OnLine First 2013

[Michael Scally MD]

Zhao D, Pan L, Zhang F, et al. Successful use of aromatase inhibitor letrozole in NOA with an elevated FSH level: a case report. Andrologia. Successful use of aromatase inhibitor letrozole in NOA with an elevated FSH level: a case report - Zhao - 2013 - Andrologia - Wiley Online Library

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

 

[Michael Scally MD]

Strahm E, Sjoberg U, Garle M, Rane A, Ekstrom L. Implication of Human UGT2B7, 2B15, and 2B17 in 19-Norandrosterone Metabolism. Front Endocrinol (Lausanne) 2013;4:75. Frontiers | Implication of Human UGT2B7, 2B15, and 2B17 in 19-Norandrosterone Metabolism | Frontiers in Experimental Endocrinology

Nandrolone (19-nortestosterone) is an anabolic androgenic steroid commonly abused for doping purposes. Nandrolone is mainly metabolized in the liver into 19-norandrosterone prior to glucuronidation and excretion through urine over an extended period of time.

Several UGTs (i.e., UGT2B7, UGT2B15, and UGT2B17) are thought to be the major enzymes responsible for conjugation of androgens in human. An in vitro study using recombinant enzymes expressed in insect cells showed that UGT1A4 and UGT2B7 are the two main enzymes responsible of 19-norandrosterone glucuronidation. However, the identity of the enzyme involved in nandrolone metabolism in vivo together with their relative contribution and regulation remain unknown.

Inhibition assays using human liver microsomes (HLM) incubated with 19-norandrosterone and selective inhibitors confirmed that UGT2B7 and UGT2B15 are involved in 19-norandrosterone glucuronidation, since the presence of the specific UGT2B7 and UGT2B15 inhibitors gemfibrozil and valproic acid inhibited the 19-norandrosterone glucuronidation by 35 and 45%, respectively.

HLM were genotyped for UGT2B15 D85Y, UGT2B7 H268Y, and the UGT2B17 deletion polymorphism. The glucuronidation activity on 19-norandrosterone was significantly higher in UGT2B15 DD than in the other UGT2B15 genotypes (p < 0.05).

Moreover, human liver cancer HepG2 cells were exposed to androgens to determine if the transcriptional activity of the genes of interest was affected. Only UGT2B7 mRNA expression was significantly increased (1.8-folds) after incubation with nandrolone decanoate.

These results show that the UGT2B7 and UGT2B15 are involved in 19-norandrosterone glucuronidation and that the UGT2B15 polymorphism (D85Y) is the only UGT genetic variation that influences the glucuronidation activity. This could partly explain the inter-individual variation in 19-norandrosterone excretion.

 

[Michael Scally MD]

McPherron AC, Guo T, Bond ND, Gavrilova O. Increasing muscle mass to improve metabolism. Adipocyte 2013;2(2):92-8. Landes Bioscience

Skeletal muscle insulin resistance is a predictor of the development of type 2 diabetes and maintenance of adequate muscle glucose disposal in muscle may help to prevent diabetes. Lipodystrophy is a type of diabetes caused by a reduction of white adipose tissue and the adipokine leptin. Lipidemia, insulin resistance and hyperphagia develop as a consequence. In a recent study, we showed that increasing skeletal muscle mass by inhibiting signaling of myostatin, a transforming growth factor beta (TGFbeta) family member that negatively regulates muscle growth, prevents the development of diabetes in a mouse model of lipodystrophy. Muscle-specific myostatin inhibition also prevented hyperphagia suggesting muscle may regulate food intake. Here we discuss these results in the context of strategies to increase muscle insulin sensitivity as well as new findings about the effects of myostatin and other TGFbeta family members on similar metabolic processes.

 

[Michael Scally MD]

Tordjman KM, Yaron M, Berkovitz A, Botchan A, Sultan C, Lumbroso S. Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation. Andrologia. Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation - Tordjman - 2013 - Andrologia - Wiley Online Library

We report on a case of a man with familial, X-linked, partial androgen insensitivity, in whom a new point mutation in the androgen receptor (AR) ligand-binding domain (causing a valine-to-alanine substitution at codon 686) was identified. High-dose prolonged testosterone therapy resulted in marked progression in patient's appearance and great improvement in sperm count and characteristics. In combination with intracytoplasmic microinjection, treatment resulted in fertility. This is believed to be the first report of such a case. This case supports high-dose testosterone therapeutic trial in this condition. Furthermore, it underscores the possibility of achieving fertility with current endocrine and assisted reproduction modalities, making some of these X-linked AR mutations paternally transmissible.

