OnLine First 2013

[Michael Scally MD]

Luconi M, Samavat J, Seghieri G, et al. Determinants of testosterone recovery after bariatric surgery: Is it only a matter of reduction of body mass index? Fertil Steril. ScienceDirect.com - Fertility and Sterility - Determinants of testosterone recovery after bariatric surgery: Is it only a matter of reduction of body mass index?

OBJECTIVE: To explore the correlation models between body mass index (BMI) and sex hormones constructed from a male cross-sectional survey and evaluate the effects of surgery-induced weight loss on sex hormones in morbidly obese subjects that are not predicted by the constructed BMI correlation models.

DESIGN: Cross-sectional population and longitudinal studies.

SETTING: Bariatric surgery center in a university hospital.

PATIENT(S): A cross-sectional survey of a male general population of 161 patients (BMI median [interquartile range] = 29.2 [24.8-41.9] kg/m2) in addition to 24 morbidly obese subjects (BMI = 43.9 [40.8-53.8] kg/m2) who were undergoing bariatric surgery were prospectively studied for 6 and 12 months.

INTERVENTION(S): Bariatric surgery on 24 morbidly obese men.

MAIN OUTCOME MEASURE(S): Cross-sectional population: construction of the best-fitting models describing the relationship between baseline BMI with total (TT) and calculated free (cFT) testosterone, E2, sex hormone-binding globulin (SHBG), FSH, and LH levels. Longitudinal study deviation between the observed sex hormone levels at 6- and 12-month follow-up and those expected on BMI bases.

RESULT(S): The correlation of BMI with sex hormones was not univocally linear (E2), but the best-fitting model was exponential for TT, cFT, FSH, LH, and TT/E2 and power for SHBG. In addition to the significant improvement of all parameters observed after surgery in the longitudinal cohort, the increase in TT and SHBG, but not in cFT, was significantly higher than expected from the corresponding weight loss at 6 months from surgery (14.80 [12.30-19.00] nM vs. 12.77 [10.92-13.64] nM and 40.0 [28.9-54.5] nM vs. 24.7 [22.5-25.8] nM for TT and SHBG, respectively), remaining rather stable at 12 months.

CONCLUSION(S): The increase in TT and SHBG, but not the increase in cFT, after bariatric surgery is greater than expected based on weight loss.

 

[Michael Scally MD]

An unusual cause of testosterone deficiency
An unusual cause of testosterone deficiency

36-year-old gentleman referred by his GP with poor libido and erectile dysfunction associated with hypogonadotrophic hypogonadism. 0900 h testosterone 0.3 nmol/l (10–35), LH <0.2 IU/l, FSH 0.1 IU/l, prolactin 71 mIU/l (50–500).

Symptoms started at time of break up of his marriage in 2011. No other symptoms of hypogonadism or of pituitary disease. Previously fit and well. Teetotal. On no medication. Patient an avid fitness fanatic. He had never knowingly used anabolic steroids. However, he had taken a ‘nutritional supplement’ called T-Bullets (purchased from a sports nutrition shop to improve his gym performance) for 20 days until just before GP’s blood test. Examination revealed a well virilised gentleman with no signs of hypogonadism.

Further investigations

0900 h cortisol 457 nmol/l (138–690); IGF1 331 ?g/l (75–344); FT4 11 pmol/l (5.6–21); Normal U&E, FBC and LFT. MRI pituitary and hypothalamus within normal limits

6 months after stopping T-Bullet, testosterone level gradually returning to normal.

04/10/12 – 6.9 nmol/l, 29/10/12 – 10.2 nmol/l

Discussion: T-Bullets are marketed as a ‘nutritional supplement’ by the makers. They are easily available online and can be purchased from some sports nutrition shops. The active ingredient is: ‘2a, 17a-dimethy-5a-androst-3-one-17b-ol 13-ethyl-3-methoxy-gona-2,5,(10)-dien-17-one’ which Martindale: the complete drug reference lists as an anabolic steroid (related to testosterone)

Conclusion:: Anabolic steroids were first artificially synthesized in the 1930s. The misuse of anabolic steroid drugs to enhance physique, body strength and athletic performance is well-known. Use of anabolic steroids can result in hypogonadotrophic hypogonadism as a result of suppression of the hypothalamo-pituitary–gonadal axis (HPG).

