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Chemistry and Structural Biology of Androgen Receptor - 0 views

www.ncbi.nlm.nih.gov/...PMC2096617 androgens Testosterone DHT dihydrotestosterone AR androgen receptors male hormones hormones
shared by Nathan Goodyear on 28 Sep 16 - No Cached
  • Healthy adult men typically produce approximately 3–10 mg of testosterone per day
  • circulating levels ranging from 300 to 700 ng/dL in eugonadal men
  • endogenous testosterone secretion is pulsatile and diurnal
  • ...15 more annotations...
  • highest concentration occurring at about 8:00 a.m. and the lowest at about 8:00 p.m.
  • Average serum concentrations and diurnal variation in testosterone diminish as men age
  • 40% is sequestered with high affinity to sex hormone-binding globulin (SHBG)
  • almost 60% is bound with low affinity to albumin
  • 2% as free, unbound hormone
  • 5α-DHT has even greater binding affinity to sex hormone-binding globulin than does testosterone
  • 5α-DHT is only about 5% as abundant in the blood as testosterone and is largely derived from peripheral metabolism of testosterone
  • Both 5α-reduction and aromatization are irreversible processes
  • Approximately 90% of an oral dose of testosterone is metabolized before it reaches the systemic circulation
  • there are three modes of action of testosterone. It may directly act through AR in target tissues where 5α-reductase is not expressed, be converted to 5α-DHT (5–10%) by 5α-reductase before binding to AR, or be aromatized to estrogen (0.2%) and act through the estrogen receptor
  • 5α-DHT is a more potent AR ligand than testosterone
  • has 2–10-fold higher potency than testosterone in androgen-responsive tissues
  • estrogen plays a major role in regulating metabolic process,74,75 mood and cognition,76 cardiovascular disease,77,78 sexual function including libido,79 and bone turnover in men
  • Free testosterone is considered the most “biologically active” form
  • testosterone is the major androgen that acts in the “DHT-independent” tissues, such as skeletal muscle, where 5α-reductase is not expressed or is expressed at a very low level
  • Nathan Goodyear on 28 Sep 16
     
    good review of androgens and AR.
14More

Salivary Testosterone and a Trinucleotide (CAG) Length Polymorphism in the Androgen Rec... - 0 views

www.ncbi.nlm.nih.gov/...PMC2825741 CAG androgen receptors AR androgen receptor Testosterone hormone hormones male men
shared by Nathan Goodyear on 22 Jun 15 - No Cached
  • Testosterone correlated inversely with participant age (r = −0.39, p = 0.012) and positively with number of CAG repeats
  • transactivation potential of the AR appears to decline in graded relation to an increasing number of CAG repeats, which are distributed over a normative range of 11–37 and, in Caucasian populations, commonly average 21–22 repeats
  • When activated by androgens, ARs translocate to the cell nucleus, where they exert transcriptional control of androgen-dependent genes by binding to androgen response elements within gene regulatory sequences
  • ...10 more annotations...
  • some evidence suggests a high number of CAG repeats may be associated with cognitive aging
  • androgens (like other steroid hormones) promote or repress the expression of genes specifying an array of cellular proteins
  • diurnal variation in testosterone levels
  • salivary testosterone correlated negatively with participant age and positively with CAG length variation in the AR gene
  • CAG repeat number varied inversely with reactivity of the ventral amygdala to facial expressions of negative affect
  • higher salivary testosterone was likewise associated with a greater number of AR CAG repeats
  • relative androgen insensitivity in ARs with a larger number of CAG repeats
  • Because circulating testosterone is regulated via negative feedback through the hypothalamic-pituitary-gonadal axis, diminished androgen sensitivity at higher CAG repeat lengths may reduce feedback suppression of luteinizing hormone (LH). LH would then be maintained at higher levels, in turn promoting higher testosterone production
  • Testosterone up-regulates AVP expression in the amygdala
  • Oxytocin exerts an inhibitory influence on AVP expression in the central amygdala, and the synthesis of oxytocin is mediated by estrogen and estrogen receptors
  • Nathan Goodyear on 22 Jun 15
     
