OnLine First 2013

[Michael Scally MD]

The changes in sex hormones that typically accompany obesity may be responsible for certain effects on the heart including alterations in the left chamber. In a small study, artificially increasing estradiol and diminishing testosterone levels in healthy young men led to a significant increase in global circumferential strain.

Short-Term Changes In Serum Sex Steroid Levels And Cardiac Function In Healthy Young Men
Short-term changes in serum sex steroid levels and cardiac function in healthy young men

Introduction: Male obesity is associated with an increase in estradiol (E2) and a decrease in testosterone (T). And, although sex steroids are associated with cardiovascular disease, direct effects on cardiac structure and function are hardly investigated in humans.

Methodology: Twenty healthy men aged 20–40 years were randomized into two groups. One group was given an aromatase inhibitor (letrozole) only, thus obtaining a high testosterone and low E2 (group T). The other group received an aromatase inhibitor plus an E2 patch (dermestril), reaching a low testosterone and high E2(group E). Serum levels of both testosterone and E2 remained within the normal reference range. The men underwent an echocardiography by a single cardiologist before the start of the intervention and after 7 days.

Results: Total and free E2 serum levels were positively associated with ejection fraction (r=0.7, P=0.002 andr=0.6, P=0.007 respectively) at baseline in the whole group. In group E global circumferential strain decreased significantly from ?25.3%±3.9 to ?19.6%±2.5 after 1 week as compared to baseline (P=0.01). No significant changes in systolic function were observed in group T. Cardiac structure remained unaltered.

Conclusion: In young healthy men, an increase in E2 and decrease in testosterone levels significantly decreased circumferential strain. The finding justifies larger studies of longer duration to discover the exact nature of the impact of changed sex steroids on cardiac function and remodelling in obesity.

 

[Michael Scally MD]

Subramoniam A, Gangaprasad A, Sureshkumar PK, Radhika J, Arun BK. A novel aphrodisiac compound from an orchid that activates nitric oxide synthases. Int J Impot Res. http://www.nature.com/ijir/journal/vaop/ncurrent/full/ijir201318a.html

Nitric oxide (NO) is known to have roles in several crucial biological functions including vasodilation and penile erection. There are neuronal, endothelial and inducible NO synthases that influence the levels of NO in tissues and blood. NO activates guanylate cyclase and thereby increases the levels of cyclic GMP (cGMP). Viagra (sildenafil), a top selling drug in the world for erectile dysfunction, inhibits phosphodiesterase-5, which hydrolyses cGMP to GMP. Thus, it fosters an NO-mediated increase in the levels of cGMP, which mediates erectile function. Here, we show the aphrodisiac activity of a novel chemical isolate from the flowers of an epiphytic orchid, Vanda tessellata (Roxb.) ex Don, which activates neuronal and endothelial, but not inducible, NO synthases. The aphrodisiac activity is caused by an increase in the level of NO in corpus cavernosum. The drug increases blood levels of NO as early as 30 min after oral administration. The active compound was isolated by column chromatography. Based on the spectral data, the active compound is found to be a new compound, 2,7,7-tri methyl bicyclo [2.2.1] heptane. We anticipate that our findings could lead to the development of a commercially viable and valuable drug for erectile dysfunction.

 

[Michael Scally MD]

Kataoka T, Hotta Y, Ohno M, Maeda Y, Kimura K. Limited effect of testosterone treatment for erectile dysfunction caused by high-estrogen levels in rats. Int J Impot Res. http://www.nature.com/ijir/journal/vaop/ncurrent/full/ijir201321a.html