The unwitting consumption of an anabolic steroid should be considered in any patient presenting with hypogonadotrophic hypogonadism who has been taking a ‘nutritional supplement’.

The unwitting consumption of an anabolic steroid should be considered in any patient presenting with hypogonadotrophic hypogonadism who has been taking a ‘nutritional supplement’.

 

[Michael Scally MD]

Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring). Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss - Saad - Obesity - Wiley Online Library

OBJECTIVE: This study analyzed the effects of normalization of serum testosterone (T)levels on anthropometric parameters in hypogonadal men.

DESIGN AND METHODS: Open-label, single-center, cumulative, prospective registry study of 255 men (aged 33-69 years, mean 58.02+/-6.30 years), with T levels below12.13 nmol/L (mean: 9.93+/-1.38).We studied 215 men for at least 2 years, 182 for 3 years, 148 for 4 and 116 for at least 5 years. They received parenteral Tundecanoate 1000 mg/12 weeks after an initial interval of 6 weeks.

RESULTS: Body weight (BW) decreased from 106.22+/-16.93 kg to 90.07+/-9.51kg. Waist circumference (WC)reduced from 107.24+/-9.14 cm to 98.46+/-7.39 cm. Body mass index (BMI, m/kg2 ) declined from 33.9+/-5.51 m/kg2 to 29.13+/-3.09 m/kg2 . All parameters examined were statistically significant with p<0.0001 vs. baseline and vs. the previous year over 5 years indicating a continuous weight loss over the full observation period. The mean per cent weight loss after 1 year was 4.16+/-0.31%, after 2 years 7.54+/-0.32%, after 3 years 9.23+/-0.33%, after 4 years 11.42+/-0.35% and after 5 years 13.57+/-0.37%.

CONCLUSIONS: Normalizing serum T to normal physiological levels produced consistent loss of BW, WC and BMI. These improvements were progressive over the full 5 years of the study.

 

[Michael Scally MD]

Borniger JC, Chaudhry A, Muehlenbein MP. Relationships among Musical Aptitude, Digit Ratio and Testosterone in Men and Women. PLoS One 2013;8(3):e57637. PLOS ONE: Relationships among Musical Aptitude, Digit Ratio and Testosterone in Men and Women

Circulating adult testosterone levels, digit ratio (length of the second finger relative to the fourth finger), and directional asymmetry in digit ratio are considered sexually dimorphic traits in humans. These have been related to spatial abilities in men and women, and because similar brain structures appear to be involved in both spatial and musical abilities, neuroendocrine function may be related to musical as well as spatial cognition.

To evaluate relationships among testosterone and musical ability in men and women, saliva samples were collected, testosterone concentrations assessed, and digit ratios calculated using standardized protocols in a sample of university students (N = 61), including both music and non-music majors.

Results of Spearman correlations suggest that digit ratio and testosterone levels are statistically related to musical aptitude and performance only within the female sample:
A) those females with greater self-reported history of exposure to music (p = 0.016) and instrument proficiency (p = 0.040) scored higher on the Advanced Measures of Music Audiation test,
B) those females with higher left hand digit ratio (and perhaps lower fetal testosterone levels) were more highly ranked (p = 0.007) in the orchestra,
C) female music students exhibited a trend (p = 0.082) towards higher testosterone levels compared to female non-music students, and
D) female music students with higher rank in the orchestra/band had higher testosterone levels (p = 0.003) than lower ranked students.

None of these relationships were significant in the male sample, although a lack of statistical power may be one cause.