    Study used saliva to measure Testosterone levels in men.  Testosterone levels were inversely associated with age, but positively associated with CAG repeat sequences in the AR.
17More

Transdermal testosterone replacement therapy in men - 0 views

www.ncbi.nlm.nih.gov/...PMC3891651 Testosterone replacement transdermal low T male hormone hormones
shared by Nathan Goodyear on 05 Feb 14 - No Cached
  • a recent study has suggested that it may sometimes be inaccurate because of abnormal fluctuation of other circulating androgens
    • Nathan Goodyear
      Nathan Goodyear on 05 Feb 14
       
      The authors are referencing the increase in the suggestions to use other testing techniques i.e. saliva.
  • Testosterone therapy can inhibit hepcidin transcription and is associated with increased iron incorporation into red blood cells and increased erythropoietin concentrations
  • Transdermal TRT has a more favorable adverse effect profile when compared to buccal testosterone formulations
  • ...13 more annotations...
  • Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)
  • the recommendation for injectable testosterone esters is to check the serum concentration midway between injections
  • it is recommended for serum testosterone to be evaluated 3 to 12 hours after application of the transdermal patch
  • testosterone concentrations should be checked 2–3 months after initiation of therapy and after adjusting the dose
  • a study from 1989 utilizing testosterone transdermally containing 5, 10, or 15 mg of testosterone showed that peak concentrations of testosterone were achieved 3 to 8 hours after scrotal application in hypogonadal men
  • It is used for many medications and has the advantage of high bioavailability, absence of hepatic first pass metabolism, increased therapeutic efficacy, and steadiness of plasma concentrations of the drug
  • evaluate serum testosterone at the end of the dosing interval for testosterone pellets
  • increased amount of fat leads to increased extragonadal aromatase activity, resulting in increased concentrations of estradiol. High circulating concentrations of estradiol down regulate the HPG axis and decrease the amount of circulating testosterone
  • Up to 80% of plasma estradiol originates from aromatization of testosterone and less than 20% of estradiol in the circulation is secreted by the testes
  • A PSA concentration, digital rectal examination, and hematocrit should be performed at baseline and at 3 months, 6 months, then yearly after TRT is initiated.
  • measure serum testosterone any time after the patient has been on treatment with gel for at least 1 week
  • If the hematocrit rises above 54%, treatment should be discontinued
  • elderly men having higher estradiol serum concentrations than postmenopausal women
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Testosterone restores insulin sensitivity in patients with diabetes and hypogonadism | ... - 0 views

www.healio.com/...with-diabetes-and-hypogonadism testosterone insulin sensitivity diabetes resistance low T hypogonadotrophic hypogonadism GLUT4 DHT fat mass lean muscle inflammation men male hormone hormones
shared by Nathan Goodyear on 19 May 14 - No Cached
  • Nathan Goodyear on 19 May 14
     
    This is the abstract from oral presentation at AACE in Las Vegas from May.  Small study finds reduction in fat mass, increase in muscle mass, increase in insulin sensitivity, and reduction in inflammation signaling with Testosterone therapy in men with low Testosterone.  These men were type 2 diabetics.  This is consistent with prior published literature.  However, men without diabetes, this association is hard to reproduce. The degree of glucose control also effects the response to Testosterone therapy i.e. the worse the glucose control, the more the response from Testosterone.   Also of note, those men with hypogonatrophic hypogonadism had decreased insulin receptor expression, decreased insulin sensitivity, and decreased GLUT-4 expression versus eugonadal men.  Remember from prior studies, it is the conversion of Testosterone to DHT that increases GLUT-4 transcription, translocation, and expression.
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Testosterone and benign prostatic hyperplasia Jarvis TR, Chughtai B, Kaplan SA, - Asian... - 0 views

