OnLine First

[Michael Scally MD]

No real surprise here except for NO changes in FSH/LH.

Gregoriou O, Bakas P, Grigoriadis C, Creatsa M, Hassiakos D, Creatsas G. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertility and sterility. http://www.fertstert.org/article/S0015-0282(12)00436-0/abstract (Elsevier)

Objective - To compare the effects of 2.5 mg letrozole with those of 1 mg anastrazole daily on the hormonal and semen profiles of a subset of infertile men with low T/E2 ratios.

Design - Prospective, nonrandomized study.

Setting - Reproductive medicine clinic.

Patient(s) - The study group consisted of 29 infertile men with a low serum T/E2 ratio (<10).

Intervention(s) - Patients were divided into two groups. Group A included 15 patients treated with 2.5 mg letrozole orally once daily for 6 months, and Group B consisted of 14 patients treated with 1 mg anastrazole orally every day for 6 months.

Main Outcome Measure(s) - Hormonal evaluation included measurement of serum FSH, LH, PRL, T, and E2. In all sperm analyses pretreatment and posttreatment total motile sperm counts (ejaculate volume × concentration × motile fraction) were evaluated.

Result(s) - The use of aromatase inhibitors (either letrozole or anastrazole) in cases of infertile men with low T/E2 ratios improved both hormonal and semen parameters.

Conclusion(s) - This study suggests that some men with severe oligospermia, low T levels, and normal gonadotropin concentration may have a treatable endocrinopathy.

 

[Michael Scally MD]

Angelova P, Momchilova A, Petkova D, Staneva G, Pankov R, Kamenov Z. Testosterone replacement therapy improves erythrocyte membrane lipid composition in hypogonadal men. Aging Male. Testosterone replacement therapy improves erythrocyte membrane lipid composition in hypogonadal men, The Aging Male, Informa Healthcare

Aim: The aim of this study was to investigate the effects of testosterone replacement therapy (TRT) on erythrocyte membrane (EM) lipid composition and physico-chemical properties in hypogonadal men. Methods: EM isolated from three patients before and after TRT with injectable testosterone undecanoate or testosterone gel were used for analysis of the phospholipid and fatty acid composition, cholesterol/phospholipid ratio, membrane fluidity, ceramide level and enzyme acivities responsible for sphingomyelin metabolism.

Results: TRT induced increase of phosphatidylethanolamine (PE) in the EMs and sphingomyelin. Reduction of the relative content of the saturated palmitic and stearic fatty acids and a slight increase of different unsaturated fatty acids was observed in phosphatidylcholine (PC). TRT also induced decrease of the cholesterol/total phospholipids ratio and fluidization of the EM.

Discussion: The TRT induced increase of PE content and the reduction of saturation in the PC acyl chains induced alterations in the structure of EM could result in higher flexibility of the erythrocutes. The increase of the SM-metabolizing enzyme neutral sphingomyelinase, which regulates the content of ceramide in membranes has a possible impact on the SM signaling pathway.

Conclusion: We presume that the observed effect of TRT on the composition and fluidity of the EM contributes for improvement of blood rheology and may diminish the thrombosis risk. Larger studies are needed to confirm the findings of this pilot study.

 

[Michael Scally MD]

Florvaag A, Oberle V, Fritzenwanger M, et al. Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells. Aging Male. Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells, The Aging Male, Informa Healthcare

Background: Endothelial progenitor cells (EPCs) are thought to contribute to reendothelialization and neoangiogenesis. Since it is known that EPCs express a testosterone receptor, we wanted to assess the prevalence of testosterone deficiency in patients with CHF and its impact on circulating EPCs.

Methods: 137 male patients with chronic heart failure (CHF) were included (age 61 +/- 13 years; BMI 29 +/- 5 kg/m(2); New York Heart Association classification (NYHA) I: n = 47, NYHA II: n = 51, NYHA III: n = 39). Numbers of different populations of circulating EPCs were quantified using flow cytometry. Levels of free testosterone and EPC-regulating cytokines were determined using ELISA.

Results: The prevalence of testosterone deficiency in our University CHF clinic was 39%. However, there was no difference between patients with and without testosterone deficiency regarding their levels of EPCs. Testosterone levels were inversely correlated with age (R(2) = -0.32, p = 0.001) and NYHA status (R(2) = 0.28, p = 0.001) and correlated with cardiorespiratory capacity (R(2) = 0.26, p = 0.03).