 

[Michael Scally MD]

Highlights
• Blue tablets were seized by Police and supposed to contain amphetamines.
• Two presumptive color tests gave ambiguous responses.
• GC–MS detected methandienone and methyltestosterone at 1.7 and 1.5 mg per tablet.
• No medicinal product containing both steroids has ever been licensed.
• Confirmatory tests are necessary in drug enforcement activities.


Favretto D, Castagna F, Maietti S, Boscolo-Berto R, Ferrara SD. When color fails: Illicit blue tablets containing anabolic androgen steroids. J Pharm Biomed Anal 2013;83:260-4. When color fails: Illicit blue tablets containing anabolic androgen steroids

The necessity of specific, confirmatory tests in the identification of seized illicit products was highlighted by the analysis of eighteen heart shaped, blue tablets confiscated by Police at a street control in the North East of Italy.

The tablets responded as amphetamines to a preliminary color test (Marquis); a subsequent, confirmatory assay by gas chromatography-mass spectrometry revealed the presence of two anabolic androgen steroids (AAS), methandienone and methyltestosterone, in concentration of 1.7 and 1.5mg respectively per tablet; no trace of amphetamine-like or nitrogen containing compounds was found. The observed orange coloration was due to the reaction of concentrated sulphuric acid, contained in the Marquis reagent, with the Delta(4) C-3 keto group of steroids.

The two AAS, banned under the world antidoping code, are not considered as psychoactive drugs of abuse in most countries, although their trafficking may entangle severe public health concerns.

 

[Michael Scally MD]

Krysiak R, Okopien B. Methyltestosterone-induced transient hyperthyroidism in a hypothyroid patient. Acta Clin Belg 2013;68(1):65-7. Methyltestosterone-induced transient ... [Acta Clin Belg. 2013 Jan-Feb] - PubMed - NCBI

In this paper we report different effects of methyltestosterone administration on thyroid function in two twin brothers, one of whom suffered from hypothyroidism, while the other was apparently healthy. Methyltestosterone, which is a non-aromatisable androgen, resulted in a marked reduction of thyroxine-binding globulin (TBG), irrespectively of the patient's hormonal status, while the impact on free thyroid hormones depended on baseline thyroid function. Our research shows that a possibility of the use of non-aromatisable androgens or other drugs affecting TBG levels should be taken into consideration in all hypothyroid patients receiving levothyroxine, in whom thyroid hormone status suddenly changes without any apparent reason.

 

[Michael Scally MD]

Henrich TJ, Hu Z, Li JZ, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis 2013;207(11):1694-702. Long-Term Reduction in Peripheral Blood HIV Type 1 Reservoirs Following Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation

BACKGROUND: The long-term impact of allogeneic hematopoietic stem cell transplantation (HSCT) on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is largely unknown.

METHODS: We studied the effects of a reduced-intensity conditioning allogeneic HSCT from donors with wild-type-CCR5(+) cells on HIV-1 peripheral blood reservoirs in 2 patients heterozygous for the ccr5Delta32 mutation. In-depth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses were performed on samples obtained before and up to 3.5 years after HSCT receipt.

RESULTS: Although HIV-1 DNA was readily detected in peripheral blood mononuclear cells (PBMCs) before and 2-3 months after HSCT receipt, HIV-1 DNA and RNA were undetectable in PBMCs, CD4(+) T cells, or plasma up to 21 and 42 months after HSCT. The loss of detectable HIV-1 correlated temporally with full donor chimerism, development of graft-versus-host disease, and decreases in HIV-specific antibody levels.

CONCLUSIONS: The ability of donor cells to engraft without evidence of ongoing HIV-1 infection suggests that HIV-1 replication may be fully suppressed during cART and does not contribute to maintenance of viral reservoirs in peripheral blood in our patients. HSCTs with wild-type-CCR5(+) donor cells can lead to a sustained reduction in the size of the peripheral reservoir of HIV-1.