The effects of testosterone are likely a small part of a poorly understood system of biological and environmental stimuli that contribute to musical aptitude. Hormones may play some role in modulating the phenotype of musical ability, and this may be the case for females more so than males.

 

[Michael Scally MD]

Structural and Functional Brain Changes in Boxers and Mixed Martial Arts Fighters Are Correlated with Fight Exposure
http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/S54.006

OBJECTIVE: This study explores the relationship between exposure to repetitive head trauma and both structural (DTI) and functional (resting state connectivity) changes in the basal ganglia.

BACKGROUND: Cumulative head trauma can result in chronic traumatic encephalopathy (CTE). The clinical manifestations of CTE include disorders of movement, cognition and behavior. Pathological deposition of tau is found in and around the basal ganglia and cortical mantle in CTE.

DESIGN/METHODS: The current analysis is cross sectional and involved 155 male fighters participating in the Professional Fighters Brain Health Study. All fighters undergo structural and functional imaging including DTI and a resting state fMRI scans. A group analysis was performed using AFNI and adjusted for age, weight, and education. Number of professional fights and number of reported knock outs were used as surrogate measures of fight exposure.

RESULTS: Both greater number of professional fights and number of knock outs were associated with: 1) decreases in transverse diffusivity in the corpus callosum and putamen (p <.005) 2): lower resting state connectivity in the putamen (p <.005).

CONCLUSIONS: Even early in the fighter's career, we found measurable relationships between structure and function of the basal ganglia and the degree of fight exposure or number of times they were knocked out. We continue the study with longitudinal follow up, and expect to see measurable changes in these structures with increased exposure over time.

 

[Michael Scally MD]

Landry D, Cloutier F, Martin LJ. Implications of leptin in neuroendocrine regulation of male reproduction. Reprod Biol 2013;13(1):1-14. ScienceDirect.com - Reproductive Biology - Implications of leptin in neuroendocrine regulation of male reproduction

Obesity is a major health problem contributing to increased subfertility in males, as well as increased morbidity for diseases related to a decline in testosterone production with aging. Leptin is a hormone produced by adipose tissue whose production increases with the amount of body fat. Several studies have supported a relationship between increased leptin production and regulation of reproductive function. Indeed, leptin acts at all levels of the hypothalamus-pituitary-gonadal (HPG) axis in males. However, most of the obese individuals become insensitive to increased endogenous leptin production and develop a functional leptin resistance. This deregulation of leptin signaling might result in abnormal endocrine and reproductive functions. Altered leptin dynamics may contribute to male infertility in different ways, leading to hypogonadism. These include leptin resistance or leptin insufficiency at the hypothalamus and leptin modulation of testicular physiology. In this review, we address the mechanisms of action of leptin at different levels of the HPG axis. Moreover, the influences of leptin on steroidogenesis and spermatogenesis, as well as seasonal variations of leptin's action on male reproduction are discussed.


Actions Of Leptin On The HPG Axis

(A) Under normal conditions, leptin produced by the adipose tissue influences several groups of neurons of the hypothalamus, leading to an increase in the production of GnRH. In addition to the induction by GnRH, pituitary gonadotropes secretory activity is stimulated by leptin. On one side, LH causes an increase in Leydig cells steroidogenesis, while FSH increases spermatogenesis by stimulating the activity of Sertoli cells.

(B) In the presence of obesity leading to leptin resistance, inability of leptin to act on the hypothalamic neurons and to activate pituitary cells secretion leads to GnRH/LH/FSH disruption. These effects are exacerbated by the rate-limiting effect of the blood–brain barrier on leptin transport. In the testis, steroidogenesis and spermatogenesis are reduced when exposed to lower levels of LH and FSH and a higher concentration of leptin.

 

[Michael Scally MD]

Charlier TD, Seredynski AL, Niessen NA, Balthazart J. Modulation of testosterone-dependent male sexual behavior and the associated neuroplasticity. Gen Comp Endocrinol. ScienceDirect.com - General and Comparative Endocrinology - Modulation of testosterone-dependent male sexual behavior and the associated neuroplasticity

Steroids modulate the transcription of a multitude of genes and ultimately influence numerous aspects of reproductive behaviors. Our research investigates how one single steroid, testosterone, is able to trigger this vast number of physiological and behavioral responses.

