OnLine First 2013

[Michael Scally MD]

Relationship Between Sexual Satiety And Motivation, Brain Androgen Receptors And Testosterone

Highlights
• We choose mandarin voles as model animal in present experiment.
• Distribution of androgen receptor is different between sexual satiety and motivation.
• Testosterone levels in brain are different between sexual satiety and motivation.
• The serum levels of androgens are unchanged by ELISA in all experimental groups.


He F, Yu P, Wu R. Relationship between sexual satiety and motivation, brain androgen receptors and testosterone in male mandarin voles. Behav Brain Res. ScienceDirect.com - Behavioural Brain Research - Relationship between sexual satiety and motivation, brain androgen receptors and testosterone in male mandarin voles

Androgen receptors participate in the neuroendocrine regulation of male sexual behavior, primarily in brain areas located in the limbic system. Males of many species present a long-term inhibition of sexual behavior after several ejaculations, known as sexual satiety. It has been shown in rats that androgen receptor expression is reduced 24h after a single ejaculation, or mating to satiety, in the medial preoptic area, nucleus accumbens and ventromedial hypothalamus. The aim of this study was to analyze these processes in another animal, the mandarin vole (Microtus mandarinus). We compared differences in androgen receptor (AR) and testosterone (T) expression in various brain areas between male mandarin voles sexually satiated and those exposed to receptive females but not allowed to mate. Sexual satiety was associated with decreased AR and T expression in the lateral septal nucleus (LS), medial amygdala (MeA), medial preoptic area (mPOA) and ventromedial hypothalamic nucleus (VMH). Males exposed to receptive females showed an increase in AR and T expression in the bed nucleus of the stria terminalis (BNST), LS, MeA and VMH. Serum testosterone levels remained unchanged after 24h in males exposed to receptive females or males mated to satiety. These data suggest a relationship between sexual activity and a decrease in AR and T expression in specific brain areas, and a relationship between sexual motivation and increased AR and T expression in other brain areas, independently of testosterone levels.

 

[Michael Scally MD]

Steyn F, Xie T, Huang L, et al. Increased insulin correlates with the suppression of pulsatile GH secretion during weight gain. J Endocrinol. http://joe.endocrinology-journals.org/content/early/2013/05/24/JOE-13-0084.abstract

Pathological changes associated with obesity are thought to contribute to growth hormone (GH) deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contribute to progressive weight gain, and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight, epididymal fat mass, circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs) and glucose. Data were obtained from male mice maintained on a standard or high fat diet. We confirm the suppression of pulsatile GH secretion following dietary induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain, and thus precedes the development of obesity. Moreover, data illustrates key interactions between GH secretion and circulating levels of insulin, and reflects the potential physiological role of GH in modulating insulin-induced lipogenesis throughout positive energy balance.

 

[Michael Scally MD]

Wang P, Menheere PPCA, Astrup A, et al. Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men. Obesity. Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men - Wang - 2013 - Obesity - Wiley Online Library

Objective Weight loss helps reduce the symptoms of the metabolic syndrome (MetS) in the obese, but weight regain after active weight loss is common. The changes and predictive role of circulating adipokines and sex hormones for weight regain in men during dietary intervention, and also the effect of basal MetS status on weight regain, were investigated.

Design and Methods Twenty-four men who continued to lose weight (WL) and 24 men who regained weight (WR) during the 6-month follow-up period after weight loss were selected from the Diogenes Study. Their circulating concentrations of leptin, adiponectin, retinol-binding protein 4 (RBP4), luteinizing hormone, prolactin, progesterone, total and free testosterone, and sex hormone-binding globulin (SHBG) were measured at baseline, after 8-week low-calorie diet-induced active weight loss, and after a subsequent 26-week ad libitum weight maintenance diet, and analyzed together with anthropometrical and physiological parameters.

Results and Conclusion Overweight and obese men with MetS at baseline had higher risk to regain weight (odds ratio = 2.8, P = 0.015). High baseline RBP4, low total testosterone, and low SHBG are predictors of weight loss regain (different between WR and WL with P = 0.001, 0.038, and 0.044, respectively) and may play roles in the link between MetS and weight loss regain.

 

[Michael Scally MD]

If you are on a statin, take CoQ10!