 

[Michael Scally MD]

Liao M, Guo X, Yu X, et al. Role of Metabolic Factors in the Association Between Osteocalcin and Testosterone in Chinese Men. Journal of Clinical Endocrinology & Metabolism. Role of Metabolic Factors in the Association Between Osteocalcin and Testosterone in Chinese Men

Objective: Osteocalcin can regulate energy metabolism and increase testosterone production. Although previous studies have shown the positive association between osteocalcin and testosterone, the effect of metabolic factors in the association is unclear.

Design and Setting: Osteocalcin, testosterone, and metabolic factors were accessed in 2400 men aged 20 to 69 years, who participated in the population-based Fangchenggang Area Male Health and Examination Survey in Guangxi province of China from September 2009 to December 2009.

Main Outcome Measures: Metabolic syndrome was defined based on the updated report of National Cholesterol Education Program Adult Treatment Panel III criteria. Serum total osteocalcin, total testosterone (TT), and sex hormone binding globulin (SHBG) were measured, whereas free testosterone (FT) and bioavailable testosterone (BT) were calculated based on Vermeulen's formula. The multivariable linear regression analysis was used.

Results: Osteocalcin was positively associated with TT, FT, and BT in the unadjusted model (all P < .001). After adjusting for age, the positive association between osteocalcin and TT remained statistically significant (? = .17, 95% confidence interval = 0.14–0.20) and was not attenuated in each MetS subgroup including hypertriglyceridemia, hyperglycemia, elevated blood pressure, and low high-density lipoprotein cholesterol, while in the group of central obesity (waist circumstance ?90 cm), the association appeared significantly stronger (? = 0.21, 95% confidence interval = 0.12–0.30). After further adjusting for SHBG, osteocalcin was positively associated with TT, FT, and BT in men with central obesity or men with any two MetS components (all P < .05).

Conclusions: Serum total osteocalcin is positively associated with testosterone, which is probably modified by SHBG and central obesity.

 

[Michael Scally MD]

Bredella MA, Gerweck AV, Lin E, et al. Effects of GH on body composition and cardiovascular risk markers in young men with abdominal obesity. Journal of Clinical Endocrinology & Metabolism. Effects of GH on body composition and cardiovascular risk markers in young men with abdominal obesity

Context: Visceral adiposity is associated with increased cardiometabolic risk and decreased GH secretion.

Objective: To determine the effects of GH administration in abdominally obese young men on body composition, including liver fat, mitochondrial function, and cardiovascular risk markers.

Design: 6-month, randomized, double-blind, placebo-controlled study.

Study participants: 62 abdominally obese men (IGF-1 below the mean, no exclusion based on GH level), 21–45y.

Main outcome measures: Abdominal fat depots, thigh muscle and fat (CT), fat and lean mass (DXA), intramyocellular (IMCL) and intrahepatic (IHL) lipids (1H-MRS), mitochondrial function (31P-MRS), cardiovascular risk markers, carotid intimal-medial thickness (IMT), endothelial function.

Results: GH administration resulted in a mean IGF-1 SDS increase from ?1.9±0.08 to ?0.2±0.3 in the GH group and a decrease in VAT, VAT/SAT, trunk/extremity fat, IHL, hsCRP and ApoB/LDL vs. placebo after controlling for the increase in weight observed in both groups. There were inverse associations between change in IGF-1 levels and change in VAT, VAT/SAT, trunk fat, trunk/extremity fat, hsCRP and ApoB. Mitochondrial function improved in the GH group compared to placebo after controlling for change in glucose. There was no change in thigh fat, muscle mass, IMCL, cholesterol, fibrinogen, IMT or endothelial function. There was no increase in fasting glucose or HbA1c in the GH vs. placebo group, although the two-hour OGTT glucose increased slightly.

Conclusion: GH replacement in abdominally obese men improves body composition, including liver fat, mitochondrial function, and markers of cardiovascular risk. Although fasting glucose was unchanged, a slight increase in 2-hour glucose during an OGTT was noted.

 

[Michael Scally MD]

Birzniece V, Umpleby MA, Poljak A, Handelsman DJ, Ho KKY. Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy. European Journal of Endocrinology. Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy

Objective: In hypopituitary men, oral delivery of unesterified testosterone (T) in doses that result in a solely hepatic androgen effect, enhances protein anabolism during GH treatment. We aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women.

Design: Eight healthy postmenopausal women received 2-weeks treatment with oral T 40 mg/day (crystalline testosterone USP). This dose increases portal T concentrations exerting androgenic effects on the liver without spill-over into the systemic circulation.

