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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

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.

there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin

Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen status

Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic control following ADT

ADT for the treatment of prostatic carcinoma in some large epidemiological studies has been shown to be associated with an increased risk of developing MetS and T2DM

Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated insulin levels and worsening glycaemic control

increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated with a decrease in Leydig cell testosterone secretion in men

The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor (AR)

Low levels of testosterone have been associated with an atherogenic lipoprotein profile, characterised by high LDL and triglyceride levels

a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic men

up to 70% of the body's insulin sensitivity is accounted for by muscle

Testosterone deficiency is associated with a decrease in lean body mass

relative muscle mass is inversely associated with insulin resistance and pre-diabetes

GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal muscle cells following testosterone treatment at low dose and short-time incubations

local conversion of testosterone to DHT and activation of AR may be important for glucose uptake

inverse correlation between testosterone levels and adverse mitochondrial function

orchidectomy of male Wistar rats and associated testosterone deficiency induced increased absorption of glucose from the intestine

(Kelley & Mandarino 2000). Frederiksen et al. (2012a) recently demonstrated that testosterone may influence components of metabolic flexibility as 6 months of transdermal testosterone treatment in aging men with low–normal bioavailable testosterone levels increased lipid oxidation and decreased glucose oxidation during the fasting state.

Decreased lipid oxidation coupled with diet-induced chronic FA elevation is linked to increased accumulation of myocellular lipid, in particular diacylglycerol and/or ceramide in myocytes

In the Chang human adult liver cell line, insulin receptor mRNA expression was significantly increased following exposure to testosterone

Testosterone deprivation via castration of male rats led to decreased expression of Glut4 in liver tissue, as well as adipose and muscle

oestrogen was found to increase the expression of insulin receptors in insulin-resistant HepG2 human liver cell line

FFA decrease hepatic insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance.

Only one, albeit large-scale, population-based cross-sectional study reports an association between low serum testosterone concentrations and hepatic steatosis in men (Völzke et al. 2010)

This suggests that testosterone may confer some of its beneficial effects on hepatic lipid metabolism via conversion to E2 and subsequent activation of ERα.

hypogonadal men exhibiting a reduced lean body mass and an increased fat mass, abdominal or central obesity

visceral adipose tissue was inversely correlated with bioavailable testosterone

there was no change in visceral fat mass in aged men with low testosterone levels following 6 months of transdermal TRT, yet subcutaneous fat mass was significantly reduced in both the thigh and the abdominal areas when analysed by MRI (Frederiksen et al. 2012b)

ADT of prostate cancer patients increased both visceral and subcutaneous abdominal fat in a 12-month prospective observational study (Hamilton et al. 2011)

Catecholamines are the major lipolysis regulating hormones in man and regulate adipocyte lipolysis through activation of adenylate cyclase to produce cAMP

deficiency of androgen action decreases lipolysis and is primarily responsible for the induction of obesity (Yanase et al. 2008)

may be some regional differences in the action of testosterone on subcutaneous and visceral adipose function

proinflammatory adipocytokines IL1, IL6 and TNFα are increased in obesity with a downstream effect that stimulates liver production of CRP

observational evidence suggests that IL1β, IL6, TNFα and CRP are inversely associated with serum testosterone levels in patients

TRT has been reported to significantly reduce these proinflammatory mediators

This suggests a role for AR in the metabolic actions of testosterone on fat accumulation and adipose tissue inflammatory response

testosterone treatment may have beneficial effects on preventing the pathogenesis of obesity by inhibiting adipogenesis, decreasing triglyceride uptake and storage, increasing lipolysis, influencing lipoprotein content and function and may directly reduce fat mass and increase muscle mass

Early interventional studies suggest that TRT in hypogonadal men with T2DM and/or MetS has beneficial effects on lipids, adiposity and parameters of insulin sensitivity and glucose control

Evidence that whole-body insulin sensitivity is reduced in testosterone deficiency and increases with testosterone replacement supports a key role of this hormone in glucose and lipid metabolism

Impaired insulin sensitivity in these three tissues is characterised by defects in insulin-stimulated glucose transport activity, in particular into skeletal muscle, impaired insulin-mediated inhibition of hepatic glucose production and stimulation of glycogen synthesis in liver, and a reduced ability of insulin to inhibit lipolysis in adipose tissue

High LH and FSH levels in the male mice indicated hypergonadotropic hypogonadism

Another mouse study reported a tendency towards low testosterone/LH ratio and Leydig cell hyperplasia in VDR null mice

The serum testosterone levels could increase to normal values in vitamin D-deficient rats replete with vitamin D

VDR knockout mice had decreased sperm count, reduced sperm motility, and histological abnormality of the testis

vitamin D supplementation increases testosterone levels in non-diabetic subjects

The data from the European Male Ageing Study [9] indicated that 25(OH)D is positively associated with total T

Endotoxin is known to reduce testosterone production by the testis, both by direct inhibition of Leydig cell steroidogenic pathways and indirectly by reducing pituitary LH drive, thereby also leading to a decline in sperm production.

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

The five most common adult malignancies (colorectal, breast, prostate, melanoma and lung cancer)

n breast cancer, the optimal regimen(s) for cytotoxicchemotherapy in recurrent/metastatic disease are still notdefined, despite over 30 years of ‘research’ and a plethora of RCTs since the original Cooper regimen was published in1969

The five most ‘chemo-sensitive’ cancers,namely testis, Hodgkin’s disease and non-Hodgkin’s lym- phoma, cervix and ovary

only 13 out of the 22 malignancies evaluated showed any improvement in 5-year survival, and theimprovement was greater than 10% in only three of those13 malignancies

the contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults is 2.3% in Australia and 2.1% in the USA

a benefit of less than 2.5% is likely to be applicable in other developed countries

  Overview The Contribution o

the benefit of cytotoxic chemotherapy may have been overestimated for cancers of oesophagus, stomach,rectum and brain.

this reflects the presentation of results as a ‘reduction in risk’ rather than asan absolute survival benefit[89,90]and by exaggerating theresponse rates by including ‘stable disease’

recent studies have documented impaired cognitive function inwomen receiving adjuvant treatment for breast cancer

the 5-year survival rate due solely to cytotoxicchemotherapy was 1.6%

the value of palliative chemotherapy has beenquestioned