Some studies suggest that high-estrogen levels lead to erectile dysfunction (ED); high-estrogen levels are known to decrease testosterone levels. However, no study has examined whether testosterone replacement can improve the ED induced by high-estrogen levels. We investigated the effects of testosterone on ED caused by high-estrogen levels in rats. Rats were distributed in the following groups: (1) control (vehicle for 2 weeks), (2) the estrogen-treated group (ES; estradiol (3 mug kg-1 day-1) for 2 weeks), and (3) the estrogen- and testosterone-treated group (ES+TE; estradiol (3 mug kg-1 day-1) and testosterone (3 mg kg-1 day-1) for 2 weeks). We measured smooth muscle function via isometric tension and erectile function by measuring the intracavernosal pressure on cavernous nerve stimulation. In the ES group, the contraction of the corpus cavernosum smooth muscle increased in response to noradrenalin, and its relaxation decreased in response to the nitric oxide donor, sodium nitroprusside. Further, the erectile function was significantly decreased. In the ES+TE group, neither smooth muscle function nor erectile function was significantly improved. In conclusion, a high-estrogen milieu affected erectile function in rats, and testosterone treatment did not improve the ED caused by high-estrogen levels.

 

[Michael Scally MD]

Li Y, Batool-Anwar S, Kim S, Rimm EB, Ascherio A, Gao X. Prospective Study of Restless Legs Syndrome and Risk of Erectile Dysfunction. American Journal of Epidemiology. Prospective Study of Restless Legs Syndrome and Risk of Erectile Dysfunction

In our previous cross-sectional study, we found that restless legs syndrome (RLS) was associated with erectile dysfunction (ED). Thus, we conducted a prospective study to examine whether RLS was associated with a higher risk of developing ED based on 6 years of follow-up among 10,394 men (mean age = 63.4 years) in the Health Professionals Follow-up Study. RLS was assessed in 2002 using a set of standardized questions recommended by the International RLS Study Group. Erectile function was assessed by means of questionnaires in 2000, 2004, and 2008. We identified 1,633 incident ED cases. Men with RLS were more likely to develop ED (relative risk = 1.38, 95% confidence interval: 1.14, 1.68; P = 0.001) than were those without the syndrome, after adjustment for potential confounders, such as age, body mass index, smoking, physical activity, other sleep disorders, and snoring status. A higher frequency of RLS symptoms was also associated with an increased risk of ED (Ptrend = 0.001). In conclusion, men with RLS had a higher risk of ED, and the magnitude of the risk increased with a higher frequency of RLS symptoms. Combinations of other sleep disorders with RLS further increased the risk of ED.

 

[Michael Scally MD]

Chronic Marijuana Use As A Potential Cause Of Hypopituitarism
Case Study Links 'Pot' to Pituitary Damage

Objective: Hypopituitarism is most often caused by a mass lesion and less commonly by inflammatory, infiltrative, or vascular disease. Tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, has ability to alter various neural transmitters in the hypothalamus or neural transmitters in the CNS which affect the hypothalamus. We report a case of hypopituitarism seemingly secondary to chronic marijuana use.

Case Presentation: A 37-year-old male presented to the Emergency Department with symptoms of dyspnea on exertion, increasing fatigue, and loss of libido. The patient reported daily use of marijuana for 15 years. There was no history of radiation exposure or head trauma. On physical exam, significant findings of bibasilar rales, gynecomastia, and bilateral atrophied testis were noted. Considering the possibility of hemochromatosis, iron studies and echocardiography were completed, which were normal.

Hormonal evaluation revealed low LH (0.2 mIU/mL), FSH (1.8 mIU/mL) and testosterone (22 ng/dL) along with high prolactin (53.3 ng/mL). Further endocrine chemistry revealed ACTH of 6 pg/mL, and cortisol at 0 and 60 minutes following administration of cosyntropin of 6.4 ug/dL, and 9.3 ug/dL respectively. Additional lab studies revealed low total T3 (30 ng/dL), high T3 resin reuptake (49%), low total T4 (3.94 ug/dL), normal free T4 (0.97 ng/dL) and low TSH (0.22 uIU/ml). In addition, growth hormone was within normal limits (5.0 ng/mL) and IGF-1 was low (75 ng/mL; Z-score of -1.3). MRI of head showed a protuberant pituitary gland that was slightly larger than expected size, but there was no identified mass lesion. The patient was started on cortisone 25 mg in the morning and 12.5 mg at bedtime and levothyroxine 25 mcg daily. Subsequent to this his fatigue and edema improved dramatically.