Outcome Measures: Whole body leucine turnover, from which leucine rate of appearance (LRa; an index of protein breakdown) and leucine oxidation (Lox; a measure of irreversible protein loss) were estimated, together with energy expenditure and substrate utilization. We measured liver transaminases, as well as testosterone, SHBG and IGF-I.

Results: T treatment significantly reduced LRa by 7.1 ± 2.5 % and Lox by 14.6 ± 4.5 % (p<0.05). Liver transaminases did not change significantly, while serum SHBG fell within the normal range by 16.8 ± 4.0 % and IGF-I increased by 18.4 ± 7.7 % (p<0.05). Peripheral T increased from 0.4 ± 0.1 to 1.1 ± 0.2 nmol/l (p<0.05), with none exceeding the upper normal limit. There was no change in energy expenditure, fat and carbohydrate utilization.

Conclusions: Hepatic exposure to unesterified T by oral delivery stimulates protein anabolism by reducing protein breakdown and protein oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified T holds promise as a simple novel treatment of protein catabolism and muscle wasting.

 

[Michael Scally MD]

Mehta A, Bolyakov A, Roosma J, Schlegel PN, Paduch DA. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor

OBJECTIVE: To evaluate surgical sperm retrieval rates in adolescents with Klinefelter syndrome and testosterone replacement therapy (TRT).

DESIGN: Case series.

SETTING: Academic medical center.

PATIENT(S): Ten patients with Klinefelter syndrome, aged 14-22 years, treated with testosterone replacement and aromatase inhibitor therapy for a period of 1-5 years before surgical sperm retrieval.

INTERVENTION(S): Microsurgical testis sperm extraction with cryopreservation of harvested tissue.

MAIN OUTCOME MEASURE(S): Presence of spermatozoa within testis tissue.

RESULT(S): Successful sperm retrieval in 7/10 patients (70%).

CONCLUSION(S): Use of topical TRT did not appear to suppress spermatogenesis in adolescents with KS. It is uncertain whether sperm retrieval rates would be higher or lower without testosterone replacement in these young males. Sperm cryopreservation should be discussed in all KS adolescents who are either receiving or considering initiating TRT.

 

[Michael Scally MD]

Blick G. Optimal diagnostic measures and thresholds for hypogonadism in men with HIV/AIDS: Comparison between 2 transdermal testosterone replacement therapy gels. Postgrad Med 2013;125(2):30-9. https://postgradmed.org/doi/10.3810/pgm.2013.03.2639

Objectives: To determine the incidence of hypogonadism in men with human immunodeficiency virus (HIV)/acquired immunodeficiency virus (AIDS), the most useful serum testosterone measurement and threshold for diagnosing hypogonadism, and the comparative efficacy of 2 testosterone replacement therapy (TRT) 1% gels (AndroGel(R) [Abbott Laboratories] and Testim(R) [Auxilium Pharmaceuticals, Inc.]).

Design and Subjects: This was a 2-stage observational study. In stage 1, patient records from 2 medical practices specializing in HIV/AIDS were reviewed. Eligible patients were aged >/= 18 years; had HIV-seropositive status confirmed by enzyme-linked immunosorbent assay and western blot test or HIV-1 viremia confirmed by HIV-1 RNA polymerase chain reaction; and had prior baseline testosterone assessments for hypogonadism (ie, presence of signs/symptoms of hypogonadism as well as total testosterone [TT] and free testosterone [FT] level measurements). Stage 2 included the evaluation of patients from stage 1 who were treated with 5 to 10 g/day of TRT. The stage 2 inclusion criteria were a diagnosis of low testosterone (defined as TT level < 300 ng/dL and/or FT level < 50 pg/mL, as per The Endocrine Society guidelines and presence/absence of hypogonadal signs and symptoms); >/= 12 months of evaluable sign and symptom assessments and TT/FT level measurements while on TRT with either Testim(R) or AndroGel(R); and >/= 4 weeks on initial TRT if the initial TRT was switched or discontinued.

Results: Four hundred one of 422 patients met the stage 1 inclusion criteria and 167 of 401 patients (AndroGel(R), n = 92; Testim(R), n = 75) met the stage 2 inclusion criteria. Total testosterone level < 300 ng/dL alone identified 24% (94 of 390) of patients as hypogonadal, but failed to diagnose an additional 111 patients (67.7%) with FT levels < 100 pg/mL and hypogonadal symptoms.