Conclusion: Testosterone deficiency is frequent in male patients with CHF but does not appear to impact the regenerative EPCs.

 

[Michael Scally MD]

Huang L, Steyn FJ, Tan HY, et al. The Decline in Pulsatile GH Secretion throughout Early Adulthood in Mice Is Exacerbated by Dietary-Induced Weight Gain. Endocrinology.http://endo.endojournals.org/content/early/2012/07/16/en.2012-1178.abstract (The Decline in Pulsatile GH Secretion throughout Early Adulthood in Mice Is Exacerbated by Dietary-Induced Weight Gain)

The transition between puberty and adulthood is accompanied by a slowing in linear growth. Although GH is a key factor that drives somatic development into adulthood, early adulthood coincides with a reduction in circulating levels of GH. To this extent, a pathological decline in postpubertal GH secretion is detrimental to attainment of peak lean muscle mass and bone mass and promotes adiposity and increases susceptibility to the development of obesity in adulthood. Here we characterized pulsatile GH secretion in C57BL/6J mice at 12 and 16 wk of age. Deconvolution analysis of these measures reveals a reduction in pulsatile GH secretion between 12 and 16 wk of age. Dietary intervention with high-fat feeding at 8 wk of age results in a significant increase in adiposity, the development of glucose intolerance, and hyperinsulinemia. We show the exacerbation of the age-associated decline in pulsatile GH secretion in high-fat-fed mice after 4 wk of dietary intervention (at 12 wk of age), and a further suppression of pulsatile GH secretion by 8 wk of dietary intervention (at 16 wk of age). Suppressed pulsatile secretion of GH did not coincide with an elevation in circulating free fatty acids. Rather, we observed increased hepatic triglyceride content and an eventual decrease in circulating levels of IGF-I. Given the established role of GH in maintaining healthy aging, we anticipate that an advancing of the age-associated decline in pulsatile GH secretion as a consequence of dietary-induced weight gain may have long-term ramifications on adult health.

 

[Michael Scally MD]

Szulc P, Schoppet M, Goettsch C, et al. Endocrine and Clinical Correlates of Myostatin Serum Concentration in Men - the STRAMBO Study. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2012/07/16/jc.2012-1273.abstract (Endocrine and Clinical Correlates of Myostatin Serum Concentration in Men—the STRAMBO Study)

Context: Myostatin is expressed mainly in skeletal muscle cells and acts as an inhibitor of muscle growth and differentiation. However, data on the determinants of serum myostatin concentrations in humans are limited.

Objective: The aim of the study was to assess the correlates of serum myostatin concentrations in men.

Design: We conducted a cross-sectional analysis of the STRAMBO cohort.

Setting: Men holding private health insurance coverage with Mutuelle de Travailleurs de la Région Lyonnaise were included in the study.

Participants: A total of 1121 male volunteers aged 20–87 yr participated in the study.

Interventions: Nonfasting blood samples were collected.

Main Outcome Measures: We measured the association of the investigated variables with circulating myostatin levels.

Results: Serum myostatin levels increased slightly with age until 57 yr and then decreased. Circulating myostatin levels showed circannual variation, with the highest concentration in spring. In men older than 57 yr, serum myostatin levels decreased across increasing quartiles of body mass index and of total central and peripheral fat mass (P<0.05 to<0.001). Serum myostatin levels were positively correlated with serum levels of 25-hydroxycholecalciferol (25OHD), even after adjustment for season. Average myostatin levels were 0.47 SD higher in men with 25OHD above 40 ng/ml, compared with those with 25OHD below 20 ng/ml (P<0.05). Current smokers had lower myostatin concentration. Neither current physical activity nor serum levels of PTH, testosterone, and 17?-estradiol were associated with myostatin concentrations.

Conclusions: In men, circulating myostatin levels show seasonal changes and are associated with age, body mass index, fat mass, smoking, and 25OHD levels.

