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[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-341] Prevalence and Predictors of Sexual Dysfunction in Older Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-341

Z Hyde, L Flicker, GJ Hankey, KA McCaul, OP Almeida, P Chubb, BB Yeap. University of Western Australia, Crawley, Australia; University of Western Australia, Crawley, Australia; Royal Perth Hospital, Perth, Australia; University of Western Australia, Perth, Australia; Royal Perth Hospital, Perth, Australia; Fremantle Hospital, Fremantle, Australia; Fremantle Hospital, Fremantle, Australia.

Context - Hypogonadism in younger men is associated with impaired libido and erectile dysfunction. Testosterone levels decline with age, but the relationship between androgens and sexual dysfunction in older men is controversial.

Objective - To determine whether testosterone levels are associated with sexual dysfunction.

Design - Prospective cohort study.

Setting - Perth, Western Australia.

Participants - 1,744 community-dwelling men aged 70-88 years (mean 76 years) at baseline.

Methods - Questionnaires in 2001-04 and 2008-09 assessed social and medical factors. Testosterone, SHBG and LH were measured in 2001-04. Sexual dysfunction was assessed by questionnaire in 2008-09 (mean follow-up period 5.2 years).

Results - Sexual problems were highly prevalent, with 50.5% (95% CI 48.2-52.9%) reporting erectile dysfunction, 46.5% (95% CI 44.2-48.8%) lacking interest in sexual activity, 38.4% (95% CI 36.1-40.6%) unable to climax, and 22.0% (95% CI 20.1%-24.0%) anxious about their ability to perform sexually. Painful and unpleasurable sex were less common (<5%). In multivariate logistic regression analyses, total testosterone levels in the lowest quintile were associated with lack of interest (OR=1.59; 95% CI 1.13-2.23), but were not associated with any other sexual problem. Cardiovascular disease, diabetes, and insomnia were the factors most commonly associated with sexual problems.

Conclusions - Androgen deficiency is unlikely to be a major cause of sexual dysfunction in older men. However, low testosterone levels may be a causal factor in impaired libido. Clinical trials should investigate this concept.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-342] Clinical Relevance of Identifying Late-Onset Hypogonadism Based on Proposed Criteria http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-342

YKD Tay, KK Ng, R Chen. Changi General Hospital, Singapore; Changi General Hospital, Singapore.

Aim - It has been proposed that late-onset hypogonadism (LOH) may be identified in older males based upon total testosterone (TT) <11 mM and free testosterone (FT) <220 pM in the presence of poor morning erections, reduced libido and erectile dysfunction. As testosterone deficiency is reportedly associated with metabolic syndrome (MetS), we sought to study the relevance of this proposed criteria in clinical practice.

Method - Cross-sectional study of 236 consecutive males, predominantly Chinese (mean age 54.6±7.6 (SD) years), self-referred to a hospital-based Men's Health clinic for perceived symptoms of androgen deficiency. Sex hormones, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG) and high-density lipoprotein (HDL) were assayed; low-density lipoprotein (LDL) and FT calculated; blood pressure (BP), waist circumference (WC) and body mass index (BMI) obtained. Subjects also answered the modified International Index of Erectile Dysfunction (IIEF-5) and Ageing Male Symptom (AMS) questionnaires. MetS was defined using the ethnic specific International Diabetes Federation guidelines.

Results - The prevalence of LOH and MetS was 8.4% and 36.5%, respectively. Men with LOH had significantly poorer IIEF-5 scores (10.1±4.5 vs 13.9±5.9, P=0.006), higher WC (94.9±8.3 vs 89.1±9.1 cm, P=0.011), BMI (27.6±3.4 vs 24.9±3.2 kg/m2, P=0.000) and FPG (7.4±2.8 vs 6.0±1.4 mM, P= 0.048); lower TT (8.6±1.2 vs 16.2±4.9 nM, P= 0.000), FT (173.7±24.4 vs 314.6±74.9 pM, P=0.000) and sex hormone binding globulin (30.4±6.8 vs 37.7±16.7 nM, P=0.000). However, the prevalence of MetS was not significantly different between groups with and without LOH (46.7% vs 35.7% P=0.396). Neither was BP (systolic 134.4±14.8 vs 129.2±18.5 mmHg, P=0.236; diastolic 81.0±10.9 vs 78.5±10.8 mmHg, P=0.353), TC (5.3±1.3 vs 5.4±0.9 mM, P=0.790), TG (2.1±2.5 vs 1.6±0.9 mM, P=0.437), HDL (1.3± 0.3 vs 1.4±0.4 mM, P=0.526), LDL (3.1±1.0 vs 3.2±0.9 mM, P=0.430) nor total AMS scores significantly different (43.9±10.4 vs 41.1±11.4, P=0.306).

Conclusion - While the proposed criteria identify hypogonadal men with sexual dysfunction, it does not appear to identify those with MetS or parameters of poor metabolic status apart from WC, BMI and FPG, suggesting that it may be of limited clinical relevance.

(1) Wu FC et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363(2):123-35.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-228] Iatrogenic Polycythemia Vera Caused by Clomiphine Citrate Therapy of Hypogonadal Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-228

N Onwubalili, MM-H Cho. UMDNJ-New Jersey Medical School, Newark, NJ; University Reproductive Associates, PC, Hasbrouck Heights, NJ.

Case 1. M.D. is a 33 year old man referred with his wife for evaluation of infertility. M.D. was found to have oligo-terazoospermia. Urology noted that the examination was unremarkable. M.D. was initiated on clomiphine citrate (CC) 25mg daily. At 3 months follow-up, MA's hematocrit increased from 48.0% to 54.1% as total testosterone increased from 216 ng/dL to 507 ng/dL.

Baseline: FSH 5.4 mIU/ml, LH 4.8 mIU/ml, estradiol 36 pg/ml, total testosterone 216 ng/dL.
After therapy: FSH 7.3 mIU/ml, LH 11.4 mIU/ml, estradiol 19.1 pg/ml, testosterone 581 ng/dL.

Case 2. D.L. is a 42 year old man referred with his wife for evaluation of secondary infertility. D.L. reported a history of “low testosterone” and has been on intramuscular testosterone therapy. D.L. was found to have severe oligo-astheno-terazoospermia. His hematocrit was 50.1%. D.L.'s testosterone therapy was discontinued, and his hematocrit decreased to 46.1%, and testosterone was 163 ng/dL. D.L. was then started on CC 25mg daily and his testosterone increased to 487 ng/dL and 47% after the first month of therapy. In the third month of CC therapy, D.L.'s testosterone was 716ng/dL and hematocrit increased to 53.5%.

Background: - A known side-effect of testosterone therapy is polycythemia vera (PV). The Endocrine Society recommends that patients on testosterone therapy have a baseline hematocrit, another one at 3-6 months, with subsequent annual testing thereafter while on testosterone therapy. Discontinuation of testosterone therapy is recommended in patients with a hematocrit >54%.

CC is a selective estrogen receptor modulator that increases production of gonadotropins by inhibiting negative feed back to the hypothalamus and pituitary. CC is used off-label for treatment of male hypogonadism (low testosterone and/or oligozoospermia). Men treated with CC have variable response to the medication. Those that respond to CC therapy have elevated levels of FSH and/or LH. Higher level of LH often results in higher levels of testosterone, some with supra-physiologic levels of testosterone.

However, men who receive CC therapy are not routinely evaluated for PV. Our cases demonstrate that PV can result from "normal" levels of testosterone in a previously hypogonadal male treated with CC.