www.ajandrology.com/preprintarticle.asp Testosterone BPH low T low Testosterone prostate cancer men male hormone hormones
shared by Nathan Goodyear on 01 Dec 14 - No Cached
  • The prevalence of hypogonadism (often defined as serum testosterone < 300 ng dl−1 ) ranges from 6% [10] to as high as 38%
  • The process of BPH, however, continues as men age and despite the fact their serum testosterone decreases
  • Liu et al. [12] demonstrated that in a group of older males (mean age 59.8 years) that there was not a significant correlation of serum testosterone levels (total, free or bioavailable) with either prostate volume or International Prostate Symptom Score (IPSS)
  • ...11 more annotations...
  • in eugonadal men, studies have demonstrated that the prostate can increase in volume by approximately 12%
  • There seems to be little doubt that the treatment with testosterone of a young hypogonadal male leads to significant growth of the prostate
  • Behre et al. [22] demonstrated increased prostate volume and prostate-specific antigen (PSA) levels in hypogonadal men
  • Most studies, however, have shown no effect of exogenous androgens on PSA or prostate volume for older hypogonadal males
  • They argue that the prostate is relatively insensitive to changes in androgen concentration at normal levels or in mild hypogonadism because the AR is saturated by androgens and therefore maximal androgen-AR binding is achieved. Conversely, the prostate is very sensitive to changes in androgen levels when testosterone is low
  • saturation model
  • visceral obesity (one of the most significant components of metabolic syndrome) is associated with prostate volume and influences prostate growth during TRT.
  • This hypothesis of inflammation induced LUTS is also argued to be a mechanism for improvement of LUTS with PDE5I
  • The concept, therefore, that treatment with TRT of hypogonadal males with metabolic syndrome might lead to improvement/stabilization of their LUTS, appears to be confirmed in recent work by Francomano et al.
  • There was also an improvement in components of the patient's metabolic syndrome (such as BMI, waist circumference, hemoglobin A1c [HbA1c], insulin sensitivity, and lipid profile) as well as inflammatory markers and C-reactive protein.
  • They concluded that TRT was safe in this group of men, and hypothesize that TRT mitigates the pro-inflammatory factors associated with metabolic syndrome.
  • Nathan Goodyear on 01 Dec 14
     
    Authors review the literature behind Testosterone and BPH.  The authors highlight the 4 proposed theories behind BPH: Testosterone, Estrogen, inflammation, and metabolic.   The conclusion is mixed: pointing out that no high level of evidence exists on either side of the debate of Testosterone and BPH.
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Testosterone and the Cardiovascular System: A Comprehensive Review of the Clinical Lite... - 0 views

jaha.ahajournals.org/...e000272 low T Testosterone cardiovascular disease CAD CHF insulin resistance type II diabetes diabetes obesity men male hormone hormones therapy
shared by Nathan Goodyear on 13 May 14 - No Cached
  • Nathan Goodyear on 13 May 14
     
    Some startling statistics in this 2013 review on Testosterone in men.  Studies reflect an inverse relationship between Testosterone and CAD severity.  That is, the lower the Testosterone levels, the increase in severity of CAD. This same association was also found with CHF.  Low Testosterone is common in those with CAD, CHF, type II diabetes, increased IMT in carotids and aorta, and obesity when compared to "healthy" individuals.  Testosterone therapy in those with CAD found benefits: prolongation of ST segment depression, coronary vasodilation, improved exercise capacity in those with CHF, shift to type I muscle fibers, shorten the QTc interval.  Testosterone therapy has been shown to improve insulin resistance, improve HgbA1c and decrease waist circumference and fat loss in obese individuals.  Otherwise, a good review of the association between a declining Testosterone and cardiovascular disease.
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Testosterone physiology in resistance exercise an... [Sports Med. 2010] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...21058750 resistance exercise physiology testosterone men male hormone hormones
shared by Nathan Goodyear on 29 Jul 14 - No Cached
  • testosterone stimulates protein synthesis
  • promotion of muscle hypertrophy by testosterone
  • intracellular androgen receptor (AR)
  • ...8 more annotations...
  • In general, testosterone concentration is elevated directly following heavy resistance exercise in men
  • Findings on the testosterone response in women are equivocal with both increases and no changes observed in response to a bout of heavy resistance exercise
  • Age also significantly affects circulating testosterone concentrations.
  • Aging beyond 35-40 years is associated with a 1-3% decline per year in circulating testosterone concentration in men
  • aging results in a reduced acute testosterone response to resistance exercise in men.
  • In women, circulating testosterone concentration also gradually declines until menopause, after which a drastic reduction is found.
  • acute increases in testosterone can be induced by resistance exercise
  • testosterone is an important modulator of muscle mass in both men and women
  • Nathan Goodyear on 29 Jul 14
     