Vaughan RA, Garcia-Smith R, Bisoffi M, Conn CA, Trujillo KA. Ubiquinol rescues simvastatin-suppression of mitochondrial content, function and metabolism: Implications for statin-induced rhabdomyolysis. Eur J Pharmacol 2013;711(1-3):1-9. ScienceDirect.com - European Journal of Pharmacology - Ubiquinol rescues simvastatin-suppression of mitochondrial content, function and metabolism: Implications for statin-induced rhabdomyolysis

Statin medications diminish cholesterol biosynthesis and are commonly prescribed to reduce cardiovascular disease. Statins also reduce production of ubiquinol, a vital component of mitochondrial energy production; ubiquinol reduction may contribute to rhabdomyolysis. Human rhabdomyosarcoma cells were treated with either ethanol and dimethyl sulfoxide (DMSO) control, or simvastatin at 5microM or 10microM, or simvastatin at 5microM with ubiquinol at 0.5microM or 1.0microM for 24h or 48h. PGC-1alpha RNA levels were determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mitochondrial content was determined using flow cytometry and immunocytochemistry. Metabolism was determined by quantification of extracellular acidification rate and oxygen consumption rate. Treatment of human rhabdomyosarcoma cells with simvastatin significantly reduced oxidative, total metabolism, and cellular ATP content in a time- and dose-dependent manner which was rescued by concurrent treatment with ubiquinol. Treatment with simvastatin significantly reduced mitochondrial content as well as cell viability which were both rescued by simultaneous treatment with ubiquinol. This work demonstrates that the addition of ubiquinol to current statin treatment regimens may protect muscle cells from myopathies.

 

[Michael Scally MD]

Highlights
• Testosterone improves hypetrophy and myonuclear accretion in cells (PD) with atrophic phenotypes.
• PD myotubes hypertrophied to same extent as control myotubes with T.
• This suggests a similar intrinsic ability to respond to exogenous T administration.
• The action of T appeared to be mediated by PI3 K/Akt pathway.


Deane CS, Hughes DC, Sculthorpe N, Lewis MP, Stewart CE, Sharples AP. Impaired hypertrophy in myoblasts is improved with testosterone administration. J Steroid Biochem Mol Biol. ScienceDirect.com - The Journal of Steroid Biochemistry and Molecular Biology - Impaired hypertrophy in myoblasts is improved with testosterone administration

We investigated the ability of testosterone (T) to restore differentiation in multiple population doubled (PD) murine myoblasts, previously shown to have a reduced differentiation in monolayer and bioengineered skeletal muscle cultures vs. their parental controls (CON) (Sharples et al., 2011, Sharples et al., 2012). Cells were exposed to low serum conditions in the presence or absence of T (100nM)+/-PI3K inhibitor (LY294002) for 72hrs and 7 days (early and late muscle differentiation respectively).

Morphological analyses were performed to determine myotube number, diameter (mum) and myonuclear accretion as indices of differentiation and myotube hypertrophy. Changes in gene expression for myogenin, mTORC1 and myostatin were also performed.

Myotube diameter in CON and PD cells increased from 17.32+/-2.56mum to 21.02+/-1.89mum and 14.58+/-2.66mum to 18.29+/-3.08mum (P </= 0.05) respectively after 72hrs of T exposure. The increase was comparable in both PD (+25%) and CON cells (+21%) suggesting a similar intrinsic ability to respond to exogenous T administration. T treatment also significantly increased myonuclear accretion (% of myotubes expressing 5+ Nuclei) in both cell types after 7 days exposure (P </= 0.05).

Addition of PI3K inhibitor (LY294002) in the presence of T attenuated these effects in myotube morphology (in both cell types) suggesting a role for the PI3K pathway in T stimulated hypertrophy. Finally, PD myoblasts showed reduced responsiveness to T stimulated mRNA expression of mTORC1 vs. CON cells and T also reduced myostatin expression in PD myoblasts only.

The present study demonstrates testosterone administration improves hypertrophy in myoblasts that basally display impaired differentiation and hypertrophic capacity vs. their parental controls, the action of testosterone in this model was mediated by PI3K/Akt pathway.

 

[Michael Scally MD]

Statins (hydroxyl-methylglutaryl-coenzyme-A reductase inhibitors) effectively lower cardiovascular morbidity and mortality. However, the full spectrum of statin musculoskeletal adverse events (AEs) is unknown. Statin-associated musculoskeletal AEs include a wide array of clinical presentations, including myalgias, muscle weakness, muscle cramps, rhabdomyolysis, autoimmune muscle disease, and tendinous diseases.

This study examined the association of statin use with musculoskeletal conditions in a propensity score–matched cohort of statin users and nonusers in a military health care system in which patients have similar health care access and standards.