Conclusion: - CC causes an increase in hematocrit in men, similar to testosterone therapy. Men treated with CC should have hematocrit monitored regularly for the development of PV.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-340] Elevated Luteinizing Hormone Predicts Ischemic Heart Disease Events in Older Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-340

Z Hyde, PE Norman, L Flicker, GJ Hankey, KA McCaul, OP Almeida, P Chubb, BB Yeap. University of Western Australia, Crawley, Australia; University of Western Australia, Crawley, Australia; University of Western Australia, Crawley, Australia; Royal Perth Hospital, Perth, Australia; University of Western Australia, Crawley, Australia; Royal Perth Hospital, Perth, Australia; Fremantle Hospital, Fremantle, Australia; Fremantle Hospital, Fremantle, Australia.

Context - Hypogonadism in men is associated with insulin resistance, elevations in pro-inflammatory cytokines and fibrinogen, and an atherogenic lipid profile. However, it is uncertain whether the age-related decline in testosterone is associated with ischaemic heart disease (IHD) events.

Objective - To determine whether testosterone, and its associated hormones, sex hormone binding globulin (SHBG) and luteinizing hormone (LH), predict IHD events.

Design - Prospective cohort study.

Methods - Between 2001-04, 3,637 community-dwelling men aged 70-88 years underwent a clinical assessment of cardiovascular risk factors, and biochemical assessment of testosterone, SHBG, and LH. Free testosterone was estimated. Participants were followed until December 2008 using electronic record linkage to capture IHD events (hospital admission or death).

Results - Mean follow-up was 5.1 years. During this period, 618 men (17.0%; 95% CI 15.8-18.3%) experienced an event, of which 160 were fatal. Men with higher baseline total or free testosterone levels experienced fewer IHD events (HR=0.89; 95% CI 0.82-0.97 and HR=0.86; 95% CI 0.79-0.94 for each one standard deviation increase in total and free testosterone, respectively). These associations were maintained after adjustment for age and waist:hip ratio, but did not persist after adjustment for prevalent IHD or other cardiovascular risk factors. SHBG was not associated with IHD events. In contrast, higher LH levels were associated with greater IHD events in both univariate (HR=1.15; 95% CI 1.08-1.22) and adjusted analyses (HR=1.08; 95% CI 1.01-1.15).

Conclusions - Dysregulation of the hypothalamic-pituitary-gonadal axis may be a risk factor for IHD. Further studies of men with either elevated LH or low testosterone are warranted.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-470] Testosterone Therapy Decreased Adiponectin and Subcutaneous Fat in Aging Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-470

L Frederiksen, K Hojlund, DM Hougaard, TH Mosbech, R Larsen, A Flyvbjerg, J Frystyk, K Brixen, M Andersen. Odense University Hospital, Odense, Denmark; Statens Serum Institut, Copenhagen, Denmark; Technical University of Denmark, Kgs Lyngby, Denmark; Aahus University Hospital, Aarhus, Denmark.

Background: Testosterone therapy has a well-known positive effect on lean body mass in hypogonadal men (Isidori et al, JCEM 2005). We found a corresponding effect on lean body mass in ageing men with low normal bioavailable testosterone. We found, however, no significant effect on insulin sensitivity using the euglycemic hyperinsulinemic clamp technique. Adiponectin is an insulin-sensitizing adipokine secreted by the adipose tissue and in young men adiponectin has been inversely associated with subcutaneous fat on the abdomen (SAT) (Frederiksen et al, JCEM 2008).

Aim: We wanted to investigate the effect of testosterone therapy on adiponectin, SAT, visceral adipose tissue (VAT) and thigh fat area (TFA) in ageing men with low normal bioavailable testosterone.

Methods: A randomized, double-blinded, placebo-controlled study of six months testosterone treatment (gel) in 38 men, aged 60-78 years, with bioavailable testosterone < 7.3 nmol/l (Nielsen et al, JCEM 2006) and a waist circumference > 94 cm. Serum total testosterone was measured by tandem mass spectrometry. Adiponectin was determined by an in-house time resolved immunofluorometric assay. SAT, VAT and TFA were measured by magnetic resonance imaging (MRI). Coefficients (b) represent the placebo-controlled mean effect of intervention.

Results: Testosterone treatment decreased adiponectin (b=-1.308 mg/l, p=0.001), SAT (b= -0.03 fat area/total area, p= 0.018) and TFA (b= -0.03 area/total area, p<0.001) while VAT (b= 0.01 area/total area; p=0.54) remained unchanged.

Conclusion: In ageing men with low normal bioavailable testosterone levels, six months of testosterone treatment reduced serum adiponectin and subcutaneous adipose tissues on abdomen and thigh, whereas no significant changes in visceral adipose tissue were observed.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-351] Effect of Application Site, Clothing Barrier and Application Site Washing on Testosterone Transfer with a 1.62% Testosterone Gel http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-351

J Stahlman, M Britto, S Fitzpatrick, C McWhirter, SL Testino, Jr, JJ Brennan, TL Zumbrunnen. Abbott, Marietta, GA; Quintiles, Inc, Overland Park, KS.

Objectives: To evaluate the effect of application site, clothing barrier and application site washing on the transfer of testosterone from males dosed with 1.62% testosterone gel (T-gel) to female partners.

Methods: An open-label, randomized, parallel group, crossover study was performed in 24 healthy male/female couples. Up to 5.0 g of gel was applied to the upper arms and shoulders or abdomens of male subjects. Skin contact occurred 2 hours after gel application between male and female subjects to compare the effect of wearing or not wearing a t-shirt and washing or not washing before contact. Serum samples were collected from females for 24-hour assessments of testosterone levels using validated LC/MS/MS methodology; maximum serum concentration (Cmax), and time-averaged concentration over the 24-hour post contact period (Cav) were assessed. Subjects were monitored for adverse events.

Results: Testosterone exposure (Cav and Cmax) in females increased by up to 27% (2.5 g) or up to 280% (5.0 g) from baseline after direct skin contact at 2 hours with the gel application site on the male partner, although Cav remained within the eugonadal range. Transfer after direct skin contact was higher when the application and contact sites were the upper arms/shoulders versus the abdomen. Transfer from the abdomen was prevented when a t-shirt was worn (2.5 g dose). When the application site was washed before contact, mean Cav was comparable to baseline and Cmax was slightly higher (14%). Testosterone concentrations returned to baseline within 48 hours after last skin contact. The 1.62% T-gel appeared to be safe and well tolerated in this study.

Conclusions: There is a risk of testosterone transfer from males using 1.62% T-gel to others who come into direct skin contact with the application site. This can be prevented by covering the application site with a t-shirt or washing the site of gel application before anticipated contact.

Sources of Research Support: Abbott.

Disclosures: JS: Employee, Abbott Laboratories. MB: Researcher, Abbott Laboratories. SF: Employee, Abbott Laboratories. CM: Employee, Abbott Laboratories. SLT: Employee, Abbott Laboratories. JJB: Employee, Abbott Laboratories. TLZ: Employee, Abbott Laboratories.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-224] High Prevalence of Micropenis and Cryptorchidism in Brazilian Patients with Congenital Hypogonadotropic Hypogonadism: Impact of Testosterone Replacement Therapy Started in Adolescence or Adulthood on Final Penile Length http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-224

AM Faria, LFG Silveira, MG Teles, AP Abreu, LP Brito, S Domenice, AC Latronico, EMF Costa, BB Mendonca. Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Background: Micropenis and cryptorchidism have been classically associated with congenital isolated hypogonadotropic hypogonadism (IHH). A previous study reported low prevalence of micropenis and cryptorchidism in IHH, lacking sensitivity to aid in the clinical diagnosis of this disorder (1).