Testosterone potency can be changed locally via aromatization into 17beta-estradiol which then activates estrogen receptors of the alpha and beta sub-types. We demonstrated that the independent activation of either receptor activates different aspects of male sexual behavior in Japanese quail.

In addition, several studies suggest that the specificity of testosterone action on target genes transcription is related to the recruitment of specific steroid receptor coactivators. We demonstrated that the specific down-regulation of the coactivators SRC-1 or SRC-2 in the medial preoptic nucleus by antisense techniques significantly inhibits steroid-dependent male-typical copulatory behavior and the underlying neuroplasticity.

In conclusion, our results demonstrate that the interaction between several steroid metabolizing enzymes, steroid receptors and their coactivators plays a key role in the control of steroid-dependent male sexual behavior and the associated neuroplasticity in quail.

 

[Michael Scally MD]

Hildreth KL, Barry DW, Moreau KL, et al. Effects of Testosterone and Progressive Resistance Exercise in Healthy, Highly Functioning Older Men With Low-Normal Testosterone Levels. Journal of Clinical Endocrinology & Metabolism. Effects of Testosterone and Progressive Resistance Exercise in Healthy, Highly Functioning Older Men With Low-Normal Testosterone Levels

Context: Aging in men is associated with reduced testosterone (T) levels and physiological changes leading to frailty, but the benefits of T supplementation are inconclusive.

Objective: We studied the effects of T supplementation with and without progressive resistance training (PRT) on functional performance, strength, and body composition.

Design, Setting, and Participants: We recruited 167 generally healthy community-dwelling older men (66 ± 5 years) with low-normal baseline total T levels (200–350 ng/dL).

Intervention: Subjects were randomized to placebo or transdermal T gel [2 doses targeting either a lower (400–550 ng/dL) or higher (600–1000 ng/dL) T range] and to either PRT or no exercise for 12 months.

Main Outcome Measure: The primary outcome was functional performance, whereas secondary outcomes were strength and body composition.

Results: A total of 143 men completed the study. At 12 months, total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group. In the PRT group, function and strength were not different between T- and placebo-treated subjects, despite greater improvements in fat mass (P = .04) and fat-free mass (P = .01) with T. In the non-PRT group, T did not improve function but improved fat mass (P = .005), fat-free mass (P = .03), and upper body strength (P = .03) compared with placebo. There were fewer cardiovascular events in the T-treated groups compared with placebo.

Conclusions: T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

 

[Michael Scally MD]

Garin MC, Burns CM, Kaul S, Cappola AR. The Human Experience with Ghrelin Administration. Journal of Clinical Endocrinology & Metabolism. The Human Experience with Ghrelin Administration

Context: Ghrelin is an endogenous stimulator of growth hormone and is implicated in a number of physiologic processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans.

Evidence Acquisition: PubMed was utilized and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans.

Evidence Synthesis: Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects.

Conclusions: Existing literature support the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, though these areas require further investigation.

 

[Michael Scally MD]

Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo) 2013;68 Suppl 1:81-8. http://www.scielo.br/pdf/clin/v68s1/a09v68s1.pdf

Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Hypogonadotropic hypogonadism can be congenital or acquired. Congenital hypogonadotropic hypogonadism is divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and congenital normosmic isolated hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism). The incidence of congenital hypogonadotropic hypogonadism is approximately 1-10:100,000 live births, and approximately 2/3 and 1/3 of cases are caused by Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism, respectively. Acquired hypogonadotropic hypogonadism can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X.