This is the first study, using propensity score matching, to show that statin use is associated with an increased likelihood of diagnoses of musculoskeletal conditions, arthropathies, and injuries.

Mansi I, Frei CR, Pugh M, Makris U, Mortensen EM. Statins and Musculoskeletal Conditions, Arthropathies, and Injuries.JAMA Intern Med. 2013:1-9. JAMA Network | JAMA Internal Medicine | Statins and Musculoskeletal Conditions, Arthropathies, and InjuriesStatins and Musculoskeletal Diseases

Importance Statin use may be associated with increased musculoskeletal adverse events, especially in physically active individuals.

Objective To determine whether statin use is associated with musculoskeletal conditions, including arthropathy and injury, in a military health care system.

Design A retrospective cohort study with propensity score matching.

Setting San Antonio Military Multi-Market.

Participants Tricare Prime/Plus beneficiaries evaluated from October 1, 2003, to March 1, 2010.

Interventions Statin use during fiscal year 2005. On the basis of medication fills, patients were divided into 2 groups: statin users (received a statin for at least 90 days) and nonusers (never received a statin throughout the study period).

Main Outcomes and Measures Using patients' baseline characteristics, we generated a propensity score that was used to match statin users and nonusers; odds ratios (ORs) were determined for each outcome measure. Secondary analyses determined adjusted ORs for all patients who met study criteria and a subgroup of patients with no comorbidities identified using the Charlson Comorbidity Index. Sensitivity analysis further determined adjusted ORs for a subgroup of patients with no musculoskeletal diseases at baseline and a subgroup of patients who continued statin therapy for 2 years or more. The occurrence of musculoskeletal conditions was determined using prespecified groups of International Classification of Diseases, Ninth Revision, ClinicalModification codes: Msk1, all musculoskeletal diseases; Msk1a, arthropathies and related diseases; Msk1b, injury-related diseases (dislocation, sprain, strain); and Msk2, drug-associated musculoskeletal pain.

Results A total of 46 249 individuals met study criteria (13 626 statin users and 32 623 nonusers). Of these, we propensity score–matched 6967 statin users with 6967 nonusers. Among matched pairs, statin users had a higher OR for Msk1 (OR, 1.19; 95% CI, 1.08-1.30), Msk1b (1.13; 1.05-1.21), and Msk2 (1.09; 1.02-1.18); the OR for Msk1a was 1.07 (0.99-1.16; P = .07). Secondary and sensitivity analyses revealed higher adjusted ORs for statin users in all outcome groups.

Conclusions and Relevance Musculoskeletal conditions, arthropathies, injuries, and pain are more common among statin users than among similar nonusers. The full spectrum of statins' musculoskeletal adverse events may not be fully explored, and further studies are warranted, especially in physically active individuals.

 

[Michael Scally MD]

Kvorning T, Christensen LL, Madsen K, et al. Mechanical Muscle Function and Lean Body Mass During Supervised Strength Training and Testosterone Therapy in Aging Men with Low-Normal Testosterone Levels. Journal of the American Geriatrics Society:n/a-n/a. Mechanical Muscle Function and Lean Body Mass During Supervised Strength Training and Testosterone Therapy in Aging Men with Low-Normal Testosterone Levels - Kvorning - 2013 - Journal of the American Geriatrics Society - Wiley Online Library

Objectives To examine the effect of strength training and testosterone therapy on mechanical muscle function and lean body mass (LBM) in aging men with low-normal testosterone levels in a randomized, double-blind, placebo-controlled 24-week study.

Design Randomized, double-blind, placebo-controlled.

Setting Odense, Denmark.

Participants Men aged 60 to 78, with bioavailable testosterone levels of less than 7.3 nmol/L and a waist circumference greater than 94 cm were randomized to testosterone (50–100 mg/d, n = 22) placebo (n = 23) or strength training (n = 23) for 24 weeks. The strength training group was randomized to addition of testosterone or placebo after 12 weeks. Subjects performed supervised strength training (2–3 sets with 6- to 10-repetition maximum loads, 3 times per week).

Measurements Testosterone levels, maximal voluntary contraction and rate of force development, and LBM were obtained at 0 and at Weeks 12 and 24 of the intervention.

Results No changes in any variables were recorded with placebo. In the strength training group, maximal voluntary contraction increased 8% after 12 weeks (P = .005). During the following 12 weeks of strength training rate of force development increased by 10% (P = .04) and maximal voluntary contraction further increased (P < .001). Mechanical muscle function was unchanged in men receiving only testosterone for 24 weeks. LBM increased only in men receiving testosterone (P = .004).