Through month 12, AndroGel(R) increased mean TT levels by +42.8% and FT levels by +66.9%, compared with +178.7% (P = 0.017) and +191% (P = 0.039), respectively, for Testim(R). Patients treated with Testim(R) showed significantly greater improvements in libido, sexual performance, nighttime energy, focus/concentration, and abdominal girth, and trends for greater improvement in fatigue and erectile dysfunction than patients treated with AndroGel(R). No patients discontinued therapy due to adverse events.

Conclusion: The most useful serum testosterone measurement and threshold for diagnosing hypogonadism in men with HIV/AIDS was FT level < 100 pg/mL, which identified 64% of men as hypogonadal with the presence of >/= 1 hypogonadal symptom. This is above currently accepted thresholds. Criteria using TT level < 300 ng/dL and FT level < 50 pg/mL only diagnosed 24% and 19% of patients, respectively, as having hypogonadism. Testim(R) was more effective than AndroGel(R) in increasing TT and FT levels and improving hypogonadal symptoms.

 

[Michael Scally MD]

Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology 2012;225(3):256-8. PayPerView: Acne and Whey Protein Supplementation among Bodybuilders - Karger Publishers

Accumulative evidence supports the role of nutritional factors in acne. I report here 5 healthy male adult patients developing acne after the consumption of whey protein, a favorite supplement of those engaged in bodybuilding. These observations are in line with biochemical and epidemiological data supporting the effects of milk and dairy products as enhancers of insulin/insulin-like growth factor 1 signaling and acne aggravation. Further prospective studies are required to determine the possible role of dietary supplements in the fitness and bodybuilding environment.

 

[Michael Scally MD]

Kim ED, Seftel AD, Goldfischer ER, Ni X, Burns PR. A Return to Normal Erectile Function with Tadalafil Once Daily after an Incomplete Response to As-Needed PDE5 Inhibitor Therapy. The Journal of Sexual Medicine. A Return to Normal Erectile Function with Tadalafil Once Daily after an Incomplete Response to As-Needed PDE5 Inhibitor Therapy - Kim - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction - An optimal outcome of an erectile dysfunction (ED) treatment is to enable a return to normal erectile function (as defined by an International Index of Erectile Function—Erectile Function [IIEF-EF] domain score ?26). As-needed (PRN) phosphodiesterase type 5 (PDE5) inhibitor treatment does not always result in a return-to-normal erectile function.

Aim - The combined studies evaluated whether treatment with tadalafil once daily would allow men to return to normal erectile function who had less than normal IIEF-EF domain scores while using a maximum dose of a PRN PDE5 inhibitor treatment.

Methods - Men were ?18 years of age, sexually active, reported a ?3-month history of ED, and had been taking the maximum dose of sildenafil citrate, vardenafil, or tadalafil PRN. Randomization to once-daily therapy with tadalafil 2.5?mg to 5?mg (N?=?207), tadalafil 5?mg (N?=?207), or placebo (N?=?209) for 12 weeks followed a 4-week maximum dose PRN PDE5 treatment and 4-week nondrug lead periods. Two identical double-blind, randomized, placebo-controlled studies were conducted; combined results are reported.

Main Outcome Measure - The main outcome measure was the percentage of subjects with a return-to-normal erectile function (IIEF-EF domain score???26) when treated with tadalafil once daily compared with placebo.

Results - In subjects not achieving normal erectile function with the maximum dose of a PRN PDE5 inhibitor, a higher percentage of subjects treated with tadalafil had an IIEF-EF domain score ?26 at end point (tadalafil 2.5- to 5-mg group [39%]; tadalafil 5-mg group [40%]) compared with the placebo group (12.1%; P?<?0.001). Tadalafil was generally well tolerated and adverse events observed were consistent with previous reports of tadalafil once daily.

Conclusions - Treatment with tadalafil once daily significantly improved erectile function in men with mild to mild-moderate impairments in erectile function following PRN PDE5 inhibitor treatment.