 

[Michael Scally MD]

Nagata N, Kawai K, Nakanishi I. Subtle structural changes in tetrahydroquinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions. J Chem Inf Model. Subtle structural changes in tetrahydroquinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions - Journal of Chemical Information and Modeling (ACS Publications)

Tetrahydroquinolines (THQs), a new class of nonsteroidal selective androgen receptor (AR) modulators, have two indispensable functional groups, i.e., a hydroxyl group for AR binding and a nitro group for agonistic activity. Interestingly, switching the nitro to a cyano group, the compound acts as an antagonist. To understand this phenomenon, molecular dynamics simulations were applied for dihydrotestosterone (DHT) and representative THQs complexes with AR. Upon ligand binding, the hydroxyl group formed a tight hydrogen-bond (H-bond) with Asn705 on Helix 3 (H3). The immobilization of Asn705 on H3 is helpful in the formation of tight H-bonds with Asp890 on loop 11-12, and this immobilization consequently leads to a stabilization of H12. The difference in the DHT carbonyl isosteres affected the presence or absence of the H-bonds between the hydroxyl group of THQ and Thr877 and the distortion of H12, which is caused by the methyl group of THQ. Thus, the binding, agonist, and antagonist functions were controlled by subtle structural changes in THQ.

 

[Michael Scally MD]

Althof SE. Psychological interventions for delayed ejaculation/orgasm. Int J Impot Res 2012;24(4):131-6. International Journal of Impotence Research - Psychological interventions for delayed ejaculation/orgasm

Of all the male sexual dysfunctions, delayed ejaculation (DE) is the least understood, least common and least studied. This paper aims to review and integrate the diverse psychological theories and proposed psychological interventions for DE. Clinicians will then be able to more clearly discern the relevant psychological/interpersonal issues of the patient/couple and implement systematically based effective interventions. After reviewing the literature, it is clear that no one theory accounts for all the varied presentations of DE, and no theory by itself has strong empirical support. However, awareness of the diverse points of view helps clinicians conduct better assessments and broaden their understanding of the patient's ejaculatory dysfunction. Similarly, no one psychological intervention works for all patients, nor will unsystematic random selection of interventions. This paper stresses on the need to clearly identify the source of the dysfunction and select treatments based upon the precipitating and maintaining factors. Much work remains to be done with regard to our understanding and treatment of DE. Specifically, we need to craft an evidence-based definition, assess the true prevalence of the dysfunction, demonstrate the efficacy of psychological interventions and design validated outcome measures.

 

[Michael Scally MD]

Veldhuis JD, Liu PY, Takahashi PY, Keenan DM. Dynamic Testosterone Responses to Near-Physiological LH Pulses are Determined by the Time-Pattern of Prior Intravenous LH Infusion. American Journal of Physiology - Endocrinology And Metabolism. http://ajpendo.physiology.org/content/early/2012/07/16/ajpendo.00200.2012.abstract (Dynamic Testosterone Responses to Near-Physiological LH Pulses are Determined by the Time-Pattern of Prior Intravenous LH Infusion)

The long-lived glycoprotein hormone, human chorionic gonadotropin (hCG), downregulates testosterone (T) biosynthesis in vitro and in vivo in animals and humans. The degree to which short-lived pulses of pituitary luteinizing hormone (LH) do so, particularly at physiological concentrations, is not known. We test the hypothesis that continuous LH infusion compared with bolus injections of LH every 1 hr or every 2 hr overnight downregulates T-secretory responses to a subsequent fixed template of 3 consecutive i.v. pulses of a physiological amount of recombinant human (rh) LH [triple stimulus]. Nineteen healthy men ages 18-49 yr each underwent four separate randomly ordered overnight GnRH-receptor antagonist treatments with superimposed i.v. infusions of saline or rhLH (1-hr pulses, 2-hr pulses, or continuously). Each 12-hr infusion protocol was followed by the triple rhLH-pulse stimulus the next morning. During the triple stimulus, basal (nonpulsatile) as well as total (basal plus pulsatile) T secretion was higher after overnight 2-hr and 1-hr rhLH pulses than after continuous rhLH or saline delivery. Approximate entropy a probabilistic measure of feedforward-induced irregularity of T-concentration time series was higher after 1-hr rhLH pulses than after continuous rhLH. Analytical estimation of pulsatile rhLH-T dose-response measures revealed higher T-secretory sensitivity and greater rhLH potency (lower EC50) after exposure to 1-hr than 2-hr rhLH pulses. Collectively, these data indicate that in vivo dynamics of LH-stimulated T secretion under standardized conditions in men depend upon the prior time mode of LH delivery into the bloodstream.