Conclusion Strength training in aging men with low-normal testosterone levels may improve mechanical muscle function, but this effect occurs without a significant increase in LBM. Clinically, only the combination of testosterone therapy and strength training resulted in an increase in mechanical muscle function and LBM.

 

[Michael Scally MD]

Papanicolaou DA, Ather SN, Zhu H, et al. A Phase IIA Randomized, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety of the Selective Androgen Receptor Modulator (SARM), MK-0773 in Female Participants with Sarcopenia. J Nutr Health Aging 2013;17(6):533-43. A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia - Online First - Springer

Background: Sarcopenia, the age-related loss of muscle mass [defined as appendicular LBM/Height2 (aLBM/ht2) below peak value by>1SD], strength and function, is a major contributing factor to frailty in the elderly. MK-0773 is a selective androgen receptor modulator designed to improve muscle function while minimizing effects on other tissues.

Objectives: The primary objective of this study was to demonstrate an improvement in muscle strength and lean body mass (LBM) in sarcopenic frail elderly women treated with MK-0773 relative to placebo.

Design: This was a randomized, double-blind, parallel-arm, placebo-controlled, multicenter, 6-month study. Participants were randomized in a 1:1 ratio to receive either MK-0773 50mg b.i.d. or placebo; all participants received Vitamin D and protein supplementation. Setting: General community.

Participants: 170 Women aged >/=65 with sarcopenia and moderate physical dysfunction.

Measurements: Dual energy X-ray absorptiometry, muscle strength and power, physical performance measures.

Results: Participants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269). Both groups showed significant improvement from baseline at Month 6 in physical performance measures, but there were no statistically significant differences between participants receiving MK-0773 and placebo. A greater number of participants experienced elevated transaminases in the MK-0773 group vs. placebo, which resolved after discontinuation of study therapy. MK-0773 was generally well-tolerated with no evidence of androgenization.

Conclusions: The MK-0773-induced increase in LBM did not translate to improvement in strength or function vs. placebo. The improvement of strength and physical function in the placebo group could be at least partly attributed to protein and vitamin D supplementation.

 

[Michael Scally MD]

Travison TG, Zhuang WV, Lunetta KL, et al. The Heritability of Circulating Testosterone, Estradiol, Estrone, and SHBG Concentrations in Men: The Framingham Heart Study. Clinical Endocrinology. The Heritability of Circulating Testosterone, Estradiol, Estrone, and SHBG Concentrations in Men: The Framingham Heart Study - Travison - Clinical Endocrinology - Wiley Online Library

Objective Circulating testosterone, estradiol, and estrone concentrations vary considerably between men. Though a substantial proportion of this variation may be attributed to morbidity and behavioral factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG), along with the genetic correlation between these factors.

Design Cross-sectional, observational analysis of data from male members of the Offspring and Generation Three cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005.

Participants A total of 3,367 community-dwelling men contributed to the analysis, including 1,066 father/son and 1,284 brother pairs among other family relationships.

Measurements Serum sex steroids (TT, E1 and E2) by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay, cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index, and smoking status.

Results Age-adjusted heritability estimates were 0.19, 0.40, 0.40, 0.30, and 0.41 for cFT, TT, E1, E2, and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (?G) indicated substantial genetic association between TT and cFT (?G=0.68), between TT and SHBG (pG = 0.87), between E1 and E2 (?G = 0.46), and between TT and E2 (?G = 0.48).

Conclusion Circulating testosterone, estradiol, and estrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and estrogen levels suggests shared genetic pathways.

 

[Michael Scally MD]

Varicocele and Hypogonadism

Accumulating evidence suggests that varicocele, long associated with male infertility, is also a risk factor for low testosterone levels. The exact pathophysiology of the negative effects of varicocele on testicular function is not well understood, but theories include venous stasis, increased testicular temperature, oxidative stress, and resulting toxic environment.

While prior studies report conflicting effects of non-microsurgical varicocelectomy on testosterone level, recent literature demonstrates that microsurgical varicocelectomy improves testosterone levels in men with varicocele and low testosterone preoperatively.