Aim: To evaluate the prevalence of micropenis and cryptorchidism in a Brazilian cohort of IHH without any prior hormonal therapy and the impact of testosterone replacement started in adolescence or adulthood on penile growth, as well as the presence of pretreatment gynecomastia.

Patients and methods: Penile length was measured as previously described (2) and compared to Brazilian standards (3). Micropenis was defined as a morphologically normal penis, with a stretched length of more than -2.5 SD below the mean value for age. Nineteen patients with Kallmann's syndrome (KS) and 10 patients with normosmic IHH (nIHH) had basal pretreatment and follow-up measures of penile length after at least 1 year of full dose intramuscular testosterone esters replacement. Mean age of initiation of therapy was 20.5 years in KS (13-41) and 20 years in nIHH (16-26). Basal median LH and total testosterone was <0.6 IU/l (<0.6-0.9) and 33.5 ng/dl (11-84) in KS, and <0.6 IU/l (<0.6-1.3) and 27 ng/dl (<14-43) in nIHH, respectively.

Results: A history of cryptorchidism was present in 63% of patients with KS and 30% with nIHH and pretreatment gynecomastia in 26% with KS and in 20% with nIHH. All patients had basal penile length compatible with micropenis. Basal average penile length was 5.63 cm (-5.17 SD) in patients with KS and 5.71 cm (-5.44 SD) in patients with nIHH. Post-treatment average penile length was 9.81 cm (-2.93 SD) in KS (gain of 4.17 cm or +2.24 SD, prevalence of micropenis=68%) and 9.87 cm (-2.89 SD) in nIHH (gain of 4.16 cm or +2.55 SD, prevalence of micropenis=50%).

Conclusions: Micropenis and cryptorchidism are highly prevalent conditions in patients with IHH. This is in accordance with the knowledge that fetal pituitary LH is important for penile growth from midgestation to birth and during the postnatal surge of testosterone during the first 4-6 months of life (2). Testosterone replacement in adolescence or adulthood markedly improves penile length, although micropenis persists in the majority of patients, mainly in KS. These findings suggest that micropenis and cryptorchidism are important clinical parameters for distinction between IHH and constitutional delay of puberty.

(1) Pitteloud N et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002; 87:152-60.

(2) Tsang S. When size matters: a clinical review of pathological micropenis. J Pediatr Health Care. 2010; 24:231-40.

(3) Gabrich PN et al. Penile anthropometry in Brazilian children and adolescents. J Pediatr (Rio J). 2007; 83:441-6.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-209] Effects of Testosterone Treatment on Inflammatory Markers in Older Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-209

M Maggio, G Ceda, Y Milaneschi, C Cattabiani, PJ Snyder, L Ferrucci. University of Parma, Parma, Italy; University Hospital, Parma, Italy; National Institutes of Health (NIH), Baltimore, MD; University of Pennsylvania School of Medicine, Philadelphia, PA.

During aging in men there is a progressive reduction in testosterone levels and an increase in inflammatory markers (1-2). A causal relationship has been hypothesized (3-5) but never been tested in a randomized clinical trial.

Aim of the Study. To test the effects of transdermal testosterone on inflammatory markers.

Methods. 108 men ?65 years were selected by testosterone levels <1 SD below the mean for normal young men, 475 ng/dL, and were randomized to receive a testosterone or placebo patch in a double blind fashion for 36 months. Ninety-six subjects completed 36 months of treatment. The present study was performed in 70 men, 42 in the testosterone group and 28 in the placebo group who had sufficient sera available for assay. We measured serum concentrations of testosterone, c-reactive protein (CRP), interleukin-6 (IL-6), soluble interleukin-6 receptors (sIL6r and sgp130),soluble TNF-alpha receptor 1 (sTNFR1) by immunoassays. Body composition had been measured previously by DXA. Statistical analyses were performed using random-effect regression analyses, modelling an unstructured covariance matrix with slope and intercept as random effects.

Results. The mean age at baseline was 71.8 ± 4.9 years in all 70 subjects. Testosterone- and placebo-treated groups had similar values for age, inflammatory markers and fat mass at baseline. The testosterone-treated group had lower levels of testosterone and BMI at baseline, but the differences were not statistically significant (p values of 0.06 and 0.07, respectively). Testosterone levels rose significantly following initiation of treatment in the testosterone-treated group but not in the placebo group. CRP levels were 1.58 ± 3.33 and 1.48 ± 2.75 at baseline in T and placebo-group, respectively. After 36 months of treatment, CRP levels increased in both the T (2.79 ± 4.10) and placebo (9.97 ± 24.77) groups. Similar trends were observed for the other inflammatory markers. A significant treatment*time interaction term, indicating a less steep increase in T-treated subjects compared to placebo-treated, was found only for CRP (p=0.03) and TNFR1 (p=0.02).No significant differences were found for IL-6 and soluble Interleukin-6 receptors (sIL6r and sgp130).

Conclusion. Transdermal testosterone treatment of men ?65 years for 36 months was associated with less steep increase in CRP and TNFR1 than placebo treatment.

1. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001; 86:724–731.

2. Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, Guralnik JM, Longo DL 2005 The origins of age-related proinflammatory state. Blood 2005; 105:2294–2299.

3. Maggio M, Basaria S, Ceda GP, Ble A, Ling SM, Bandinelli S, Valenti G, Ferrucci L. The relationship between testosterone and molecular markers of inflammation in older men. J Endocrinol Invest. 2005;28(11 Suppl Proceedings):116-9.

4. Maggio M, Basaria S, Ble A, Lauretani F, Bandinelli S, Ceda GP, Valenti G, Ling SM, Ferrucci L. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J Clin Endocrinol Metab. 2006;91(1):345-7.

5. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004; 89:3313–3318.

Sources of Research Support: National Institute on Aging.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-210] Is the Hematopoietic Effect of Testosterone Mediated by Erythropoietin? The Results of a Clinical Trial in Older Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-210

M Maggio, G Ceda, Y Milaneschi, F Lauretani, C Cattabiani, PJ Snyder, L Ferrucci. University of Parma, Parma, Italy; University Hospital, Parma, Italy; National Institutes of Health (NIH), Baltimore, MD; University of Pennsylvania School of Medicine, Philadelphia, PA.

In the elderly, low testosterone levels are predictors of anemia(1),which is consistent with the known stimulatory effect of testosterone on erythropoiesis (2). The mechanism(s) underlying the erythropoietic effect of testosterone are unknown.

Aim of the Study - To test the effects of transdermal testosterone on hemoglobin and erythropoietin levels in older men with low-normal levels of testosterone.

Methods - 108 men >65 years old were selected by a serum testosterone concentration ?1 SD below the mean for normal young men (<475 ng/dL) and randomized to receive a testosterone or placebo patch in a double blind fashion for 36 months. Ninety-six subjects completed 36 months of treatment. The present analysis was performed on 70 men, 42 in the testosterone treatment group and 28 in placebo group who had sufficient sera remaining for assay of testosterone, hemoglobin, erythropoietin, and creatinine. Total testosterone was assessed by electrochemiluminescence immunoassay with minimum detective concentration (MDC) of 2 ng/dl and interassay coefficients of variation (CV) <10%. Erythropoietin was assessed by ELISA with MDC of 2.5 mIU/ml and interassay CV <10%.

Statistical analyses were performed using random-effect regression, modelling an unstructured covariance matrix with slope and intercept as random effects. Random-effects models were valuable in this context, allowing the detection of variation between subjects and autocorrelation between repeated measurements of the same participants over time.

