosterone production in both humans and mice
  • Testosterone deficiency and metabolic diseases such as obesity appear to inter-digitate in complex cause-and-effect relationships
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  • dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice
  • These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health
  • all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.
  • The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.
  • feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight
  • mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique
  • Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles
  • the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's
  • The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months
  • mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed
  • blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics
  • previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling
  • Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice
  • Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls
  • xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls
  • Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism
  • One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells
  • Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation
  • insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes
  • Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders
  • Physiological feedback loops apparently exist between microbes, host hormones, and immunity
  • The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression
  • studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism
  • We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.
  • Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.
  • Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium
  • L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells
  • the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH
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    Fascinating study on how the addition of Lactobacillus reuteri increased Testicular size, prevented testicular atrophy, increased serum Testosterone production and protected against diet-induced/obesity-induced hypogonadism.  This was a mouse model
Nathan Goodyear

Induction of Testicular Aromatization by Luteinizing Hormone in Mature Rats - 0 views

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    very interesting study in rats.  LH induced a dose-dependent increase in testicular estrogen production through aromatase activity.  Yes, LH stimulates the leydig cells to produce testosterone, but there is a point at which LH will actually increase aromatase activity and thus estrogen production at the testicular level.
Nathan Goodyear

PLOS ONE: The Gut Microbiota and Developmental Programming of the Testis in Mice - 0 views

  • The intra-testicular level of testosterone in GF mice was found to be significantly lower than in SPF and CBUT mice
  • This study establishes a novel role for the commensal gut microbiota in the regulation of testicular development and function
  • Absence of the normal microbiota influences the formation and the integrity of the BTB as well as the intra-testicular levels of testosterone and serum levels of LH and FSH.
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  • Nutritional, socioeconomic, lifestyle and environmental factors (among others) are involved in the regulation of normal spermatogenesis.
  • he gut microbiota is one such potential source of environmental factors/products that has developed an intimate symbiotic relationship with host's physiology.
  • Manipulation of the gut microbiotia through dietary modification, pre- and probiotics can therefore be beneficial for the host's reproductive health.
  • In the current study, colonizing GF mice with CBUT resulted in an increased sperm production, suggesting that bacterial products, e.g. of fermentation, directly or indirectly, can affect the testis.
  • the absence of gut microbiota influenced testosterone levels
  • A recent study demonstrated that dietary supplementation of the probiotics Lactobacillus reuteri increased and restored testosterone levels in aging mice
  • bacterial metabolites such as butyrate have been shown to increase the levels of LH [43] and FSH
  • This suggests that butyrate most likely regulates testosterone production at the testicular level by stimulation of gene expression in Leydig cells and with little or no effect at the pituitary- hypothalamic levels.
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    gut micro biome effects spermatogenesis, Testosterone production, and the brain-testicle-barrier.
Nathan Goodyear

Testicular toxicity induced by dietary cadmium is ... [Biometals. 2004] - PubMed result - 0 views

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    cadmium toxicity induces Testicular damage
Nathan Goodyear

Hypothalamic-Pituitary-Testicular Axis Disruptions in Older Men Are Differentially Link... - 0 views

  • 0.4–2% annual decline
  • the age trend in free T was more substantial (−1.3% per annum)
  • The core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total T and progressively blunted free T associated with higher LH.
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  • Obesity was associated with progressively lower total and free T independent of the simultaneous decrease in SHBG.
  • our data highlight the fact that LH was unchanged or even lower in older men in the face of lower T in obesity, suggesting that there may be a failure at the hypothalamic-pituitary level.
  • a change in BMI from nonobese to obese may be equivalent to a 15 yr fall in T.
  • This pattern supports the hypothesis that different underlying mechanisms influence the functions of the HPT axis: age predominantly affects testicular function, whereas obesity impairs hypothalamic/pituitary function.
  • the effects of aging on testicular function can be moderated by increased LH compensation for many decades
  • obesity impairs hypothalamic/pituitary function independent of age, arguably an adaptive response for which there should be no compensatory mechanism.
  • the concurrent but opposite (and separate) effects of obesity and age on SHBG
  • SHBG was negatively associated with increasing strata of obesity
  • Obesity is associated with insulin resistance (28), and the increased circulating insulin inhibits hepatic SHBG synthesis
  • the SHBG increase with age may be related to relative IGF-I deficiency (27), although this has not been directly proven.
  • Obesity is associated with peripheral and central insulin resistance (30) and proinflammatory cytokine production (TNFα and IL-6) from adipocytes (31) and central nervous system endocannibinoid release (32), all of which are potential candidates for abrogating hypothalamic endocrine and downstream reproductive axis functions.
    • Nathan Goodyear
       
      The HPA axis effect may be the result of inflammation.
  • The relationship between obesity and T can be bidirectional: low T may be the cause rather than consequence of obesity
  • chronic alcohol abuse is known to suppress LH (40), our data showed no significant association among the three hormones or SHBG and alcohol intake.
  • increase in total T in smokers occurs through a primary increase in SHBG with a compensatory rise in LH
  • the effects of obesity (BMI or waist circumference) was by far the most important determinant of variance in total T, whereas age per se was important for SHBG, LH, and free T with comorbidity and smoking being comparatively minor contributors
  • It is noteworthy that these predisposing lifestyle and health factors are modifiable. This implies that the apparent age-related decline in T may constitute a barometer of health and thus be potentially preventable and/or reversible.
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    Age induced decline in Testosterone is more associated with a decline in leydig cell function and thus elevated LH will be associated.  In contrast, obesity is more of a HPA axis disruption and thus LH may be normal to low.  The pulse amplitude is decrease.  No change in pulse frequency is noted.   With obesity, a decline in TT and fT was independent of SHBG. Aging is associated with a greater decrease in fT versus TT.
Nathan Goodyear