 

[Michael Scally MD]

Nardozza Junior A, Szelbracikowski Sdos S, Nardi AC, Almeida JC. Age-related testosterone decline in a Brazilian cohort of healthy military men. Int Braz J Urol 2012;37(5):591-7. :: International Braz J Urol :: / http://www.brazjurol.com.br/september_october_2011/Nardozza_591_597.pdf

INTRODUCTION: Androgen decline in the aging man has become a topic of increasing clinical relevance worldwide, as the reduction in testosterone levels has been reported to be accompanied by loss of muscle mass, accumulation of central adiposity, impaired mobility and increase risk of bone fractures. Although well-established in studies conducted in developed countries, progressive decline in serum testosterone levels with age has been poorly investigated in Brazil.

AIM: To determine the pattern of blood testosterone concentrations decline with age in a cohort of Brazilian healthy military men.

MATERIALS AND METHODS: We retrospectively reviewed data on serum testosterone measurements of healthy individuals that had undergone a routine check-up at the Military Biology Institute. Blood samples were obtained early in the morning, and total testosterone concentration was determined using a commercial chemoluminescent immunoassay. Mean values were analyzed in five age groups: </= 40, 41 to 50, 51 to 60, 61 to 70, and > 70 years.

MAIN OUTCOME MEASURE: Mean total testosterone levels.

RESULTS: 1,623 subjects were included in the analysis; mean age was 57 years (24 to 87), and mean testosterone level was 575.5 ng/dL (25.0 to 1308.0 ng/dL). The evaluation of age-related changes in total testosterone levels revealed a progressive reduction in serum levels of this hormone with increasing age. Testosterone levels below 300 ng/dL were reported in 321 participants, a prevalence of nearly 20% in the study population.

CONCLUSION: In agreement with other findings, a reduction of total testosterone levels with age was reported for healthy Brazilian men.

 

[Michael Scally MD]

Estradiol & Aggression

Vaillancourt KL, Dinsdale NL, Hurd PL. Estrogen receptor 1 promoter polymorphism and digit ratio in men. Am J Hum Biol. Estrogen receptor 1 promoter polymorphism and digit ratio in men - Vaillancourt - 2012 - American Journal of Human Biology - Wiley Online Library

OBJECTIVES: The 2D:4D digit ratio, the relative lengths of the index and ring fingers in humans, is a widely used proxy measure for prenatal testosterone exposure. Varying distributions of androgen and estrogen receptors on the second and fourth digits, both of which regulate digit development, appears to be the basis for this effect. Polymorphism in a tandem repeat in the gene coding for the estrogen receptor alpha (ESR1) in zebra finches (Taeniopygia guttata) not only explains a significant amount of variation in digit ratio but also seems to explain the significant correlation between digit ratio and sexual behavior in these birds. Here, we investigate the effect of TA polymorphism in ESR1 on 2D:4D and aggressive behavior in men.

METHODS: We genotyped ESR1 polymorphism in samples collected for a previous study in which we had demonstrated an association between androgen receptor polymorphism and aggression, but not 2D:4D.

RESULTS: We found a significant effect of ESR1 TA repeat number on left hand 2D:4D ratio. More TA repeats were associated with higher, more feminized, digit ratios. We found no effect on right hand 2D:4D. We also found an effect of ESR1 polymorphism on aggressive behavior. Greater heterozygosity in TA(n) was associated with lower physical aggression.

CONCLUSIONS: Our results suggest that a significant amount of left hand 2D:4D variation and aggressive behavior is due to this variation in ESR1, and that some of the correlation between digit ratio and social behavior is due to pleiotropic effects of ESR1 variation on the two traits.

 

[Michael Scally MD]

Genetic Markers for Testosterone and Estrogen Level Regulation Identified

Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer.

SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. Researchers conducted a large study of the association of SHBG concentrations with markers in the human genome in ~22,000 white men and women to determine which loci influence SHBG concentrations.

Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR,ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.