Dabaja A, Wosnitzer M, Goldstein M. Varicocele and Hypogonadism. Curr Urol Rep. Varicocele and Hypogonadism. [Curr Urol Rep. 2013] - PubMed - NCBI

 

[Michael Scally MD]

Aromatase Deficiency, A Rare Syndrome: Case Report

Aromatase deficiency (AD) is a rare autosomal recessive inheritance syndrome. Its worldwide incidence is unknown, and there are few case reports in the literature. Aromatase dysfunction develops due to CYP19A1 gene mutation and a decrease in estrogen synthesis. Estrogen deficiency can induce delayed epiphyseal closure, eunuchoid body habitus, osteopenia, and osteoporosis in both genders.

Our patient was a 27-year-old male who presented with bone pain, recurrent bone fractures associated with minimal trauma starting in puberty, and a progressive increase in height. Laboratory tests revealed that the blood levels of follicle-stimulating hormone and luteinizing hormone were above normal, testosterone level was normal, and estrogen was undetectable. Plain bone radiography of the left wrist and hand demonstrated that the epiphyses were still unfused. Lumbar osteoporosis was detected in bone densitometry.

In the genetic analysis, homozygous R375H guanine-adenine (G-A) mutation was detected in the CYP19A1 gene, and a diagnosis of AD was reached.

Treatment with 25 g transdermal estradiol was started.

All family members were examined. Homozygous R375H G-A mutation was detected in the patient's younger brother. Heterozygous R375H G-A mutation was found in his mother, father, and older brother.

In conclusion, this AD patient requires lifetime estrogen replacement in order to provide sufficient bone mineralization, to reduce the risk of bone fractures, and to lead a healthy life. The best method to prevent the possible complications is to diagnose the AD syndrome at early ages and to provide adequate estrogen replacement starting at puberty.

Baykan EK, Erdogan M, Ozen S, Darcan S, Saygili LF. Aromatase deficiency, a rare syndrome: case report. J Clin Res Pediatr Endocrinol 2013;5(2):129-32. http://www.jcrpe.org/eng/makale/422/46/Full-Text

 

[Michael Scally MD]

Auer M, Stalla GK, Athanasoulia AP. [Isolated gonadotropic deficiency after multiple concussions in a professional soccer player]. Dtsch Med Wochenschr 2013;138(16):831-3. https://www.thieme-connect.com/DOI/DOI?10.1055/s-0033-1343099

HISTORY AND CLINICAL PRESENTATION: A 27-year-old man was admitted to our outpatient clinic with symptoms of loss at libido, erectile dysfunction and fatigue. He had been playing soccer from the age of 7, for the last 10 years as a high-level professional. During that time repeated mild head-trauma without loss of consciousness had occurred, mainly triggered by excessive header-training and occasional collisions.

INVESTIGATIONS: Serum levels of testosterone and luteinizing hormone were low. A gonadotropin releasing hormone loading test revealed significant gonadotropin responses, therefore pituitary gonadotropic insufficiency was unlikely. Further pituitary insufficiency of any other axis was also excluded by insulin hypoglycemia test. Magnetic resonance imaging of the brain revealed no significant abnormalities of the hypothalamic-pituitary unit.

TREATMENT AND COURSE: Testosterone substitution, at first applied transdermally, then intramuscularly, was initiated after approval by the National Anti Doping Agency. Four months later most of the symptoms had regressed.

CONCLUSION: Pituitary deficiency in the course of craniocerebral trauma is frequent and may be transient or permanent, mostly affecting somatotropic or gonadotropic function. Hormonal imbalances may also be observed after mild but repeated trauma without loss of consciousness and should be considered in cases of isolated pituitary dysfunction, since such traumas may often occur in contacts sports such as boxing or intensive soccer play.

 

[Michael Scally MD]

Shimon I, Benbassat C. Male prolactinomas presenting with normal testosterone levels. Pituitary. Male prolactinomas presenting with normal testosterone levels - Online First - Springer