Results- The mean age ± SD of the 70 subjects at baseline was 71.8 ± 4.9 years. The testosterone and placebo groups did not differ at baseline in age, hemoglobin, and erythropoietin. The testosterone-treated group had lower baseline testosterone and BMI than the placebo group but neither was quite statistically significant (p=0.06 and p=0.07, respectively). Testosterone replacement therapy for 36 months, as compared to placebo, induced a significant increase in haemoglobin (beta ± SE = 0.86 ± 0.31, p = 0.01) but no change in erythropoietin levels (beta ± SE = -0.24 ± 2.16, p=0.91).

Conclusion - Transdermal testosterone treatment of men ? 65 years for 36 months significantly increased their hemoglobin levels but not their erythropoietin levels. Other mechanisms should be explored to explain the hematopoietic effect of testosterone.

1) Ferrucci L,Maggio M,Bandinelli S,Basaria S, Lauretani F, Ble A, Valenti G,Ershler WB, Guralnik JM and Longo DL. Low Testosterone Levels and the Risk of Anemia in Older Men and Women.Arch Intern Med. 2006 July 10; 166(13):1380–1388.

2) Shahani S, Braga-Basaria M, Maggio M, Basaria S. Androgens and erythropoiesis: past and present. J Endocrinol Invest. 2009 Sep;32(8):704-16.

3) Rishpon-Meyerstein N, Kilbridge T, Simone J, Fried W. The effect of testosterone on erythropoietin levels in anemic patients. Blood 1968, 31: 453-60.

4) Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB and Bhasin S. Effects of graded doses of Testosterone on Erythropoiesis in Healthy Young and Older Men. J Clin Endocrinol Metab, March 2008, 93(3): 914-19.

Sources of Research Support: National Institute on Aging.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-207] Safety and Tolerability of LGD-4033, a Novel Non-Steroidal Oral Selective Androgen Receptor Modulator (SARM), in Healthy Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-207

S Basaria, L Collins, M Sheffield-Moore, EL Dillon, K Orwoll, KM Lakshman, R Miciek, T Storer, J Ulloor, A Zhang, S Bhasin. Boston University School of Medicine, Boston, MA; University of Texas Medical Branch, Galveston, TX.

Background: Sarcopenia is a common consequence of aging and chronic illness. Testosterone administration increases muscle mass and strength, but concerns about potential adverse effects on the prostate have restrained enthusiasm for its use as anabolic therapy. Selective Androgen Receptor Modulators (SARMs) are a class of androgen receptor (AR) ligands that display tissue-selective activation of androgenic signaling. LGD-4033 is a novel non-steroidal, orally active SARM that binds to AR with a Ki of ?1nM and high selectivity (?4,000-fold) compared to other nuclear receptors. In animal models, LGD-4033 demonstrated an anti-resorptive and anabolic activity in muscles and bones, and high degree of selectivity for muscle versus prostate. In single ascending dose study, the safety and tolerability of LGD-4033 has been established up to 22 mg. In this Phase-1 study, we evaluated the safety and tolerability of multiple ascending doses of LGD-4033 administered daily for 20 days in healthy men.

Methods: In this placebo-controlled, Phase-1 multiple ascending dose study, healthy men (age 21-50) were randomized to 0.1, 0.3, or 1 mg LGD-4033 or placebo daily for 20 days. Liver function tests, fasting lipids, blood counts, PSA and ECG were monitored throughout the treatment period and the subsequent 5 weeks of observation phase. As an exploratory objective, body composition was measured using DEXA scan and maximal voluntary strength was measured using 1-RM method.

Results: LGD-4033 was well tolerated. There were no drug-related serious adverse event and none of the subjects was discontinued due to adverse events. All adverse events were mild to moderate in nature with no statistical difference between the active and placebo groups. There were no significant changes in hemoglobin, hematocrit or serum PSA at any dose. QT-interval did not change significantly during the intervention period. There was no indication of hepatotoxicity. Dose-dependent reduction in HDL cholesterol was seen in the LGD-4033 groups. Total lean body mass increased while fat mass decreased in the LGD-4033 groups. No changes in maximal voluntary strength were seen over the short treatment period.

Conclusion: In healthy young men, short-term treatment with LGD-4033 was safe and well tolerated. Longer intervention studies are needed to evaluate the efficacy of this non-steroidal SARM on body composition, muscle strength, and physical function.

Sources of Research Support: Ligand Pharmaceuticals, La Jolla, CA.

 

[Michael Scally MD]

BPH & Prostate Cancer

A re-analysis of data from patients enrolled in the Prostate Cancer Prevention Trial (PCPT) has now provided “the strongest evidence to date” that a diagnosis of symptomatic benign prostatic hyperplasia (BPH) is not associated with any increase in risk for prostate cancer.

This study, just published on line by Schenk et al. in the American Journal of Epidemiology, was designed to investigate the possibility of any association between symptomatic BPH and prostate cancer risk. The study cohort was made up of 5,068 participants in the PCPT, all enrolled between 1993 and 2003 and randomized to the placebo arm of the trial.

A total of 1,225/5,068 men in this study cohort (24.2 percent) were found to have prostate cancer during the 7-year-long trial. The other 3,843 men were shown to be prostate cancer-free as a result of a prostate biopsy that was negative for prostate cancer at the trial’s conclusion. The occurrence of symptomatic BPH was assessed among the study cohort based on one or more of the following:

• Self-reporting of surgical or medical treatment for BPH

• The presence of moderately severe symptoms of BPH (International Prostate Symptom Score >14)

• Physician diagnosis

Data analyses were based on BPH status at baseline (prevalent) or the presence of BPH prior to cancer diagnosis or study end (prevalent + incident).

After data were controlled for age, race, and body mass index:

• There was no association between the presence of prevalent, symptomatic BPH and risk for prostate cancer (risk ratio [RR] = 1.03).

• There was no association between the presence of prevalent + incident , symptomatic BPH and risk for prostate cancer (RR = 0.96).

• The lack of evidence for any association was consistent across subgroups defined by

o Type of BPH-defining event (treatment, symptoms, or physician diagnosis)

o Prompt for prostate cancer diagnosis, and

o Prostate cancer grade


Schenk JM, Kristal AR, Arnold KB, et al. Association of Symptomatic Benign Prostatic Hyperplasia and Prostate Cancer: Results from the Prostate Cancer Prevention Trial. American Journal of Epidemiology 2011;173(12):1419-28. Association of Symptomatic Benign Prostatic Hyperplasia and Prostate Cancer: Results from the Prostate Cancer Prevention Trial

This study examined the association between symptomatic benign prostatic hyperplasia (BPH) and prostate cancer risk in 5,068 placebo-arm participants enrolled in the Prostate Cancer Prevention Trial (1993-2003). These data include 1,225 men whose cancer was detected during the 7-year trial - 556 detected for cause (following abnormal prostate-specific antigen or digital rectal examination) and 669 detected not for cause (without indication), as well as 3,843 men who had biopsy-proven absence of prostate cancer at the trial end. Symptomatic BPH was assessed hierarchically as self-report of surgical or medical treatment, moderately severe symptoms (International Prostate Symptom Score >14), or physician diagnosis, and analyses were completed by BPH status at baseline (prevalent) or BPH prior to cancer diagnosis or study end (prevalent plus incident). Controlled for age, race, and body mass index, neither prevalent (risk ratio = 1.03, 95% confidence interval: 0.92, 1.14) nor prevalent plus incident (risk ratio = 0.96, 95% confidence interval: 0.87, 1.06) symptomatic BPH was associated with prostate cancer risk. This lack of association was consistent across subgroups defined by type of BPH-defining event (treatment, symptoms, or physician diagnosis), prompt for prostate cancer diagnosis, and prostate cancer grade. This study provides the strongest evidence to date that BPH does not increase the risk of prostate cancer.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-229] ACE-031 (Soluble Activin Receptor Type IIB-IgG1) Increases Muscle Mass by Inhibiting Myostatin and Other Negative Regulators of Muscle: Non-Clinical and Clinical Studies http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-229

