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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 BD), 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

Sex hormone synthesis, regulation, and function | McMaster Pathophysiology Review - 0 views

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    Good review of the HPA-sex hormone pathways, called the Hypothalamic-Pituitary-Gondal axis, including HP feedback.  This is not a study but has nice diagrams. This is based on 14 referenced articles and 1 book chapter.
Nathan Goodyear

Effects of transdermal application of DHEA on the levels of steroids, gonadotropins and... - 0 views

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    topical DHEA found to significantly decrease LH.
Nathan Goodyear

Effect of acute DHEA administration on free testosterone in middle-aged and young men f... - 0 views

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    Decline in free Testosterone, especially in physically unfit men, blunted by oral 50 mg DHEA night before exercise.  Total Testosterone and DHEA remained significantly low up to 24 hours post HIIT.
Nathan Goodyear

Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men | The J... - 0 views

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    Study finds injectable contraception in men leaves delayed suppressed LH and Testosterone. This drug design is by those devoid of overall knowledge of physiology. Lower Testosterone in men has significant negative metabolic effect, neurotransmitter impact, and what about epigenetics. Some men have epigenetically increased risk of hypogonadism. This contraception is a bad idea physiologically.
Nathan Goodyear

Mendelian randomization suggests non-causal associations of testosterone with cardiomet... - 0 views

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    Study questions causal associations of testosterone and cardiometabolic risk.  In this analysis they used to SNPs, one on the SHBG gene rs12150660 and the other on the X chromosome rs59344505.
Nathan Goodyear

The rs5934505 single nucleotide polymorphism (SNP) is associated with low testosterone ... - 0 views

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    Four SNPs, rs12150660, rs727428, rs5934505, and rs10822184 associated with late-onset hypogonadism (low T) and obesity in men of European descent.  In Chinese populations, rs5934505 was associated with increased risk of low Total Testosterone and calculated free Testosterone.  OR was 2.01 for low TT and 2.14 for low calculated free Testosterone.
Nathan Goodyear

Genetic Determinants of Serum Testosterone Concentrations in Men - 0 views

  • mean serum testosterone concentrations were found to be lower in men with GG than in those with TT genotype for rs12150660
  • men with the CT genotype for rs6258 had lower serum testosterone concentrations than those with CC genotype.
  • The two autosomal SNPs identified by GWAS had a significant influence on the risk of having low serum testosterone (serum testosterone <300 ng/dl) in both the discovery and the replication cohorts with a combined odds ratio (OR) per minor allele of 0.72 (95% CI, 0.65 – 0.79) and 2.7 (95% CI, 2.1 – 3.5) for rs12150660 and rs6258, respectively
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  • The risk of having low serum testosterone concentrations increased by the number of risk alleles with an OR of 1.62 (95% CI, 1.41 – 1.86) for each risk allele (Figure S4). Low serum testosterone concentrations were 6.5-times more prevalent in men with ≥3 risk alleles (30.1% prevalence of low serum testosterone) compared to men without any risk allele (4.6% prevalence of low serum testosterone;
  • SNP rs5934505 was associated with serum testosterone without SHBG-adjustment (combined p-value of 1.7×10−9) and with free testosterone (combined p-value of 6.7×10−15), but not with SHBG
  • The mean serum testosterone and calculated free testosterone but not SHBG concentrations were lower in men with T genotype than in those with C genotype for rs5934505
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    Genetic SNP rs5934505 associated with lower total Testosterone and lower calculated free Testosterone.  No effects on SHBG.
Nathan Goodyear

Age and BMI Adjusted Comparison of Reproductive Hormones in PCOS - 0 views

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    study of Saudi women with PCOS finds elevated LH/FSH ratio and elevated total Testosterone levels independent of age and weight; in addition, lower FSH, SHBG, and progesterone levels we found.
Nathan Goodyear

Genetic Determinants of Serum Testosterone Concentrations in Men - 0 views

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    SNP as significant contributor to low Testosterone in men via SHBG polymorphism and reduces the free Testosterone.
Nathan Goodyear

Effect of 1 Week of Sleep Restriction on Testosterone Levels in Young Healthy Men | End... - 0 views

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    Small study of young men, average age 24.5, found a 10-15% reduction in Testosterone levels with 1 week of sleep deprivation.  Sleep was reduced to 5 hours per night for just 1 week.
Nathan Goodyear

Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosi... - 0 views

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    VTE in man as a result of supra-physiologic Testosterone and high aromatase activity prior to and on anticoagulant therapy.
Nathan Goodyear

Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy - Mayo Clinic Proc... - 0 views

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    Venous thromboembolism found not be associated with prior Testosterone therapy in men.
Nathan Goodyear

Association Between Testosterone Replacement Therapy and the Incidence of DVT... - 0 views

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    Testosterone therapy in men with low Testosterone and mild/moderate clot risk found to not increase risk of clots
Nathan Goodyear

Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig... - 0 views

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    The authors conclusion here is all wrong.  The men with low T had improvement in energy and LDL, but no improvement in mood and sexual function.
Nathan Goodyear

Increased serum C-reactive protein levels in normal weight women with polycystic ovary ... - 0 views

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    Study doesn't directly link causation, but increased Testosterone in women of normal weight with PCOS associated with increased CRP.
Nathan Goodyear

Testosterone therapy for reduced libido in women - 0 views

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    Testosterone and libido in women: the data is limited.  The data that links low T in women to low libido is not present.  That questions the whole low T, libido theory in women.
Nathan Goodyear

http://www.imperialendo.co.uk/mohr.pdf - 0 views

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    Massachusetts Male Aging Study (MMAS).
Nathan Goodyear

A Validated Age-Related Normative Model for Male Total Testosterone Shows Increasing Va... - 0 views

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    Interesting read: study finds peak Testosterone at age 19 in men; Testosterone decline was see up to age 40 at which decline was variable beyond age 40
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Nathan Goodyear

Hypogonadism in the Aging Male Diagnosis, Potential Benefits, and Risks of Testosterone... - 0 views

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    Review of the literature on Low T, causes of low T, and associated symptoms.
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