In men harboring prolactinoma the most common symptoms are related to hypogonadism, including decreased libido, erectile dysfunction, and gynecomastia. These men characteristically present with elevated serum prolactin (PRL) levels, suppressed gonadotropins, and low testosterone levels. We studied a group of 11 unique men with prolactinomas presenting with testosterone levels within the normal range (>/=2.6 ng/ml; cohort A), and compared them to 11 prolactinoma men with borderline baseline testosterone (2.1-2.5 ng/ml; cohort B) and to a cohort of 34 prolactinoma patients with low testosterone levels (</=2 ng/ml; cohort C). Mean testosterone levels at presentation were 3.91 +/- 0.9 ng/ml in cohort A (range, 2.6-5.2 ng/ml), 2.44 +/- 0.16 ng/ml in cohort B and 0.96 +/- 0.6 in cohort C (p < 0.001). Mean baseline PRL levels were >20 times above normal in cohort A compared to >100 times above normal in cohorts B and C. Symptoms of hypogonadism were present in 55, 64 and 76 % of men in groups A, B and C, respectively. There was a trend towards a larger tumor size in the low testosterone group (p = 0.06). Visual fields defects at presentation were more prevalent in this cohort (C). With cabergoline, testosterone level increased from 3.91 to 6.42 ng/ml (Delta = 2.51 ng/ml) in cohort A, from 2.44 to 5.63 ng/ml (Delta = 3.19 ng/ml) in cohort B, and from 0.96 to 3.30 ng/ml (Delta = 2.34 ng/ml) in cohort C (p < 0.05 for each group). Symptoms of hypogonadism improved following treatment in 83 % of symptomatic men in cohort A. Normal testosterone does not exclude the likelihood of prolactinoma in men. When treated with cabergoline, testosterone levels in these men can increase higher within the normal range together with clinical improvement.

 

[Michael Scally MD]

Pearl JA, Berhanu D, Francois N, et al. Testosterone Supplementation Does Not Worsen Lower Urinary Tract Symptoms. J Urol. Elsevier

INTRODUCTION AND OBJECTIVES: Testosterone replacement therapy (TRT) is commonly used to treat men with hypogonadism; however, there has been caution in using TRT in men with moderate to severe lower urinary tract symptoms (LUTS) for fear of worsening their symptoms. The primary objective of this study was to examine the effect of TRT on LUTS in hypogonadal men.

METHODS: We retrospectively reviewed our outpatient database and identified patients with a diagnosis of hypogonadism who received TRT from 2002 to 2012. LUTS were assessed by use of the American Urological Association Symptom Index (AUASI) pre- and post- TRT. Testosterone and PSA were also continuously measured, and all patients were closely monitored for side effects to TRT. Patients who had progression of their LUTS to the point of requiring surgery were included in the study.

RESULTS: We identified 120 hypogonadal men who underwent TRT, the majority of whom had topical therapy or a combination of topical and pellet based therapy (57.5% and 20.8%, respectively). The mean baseline AUASI was 10.8 (+/-7.8) and our mean duration of TRT was 692 days (+/-773). The mean change in AUASI was -1.07 (+/-6.06). The mean baseline PSA was 1.6 (+/-1.9) and the mean change in PSA was 0.44 (+/-2.2). 8.1% of patients had a baseline PSA >4.0, and they had greater improvement in AUASI than those patients with baseline PSA <4.0 (-1.9 vs. -1.0, pNS). 45.8% of patients had <3-point change in AUASI in either direction. 38/120 (31.7%) had improvement in their AUASI >/= 3 points while 27/120 (22.5%) had worsening of their AUASI >/= 3 points. Patients with an improved AUASI had a mean PSA change of 0.3 (+/-3.4), while those who had worsening of their AUASI had a mean PSA change of 0.7 (+/-2.2)(pNS). Approximately 9/120 (7.5%) of these men initiated new medications for their LUTS during the course of the study. There was no significant change in their AUASI when compared to patients without any use of LUTS medications. Additionally, 4/120 (3.3%) of patients had progression of their LUTS and required transurethral resection of the prostate.

CONCLUSIONS: We demonstrate that initiating TRT in hypogonadal men has a low risk of worsening LUTS. In fact many men have an improvement in symptoms while PSA changes appear minor. Future research should focus on larger patient population studies to further examine this relationship.

 

[Michael Scally MD]

Shi Z, Araujo AB, Martin S, O’Loughlin P, Wittert GA. Longitudinal changes in testosterone over five years in community-dwelling men. Journal of Clinical Endocrinology & Metabolism. Longitudinal changes in testosterone over five years in community-dwelling men

Context There are few population-based studies reporting longitudinal changes in total testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG) levels, and limited information on risk factors for their change.

Objective The objective of the study was to examined 5-year changes in serum T, LH, FSH, and SHBG levels among Australian men.

Design A randomly selected, community based cohort of 1,588 men age 35 or older at recruitment (mean age 54±11y), with available data at two visits. Men on medications known to affect, or with established pathology of, the hypothalamo-pituitary gonadal axis were excluded, leaving 1,382 for analysis.