KM Attie, JL Lachey, Y Yang, D Wilson, E Haltom, ML Sherman. Acceleron Pharma, Cambridge, MA; Acceleron Pharma, Cambridge, MA. http://www.acceleronpharma.com/content/products/ace-031.jsp (ACE-031 (Muscle Growth))

Introduction. Myostatin is a potent inhibitor of muscle development, expressed post-natally exclusively in skeletal muscle. Congenital loss of myostatin leads to marked increases in muscle mass. Additional members of the TGF-? superfamily also act as negative regulators of muscle through the activin receptor type IIB (ActRIIB). ACE-031 is an investigational ActRIIB-IgG fusion protein therapeutic designed to act as a decoy receptor to bind myostatin and related ligands and block their signaling through endogenous ActRIIB receptors. ACE-031 is also designed to bind ligands that are involved in the regulation of other tissues, including fat and bone. ACE-031 is currently being developed to treat the neuromuscular disease Duchenne muscular dystrophy (DMD).

Non-clinical Studies. Animal studies have shown increased muscle mass, strength, and function in various models of neuromuscular disease, including the mdx mouse model for DMD. Studies using the murine version of ACE-031 (RAP-031) in mdx mice and/or other animal models have demonstrated increased lean mass (skeletal muscle), increased grip strength, decreased fibrosis and fat in muscle, increased utrophin expression, decreased creatine kinase, increased bone mass, and decreased fat mass.

Clinical Studies. Two phase 1, double-blind, placebo-controlled, studies (single ascending dose and multiple ascending dose, MAD) have been completed in healthy post-menopausal women (total n=118). In these studies, ACE-031 was generally well tolerated. Most adverse events were mild and transient, and included injection site erythema, headache, and epistaxis. Studies were not powered for pharmacodynamic (PD) endpoints. Preliminary PD data in the MAD study included the following mean maximum % changes from baseline: total body lean mass (DXA) increased 5.2% and mean thigh muscle volume (MRI) increased 4.1% in the 1 mg/kg q2wk group at Day 36. Total body fat mass decreased 8.2% in the 3 mg/kg q4wk group at Day 113. Bone biomarkers CTX decreased 55.4% in the 2 and 3 mg/kg q4wk groups at Day 57 and BSAP increased by 26.3% in the 1 mg/kg q4wk group at Day 15.

Conclusions. Preliminary data demonstrate that ACE-031 was generally well-tolerated in humans and had salutary effects on muscle, fat and bone. These results support further studies of ACE-031 in neuromuscular diseases to investigate its potential to improve muscle mass, strength, and function. A phase 2 study of ACE-031 in DMD is ongoing.

Sources of Research Support: Acceleron Pharma Inc.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[This is a series of abstracts apparently done on the same male subjects. The first abstract is important at least insofar it describes a study finally on the possible role of E2 in libido!!! There are other animal studies consistent with the abstract. I am hopeful there will be a follow-up with a full-text article. And, further studies on the role of E2 in libido and erection function. I have posted far too many times that E2 manipulation for libido and erection function is without support. However, the anecdotal evidence is there and studies will hopefully clarify the issue.]

[P3-206] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Sexual Desire in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-206

BZ Leder, H Lee, EW Yu, S-AM Burnett-Bowie, JC Pallais, ML Webb, KE Wulczyn, AB Servais, JS Finkelstein. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.

Testosterone (T) is thought to be the primary hormonal regulator of libido/sexual desire (SD) in men.

Methods: To determine if SD is also regulated by estrogen (E), we recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous T and E. Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of a T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E. SD was assessed using both the International Index of Erectile Function (SD-M1) and a previously-validated question asking subjects to compare their sex drive now with baseline levels (-2=much less, -1=somewhat less, 0=the same, +1=somewhat more, +2=much more) (SD-M2).

Changes were assessed within the T/E- cohort to assess T effects and between cohorts to assess E effects. Specifically, if T has an independent effect on SD, subjects in the T/E- cohort who receive no or little testosterone replacement should experience decreased SD compared to those receiving higher doses (as E levels will be the same). Conversely, if E has an independent effect on SD, differences between the T/E+ and T/E- cohorts should be observed in Groups 2-5 but not G1 (because E levels should be similarly low in subjects in G1 of both cohorts but higher in G2-5 in the T/E+ cohort).

Results: Mean serum T levels in G1-5 were 43, 173, 346, 477, and 882 ng/dL in the T/E+ cohort and 34, 199, 329, 475, and 857 ng/dL in the T/E- cohort (P=NS at each dose between cohorts). SD declined more in men receiving placebo T than in the other T dose groups in both the T/E+ (P<0.005 vs G2, 3, 4 and 5 by SD-M1 and SD-M2) and the T/E- (P<0.02 vs G4 and G5 by SD-M1 and P<0.01 vs G3, 4, and 5 by SD-M2) cohorts. Aromatase inhibition further reduced SD in men receiving T gel (G2-5, P<0.0001 by both SD-M1 and SD-M2) but had no effect on SD in men receiving placebo T gel (G1, P=0.72 by SD-M1 and P=0.53 by SD-M2).

Conclusions: As expected, lowering T levels reduces SD in men. Surprisingly, S[exual]D[esire] is further reduced in men treated with an aromatase inhibitor to reduce E production. These results suggest that non-aromatizable androgens may be less effective than aromatizable androgens for hypogonadal men with low sexual desire.


[P3-204] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Body Composition in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-204

JS Finkelstein, S-AM Burnett-Bowie, BZ Leder, JC Pallais, EW Yu, BJ Thomas, ML Webb, KE Wulczyn, JM Youngner, H Lee. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.

Testosterone (T) therapy increases lean mass and decreases fat mass in men.

Methods: To determine if these effects are due to T itself or to its conversion to estrogen (E), we recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous T and E. Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of a T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E. Total body fat and lean mass were assessed by DXA and subcutaneous (SC) fat and thigh muscle areas were measured by CT at wk 0 and 16.

Changes were assessed within the T/E- cohort to assess T effects and between cohorts to assess E effects. If T has an independent effect on body composition, differences vs the placebo T group should most likely occur as the T dose increases within the T/E- cohort because E levels should be similarly low in all groups while T levels become progressively more discordant. Conversely, if E has an independent effect on body composition, differences between the T/E+ and T/E- cohorts should be observed in Groups 2-5 but not G1 because E levels should be similarly low in subjects in G1 of both cohorts but higher in G2-5 in the T/E+ cohort.

Results: Mean serum T levels in G1-5 were 44, 187, 332, 538, and 829 ng/dL in the T/E+ cohort and 41, 186, 339, 435, and 786 ng/dL in the T/E- cohort (P=NS at each dose between cohorts). Changes in fat measures were similar across groups within the T/E- cohort. In men who received placebo T (G1), aromatase blockade had no effect on total body fat (P=0.36) or SC fat area (P=0.66). However, in men receiving T gel (G2-5), total body fat (P<0.001) and SC fat area (P<0.001) increased more in the T/E- than the T/E+ cohort. Lean mass and thigh muscle area decreased significantly in G1 vs G2-5 in the T/E- cohort (P<0.01 for all comparisons). Aromatase blockade had no effect on changes in lean mass (P=0.17 for G1, P=0.39 for G2-5) or thigh muscle area (P=0.65 for G1, P=0.36 for G2-5).