    Resistance training to increase endogenous Testosterone production: more specific, the exercise must be high rep or as the authors call it--high volume.  To do this, the weight needs to be light.
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Fifty- two-Week Treatment With Diet and Exercise Plus Transdermal Testosterone Reverses... - 0 views

onlinelibrary.wiley.com/...full diet exercise nutrition diabetes metabolic syndrome men male hormone hormones low T low Testosterone
shared by Nathan Goodyear on 04 Mar 15 - No Cached
  • there appears to be a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance (Pitteloud et al, 2005), and this relationship is at least partially direct and not fully dependent on (changes in) elements of the MetS
  • supervised D&E alone led to significant improvements in testosterone concentrations, glycemic control, and components of the MetS
  • diet control, exercise, and testosterone supplementation may be beneficial in the management of men with T2D
  • ...7 more annotations...
  • androgen-deprivation therapy in males with prostatic cancer may be associated with an increased risk for T2D, which may be caused by negative effects on insulin sensitivity
  • insulin sensitivity, measured by HOMA, improved in both groups and with a significantly greater degree when testosterone was added to supervised D&E
  • Fasting insulin concentrations, a good representative of insulin sensitivity, did show a significant correlation with changes in circulating androgen levels, an observation in support of Pitteloud et al (2005), who showed a direct relationship between insulin sensitivity and circulating testosterone concentrations using the hyper-insulinemic euglycemic clamp technique
  • 52 weeks of testosterone treatment also significantly improved circulation levels of adiponectin and hsCRP, key serum markers of insulin sensitivity and hepatic steatosis
  • The changes in both adiponectin and hsCRP were significantly correlated with the therapy-induced changes in bioavailable testosterone
  • a negative correlation was found between hsCRP levels and bioavailable testosterone
  • serum PSA concentrations did not differ between the 2 treatment groups, indicating that short-term testosterone administration appears to be acceptably safe
  • Nathan Goodyear on 04 Mar 15
     
    Study of men with metabolic syndrome and type II Diabetes finds that diet and exercise alone improved glucose control and metabolic syndrome components by 31%.  The addition of Testosterone therapy increased this % to 81%.
1More

Testosterone replacement: Medical alternative to bariatric surgery? : Clinica... - 0 views

www.clinicalendocrinologynews.com/...9ebe07503b9647c5b63b63de0.html Testosterone low T low Testosterone men male hormones obese obesity
shared by Nathan Goodyear on 14 Oct 14 - No Cached
  • Nathan Goodyear on 14 Oct 14
     
    Testosterone therapy aids weight loss in study of obese men.  The presentation of the potentially biased study (study was funded by the makers of the Testosterone used in the study) proposes Testosterone as a pharmacologic bariatric treatment.  That conclusion is ludicrous!  Testosterone therapy has been shown to improve insulin sensitivity, improve glucose uptake, reduces inflammation, improve muscle building, and reduce the parameters of metabolic syndrome--all of which underlies the obesity.  Thus, men with low T and obesity, Testosterone therapy is playing a causal role in the obesity and thus Testosterone therapy is treating the cause.  But to describe it as pharmacologic bariatric therapy is false and misleading. http://ow.ly/CKrje 
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Testosterone: a vascular hormone in health and disease - 0 views

joe.endocrinology-journals.org/...JOE-12-0582.full.pdf+html low T low Testosterone testosterone low cardiovascular cardiovascular disease CVD health hormone hormones men male
shared by Nathan Goodyear on 23 Apr 13 - No Cached
  • Nathan Goodyear on 23 Apr 13
     