Results Mean baseline and follow-up T levels were 16.2±1.4nmol/L and 15.6±1.4nmol/L; a change of -0.13nmol/L/y. Annualized T changes were associated with being unmarried, obesity, and smoking at baseline, but not diabetes, hypertension, or cardiovascular disease. T declined in men with persistent depression, or who developed chronic disease, and increased in men who were married, as compared to unmarried, at both time points. In the multivariate analysis, smoking cessation, development of central (waist ?100cm) or generalised (BMI ? 30) obesity resulted in T decreases of 0.36, 0.25, and 0.20nmol/L/y respectively. Quitting smoking, developing obesity, and having persisting depression were inversely related to SHBG change.

Conclusions An age-related decline in T levels is not inevitable but largely explained by smoking behaviour and intercurrent changes in health status, particularly obesity and depression.

 

[Michael Scally MD]

Andreassen M, Frystyk J, Faber J, Kristensen LO, Juul A. Growth hormone (GH) activity is associated with increased serum oestradiol and reduced Anti-Mullerian Hormone in healthy male volunteers treated with GH and a GH antagonist. Andrology 2013;1(4):595-601. Growth hormone (GH) activity is associated with increased serum oestradiol and reduced Anti-M[]llerian Hormone in healthy male volunteers treated with GH and a GH antagonist - Andreassen - 2013 - Andrology - Wiley Online Library

Growth hormone (GH) and insulin-like growth factor I (IGF-I) receptors are present on pituitary gonadotrophs and on testicular Leydig and Sertoli cells. Thus, the GH/IGF-I system may modulate the pituitary-gonadal axis in males. This is a randomized cross-over study. Eight healthy male volunteers (mean age 35, range 29-46 years) were treated with GH for 3 weeks (1st week 0.01, 2nd week 0.02, 3rd week 0.03 mg/day/kg) or a GH receptor antagonist (Pegvisomant) (1st week 10, last 2 weeks 15 mg/day), separated by 8 weeks of washout. Before and after the two treatment periods, concentrations of luteinizing hormone (LH), follicle-stimulating hormone, testosterone, oestradiol, sex hormone-binding globulin, inhibin B and Anti-Mullerian Hormone (AMH) were measured. During GH treatment, IGF-I increased [(median (IQR)] 166 (162-235) vs. 702 (572-875) mug/L, p < 0.001) together with oestradiol [(mean +/- SD) 78 +/- 23 vs. 111 +/- 30 pm, p = 0.019], and the oestradiol/testosterone ratio (p = 0.003). By contrast, AMH (42 +/- 14 vs. 32 +/- 7 pm, p = 0.018), Inhibin B (211 (146-226) vs. 176 (129-204) ng/L, p = 0.059) and LH (3.8 +/- 1.5 vs. 3.2 +/- 1.2 U/L, p = 0.096) decreased. During pegvisomant treatment IGF-I (204 (160-290) vs. 106 (97-157) mug/L, p = 0.001) and oestradiol (86 +/- 28 vs. 79 +/- 25 pm, p = 0.060) decreased. No significant changes or trends in the other reproductive hormones occurred during the two treatment regimens. GH/IGF-I activity was positively associated with serum oestradiol, suggesting that GH/IGF-I stimulates aromatase activity in vivo. As a novel observation, we found that high GH activity was associated with reduced levels of the Sertoli cell marker AMH. Further studies are needed to evaluate possible effects of GH on Sertoli cell function and/or spermatogenesis.

 

[Michael Scally MD]

Yassin AA, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clinical Obesity. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss - Yassin - 2013 - Clinical Obesity - Wiley Online Library

What is already known about this subject
* Hypogonadism is associated with increased fat mass and reduced muscle mass, which contributes to obesity and health risks, such as cardiovascular disease.
* Testosterone treatment of hypogonadal men improves muscle mass and reduces fat mass; however, many of these studies are of short duration.
* Thus, the long-term effects of testosterone on body anthropometry are not known.

What this study adds
* Long-term testosterone treatment of hypogonadal men, up to 5 years duration, produced marked and significant decrease in body weight, waist circumference and body mass index.

Hypogonadism contributes to reduced muscle mass and increased adiposity. Testosterone treatment ameliorates loss of muscle mass and reduces fat accumulation associated with hypogonadism.

In this study, we evaluated the long-term effects of normalizing testosterone (T) levels in hypogonadal men on anthropometric parameters. Open-label, single-center, cumulative, prospective registry study of 261 men (32–84 years, mean 59.5?±?8.4 years, with T levels ?12?nmol?L?1 [mean: 7.7?±?2.1]).