 

[Michael Scally MD]

Grover S, Avasthi A, Aneja J, et al. Comprehensive Questionnaire for Assessment of Dhat Syndrome: Development and Use in Patient Population. The Journal of Sexual Medicine. Comprehensive Questionnaire for Assessment of Dhat Syndrome: Development and Use in Patient Population - Grover - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Dhat syndrome is a culture-bound syndrome, characterized by the core belief of loss of semen accompanied by symptoms of general weakness, lack of energy and concentration, impaired sexual functions, and vague somatic troubles, often associated with an anxious or dysphoric mood state. Although many studies have described the clinical picture of Dhat syndrome, there is lack of availability of an instrument which can comprehensively assess patients presenting with Dhat syndrome.

Aim The aim of this article is to develop a questionnaire that can comprehensively assess Dhat syndrome and guide the clinicians in managing such patients.

Methods Initially, an extensive literature review was done to prepare a comprehensive list of clinical features, beliefs associated with the passage of “Dhat,” and attribution of the symptoms by the patients. These items were converted into a questionnaire for investigational interview. The questionnaire thus developed was administered to 54 patients and was also sent to eight subject experts for their opinion on the questionnaire.

Main Outcome Measure To develop and evaluate the content validity of the Comprehensive Questionnaire for Assessment of Dhat Syndrome.

Results As per the opinion of experts, the questionnaire had good content validity and was useful for not only clinicians dealing with patients of Dhat syndrome but was also considered useful for the patients presenting with Dhat syndrome. All the experts found the questionnaire to be comprehensive, and two-third of the experts regarded the length to be adequate. Although none of them suggested any deletion of items, yet some additions were suggested. The language of the questionnaire was rated from simple to very simple. Results of administration of the questionnaire on 54 patients of Dhat syndrome established that the questionnaire was helpful in providing comprehensive clinical picture of Dhat syndrome.

Conclusion The questionnaire designed for the purposes of this study is a useful instrument for comprehensive assessment of the clinical picture of Dhat syndrome.

 

[Michael Scally MD]

Rastrelli G, Corona G, Lotti F, Boddi V, Mannucci E, Maggi M. Relationship of Testis Size and LH Levels with Incidence of Major Adverse Cardiovascular Events in Older Men with Sexual Dysfunction. The Journal of Sexual Medicine. Relationship of Testis Size and LH Levels with Incidence of Major Adverse Cardiovascular Events in Older Men with Sexual Dysfunction - Rastrelli - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Measurement of testis volume (TV) is a reliable clinical procedure that predicts reproductive fitness. However, the role of TV in overall and cardiovascular (CV) fitness has never been studied.

Aim The study aims to analyze the clinical correlates of TV in patients with sexual dysfunction (SD) and to verify the value of this parameter and its determinants (i.e., luteinizing hormone [LH] levels) in predicting major adverse CV events (MACE).

Methods A consecutive series of 2,809 subjects without testiculopathy (age 51.2?±?13.1) consulting for SD was retrospectively studied. A subset of this sample (n?=?1,395) was enrolled in a longitudinal study.

Main Outcome Measures Several clinical and biochemical parameters were investigated.

Results - After adjusting for confounders, TV was negatively associated with both LH (Adj. r = −0.234; P < 0.0001) and follicle-stimulating hormone (Adj. r = −0.326; P < 0.0001). In addition, overweight/obesity, smoking, and alcohol abuse increased as a function of TV (hazard ratio

---

 = 1.041 [1.021–1.061], P < 0.0001; 1.024 [1.005–1.044], P = 0.012; 1.063 [1.015–1.112], P = 0.009, respectively). Furthermore, mean blood pressure was positively related to increased TV (Adj. r = 0.157; P < 0.0001). The effect of these lifestyle factors on TV were only partially related to changes in gonadotropin levels. In the longitudinal analysis, after adjusting for confounders, TV was associated with a higher incidence of MACE (HR = 1.066 [1.013–1.122]; P = 0.014), and the stepwise introduction in the Cox model of lifestyle factors, mean blood pressure and body mass index progressively smoothed out the association, which was no longer statistically significant in the fully adjusted model. Conversely, the association of higher LH levels with increased incidence of MACE was not attenuated by the progressive introduction of the aforementioned confounders in the model.

Conclusions Our data show that in SD subjects, TV and LH are associated with an adverse CV risk profile that mediate the higher TV-associated incidence of MACE. High LH levels are an independent marker of CV risk. Further studies are needed for clarifying determinants and mechanisms of testis enlargement that, beyond gonadotropins, could mediate the increased incidence of MACE.