    testosterone therapy has tremendous cardiovascular benefit in men with low T.  The key here is physiologic replacement of Testosterone.  Testosterone is a vasodilator and anti-inflammatory agent in men with low T.  Testosterone therapy improves cardiac function in those with DHF and angina.  Testosterone is found to be a Ca++ channel blocker--anyone say hypertension treatment?
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Androgens and prostate disease Cooper LA, Page ST - Asian J Androl - 0 views

www.ajandrology.com/article.asp prostate disease cancer Testosterone DHT 5-alpha reductase men male hormone hormones
shared by Nathan Goodyear on 15 Jan 14 - No Cached
  • intraprostatic androgens are not concomitantly increased when serum androgen levels are raised.
  • The "saturation model" proposes that the prostate is sensitive to very low concentrations of circulating androgens, but that once maximal AR binding is achieved, which occurs at relatively low concentrations of circulating T, further increases in serum T have little impact
  • men with metastatic prostate cancer given T who had been previously treated with castration had worsening of disease, whereas those without prior castration did not
  • ...3 more annotations...
  • There is little data to support the withholding of T therapy on the basis of concern for precipitating prostate cancer.
  • Both intervention data and physiology studies point to minimal effects on the prostate gland when serum T levels are increased to the mid-normal range with T therapy
  • an individualized care plan to assess the possible risks and benefits of T therapy for each patient is critical to optimizing the use of androgens in male health.
  • Nathan Goodyear on 15 Jan 14
     
    Nice review of the mixed data on Testosterone and Prostate disease. It is clear that Testosterone does not precipitate prostate cancer.  The intraprostatic hormone milieu likely is different than that present in the serum.  No surprise there.  5alpha reductase decreases prostate volume, PSA, and low-grade prostate cancer, but actually increases aggressive prostate cancer. Supraphysiologic doping in young men associated with no increase in prostate disease. PSA no longer to be followed in men < 55.  Mortality rate not changed.  PSA change of 1.4 ng/ml is appropriate for additional prostate evaluation.  Testosterone therapy on average increased 0.5 ng/ml. Still, no mention of aromatase activity in this article.  Why is it that hormone sensitive disease in men is only with regards to androgens and women estrogen.
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Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Nor... - 0 views

press.endocrine.org/...jc.2015-4106 low T low Testosterone Testosterone free Testosterone men male hormones
shared by Nathan Goodyear on 27 Jul 16 - No Cached
  • Nathan Goodyear on 27 Jul 16
     
    hormones are best evaluated in toto.  For men, the story doesn't begin/end with total Testosterone.  New study finds that low free Testosterone (calculated) is associated with symptoms of low Testosterone despite normal total testosterone levels.
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Leptin and Androgens in Male Obesity: Evidence for Leptin Contribution to Reduced Andro... - 0 views

press.endocrine.org/...jcem.84.10.6082 obesity leptin low T low Testosterone Testosterone low T leydig cells LH leutenizing hormone men male hormones hormone
shared by Nathan Goodyear on 04 Sep 14 - No Cached
  • in male obesity basal and LH-stimulated androgen levels are reduced and inversely correlated with circulating leptin
  • functional leptin receptors are present in rodent Leydig cells
  • it is conceivable that in males high leptin concentrations may have a direct inhibitory effect(s) on Leydig cell function.
  • ...18 more annotations...
  • insulin is an important inhibitor of the synthesis of SHBG
  • no correlation between leptin and SHBG levels
  • SHBG reduction in obesity is a minor determinant of lowered androgen levels
  • SHBG can explain only up to 3% of the correlation
  • testicular T de novo production is impaired in obese men and that leptin seems to be the best hormonal predictor of this blunted response to LH stimulation
  • The low basal 17-OH-P levels found in massively obese men are consistent with a global impairment of Leydig cell steroidogenic function in this group of subjects.
  • These findings indicate that obese men have a FM-related defect in the enzymatic conversion of 17-OH-P to T, which is revealed by hCG stimulation.
  • Other studies have investigated the adrenal function in male obesity and have shown that basal cortisol and 17-OH-progesterone levels tend to decrease with the increase in the degree of obesity
  • High E2 can inhibit the expression and activity of the 17,20-lyase and may be responsible for this steroidogenic lesion
  • However, stimulated E2 levels were not higher in the obese than in controls, excluding the fact that the lower androgen response was due to an increased aromatization of T to E2 and that estrogens have a major role in the observed defect of 17,20-lyase activity in obese men.
  • the percentage increase in the 17-OH-progesterone to T molar ratio paralleled the increase in leptin levels of obese men
  • Multiple regression analysis indicated that the best hormonal predictor of the obesity-related reduction in T and FT basal levels and androgen changes after hCG stimulation was serum leptin concentration
  • insulin has no negative influences on androgen production in obese men
  • insulin is known to have stimulatory actions on T production that have been demonstrated in obese and normal weight men (57) and in Leydig cells in culture
  • the negative correlation between insulin and basal T can be partly explained by the inhibitory action of insulin on SHBG production
  • hypogonadal men have higher circulating leptin levels compared with hypogonadal patients under effective androgen substitution therapy
  • The impaired androgen response to LH stimulus was due to a defect in the enzymatic conversion of 17-OH-progesterone to T, which was disclosed by a leptin-related increase in 17-OH-progesterone to T ratio
  • Estrogens, which are inhibitory modulators of LH pulsatility and bioactivity
  • Nathan Goodyear on 04 Sep 14
     