The clinical characteristics of hypogonadotropic hypogonadism are androgen deficiency and a lack/delay/stop of pubertal sexual maturation. Low blood testosterone levels and low pituitary hormone levels confirm the hypogonadotropic hypogonadism diagnosis. A prolonged stimulated intravenous GnRH test can be useful. In Kallmann syndrome, cerebral MRI can show an anomalous morphology or even absence of the olfactory bulb.

Therapy for hypogonadotropic hypogonadism depends on the patient's desire for future fertility. Hormone replacement with testosterone is the classic treatment for hypogonadism. Androgen replacement is indicated for men who already have children or have no desire to induce pregnancy, and testosterone therapy is used to reverse the symptoms and signs of hypogonadism. Conversely, GnRH or gonadotropin therapies are the best options for men wishing to have children.

Hypogonadotropic hypogonadism is one of the rare conditions in which specific medical treatment can reverse infertility. When an unassisted pregnancy is not achieved, assisted reproductive techniques ranging from intrauterine insemination to in vitro fertilization to the acquisition of viable sperm from the ejaculate or directly from the testes through testicular sperm extraction or testicular microdissection can also be used, depending on the woman's potential for pregnancy and the quality and quantity of the sperm.

 

[Michael Scally MD]

Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MKM. Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study. Journal of Clinical Endocrinology & Metabolism. Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study

Context: Patients previously treated with desiccated thyroid extract (DTE), when being switched to levothyroxine (L-T4), occasionally did not feel as well despite adequate dosing based on serum TSH levels.

Objective: Our objective was to investigate the effectiveness of DTE compared with L-T4 in hypothyroid patients.

Design and Setting: We conducted a randomized, double-blind, crossover study at a tertiary care center.

Patients: Patients (n = 70, age 18–65 years) diagnosed with primary hypothyroidism on a stable dose of L-T4 for 6 months were included in the study.

Intervention: Patients were randomized to either DTE or L-T4 for 16 weeks and then crossed over for the same duration.

Outcome Measures: Biochemical and neurocognitive tests at baseline and at the end of each treatment period were evaluated.

Results: There were no differences in symptoms and neurocognitive measurements between the 2 therapies. Patients lost 3 lb on DTE treatment (172.9 ± 36.4 lb vs 175.7 ± 37.7 lb, P < .001). At the end of the study, 34 patients (48.6%) preferred DTE, 13 (18.6%) preferred L-T4, and 23 (32.9%) had no preference. In the subgroup analyses, those patients who preferred DTE lost 4 lb during the DTE treatment, and their subjective symptoms were significantly better while taking DTE as measured by the general health questionnaire-12 and thyroid symptom questionnaire (P < .001 for both). Five variables were predictors of preference for DTE.

Conclusion: DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (48.6%) of the study patients expressed preference for DTE over L-T4. DTE therapy may be relevant for some hypothyroid patients.

 

[Michael Scally MD]

Herbenick D, Schick V, Reece M, Sanders SA, Fortenberry JD. The Development and Validation of the Male Genital Self-Image Scale: Results from a Nationally Representative Probability Sample of Men in the United States. The Journal of Sexual Medicine. The Development and Validation of the Male Genital Self-Image Scale: Results from a Nationally Representative Probability Sample of Men in the United States - Herbenick - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Numerous factors may affect men's sexual experiences, including their health status, past trauma or abuse, medication use, relationships, mood, anxiety, and body image. Little research has assessed the influence of men's genital self-image on their sexual function or behaviors and none has done so in a nationally representative sample.

Aims The purpose of this study was to, in a nationally representative probability sample of men ages 18 to 60, assess the reliability and validity of the Male Genital Self-Image Scale (MGSIS), and to examine the relationship between scores on the MGSIS and men's scores on the International Index of Erectile Function (IIEF).

Methods The MGSIS was developed in two stages. Phase One involved a review of the literature and an analysis of cross-sectional survey data. Phase Two involved an administration of the scale items to a nationally representative sample of men in the United States ages 18 to 60.

Main Outcome Measures Measures include demographic items, the IIEF, and the MGSIS.