Coviello AD, Haring R, Wellons M, et al. A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation. PLoS Genet 2012;8(7):e1002805. PLoS Genetics: A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies.

We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10?106),PRMT6 (rs17496332, 1p13.3, p = 1.4×10?11), GCKR (rs780093, 2p23.3, p = 2.2×10?16), ZBTB10(rs440837, 8q21.13, p = 3.4×10?09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10?35), SLCO1B1(rs4149056, 12p12.1, p = 1.9×10?08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10?12), ZNF652(rs2411984, 17q21.32, p = 3.5×10?14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10?14), LHCGR(rs10454142, 2p16.3, p = 1.3×10?07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10?08), andUGT2B15 (rs293428, 4q13.2, p = 5.5×10?06).

These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10?08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBGgene that together almost double the proportion of variance explained at the locus.

Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

 

[Michael Scally MD]

Darras VM, Van Herck SLj. Iodothyronine deiodinase structure and function: from ascidians to humans. Journal of Endocrinology. http://joe.endocrinology-journals.org/content/early/2012/07/23/JOE-12-0204.full.pdf

Iodothyronine deiodinases are important mediators of thyroid hormone action. They are present in tissues throughout the body where they catalyze T3 production and degradation via respectively outer and inner ring deiodination (ORD/IRD).

Three different types of deiodinases (D1, D2, D3) have been identified in vertebrates from fish to mammals. They share several common characteristics, including a selenocysteine residue in their catalytic centre, but show also some type-specific differences. These specific characteristics seem very well conserved for D2 and D3, while D1 shows more evolutionary diversity related to its Km, PTU sensitivity and dependence on DTT as a cofactor in vitro.

The three deiodinase types all have an impact on systemic T3 levels and they all contribute directly or indirectly to intracellular T3 availability in different tissues. The relative contribution of each of them, however, varies amongst species, developmental stages and tissues. This is especially true for amphibians, where the impact of D1 may be minimal. D2 and D3 expression and activity respond to thyroid status in an opposite and conserved way, while the response of D1 is variable, especially in fish.

Recently a number of deiodinases have been cloned from lower chordates. Both urochordates and cephalochordates possess selenodeiodinases, although they cannot be classified in one of the three vertebrate types. In addition, the cephalochordate amphioxus also expresses a non-selenodeiodinase. Finally, deiodinase-like sequences have been identified in the genome of non-deuterostome organisms, suggesting that deiodination of externally derived thyroid hormones may even be functionally relevant in a wide variety of invertebrates.

 

[Michael Scally MD]

Measurement Of Salivary Cortisol In 2012 – Laboratory Techniques And Clinical Indications

Inder WJ, Dimeski G, Russell A. Measurement of salivary cortisol in 2012 – laboratory techniques and clinical indications. Clinical Endocrinology. Measurement of salivary cortisol in 2012 &ndash; laboratory techniques and clinical indications - Inder - Clinical Endocrinology - Wiley Online Library

The utility of measuring salivary cortisol has become increasingly appreciated since the early 1980s. Salivary cortisol is a measure of active free cortisol and follows the diurnal rhythm of serum or plasma cortisol. The saliva sample may be collected by drooling or through the use of absorbent swabs which are placed into the mouth until saturated. Salivary cortisol is therefore convenient for patients and research participants to collect non-invasively on an outpatient basis. Several assay techniques have been used to measure salivary cortisol including radioimmunoassay and more recently liquid chromatography-tandem mass spectrometry. The analytical sensitivity varies between these assay methods, as does the potential for cross reactivity with other steroids. The interpretation of salivary cortisol levels relies on rigorous standardization of sampling equipment, sampling protocols and assay technology with establishment of a local reference range. Clinically, the commonest use for salivary cortisol is measuring late night salivary cortisol as a screening test for Cushing's syndrome. Several studies have shown diagnostic sensitivities and specificities of over 90%, which compares very favourably with other screening tests for Cushing's syndrome such as the 24 hour urinary free cortisol and the 1mg overnight dexamethasone suppression test. There are emerging roles for the use of salivary cortisol in diagnosing adrenal insufficiency, particularly in conditions associated with low cortisol binding globulin levels, and in the monitoring of glucocorticoid replacement. Finally, salivary cortisol has been used extensively as a biomarker of stress in a research setting, especially in studies examining psychological stress with repeated measurements.