    Leptin appears to be a good marker of low Testosterone.  This study proposes that the mechanism of action is potentially 2 fold: first, a decrease in LH release by leptin (kisspeptin?) and 2nd, a directed decrease in Testosterone production by the leydig cells in the testes.
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Effect of Testosterone Replacement Therapy on Cognitive Performance and Depression in M... - 0 views

www.ncbi.nlm.nih.gov/...PMC5209560 low T Low testosterone Testosterone male hormones Testosterone therapy depression brain cognition ED erectile dysfunction
shared by Nathan Goodyear on 09 Jan 17 - No Cached
  • Azad et al [15] used single photon emission computed tomography and showed that, after 3~5 weeks of TRT, cerebral perfusion was increased in the midbrain and the superior frontal gyrus in seven men with hypogonadism
  • After 12~14 weeks, increased perfusion was still observed in the midbrain as well as in the midcingulate gyrus
  • TDS patients who received TRT showed significant improvement in cognitive function only if mild cognitive impairment was present at baseline
  • ...4 more annotations...
  • Cherrier et al [17] evaluated a sample of 32 subjects, which included 17 men with mild cognitive impairment and 15 with Alzheimer's disease. At the 6-week follow-up, patients who received TRT showed significantly better scores regarding spatial memory, constructional abilities, and verbal memory compared to those noted in the placebo group. Taken together, these results suggest that TRT has a beneficial effect on cognitive function
  • TRT improved mood and well-being, and reduced fatigue and irritability in hypogonadal men
  • The study by Pope et al [20] involved men with depression refractory to standard anti-depressants, and found that TRT lowered the Hamilton Depression score,
  • depression tends to increase as testosterone levels decrease [21], it is highly likely that TRT improved symptoms of depression by increasing testosterone levels.
  • Nathan Goodyear on 09 Jan 17
     
    men with Testosterone <300 ng/dl with levels after 8 months of therapy achieving +680 ng/dl.
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Ibuprofen alters human testicular physiology to produce a state of compensated hypogona... - 0 views

www.pnas.org/...1715035115.full ibuprofen Testosterone epigenetics hormones low Testosterone low T
shared by Nathan Goodyear on 09 Jan 18 - No Cached
  • 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
  • ...27 more annotations...
  • 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 &lt; 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
  • Nathan Goodyear on 09 Jan 18
     
    ibuprofen alters genetic expression that results in decreased Testosterone production.
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http://press.endocrine.org/doi/pdf/10.1210/jc.2014-1872 - 0 views

press.endocrine.org/...jc.2014-1872 low T Testosterone treatment therapy diabetes obesity men male hormone hormones
shared by Nathan Goodyear on 29 Jul 14 - No Cached
  • Nathan Goodyear on 29 Jul 14
     