Results Overall, most men felt positively about their genitals. However, 24.6% of men expressed some discomfort letting a healthcare provider examine their genitals and about 20% reported dissatisfaction with their genital size. The MGSIS was found to be reliable and valid, with the MGSIS-5 (consisting of five items) being the best fit to the data.

Conclusion The MGSIS was found to be a reliable and valid measure. In addition, men's scores on the MGSIS-5 were found to be positively related to men's scores on the IIEF.

 

[Michael Scally MD]

McKinney AR, Cawley AT, Young EB, et al. The metabolism of anabolic-androgenic steroids in the greyhound. Bioanalysis 2013;5(7):769-81. An Error Occurred Setting Your User Cookie

Background: Effective control of the use of anabolic-androgenic steroids (AASs) in animal sports is essential in order to ensure both animal welfare and integrity. In order to better police their use in Australian and New Zealand greyhound racing, thorough metabolic studies have been carried out on a range of registered human and veterinary AASs available in the region.

Results: Canine metabolic data are presented for the AASs boldenone, danazol, ethylestrenol, mesterolone, methandriol, nandrolone and norethandrolone. The principal Phase I metabolic processes observed were the reduction of A-ring unsaturations and/or 3-ketones with either 3alpha,5beta- or 3beta,5alpha-stereochemistry, the oxidation of secondary 17beta-hydroxyl groups and 16alpha-hydroxylation. The Phase II beta-glucuronylation of sterol metabolites was extensive.

Conclusion: The presented data have enabled the effective analysis of AASs and their metabolites in competition greyhound urine samples.

 

[Michael Scally MD]

Guay AT, Traish AM, Hislop-Chestnut DT, Doros G, Gawoski JM. Are there Variances of Calculated Free Testosterone Attributed to Variations in Albumin and Sex Hormone Binding Globulin Concentrations in Men? Endocr Pract 2013:1-21. Are there Variances of Calculated Free Testosterone Attributed to Variations in Albumin and Sex Hormonebinding Globulin Concentrations in Men? - Endocrine Practice - American Association of Clinical Endocrinologists

Objective: Calculated free testosterone (cFT) is determined from total testosterone (TT), sex hormone binding globulin (SHBG) and Albumin (Alb) using mathematical formulae. Variations in cFT due to changes in SHBG or Alb have not been investigated. We evaluated potential cFT variances determined with fixed Alb (4.3 g/dL) compared to measured Alb, and the point at which low SHBG and Alb combinations produced significant cFT variance.

Method: We analyzed 11,176 data points in 5,797 men. cFT values with fixed versus actual Alb values were evaluated and contrasted. cFT levels were determined theoretically for all possible combinations of TT, SHBG and Alb, in 8,343,552 combinations. Agreement between the two measures was assessed with Lin's concordance coefficient. Statistical analyses were performed using R software version 2.12.1.

Results: Mean Alb was 4.06 +/- 0.32 g/dL. Mean SHBG was 39.0 +/- 23.6 nmol/L. A fixed Alb of 4.3 g/dL produced no significant variance for most evaluations of cFT. The accuracy decreased with Alb </= 3.5 g/dL in combination with SHBG </= 30 nmol/L, and exists in 1.2% of the data points in men.

Conclusion: A fixed Alb of 4.3 g/dL is acceptable for most clinical evaluations. If Alb is </= 3.5 g/dL, along with SHBG </= 30 nmol/L, the variance increases, then a free testosterone (FT) measurement by equilibrium dialysis is warranted for better accuracy.

 

[Michael Scally MD]

McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP. Melatonin Secretion and the Incidence of Type 2 Diabetes. JAMA.2013;309(13):1388-1396. JAMA Network | JAMA | Melatonin Secretion and the Incidence of Type 2 DiabetesMelatonin Secretion and Type 2 Diabetes

Importance - Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance.

Objective - To study the association between melatonin secretion and the risk of developing type 2 diabetes.

Design, Setting, and Participants - Case-control study nested within the Nurses' Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, we identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls using risk-set sampling.