 

[Michael Scally MD]

Negative Effect Of Pioglitazone On Testosterone

Sridhar S, Walia R, Sachdeva N, Bhansali A. Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: A randomized double blind placebo-controlled study. Clin Endocrinol (Oxf). Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: A randomized double blind placebo-controlled study - Sridhar - Clinical Endocrinology - Wiley Online Library

OBJECTIVES: Pioglitazone is an insulin sensitizer used for the management of type 2 diabetes mellitus (T2DM). It has been shown to reduce testosterone level in patients with polycystic ovarian syndrome. However, its effect on testosterone in men has not been studied.

RESEARCH DESIGN AND METHODS: A randomized, double blind, placebo-controlled trial with six months follow-up. Fifty (25 in each group) eugonadal men (well virilized and total testosterone >/= 12 nmol/L) with T2DM, aged 30-55 yr, and HbA1c of </= 7.5%, were randomly assigned to receive pioglitazone 30 mg per day or placebo along with existing glimepiride and metformin therapy. RESULTS: As compared to placebo, six months of pioglitazone therapy in patients with T2DM resulted in significant reduction in mean total testosterone level (16.1 to 14.9 vs 17.1 to 17.0 nmol/L; p = 0.031), calculated free testosterone (p = 0.001) and bioavailable testosterone (p = 0.000) despite significant increase in sex hormone binding globulin (p = 0.000). Plasma androstenedione ((4) ) level increased (1.5 to 1.9 ng/ml; p = 0.051) following pioglitazone therapy. The decrease in testosterone was independent of change in body weight, body fat, and HbA1c.

CONCLUSION: Pioglitazone therapy significantly decreases total, free and bioavailable testosterone in eugonadal men with T2DM. The effects of these alterations need to be determined by further long term studies.

 

[Michael Scally MD]

Eichholzer M, Barbir A, Basaria S, et al. Serum sex steroid hormones and frailty in older American men of the Third National Health and Nutrition Examination Survey (NHANES III). Aging Male. Serum sex steroid hormones and frailty in older American men of the Third National Health and Nutrition Examination Survey (NHANES III), The Aging Male, Informa Healthcare

Objective: To determine whether frailty is associated with circulating total and free testosterone, total and free estradiol, and sex hormone-binding globulin (SHBG) in older men.

Methods: With NHANES III data of 461 men aged 60 years and older, we used logistic regression to analyze the associations between serum concentrations of sex steroid hormones, SHBG and frailty. Participants meeting any three or more of the five frailty criteria were classified as "frail", all others were considered as non-frail.

Results: 2.5% of men were frail. Men with SHBG >/=66 nmol/L had three times the odds of frailty (OR = 2.97; 95% CI 1.28-6.86) compared to men with SHBG <66 nmol/L. Men with free testosterone levels below 243 pmol/L had an increased odds of frailty (OR = 3.92; 95% CI 1.29-11.89). None of these associations was statistically significant after additionally adjusting for body mass index, smoking and history of cardiovascular diseases (CVD). Total testosterone, and total and free estradiol serum levels were not statistically significantly associated with frailty.

Conclusions: In this US nationally representative study of older men, low free testosterone and high SHBG serum levels were associated with a significantly increased odds of frailty after adjustment for age and race/ethnicity. These associations may, however, be explained by confounding due to obesity, smoking, and the higher prevalence of CVD in frail men or by low hormones or high SHBG mediating the association between obesity, smoking, CVD and frailty.

 

[Michael Scally MD]

Hyde Z, Flicker L, McCaul KA, et al. Associations between Testosterone Levels and Incident Prostate, Lung, and Colorectal Cancer. A Population-Based Study. Cancer Epidemiol Biomarkers Prev. Associations between Testosterone Levels and Incident Prostate, Lung, and Colorectal Cancer. A Population-Based Study

BACKGROUND: The relationship between testosterone and cancer is relatively unexplored. We sought to examine whether testosterone and related hormones are associated with incident prostate, lung, and colorectal cancer.

METHODS: This was a population-based cohort study. Demographic and clinical predictors of cancer, and testosterone, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were measured between 2001 and 2004 in 3,635 community-dwelling men aged 70 to 88 years (mean 77 years). Cancer notifications were obtained via electronic record linkage until December 31, 2010.