Conclusions: These results suggest that T alone regulates lean mass and muscle size while E, but not T, regulates fat mass in men. Treatment of hypogonadal men with non-aromatizable androgens may have undesirable effects on fat accumulation.


[P3-205] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Lipid Profiles in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-205

S-AM Burnett-Bowie, AF Moore (deceased), BZ Leder, HS Lee, EW Yu, LF Borges, BF Jones, AH Linker, JS Finkelstein. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.

Studies examining the effects of androgens and estrogens on lipids in men have produced inconsistent results.

Methods: To assess the effects of androgens and estrogens on lipids in men, we recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous testosterone (T) and estradiol (E). Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of a T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E. Fasting total cholesterol, HDL, LDL, and triglycerides were measured every 4 weeks.

Changes were assessed within the T/E- cohort to assess T effects and between cohorts to assess E effects. If T has an independent effect on lipids, differences vs the placebo T group should most likely occur as the T dose increases within the T/E- cohort because E levels should be low in all groups while T levels become more discordant. Conversely, if E has an independent effect on lipids, differences between the T/E+ and T/E- cohorts should be observed in Groups 2-5 but not G1 because E levels should be similarly low in subjects in G1 of both cohorts but higher in G2-5 in the T/E+ cohort.

Results: Mean serum T levels in G1-5 were 44, 187, 332, 538, and 829 ng/dL in the T/E+ cohort and 41, 186, 339, 435, and 786 ng/dL in the T/E- cohort (P=NS at each dose between cohorts). Changes in LDL were similar in G1 vs G2-5 in both cohorts. Aromatase blockade had no effect on changes in LDL (P=0.48 for G1, P=0.37 for G2-5). In both cohorts, HDL levels increased more in men who received placebo T (G1) than in men who received T (G2-5) (P<0.03 vs G3, 4, and 5 of T/E+ and P<0.005 vs each group of T/E-). Aromatase blockade had no effect on the rise in HDL in men receiving placebo T gel (G1, P=0.69). However, in men receiving T gel (G2-5), HDL increased less (P<0.01) in the T/E- than the T/E+ cohort.

Conclusions: Across a wide range of levels, androgens and estrogens have no effect on LDL levels in men. In contrast, T withdrawal increases HDL levels in men and aromatase blockade attenuates these increases. These results suggest that using non-aromatizable androgens to treat hypogonadal men may have undesirable effects on HDL levels in adult men.


[OR35-4] Hypogonadism with Estrogen Removal (HER): Effects of Androgens and Estrogens on Prostate-Specific Antigen in Young Adult Men http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_OR35-4

JC Pallais, H Lee, EW Yu, S-AM Burnett-Bowie, BZ Leder, CW Hahn, NE Perros, CV Barry, JS Finkelstein. Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital, Boston, MA.

Using a GnRH agonist and different doses of testosterone (T) add-back, we had previously shown that lowering T levels below baseline reduced PSA levels whereas increasing T levels above baseline did not alter PSA levels in young men.

Methods: To determine if these effects are due to T itself or to its conversion to estrogen (E), we recruited 2 cohorts of healthy men age 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous T and E. Men in Cohort 1 (T/E+, n=198) were randomized to treatment with 1 of 5 doses of T gel (AndroGel®, Abbott) daily for 16 weeks (G1-placebo; G2-1.25g; G3-2.5g; G4-5g; G5-10g). Men in Cohort 2 (T/E-, n=200) were randomized to the same T doses plus anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block T to E conversion. A third control cohort (n=35) received only placebo medications. Serum PSA levels were measured at baseline and every 4 wks for 16 wks. Within the T/E- cohort, changes in PSA between T dose groups were evaluated to assess independent T effects. PSA changes between same T dose groups were compared across the T/E+ and T/E- cohorts to assess independent E effects.

Results: Mean serum T levels in Groups 1-5 were 44, 187, 332, 538, and 829 ng/dL in the T/E+ cohort, 41, 186, 339, 435, and 786 ng/dL in the T/E- cohort (P=NS at each dose between cohorts), and 584 ng/dL in the control cohort (P=NS vs men receiving 5g of T in the T/E+ and T/E- cohorts). Within both the T/E+ and T/E- cohorts, there was a strong dose response relationship between T doses and change in PSA. The percent changes in PSA in Groups 1-5 of the T/E+ and T/E- cohorts were -59%, -38%, -28%, -18%, and -1% and -52%, -42%, -24%, -15%, and -6%, respectively. Compared with the percent change in PSA in the control cohort (2%), PSA values decreased in men in both cohorts treated with less than 5g of T, but did not change in those receiving more than 5g of T. Aromatase inhibition had no effect on PSA changes at any T dose when compared across the T/E+ and T/E- cohorts.

Conclusions: Androgens regulate PSA levels in a dose-dependent manner in healthy young men. Prostate responsiveness is more sensitive to androgen deficiency rather than excess, at least in the short term. E does not appear to be involved in the hormonal regulation of PSA at T levels ranging from pre-pubertal to the upper end of the reference range.


[P1-473] Letrozole Normalizes Serum Testosterone but Has No Clinical Effects in Men with Obesity-Related Hypogonadotropic Hypogonadism http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-473

S Loves, J de Jong, A van Sorge, D Telting, A Hermus, H de Boer. Rijnstate Hospital, Arnhem, Netherlands; Rijnstate Hospital, Arnhem, Netherlands; Rijnstate Hospital, Arnhem, Netherlands; Rijnstate Hospital, Arnhem, Netherlands; Radboud University Medical Centre, Nijmegen, Netherlands.

Introduction: Hypogonadotropic hypogonadism is frequently observed in morbidly obese men, due to aromatase-dependent conversion of androgens to estrogens in adipocytes. The clinical impact of this sex hormone imbalance is not known.

Aim: To evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypogonadism.

Methods: Double-blind, placebo-controlled, 6-month trial in severely obese men (BMI > 35 kg/m2) with obesity-related hypogonadism (serum total testosterone < 10 nmol/l). Predefined drug regimen (letrozole or placebo): Starting dose 1 tablet/week, subsequent dose escalation every month up to a maximum of 7 tablets/week or until a serum total testosterone of 20 nmol/L. The dose was reduced if serum estradiol decreased below 40 pmol/L.

Results: 42 patients were included and 39 completed the study according to protocol: 18 on Letrozole and 21 receiving placebo. Mean age 44.6 ± 1.1 years (mean ± SE), BMI 41.1 ± 0.8 kg/m². At baseline, both groups were well matched for all study parameters. Placebo treatment did not affect serum hormone levels, whereas Letrozole decreased serum estradiol from 119.1 ± 10.1 to 59.2 ± 6.1 pmol/L (P = 0.0001, normal range (NR) 40 - 160 pmol/L), increased serum LH from 3.3 ± 0.3 to 8.8 ± 0.9 U/L (P < 0.0001, NR: 2.0 – 9.0 U/L) and free testosterone from 244 ± 19 to 691 ± 39 pmol/L (P < 0.0001, NR: 225 - 625 pmol/L). Both groups demonstrated a comparable decrease in body weight of about 5 kg, and a decrease in abdominal circumference of about 4 cm. Changes in fat free mass, fat mass and bone density also did not differ between groups. Glucose metabolism, lipid profiles, physical exercise capacity and psychological characteristics did not change during treatment.

Conclusion: Despite a marked rise in serum free testosterone, low dose aromatase inhibition had no somatic or psychological effects in men with obesity-related hypogonadotropic hypogonadism. We hypothesize that, with respect to non-sexual somatic and psychological parameters, males primarily thrive on oestrogens, not testosterone.