    New study finds Testosterone therapy provides less than statistical significant improvement in constitutional/sexual symptoms, in obese men with type II diabetes with symptoms classified as mild-moderate with modest reductions in Total Testosterone.  This study highlights that low Testosterone is a biomarker of poor health and multiple comorbidities and that simply adding in Testosterone therapy will not cure all male woes.  The authors did state that ED and low T are separate issues and I will differ with them on this--they are in fact link.  This association may vary between individuals, but to flatly state they are completely separate issues is devoid of the fact that testosterone has been shown to reduce inflammatory cytokines and improve PDE5 therapy.  
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Testosterone replacement therapy and the risk of prostate cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC4814970 Testosterone testosterone therapy saturation theory cancer prostate cancer male hormones
shared by Nathan Goodyear on 01 Oct 16 - No Cached
  • When the level of circulating androgen is below normal, some androgen receptors are inactive, and the secondary downstream effects are decreased. Once androgen receptors within the prostate are saturated, however, increasing testosterone will no longer have an effect
  • the saturation point is thought to occur at low physiologic testosterone levels
  • Only the subset of individuals with pretreatment testosterone level &lt;250 ng dl−1 had PSA level correlating with free and total testosterone level
  • ...7 more annotations...
  • none of the men stopped testosterone supplementation due to prostate cancer recurrence, and none demonstrated cancer progression
  • PSA level did transiently rise in one patient; however, none exceeded a PSA of 1.5 ng ml−1 to raise concern for biochemical recurrence
  • after 19 months on TRT, 10 hypogonadal patients with a history of undergoing a radical retropubic prostatectomy for prostate cancer had no PSA recurrence and had statistically significant improvements in serum total testosterone and hypogonadal symptoms
  • Similarly, Kaufman and Graydon14 examined case records of seven hypogonadal men who had undergone curative RP with symptoms of hypogonadism and low serum testosterone levels treated with testosterone replacement. No biochemical or clinical evidence of cancer recurrence was noted
  • In a much larger case series, Khera et al.15 reviewed the records of 57 men who received TRT following RP. After an average of 36 months following RP, testosterone replacement was initiated and followed for an average of 13 months. Mean testosterone values rose significantly and once again, there was no increase in PSA values and, therefore, no diagnosed biochemical recurrence
  • Four of the patients in the treatment group were found to have cancer recurrence, compared with eight in the control group
  • All biochemical recurrences were seen in individuals with high-risk disease
  • Nathan Goodyear on 01 Oct 16
     
    Good review of data on Testosterone therapy and prostate cancer risk: the take home is there is no increased risk.  Also, included is a discussion of the prostate saturation theory.
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Review of health risks of low testosterone and testosterone administration - 0 views