Main Outcome Measures - Associations between melatonin secretion at baseline and incidence of type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction.

Results - The median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg (5%-95% range, 5.5-84.2 ng/mg) among cases and 36.3 ng/mg (5%-95% range, 6.9-110.8 ng/mg) among controls. Women with lower ratios of 6-sulfatoxymelatonin to creatinine had increased risk of diabetes (multivariable odds ratio, 1.48 [95% CI, 1.11-1.98] per unit decrease in the estimated log ratio of 6-sulfatoxymelatonin to creatinine). Compared with women in the highest ratio category of 6-sulfatoxymelatonin to creatinine, those in the lowest category had a multivariable odds ratio of 2.17 (95% CI, 1.18-3.98) of developing type 2 diabetes. Women in the highest category of melatonin secretion had an estimated diabetes incidence rate of 4.27 cases/1000 person-years compared with 9.27 cases/1000 person-years in the lowest category.

Conclusions and Relevance - Lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population.

 

[Michael Scally MD]

Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. Journal of Endocrinology. http://joe.endocrinology-journals.org/content/early/2013/04/02/JOE-12-0582.full.pdf

Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease. Furthermore, low testosterone is associated in some but not all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors which include cholesterol, endothelial dysfunction and inflammation; key mediators of atherosclerosis.

A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicate attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone which predominantly has vasodilatory actions on several vascular beds although some studies report conflicting effects.

In clinical studies acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies consistently demonstrate that testosterone is atheroprotective whereas testosterone deficiency promotes early stages of atherogenesis.

Translational effects of testosterone between in vitro, animal and human studies, some of which have conflicting effects, will be discussed. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with cardiovascular disease, and some of the possible underlying mechanisms.

 

[Michael Scally MD]

Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P. Testosterone Replacement Therapy with Long-Acting Testosterone Undecanoate Improves Sexual Function and Quality-of-Life Parameters vs. Placebo in a Population of Men with Type 2 Diabetes. The Journal of Sexual Medicine. Testosterone Replacement Therapy with Long-Acting Testosterone Undecanoate Improves Sexual Function and Quality-of-Life Parameters vs. Placebo in a Population of Men with Type 2 Diabetes - Hackett - 2013 - The Journal of Sexual Medicine - Wiley Onlin

Introduction - Sexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED.

Aim - This study aimed to determine the effect of testosterone replacement with long-acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open-label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits.

Methods - The male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12?nmol/L or less or with free testosterones of 250?pmol/L or less. Two hundred eleven men were screened. A double-blind placebo-controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000?mg of TU or matching placebo followed by 52-week open-label follow on.

Main Outcome Measures - The primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self-reported quality of life.

Results - Testosterone replacement therapy with long-acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P?=?0.005; intercourse satisfaction, P?=?0.015; sexual desire, P?=?0.001; overall satisfaction, P?=?0.05; and orgasm, P?=?0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P?=?0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double-blind phase but a nine-point improvement in EF domain during 52-week open-label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open-label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events.

Conclusion - TU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52-week open-label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3–6 months suggested in current guidelines.

 

[Michael Scally MD]

Pikwer M, Giwercman A, Bergstrom U, Nilsson J, Jacobsson LTH, Turesson C. Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case-control study. Annals of the Rheumatic Diseases. Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case–control study -- Pikwer et al. -- Annals of the Rheumatic Diseases

Objectives Rheumatoid arthritis (RA) is less common among men than women, and sex hormones have been suggested to play a part in the pathogenesis. Lower levels of testosterone have been demonstrated in men with RA, but it is not known if these changes precede the disease.

Methods In a nested case–control study, using information and blood samples from a population-based health survey, we identified incident cases of RA by linking the cohort to local and national RA registers. Two controls for each validated case, matched for age, sex and year of screening, were selected from the health survey. Using stored blood samples, collected between 08:00 and 10:00 am after an overnight fast, we analysed levels of testosterone and other reproductive hormones.