 

[Michael Scally MD]

See: https://thinksteroids.com/community/posts/765420

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P2-41] Prostate Health & Safety Parameters: Hypogonadal Patients on TRT Are Not at Higher Risk Than Eugonadal Subjects of Age-Matched Control Group — Prospective Comparative 6-Year FU Analysis http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-41

AA Yassin, AD-J Yassin, A Haider, F Saad. Institute of Urology & Andrology, Norderstedt-Hamburg, Germany; Asklepios Klinik Barmbek, Hamburg, Germany; Private Urologic Practice, Bremerhaven, Germany; Bayer Schering Pharma AG, Berlin, Germany.

Background: Prostate Safety, LUTS, BPH and the risk of prostate cancer are still the major concern when treating testosterone-deficient men with testosterone.

Objective: To evaluate prostate safety parameters in subjects under TRT in comparison with age-matched control group prospectively in follow up of many years.

Material & Methods: 154 testosterone deficient patients (baseline average age 58 ± 1.7 years and mean follow-up of 42 months, range: 38-61 months), receiving longacting injectable testosterone undecanoate 1000mg) were compared to a control cohort of 160 eugonadal men (average age 59 ± 2.8 years) with similar characteristics visiting the clinic for preventive medical check up. They underwent monitoring at baseline and 6-monthly including co-morbidities, concomitant medication, International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), digital rectal examination (DRE), total prostate volume and transitional zone measured by transrectal ultrasound (TRUS). Residual postvoiding urine volume and measuring bladder wall thickness. TRUS-guided biopsies were performed when indicated by PSA velocity > 0.75 ?g/L, or elevation over 4.0 ?g/L.

Results: At baseline, hypogonadal patients showed lower PSA values and lower prostate volumes (0.68 ± 0.4 ?g/L and 25.6 ± 1.4 ml, respectively). Subjects in the control group had PSA levels of 2.42 ± 1.2 ?g /L, and prostate volume 38.4 ± 2.42 ml at baseline. IPPS, residual postvoiding urine volume and bladder wall thickness were slightly improving. Prostate transitional zone and total volume increased as higher as in control group. No acute urinary retention and/or surgery had been noticed in TRT group, but in controls.

Conclusions:

1) Subjects with T-deficiency have lower prostate volumes and PSA levels than eugonadal ones.

2) Testosterone therapy does not worsen LUTS/BPH symptoms

3) Within 6 years follow up, the group on testosterone treatment had no adverse events such as AUR or prostate surgery as met in controls.

4) Hypogonadism offers no protection against the development of symptomatic BPH. Low to normal levels of total testosterone or free testosterone were associated with an increased risk of cancer.


[P2-44] Testosterone Treatment in Elderly Hypogonadal Patients Does Not Increase Prostate Cancer Risk: Prospective Comparative 6-Year Follow-up Analysis with Age-Matched Controls http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P2-44

AA Yassin, AD-J Yassin, A Haider, F Saad. Institute of Urology & Andrology, Norderstedt-Hamburg, Germany; Asklepios Klinik Barmbek, Hamburg, Germany; Private Urologic Practice, Bremerhaven, Germany; Bayer Schering Pharma AG, Berlin, Germany.

Objective: Evaluation of prostate safety parameter including prevalence of prostate cancer in elderly hypogonadal subjects under testosterone treatment in comparison with age- and characteristic matched control groups.Methods: 154 testosterone deficient patients (average age 58 ± 1.7 years and mean follow-up of 42 months, range: 38-61 months), receiving inj. long-acting TU 1000 mg, compared to a control cohort of 160 eugonadal men (average age 59 ± 2.8 years) with similar characteristics visiting clinic for preventive medical check up.

They underwent monitoring at baseline and 6-monthly including co-morbidities, concomitant medication, International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), digital rectal examination (DRE), total prostate volume and transitional zone measured by transrectal ultrasound (TRUS). TRUS-guided biopsies were performed when indicated by PSA velocity > 0.75 ?g/L, or elevation over 4.0?g/L.

Results: At baseline, hypogonadal patients showed lower PSA values and lower prostate volumes(0.68 ± 0.4 ?g/L and 25.6 ± 1.4 ml, respectively).Subjects in the control group had PSA levels of 2.42 ± 1.2 ?g /L, and prostate volume 38.4 ± 2.42 ml at baseline. Hypogonadal patients whose PSA velocity in the observation period was > 0,75 ?g /L, underwent TRUS-guided prostate biopsies (10 cores 2.2 cm each or saturating biopsies 24-32 cores 2.2 cm each in those men for whom a repeat biopsy was indicated). We found CaP in 5/22 biopsies, three of them unilateral with up to 10% tumor cells in a core. Gleason scores were 3+2 or 3+3. Two patients had a high grade prostate intra-epithelial neoplasia (PIN). In the 160 control subjects, 16/39 subjects who underwent biopsies showed CaP, 4 of them bilateral, with significantly higher Gleason score of 3+3 till 4+5 and up to 80% tumor cells in a core. No subject of both groups showed any abnormality in rectal palpation.

Conclusions: Subjects with T-deficiency have lower prostate volumes and PSA levels than eugonadal ones. Testosterone therapy does not increase CaP incidence. The group on testosterone treatment had smaller tumors and less malignancy (better differentiation). Hypogonadism offers no protection against the development of biopsy-detectable prostate cancer. Lower levels of total testosterone or free testosterone were associated with an increased risk of cancer. Hypogonadal patients untreated with TRT could be at higher risk to have bigger and more aggressive prostate cancers.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-212] Polycythemia Is Common during Any Testosterone Replacement and Suppressed Gonadotropin May Predict Polycythemia in Primary Hypogonadism http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-212

TT Agustsson, B McGowan, J Powrie, PV Carroll. Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background - Testosterone replacement therapy results in a wide range of benefits for men with hypogonadism. Associated risks include polycythaemia. The aim of this study is to assess the prevalence of polycythaemia in men treated with different testosterone replacement therapies and to assess changes in associated biochemical markers with possible implications for patient management.

Methods - This is a retrospective observational study. We analysed biochemical and haematological parameters of all men on testosterone therapy who attended our endocrinology unit from the 1st of January 2009 until the 30th of June 2010. Of a total of 173 men, 86 (50%) were treated with testosterone undeconate (Nebido®), 57 (33%) with transdermal testosterone gel, and 30 (17%) with intramuscular testosterone in the form of Sustanon®. Data were collected on haemoglobin concentrations, packed cell volumes, gonadotrophins, and total serum testosterone concentrations. Polycythaemia was defined as haemoglobin concentration >17 g/dl or packed cell volume >0.505.

Results - Out of the 173 men, 25 (14.5%) developed polycythaemia on at least one blood sample during the follow up period. 12 of the 86 men treated with Nebido® (14%), 8 out of the 57 men treated with transdermal gel (14%), and 5 of the 30 men treated with Sustanon® (17%) developed polycythaemia. There was no significant difference between the different treatment modalities.

Twenty eight percent of all men with polycythaemia had at least one elevated testosterone reading compared with 26% of men without polycythaemia. There was no significant difference in mean testosterone (16.1 mmol/L vs 16.9 mmol/L). 69.8% of men with primary hypogonadism and polycythaemia had suppressed gonadotrophins compared with 25% of men without polycythaemia.

Conclusions - We found no reliable correlation between testosterone levels and polycythaemia but suppressed gonadotrophin was associated with the development of polycythaemia in primary hypogonadism.