www.ncbi.nlm.nih.gov/...PMC4391003 low Testosterone low T Testosterone men male hormone hormones health
shared by Nathan Goodyear on 28 Apr 15 - No Cached
  • Hypogonadism may be defined either as serum concentration of T (either total T, bioavailable T or free T) or as low T plus symptoms of hypogonadism
  • The Baltimore Longitudinal Study on Aging reported the incidence of total serum T &lt; 325 ng/dL to be 20% for men in their 60s, 30% for men in their 70s and 50% for men over 80
  • The Massachusetts Aging Male Study reported that 12.3% of men aged 40 to 70 had a total serum T of &lt; 200 ng/dL with 3 or more symptoms of hypogonadism
  • ...19 more annotations...
  • The Boston Area Community Health Study reported that 5.6% of men aged 30 to 70 were hypogonadal, as defined by total serum T &lt; 300 ng/dL; or, free serum T &lt; 5 ng/dL plus 3 or more symptoms of hypogonadism
  • In a health screening project among 819 men in Taiwan, the prevalence of hypogonadism (total serum T &lt; 300 ng/dL) ranged from 16.5% for men in their 40s, 23.0% for men in their 50s, 28.9% for men in their 60s, and 37.2% for men older than 70 years of age
  • The prevalence of hypogonadism among men in Taiwan is higher than the prevalence reported in the Massachusetts Male Aging Study
  • CAG repeat sequence, within the androgen receptor (AR). Rajender et al[12] reviewed over 30 studies on the AR trinucleotide repeat and infertility
  • suggestion that CAG repeat length may determine androgen responsiveness, this issue is not clearly settled
  • reported prevalence of low T in older men range from 5.6% to 50%
  • Those in the hypogonadal group (n = 4269) had direct health care costs, that exceeded the eugonadal group (n = 4269) by an average of $7100 over the course of the observation window
  • higher economic burden and presence of co-morbidities for hypogonadism
  • minor to moderate improvements in lean mass and muscle strength
  • increased bone mineral density
  • modest enhancement in sexual function
  • reduced adiposity
  • lessening of depressive symptoms
  • Meta-analyses of clinical TRT trials as of 2010 have identified three major adverse events resulting from TRT: (1) polycythemia; (2) an increase in prostate-related events; and (3) and a slight reduction in serum high-density lipoprotein (HDL) cholesterol
  • polycythemia (&gt; 3.5-fold increase in risk
  • TRT produced a 40% prostate enlargement in older hypogonadal male Veterans over 12 mo
  • no published analysis has reported measurable increases in prostate cancer risk or Gleason score in men undergoing TRT, or in hypogonadal men with a history of prostate cancer undergoing TRT
  • the prostate which highly expresses the type II 5α-reductase enzyme. Inhibition of this enzyme via finasteride (a type II 5α-reductase inhibitor) or dutasteride (a dual type I and II 5α-reductase inhibitor) reduces circulating DHT 50%-75% and &gt; 90%, respectively[47], and reduces prostate mass[48] and prostate cancer risk
  • Normally estradiol partially regulates testosterone levels, at the hypothalamus, blunting LH and FSH release from the pituitary. As a selective estrogen receptor modulator, CC interrupts this pathway, and consequently there is a greater stimulation for the production of testosterone in Leydig cells
    • Nathan Goodyear
      Nathan Goodyear on 28 Apr 15
       
      this would only apply if E1 and/or E2 levels were elevated, which the authors make no mention of.
  • Nathan Goodyear on 28 Apr 15
     
    to be read
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Secular Decline in Male Testosterone and Sex Hormone Binding Globulin Serum Levels in D... - 0 views

jcem.endojournals.org/...4696.long decline male testosterone hormone danish low t low Testosterone men SHBG serum levels
shared by Nathan Goodyear on 10 Dec 12 - No Cached
  • Serum SHBG levels are negatively associated with obesity and various measures of insulin resistance
  • SHBG levels increase during pharmacological oral estrogen treatment
  • insulin decreases SHBG productio
  • ...5 more annotations...
  • The secular decline in SHBG and testosterone serum levels did not lead to a change in the level of free testosterone
  • existence of specific binding sites for SHBG at the cell membrane of steroid-responsive tissues has been shown
  • it is alarming that changes of this magnitude can be detected over such a relatively short time
  • Sex steroids stimulate SHBG production and secretion in vitro
  • Serum testosterone levels decreased and SHBG levels increased with increasing age
  • Nathan Goodyear on 10 Dec 12
     
    lower levels of SHBG and serum testosterone were found in more recently born men.  Preceding generations of men produced higher testosterone levels than men born in more recent generations.
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Treatment of Men for &quot;Low Testosterone&quot;: A Systematic Review - 0 views

www.ncbi.nlm.nih.gov/...PMC5031462 low T low Testosterone Testosterone Testosterone therapy disease male hormones
shared by Nathan Goodyear on 09 Jan 17 - No Cached
  • Nathan Goodyear on 09 Jan 17
     
    Systematic review finds very little clinical benefit from Testosterone therapy.  The problem here is one typically made by allopathic medicine.  They look for a benefit in a box.  They look for one therapy to cure all.  Testosterone therapy should be the last thing you prescribe as usually low Testosterone is the effect and early is not the cause.  Clearly, in the right individual, Testosterone therapy can have tremendous positive effects; however, it must accompany nutrition, exercise, inflammation control...  Testosterone is just one piece of a very complex male physiologic puzzle.
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