Case Report: Testicular failure possibly associated with chronic us... - PubMed - NCBI - 0 views

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    Case report links possible methylphenidate, Ritalin, use to Testicular failure. 
Nathan Goodyear

Early life events predict adult testicular function; data derived from the Western Aust... - 0 views

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    optimal weight associated with higher testicular volume and Testosterone levels in men.  Maternal smoking and higher cord bleed estrogens associated with lower sperm output.  This would with the other literature on EDCs.
Nathan Goodyear

Influence of tumor necrosis factor α inhibitors on testicular function and se... - 0 views

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    Cause and effect cannot be taken from this study.  However, TNF-alpha is known to disrupt testicular function, in this case the study found decreased sperm motility, lower Testosterone levels, and increased LH and FSH at baseline.  Improvement was seen after anti-TNF-alpha therapy. The point of this study should be why the elevated TNF-alpha and attack there.
Nathan Goodyear

Phthalate-Induced Pathology in the Foetal Testi... [Reproduction. 2013] - PubMed - NCBI - 0 views

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    This study found a 2 fold increased in estradiol levels in rats exposed to phthalates in-utero.  This could have been due to increased aromatase activity and/or xenoestrogenic effect.  This study proposes a link between phthalate exposure in-uteruo, increased estrogen production and testicular dysgenesis syndrome.  Take home: in this model male testicles were altered prior to birth by phthalate exposure.
Nathan Goodyear

Testicular Synthesis and Vitamin D Action: The Journal of Clinical Endocrinology & Meta... - 0 views

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    Cholecalciferol (vitamin D3) was found to increase male Testosterone production in cell culture model.  This fits with other data that low vitamin D and low T often go hand in hand.  This study actually shows improved D levels increase Testicular Testosterone production, though in cell culture.
Nathan Goodyear

Age-related testosterone decline is due to waning of both testicular and hypothalamic-p... - 0 views

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    Only abstract available here, but low T is the result of primary (testicular failure) and/or secondary (HPA failure). 
Nathan Goodyear

Testosterone deficiency and quality of life in ... [Intern Med J. 2014] - PubMed - NCBI - 0 views

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    Small study in men s/p Testicular cancer found no association between Testosterone levels and quality of life measures.
Nathan Goodyear

Effects of chronic celecoxib on testicular function in normal and lipopolysaccharide-tr... - 0 views

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    Animal study from '09 found that COX2 inhibitor blunted LPS decrease in testes weight, decrease in testicular interstitial fluid, and serum Testosterone.  The point here is that LPS, in this animal model, decreased gonadal weight and Testosterone production and the anti inflammatory, COX2, blunted that effect.
Nathan Goodyear

Ibuprofen alters human testicular physiology to produce a state of compensated hypogona... - 0 views

  • The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
  • This increase was even more pronounced at 44 d, at 33%
  • We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial, which occurred as early as 14 d and was maintained until the end of the trial at 44 d
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  • We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
  • The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration
  • Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
  • Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA
  • Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.
  • Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
  • A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
  • We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
  • the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.
  • Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
  • ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
  • The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action
  • AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
  • ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis
  • a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human
  • The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription
  • Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
  • ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected
  • short-term exposure
  • In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality
  • compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
  • an inverse relationship was recently reported between endurance exercise training and male sexual libido
  • AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels
  • inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
  • the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
  • after administration of 600 mg of ibuprofen to healthy volunteers
  • 14 d or at the last day of administration at 44 d
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    ibuprofen alters genetic expression that results in decreased Testosterone production.
Nathan Goodyear

A Cohort Effect on Serum Testosterone Levels in Finnish Men - 0 views

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    Finnish study of 3,271 men found that there was a decline in serum free testosterone levels in recently born boys compared to previous generations.  Additionally, they found inappropriate HPA response to this decline in testicular testosterone.
Nathan Goodyear

Environmental anti-androgens and male reproductive health: focus on phthalates and test... - 0 views

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    good review of the effect of environmental xenoestrogens and low T in men.
Nathan Goodyear

Journal of Endocrinological Investigation - 0 views

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    Testosterone levels fluctuate seasonally, with the peak production in the fall of the year.  Contrast that with LH, with it's peak in the spring of the year.  This study found that men with Klinefelter's syndrome had only seasonal fluctuations of testosterone, suggesting a testicular independent role.  This is a small study.  
Nathan Goodyear

PLOS ONE: Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and ... - 0 views

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    Bisphenol A decreases testicular testosterone production at the sight of the leydig cells.
Nathan Goodyear

Pesticide-induced decrease in rat tes... [Ecotoxicol Environ Saf. 2013] - PubMed - NCBI - 0 views

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    Pesticides disrupt the testicular function, in part, through oxidative damage.  This study found Alpha lipoic acid  to be a promising, effective mechanism to reduce the oxidative stress.  They also found tocopherols to be effect, but to a lesser extent.
Nathan Goodyear

Serum vitamin D and sex hormones levels in men and women: The Multi-Ethnic Study of Ath... - 0 views

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    cross sectional study finds low vitamin D associated with a decrease in SHBG and an increase in free Testosterone;  a decrease in estradiol and an increase in DHEA was seen in women.  No association with total Testosterone was found.  There are studies that show a direct decrease in testicular Testosterone production in men with low vitamin D and decrease in AR function.
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