 

[Michael Scally MD]

Spiller HA, James KJ, Scholzen S, Borys DJ. A Descriptive Study of Adverse Events from Clenbuterol Misuse and Abuse for Weight Loss and Bodybuilding. Subst Abus 2013;34(3):306-12. An Error Occurred Setting Your User Cookie

Background: Clenbuterol is a beta2-agonist approved in the United States for veterinary use in nonfood animals. Clenbuterol use is emerging among bodybuilders and fitness enthusiasts attracted to the hypertrophic and lipolytic effects.

Cases: This was a retrospective chart review of clenbuterol exposures reported to 2 poison control centers. Misuse of clenbuterol for weight loss and bodybuilding was reported in 11 of 13 clenbuterol users.

Reported clinical effects included tachycardia, widened pulse pressure, tachypnea, hypokalemia, hyperglycemia, ST changes on electrocardiogram (ECG), elevated troponin, elevated creatine phosphokinase (CPK), palpitations, chest pain, and tremor. Measured serum clenbuterol concentration was 2983 pg/mL post 4.5 mg ingestion. Coingestants included T3 and anabolic steroids.

Treatments included activated charcoal, benzodiazepines, beta-blockers, potassium replacement, and intravenous (IV) fluid.

Conclusions: There is an increasing use of the Internet for illicit drug use for bodybuilding and weight loss purposes. These patients may not present as the stereotype of illicit drug abusers, but as healthy athletic low-risk patients. Clinical effects persisted greater than 24 hours with evidence of myocardial injury in 2 patients.

Clenbuterol is increasingly being abused within the bodybuilding subculture. These cases illustrate the hidden dangers of clenbuterol abuse among bodybuilders and fitness enthusiasts.

 

[Michael Scally MD]

Jenkinson C, Petroczi A, Naughton DP. Effects of Dietary Components on Testosterone Metabolism via UDP-Glucuronosyltransferase. Front Endocrinol (Lausanne) 2013;4:80. Frontiers | Effects of Dietary Components on Testosterone Metabolism via UDP-Glucuronosyltransferase | Frontiers in Experimental Endocrinology

The potential interference in testosterone metabolism through ingested substances has ramifications for: (i) a range of pathologies such as prostate cancer, (ii) medication contra-indications, (iii) disruption to the endocrine system, and (iv) potential confounding effects on doping tests. Conjugation of anabolic steroids during phase II metabolism, mainly driven by UDP-glucuronosyltransferase (UGT) 2B7, 2B15, and 2B17, has been shown to be impaired in vitro by a range of compounds including xenobiotics and pharmaceuticals. Following early reports on the effects of a range of xenobiotics on UGT activity in vitro, the work was extended to reveal similar effects with common non-steroidal anti-inflammatory drugs. Notably, recent studies have evidenced inhibitory effects of the common foodstuffs green tea and red wine, along with their constituent flavonoids and catechins. This review amalgamates the existing evidence for the inhibitory effects of various pharmaceutical and dietary substances on the rate of UGT glucuronidation of testosterone; and evaluates the potential consequences for health linked to steroid levels, interaction with treatment drugs metabolized by the UGT enzyme and steroid abuse in sport.

 

[Michael Scally MD]

Growth Hormone Axis and Aging

Key Points

• Growth hormone (GH) and/or ghrelin mimetics represent potential treatment and/or prevention options for musculoskeletal impairment associated with aging.

• Use of improvement in muscle function as an outcome in studies of GH and ghrelin mimetics is complicated by the lack of a standardized definition for clinically meaningful efficacy of this end point.

• Based on preliminary study results, the use of ghrelin mimetics may be more suitable for use in this age group than GH itself.

• There are still several unanswered questions related to the use of ghrelin mimetics in the elderly, which prevents recommendation for its use at the current time.

MK-677 is an orally active, long-acting Growth Hormone Secretagogue (GHS) that acts as a ghrelin mimetic at the ghrelin receptor. Ghrelin or ghrelin mimetics have been shown to enhance the preexisting pulsatile GH release and several studies demonstrate a GH increasing effect in the elderly.

In a 4-week double-blind placebo controlled study, once-daily oral MK-677, given to healthy older adults, enhances pulsatile GH release and IGF-I concentrations reaching levels seen in young adults.