RESULTS: During a mean follow-up period of 6.7 +/- 1.8 years, there were 297, 104, and 82 cases of prostate, colorectal, and lung cancer. In adjusted competing risks proportional hazards models, each one SD increase in free testosterone was associated with a 9% increase in prostate cancer risk (95% confidence interval [CI], 1.00-1.18), but other hormones were not significantly associated. No significant associations were observed between hormonal parameters and colorectal cancer. Higher total testosterone was associated with lung cancer. Compared with the mean of 15 nmol/L, men with levels of 20 nmol/L were 1.38 times more likely to be cases (95% CI, 1.21-1.57), whereas those with levels of 30 nmol/L were 3.62 times more likely to be cases (95% CI, 2.53-5.18). Higher free testosterone was also associated with lung cancer, though SHBG and LH were not. Associations were maintained after exclusion of current smokers.

CONCLUSIONS: Higher free testosterone was associated with incident prostate cancer. Higher testosterone levels may also be associated with lung cancer.

Impact: Further studies should investigate whether these risks apply to men receiving testosterone therapy.

 

[Michael Scally MD]

Kaufman JM, Miller MG, Fitzpatrick S, McWhirter C, Brennan JJ. One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study. J Sex Med 2012;9(4):1149-61. One-Year Efficacy and Safety Study of a 1.62% Testosterone Gel in Hypogonadal Men: Results of a 182-Day Open-Label Extension of a 6-Month Double-Blind Study - Kaufman - 2012 - The Journal of Sexual Medicine - Wiley Online Library

INTRODUCTION: A new formulation of testosterone gel (1.62% testosterone gel) with increased viscosity and reduced volume of application has been shown to be safe and efficacious after 182 days of use in a phase 3, double-blind study in adult hypogonadal males. AIM: The objective of this study was to evaluate the efficacy and safety of the 1.62% testosterone gel after daily application to the skin in a 182-day (6-month) open-label extension of the initial 182-day double-blind study.

METHODS: One hundred and sixty-three subjects, aged 26 to 77 years, continued on active (Continuing Active subjects) 1.62% testosterone gel for the remainder of the study (364 days total). In 28 subjects who had previously received placebo (Formerly Placebo subjects), the dose was titrated to normal levels of serum total testosterone (300-1,000 ng/dL). Dose adjustments for both groups were allowed at specific visits to maintain serum testosterone within a normal range.

MAIN OUTCOME MEASURE: The main outcome measure was the percentage of subjects with serum total testosterone average concentrations (C(av) ) within the normal range at day 364.

RESULTS: On day 364, 77.9% (95% confidence interval: 70.0, 84.6) of the Continuing Active subjects and 87.0% (66.4, 97.2) of the Formerly Placebo subjects had C(av) values within the eugonadal range. The 1.62% testosterone gel was safe and well tolerated in this study.

CONCLUSION: Treatment with 1.62% testosterone gel for up to 1 year (182 days for the Formerly Placebo subjects, 364 days for the Continuing Active subjects) was safe and efficacious, resulting in >77% of treated subjects achieving normal serum testosterone levels at final visit.

 

[Michael Scally MD]

Zupancic ML, Cantarel BL, Liu Z, et al. Analysis of the Gut Microbiota in the Old Order Amish and Its Relation to the Metabolic Syndrome. PLoS ONE 2012;7(8):e43052. PLoS ONE: Analysis of the Gut Microbiota in the Old Order Amish and Its Relation to the Metabolic Syndrome

Obesity has been linked to the human gut microbiota; however, the contribution of gut bacterial species to the obese phenotype remains controversial because of conflicting results from studies in different populations. To explore the possible dysbiosis of gut microbiota in obesity and its metabolic complications, we studied men and women over a range of body mass indices from the Old Order Amish sect, a culturally homogeneous Caucasian population of Central European ancestry. We characterized the gut microbiota in 310 subjects by deep pyrosequencing of bar-coded PCR amplicons from the V1–V3 region of the 16S rRNA gene. Three communities of interacting bacteria were identified in the gut microbiota, analogous to previously identified gut enterotypes. Neither BMI nor any metabolic syndrome trait was associated with a particular gut community. Network analysis identified twenty-two bacterial species and four OTUs that were either positively or inversely correlated with metabolic syndrome traits, suggesting that certain members of the gut microbiota may play a role in these metabolic derangements.