Polycthaemia is a common risk with any testosterone treatment modality. Some previous studies have indicated that this is less likely with transdermal preparations, but we found the risk to be equal in all treatment groups.

These findings demonstrate the importance of careful monitoring of haematological variables during any testosterone treatment and suggest that suppressed gonadotrophin may have a greater predictive value than testosterone measurements in hypogonadism.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P3-208] Effects of Testosterone and rhGH on Metabolic Syndrome Components in Older Men: The HORMA Study http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P3-208

J He, S Bhasin, E Binder, C Castaneda-Sceppa, K Yarasheski, ET Schroeder, SP Azen, R Roubenoff, FR Sattler. Los Angeles, Los Angeles, CA; Boston University, Boston, MA; Washington University, St Louis, MO; Northeastern University, Boston, MA; University of Southern California, Los Angeles, CA; University of Southern California, Los Angeles, CA; University of Southern California, Los Angeles, CA; Tufts University, Boston, MA.

Background: Older persons are at risk for complications of the Metabolic Syndrome (MS) including heart attack, stroke, and vascular disease.

Methods: Men 65-90 years-old (n=112) with testosterone (T) <550ng/dL and IGF-1 in lower adult tertile were randomly assigned to receive transdermal T (5 vs 10g/day) and rhGH (0, 3, or 5?g/kg/day)(1). Lean body mass (LBM) and fat mass were measured by DEXA, T levels by mass spectrometry, and insulin, IGF-1, and adiponectin by chemiluminescence (automated immulite analyzer). MS parameters were scored as -1 if favorable and +1 if adverse predetermined thresholds were achieved; values not reaching these thresholds were assigned 0. MS parameters were related to changes in T and IGF-1 levels and body composition using pathway analysis.

Results: After 16 weeks of treatment, the following parameters changed significantly (p<0.05): T (+320±478ng/dL), IGF-1 (+58±59ng/mL), total LBM (+1.79±1.89kg), total fat mass (-1.33±1.74kg), trunk fat (-0.88±1.21kg)*, BMI (+0.16±0.64), systolic blood pressure (+12.4±14.4mmHg)*, fasting triglycerides (-18.2±57.0mg/dL)*, HDL cholesterol (+3.46±6.65mg/dL)*, insulin sensitivity (QUICKI, -0.0011±0.0153)*, and HMW adiponectin (-0.18±0.76)*. MS scores (composite of MS elements designated by *) decreased -0.58±1.91 (p=0.002). In the pathway analysis, ? in T and IGF-1 were significant (p<0.05) predictors of change in total fat and LBM, which were mediators (p<0.05) of change in BMI which was then a mediator (p<0.05) of change in MS parameters leading to change (?) in MS scores. The model fits the data well (overall chi-square=32.25, with 37 degrees of freedom, null p=0.65) as depicted by ? in T and IGF-1?? in LBM and total fat?? in BMI?? in MS parameters ?improved MS scores. In the pathway, change in T and IGF-1 were only associated with changes in LBM and fat (except change in T independently affected adiponectin) which were not associated with change in MS components but latter were directly affected by change in BMI. None of the parameters explained increases in blood pressure.

Conclusions: In older men, T supplementation with or without rhGH affects some components of the MS beneficially and others adversely but together improve MS composite scores. Change in BMI is the best predictor of change in MS elements and is jointly affected by both total fat and LBM.

(1) Sattler FR, Castaneda-Sceppa C, Binder EF, Schroeder ET, Wang Y, Bhasin S, Kawakubo M, Stewart Y, Yarasheski KE, Hahn C, Colletti P, Roubenoff R, Azen SP. Testosterone and growth hormone improve body composition and muscle performance in older men: The HORMA trial. J Clin Endocrinol Metab 94(6):1991-2001, 2009.

 

[jtmoy19607]

High Prevalence of Micropenis and Cryptorchidism in Brazilian Patients with Congenital Hypogonadotropic Hypogonadism: Impact of Testosterone Replacement Therapy Started in Adolescence or Adulthood on Final Penile Length

that is good stuff I was just wondering about that.


I still hate endocrinologists, they say thatt 350 is normal levels for an 18 year old, but if a woman wants to become a man higher dosages are ok?

sorry, just a little bitter.

 

[zkt]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

http://www.acceleronpharma.com/content/company/index.jsp (Our Company)

Follistatin/Myostatin

<60 seconds. Gotta love the net.
It certainly is tempting.

 

[Michael Scally MD]

Re: The Endocrine Society 2011: The 93rd Annual Meeting & Expo [ENDO 2011]

[P1-329] Changes in Reproductive Hormone Concentrations Predict the Prevalence and Progression of the Frailty Syndrome in Older Men: The Concord Health and Aging in Men Project http://www.abstracts2view.com/endo/view.php?nu=ENDO11L_P1-329

TG Travison, A-H Nguyen, DJ Handelsman. Boston University, Boston, MA; University of Sydney, Sydney, Australia.

Background: Frailty, a syndrome of multiple morbidities, weakness, and immobility in aging, is an urgent threat to public health (1). Single measures of low serum androgen have demonstrated suggestive associations with the frailty syndrome (2-4), but the contributory role ofwithin-subject hormonal changes with time has not been assessed.

Objective: To determine, using longitudinal measurements, the contributions of serum androgens, estrogens, gonadotropins, and sex hormone-binding globulin(SHBG) to the prevalence and progression of frailty in older men.

Methods: The CHAMP study cohort is a representative sample of 1645 men (age 70+) living in Concord, Sydney, Australia (5). All measures were conducted at baseline (2005-07) and two-year followup (2007-09). The major androgens testosterone (T) and dihydrotestosterone (DHT), and estrogens estradiol (E2) and estrone (E1), were measured by liquid chromatography-tandem mass spectrometry. SHBG and the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone were measured by immunoassay. Frailty was assessed using both the Cardiovascular Health Study (CHS) index by Fried and colleagues (6) and Study of Osteoporotic Fractures (SOF) index by Ensrud and colleagues (7); each categorizes subjects as either 'robust', 'pre-frail' or 'frail.' Analyses employed logistic and proportional odds regression via generalized estimating equations (8).

Results: The frailty indices exhibited moderate subject-level agreement (intraclass correlation coefficient ? 0.5); independently, each indicated that 41% of subjects were pre-frail and 9% frail. Androgens and estrogens showed uniformly significant age-adjusted associations with frailty status measured by either index. Subjects in the lowest T quintile had 2.2-fold odds of exhibiting more significant CHS frailty as compared to the highest T quintile (p < 0.001); results for DHT, E2, E1 and calculated free T were similar, and were unchanged when SOF frailty was substituted for the CHS index. A one standard deviation two-year decrease in T, FT or LH was associated with a 1.2 to 1.3-fold increase in the odds of concurrent progression (increase in severity) of frailty, whereas baseline estrogen levels were (inversely) associated with frailty development or progression. Controlling for the presence of comorbid medical conditions did not affect results.

Conclusions: Age-related decreases in blood androgens and estrogens may accelerate the development of frailty in men.

(1) Xue CL, Clin Geriatr Med 2011; 27:1

(2) Mohr B et al., J Am Geriatr Soc 2007; 55:548

(3) Cawthon PM et al., J Clin Endocrinol Metab 2009; 94:3806

(4) Hyde Z et al., J Clin Endocrinol Metab 2010; 95:3165

(5) Cumming RG et al., Int J Epidemiol 2009; 38:374

(6) Fried LP et al., J Gerontol A Biol Sci Med Sci 2001; 56:M146

(7) Ensrud KE et al., Arch Intern Med 2008; 168:382

(8) Zeger, SL and Liang KY, Biometrics 1986; 42:121