A 2-year study using an orally active ghrelin mimetic in healthy older adults study found that 1-year treatment with MK-677 resulted in an increase in fat-free mass by 1.1 kg and that the effect was maintained through the second year. No significant increase in total body fat was found; however, there was a significant increase in subcutaneous limb fat.

The changes in muscle mass did not result in measurable changes in muscle strength or function. This study included mainly physically fit, active, healthy older adults. This may explain the apparent discrepancy between the increase in muscle mass and lack of detectable change in function and strength, whereas in a similar study examining frail subjects, functional improvements were detectable.

Mean Changes In Fat And Fat-Free Mass (FFM) At 12 Months Treatment With MK-677 Or Placebo In Healthy Older Adults
Limb = appendicular lean soft tissue and appendicular fat;
nonlimb = total minus limb.

Nass R. Growth Hormone Axis and Aging. Endocrinol Metab Clin North Am 2013;42(2):187-99. Growth Hormone Axis and Aging

Growth hormone (GH) and/or ghrelin mimetics represent potential treatment and/or prevention options for musculoskeletal impairment associated with aging. Use of improvement in muscle function as an outcome in studies of GH and ghrelin mimetics is complicated by the lack of a standardized definition for clinically meaningful efficacy of this end point. Based on preliminary study results, the use of ghrelin mimetics may be more suitable for use in this age group than GH itself. There are still several unanswered questions related to the use of ghrelin mimetics in the elderly, which prevents recommendation for its use at the current time.

 

[Michael Scally MD]

Wiehle R, Cunningham GR, Pitteloud N, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU International. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics - Wiehle - BJU International - Wiley Online Library

Objectives - To determine the pharmacodynamic (PD) profile of serum total testosterone levels (TT) and luteinizing hormone (LH) in men with secondary hypogonadism following initial and chronic daily oral doses of enclomiphene citrate in comparison to transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate (Androxal®) in comparison to transdermal testosterone on other hormones and markers in men with secondary hypogonadism.

Patients and Methods - This was a randomized, single blind, two-center phase II study to evaluate three different doses of enclomiphene citrate (6.25mg, 12.5mg and 25 mg Androxal®), versus AndroGel®, a transdermal testosterone, on 24-hour LH and TT in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (ITT Population), but 4 men had T levels >350 ng/dL at baseline. Forty-four men completed the study per protocol (PP population). All subjects enrolled in this trial had serum TT in the low range (<350 ng/dL) and had low to normal LH (<12 IU/L) on at least two occasions.

TT and LH levels were assessed each hour for 24 hours to examine the effects at each of three treatment doses of enclomiphene versus a standard dose (5 grams) of transdermal testosterone (AndroGel). In the initial profile TT and LH were determined in a naïve population following a single initial oral or transdermal treatment (Day 1). This was contrasted to that seen after six weeks of continuous daily oral or transdermal treatment (Day 42). The pharmacokinetics of enclomiphene was performed in a select subpopulation. Serum samples were obtained over the course of the study to determine levels of various hormones and lipids.

Results - After six weeks of continuous use, the mean ± SD concentration of TT at Day 42 C0hrTT, was 604 ± 160 ng/dL for men taking the highest of dose of enclomiphene citrate (enclomiphene, 25 mg daily) and 500 ± 278 ng in those men treated with transdermal testosterone. These values were higher than Day 1 values but not different from each other (p = 0.23, T-test). All three doses of enclomiphene increased C0hrTT, CavgTT, CmaxTT, CminTT and CrangeTT. Transdermal testosterone also raised TT, albeit with more variability, and with suppressed LH levels. The patterns of TT over 24 hour period following six weeks of dosing could be fit to a non-linear function with morning elevations, mid-day troughs, and rising night-time levels. Enclomiphene and transdermal testosterone increased levels of TT within two weeks, but they had opposite effects on FSH and LH Treatment with enclomiphene did not significantly affect levels of TSH, ACTH, cortisol, lipids, or bone markers. Both transdermal testosterone and enclomiphene citrate decreased IGF-1 levels (p<0.05) but suppression was greater in the enclomiphene citrate groups.

Conclusions - Enclomiphene citrate increased serum LH and TT; however, there was not a temporal association between the peak drug levels and the Cmax levels LH or TT. Enclomiphene citrate consistently increased serum TT into the normal range and increased LH and FSH above the normal range. The effects on LH and TT persisted for at least one week after stopping treatment.