Results Serum was available from 104 cases (median time from screening to RA diagnosis 12.7 years (range 1–28); 73% rheumatoid factor (RF) positive at diagnosis or later) and 174 matched controls. In conditional logistic regression models, adjusted for smoking and body mass index, lower levels of testosterone were associated with subsequent development of RF-negative RA (OR 0.31 per SD, 95% CI 0.12 to 0.85), with a weaker association with RF-positive RA (OR 0.87 per SD; 95% CI 0.53 to 1.43). Levels of follicle-stimulating hormone were significantly increased in pre-RF-negative RA (p=0.02), but decreased in pre-RF-positive RA (p=0.02).

Conclusions Lower levels of testosterone were predictive of RF-negative RA, suggesting that hormonal changes precede the onset of RA and affect the disease phenotype.

 

[Michael Scally MD]

Bang JK, Lim JJ, Choi J, et al. Reversible infertility associated with testosterone therapy for symptomatic hypogonadism in infertile couple. Yonsei Med J 2013;54(3):702-6. http://www.eymj.org/Synapse/Data/PDFData/0069YMJ/ymj-54-702.pdf

Purpose: Androgen replacement therapy has been shown to be safe and effective for most patients with testosterone deficiency. Male partners of infertile couples often report significantly poorer sexual activity and complain androgen deficiency symptoms. We report herein an adverse effect on fertility caused by misusage of androgen replacement therapy in infertile men with hypogonadal symptoms.

Materials and Methods: The study population consisted of 8 male patients referred from a local clinic for azoospermia or severe oligozoospermia between January 2008 and July 2011. After detailed evaluation at our andrology clinic, all patients were diagnosed with iatrogenic hypogonadism associated with external androgen replacement. We evaluated changes in semen parameters and serum hormone level, and fertility status.

Results: All patients had received multiple testosterone undecanoate (Nebido(R)) injections at local clinic due to androgen deficiency symptoms combined with lower serum testosterone level. The median duration of androgen replacement therapy prior to the development of azoospermia was 8 months (range: 4-12 months). After withdrawal of androgen therapy, sperm concentration and serum follicle-stimulating hormone level returned to normal range at a median 8.5 months (range: 7-10 months).

Conclusion: Misusage of external androgen replacement therapy in infertile men with poor sexual function can cause temporary spermatogenic dysfunction, thus aggravating infertility.

 

[Michael Scally MD]

Ukkola O, Huttunen T, Puurunen VP, et al. Total testosterone levels, metabolic parameters, cardiac remodeling and exercise capacity in coronary artery disease patients with different stages of glucose tolerance. Ann Med. An Error Occurred Setting Your User Cookie

Objective and Methods. The correlation between total testosterone levels, exercise capacity, and metabolic and echocardiographic parameters was studied in 1097 male subjects with coronary artery disease (CAD) and different stages of glucose tolerance.

Results. Testosterone level was the lowest among diabetics as compared to prediabetics or controls (P < 0.001). Total and abdominal adiposity were the highest in the subjects with the lowest testosterone. Independent of adiposity, fasting glucose, insulin, and leptin were higher (P < 0.03 to < 0.001) among diabetic and control groups in the lowest, and HbA1c values (P < 0.001) higher among diabetics in the lowest, than in the highest testosterone tertile. Controls and prediabetic subjects with the lowest testosterone levels had the lowest HDL-cholesterol levels, and controls also the highest triglycerides. An association between low testosterone level and low maximal exercise capacity was observed in diabetics (P < 0.001) and controls (P < 0.03). Independent of adiposity and metabolic parameters, low testosterone levels were associated with the highest septal wall thickness (P < 0.03) among diabetics.

Conclusion. A negative correlation between low testosterone and dysmetabolic features was observed. Independent of metabolic status, low plasma testosterone seems to be an indicator of impaired maximal exercise capacity and cardiac hypertrophy among CAD patients with type II diabetes.