Among the 261 men on T treatment, we followed up on 260 men for at least 2 years, 237 for 3 years, 195 for 4 years and 163 for at least 5 years. Subjects received parenteral T undecanoate 1000?mg every 12 weeks after an initial interval of 6 weeks.

Body weight (BW), waist circumference (WC) and body mass index (BMI) were measured at baseline and yearly after treatment with T.

BW decreased from 100.1?±?14.0?kg to 92.5?±?11.2?kg and WC was reduced from 107.7?±?10.0?cm to 99.0?±?9.1?cm. BMI declined from 31.7?±?4.4?m?kg?2 to 29.4?±?3.4?m?kg?2. All parameters examined were statistically significant vs. baseline and vs. the previous year over 5 years, indicating a continuous weight loss (WL) over the full observation period. The mean per?cent WL was 3.2?±?0.3% after 1 year, 5.6?±?0.3%, after 2 years, 7.5?±?0.3% after 3 years, 9.1?±?0.3% after 4 years and 10.5?±?0.4% after 5 years.

The data obtained from this uncontrolled, observational, registry study suggest that raising serum T to normal physiological levels in hypogonadal men produces consistent loss in BW, WC and BMI. These marked improvements were progressive over the 5 years of the study.

 

[Michael Scally MD]

Duarte RV, Raphael JH, Southall JL, Labib MH, Whallett AJ, Ashford RL. Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy. BMJ Open 2013;3(6). Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy -- Duarte et al. 3 (6) -- BMJ Open

OBJECTIVES: This study aimed to investigate the hypothalamic-pituitary-gonadal axis in a sample of male patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain and the presence of osteopaenia and/or osteoporosis in those diagnosed with hypogonadism.

DESIGN: Observational study using health data routinely collected for non-research purposes.

SETTING: Department of Pain Management, Russells Hall Hospital, Dudley, UK.

PATIENTS: Twenty consecutive male patients attending follow-up clinics for intrathecal opioid therapy had the gonadal axis evaluated by measuring their serum luteinising hormone, follicle stimulating hormone, total testosterone, sex hormone binding globulin and calculating the free testosterone level. Bone mineral density was measured by DEXA scanning in those patients diagnosed with hypogonadism.

RESULTS: Based on the calculated free testosterone concentrations, 17 (85%) patients had biochemical hypogonadism with 15 patients (75%) having free testosterone <180 pmol/L and 2 patients (10%) between 180 and 250 pmol/L. Bone mineral density was assessed in 14 of the 17 patients after the exclusion of 3 patients. Osteoporosis (defined as a T score </=-2.5 SD) was detected in three patients (21.4%) and osteopaenia (defined as a T score between -1.0 and -2.5 SD) was observed in seven patients (50%). Five of the 14 patients (35.7%) were at or above the intervention threshold for hip fracture.

CONCLUSIONS: This study suggests an association between hypogonadism and low bone mass density in patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain. Surveillance of hypogonadism and the bone mineral density levels followed by appropriate treatment may be of paramount importance to reduce the risk of osteoporosis development and prevention of fractures in this group of patients.

 

[Michael Scally MD]

Demontis F, Piccirillo R, Goldberg AL, Perrimon N. The influence of skeletal muscle on systemic aging and lifespan. Aging Cell. The influence of skeletal muscle on systemic aging and lifespan - Demontis - Aging Cell - Wiley Online Library

Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age-related diseases such as metabolic syndrome, cancer, Alzheimer's disease, and Parkinson's disease. Here we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle-derived growth factors and cytokines, known as myokines, modulate systemic physiology. Myokines may influence the progression of age-related diseases and contribute to the inter-tissue communication that underlies systemic aging.

 

[Michael Scally MD]

Zhao D, Pan L, Zhang F, et al. Successful use of aromatase inhibitor letrozole in NOA with an elevated FSH level: a case report. Andrologia. http://onlinelibrary.wiley.com/doi/10.1111/and.12122/abstract

Aromatase inhibitors inhibit the conversion of testosterone to oestrogens and could reduce serum oestradiol concentrations. Letrozole is one of aromatase inhibitors frequently used in treatment of men with oligospermia. We present the case of an infertile man with small testes and an elevated FSH level, which was diagnosed as NOA, hypospermatogenesis proven by testicular biopsy. After taking letrozole for 3 months, semen analyses by computer-aided sperm analysis present that this man had normal spermatogenesis. This is the first case report of the activation of spermatogenesis, in man who was NOA with elevated FSH level, resulting from the use of the one of aromatase inhibitors.