 

[Michael Scally MD]

Qin F, Zhang J, Cao H, et al. Effects of 1800-MHz Radiofrequency Fields on Circadian Rhythm of Plasma Melatonin and Testosterone in Male Rats. J Toxicol Environ Health A 2012;75(18):1120-8. An Error Occurred Setting Your User Cookie

Radiofrequency fields (RF) at 1800 MHz are known to affect melatonin (MEL) and testosterone in male rats, but it remains to be determined whether RF affected circadian rhythm of these plasma hormones. Male Sprague-Dawley rats were exposed to 1800-MHz RF at 208 muw/cm(2) power density (SAR: 0.5762 W/kg) at different zeitgeber (ZT) periods of the day, including 0 (ZT0), 4 (ZT4), 8 (ZT8), 12 (ZT12), 16 (ZT16), and 20 (ZT20) h. RF exposure was 2 h/d for 32 d. From each rat, the concentrations of plasma MEL and testosterone were determined in plasma after RF exposure and compared with controls. The results confirmed the existence of circadian rhythms in the synthesis of MEL and testosterone, but revealed an inverse relationship in peak phase of these rhythms. These rhythms were disturbed after exposure to RF, with the effect being more pronounced on MEL than testosterone. The most pronounced effect of RF exposure on MEL and testosterone appears to be in rats exposed to RF at ZT 16 and ZT0 h, respectively. Data suggest that regulation of testosterone is controlled by MEL and that MEL is more sensitive to RF exposure.

 

[Michael Scally MD]

KNDy [Kisspeptin (KP), Neurokinin B (NKB), and Dynorphin A (DYN)] Neuron Concept Challenged

Hrabovszky E, Sipos MtT, Molnar CS, et al. Low Degree of Overlap Between Kisspeptin, Neurokinin B, and Dynorphin Immunoreactivities in the Infundibular Nucleus of Young Male Human Subjects Challenges the KNDy Neuron Concept. Endocrinology. http://endo.endojournals.org/content/early/2012/08/16/en.2012-1545.abstract (Low Degree of Overlap Between Kisspeptin, Neurokinin B, and Dynorphin Immunoreactivities in the Infundibular Nucleus of Young Male Human Subjects Challenges the KNDy Neuron Concept)

Previous immunohistochemical and in situ hybridization studies of sheep, goats, and rodents indicated that kisspeptin (KP), neurokinin B (NKB), and dynorphin A (DYN) are extensively colocalized in the hypothalamic arcuate nucleus, thus providing a basis for the KP/NKB/DYN (KNDy) neuron concept; in both sexes, KNDy neuropeptides have been implicated in the generation of GnRH neurosecretory pulses and in the negative feedback effects of sexual steroids to the reproductive axis.

To test the validity and limitations of the KNDy neuron concept in the human, we carried out the comparative immunohistochemical analysis of the three neuropeptides in the infundibular nucleus (Inf; also known as arcuate nucleus) and stalk of young male human individuals (<37 yr). Results of quantitative immunohistochemical experiments established that the regional densities of NKB immunoreactive (IR) perikarya and fibers, and the incidence of afferent contacts they formed onto GnRH neurons, were about 5 times as high as those of the KP-IR elements. Dual-immunofluorescent studies confirmed that considerable subsets of the NKB-IR and KP-IR cell bodies and fibers are separate, and only about 33% of NKB-IR perikarya and 75% of KP-IR perikarya were dual labeled. Furthermore, very few DYN-IR cell bodies could be visualized in the Inf. DYN-IR fibers were also rare and, with few exceptions, distinct from the KP-IR fibers. The abundance and colocalization patterns of the three immunoreactivities showed similar trends in the infundibular stalk around portal blood vessels.

Together these results indicate that most NKB neurons in the Inf do not synthesize detectable amounts of KP and DYN in young male human individuals. These data call for a critical use of the KNDy neuron terminology when referring to the putative pulse generator system of the mediobasal hypothalamus. We conclude that the functional importance of these three neuropeptides in reproductive regulation considerably varies among species, between sexes, and at different ages.