Discussion: THC impairs GnRH release resulting in lowered LH and FSH, which is responsible for reduced testosterone production by the Leydig cells of the testis. Several studies have also shown impaired cortisol response to stress resulting from cannabis exposure. Similarly, animal models have shown that exogenous cannabinoids suppresses multiple hypothalamic-pituitary pathways, including growth hormone, and thyroid hormone. Given these findings, we postulate that chronic cannabis use, by modulating the hypothalamic-pituitary axis, is a potential cause of hypopituitarism.

Conclusion: Given the climate of increasing legalization of cannabis in the United States, the relationship between chronic marijuana use and its potential effects on the endocrine system warrants further study.

 

[Michael Scally MD]

Testosterone Replacement Increases Insulin Sensitivity In Hypogonadal Men With Type 2 Diabetes
http://am.aace.com/sites/all//files/2013_abstract_book_nocover.pdf

Objective: One third of men with type 2 diabetes (T2D) have hypogonadotropic hypogonadism (HH). Testosterone (T) concentrations are inversely related to BMI. We conducted a randomized placebo controlled trial to evaluate the effect of T replacement on insulin resistance in T2D men with HH.

Methods: 50 men with T2D were recruited into the study. HH was defined as free T concentrations <5 ng/dl with normal or low LH and FSH. 26 men had HH (mean total T 247±82ng/dl; free T 4.2±1.1ng/dl) and 24 men had normal total and free T concentrations (means 527±205 and 7.3±2.0ng/dl). Insulin sensitivity was calculated from the glucose infusion rate (GIR) during the last 30 min of a 4 hour hyperinsulinemic-euglycemic clamp (80mU/m2/ min) and expressed as mg/kg body weight/min. Lean mass and fat mass were measured by DEXA. Men with HH were randomized to receive intramuscular injections of T (250 mg) or placebo (1ml saline) every 2 weeks for 6 months (n=13 in each group). Clamps and DEXA were repeated at 6 months.

Results: Men with HH had similar age (54±8 vs. 53±10years, p=0.56) but higher BMI (40±9 vs. 34±7kg/ m2, p=0.02) than eugonadal men. Men with HH had higher fat mass (45±15 vs. 34±15kg, p=0.02) but similar lean mass (73±21 vs. 66±9kg, p=0.12) as compared to eugonadal men. Mean GIR was lower in men with HH as compared to eugonadal men (4.1±2.4 vs. 6.9±3.6 mg/ kg/min, p=0.003) even after adjustment for fat mass, lean mass and age (4.6±2.7 vs. 6.4±2.7 mg/kg/min, p=0.05).

Total and free T concentrations increased after 6 months of T therapy (273±96 vs 561±249 ng/dl, p=0.01; 4.2±1.1 vs. 11.8±7.1 ng/dl, p=0.007; blood sample drawn 1 week after the final T injection) but did not change in placebo group (271±40 vs 349±215 ng/dl, p=0.23; 4.0±0.8 vs. 4.8±2.1 ng/dl, p=0.3).

There was no change in SHBG concentrations in either group (30±15 vs. 27±10nmol/l, p=0.17 in T group; 35±14 vs. 34±19nmol/l, p=0.67 in placebo group). There was no change in weight (123±23 vs 122±24kg, p=0.37) or fat mass (46±15 vs 43±13kg, p=0.24) but lean mass (71±9 vs 72±10kg, p=0.03) increased slightly but significantly after 6 months of T therapy. There was no change in weight (111±38 vs 112±38kg, p=0.85), fat mass (37±16 vs 36±14kg, p=0.19) or lean mass (67±14 vs 67±13kg, p=0.57) in placebo group.

GIR increased by 30% after 6 months (4.1±2.0 vs 5.3±2.3 mg/kg/min, p=0.005) of T therapy but did not change in placebo group (3.4±1.5 vs 3.5±1.8 mg/kg/min, p=0.88). Change in GIR did not relate to increase in free T (r=-0.16, p=0.68) or to change in lean mass (r=-0.13, p=0.73) in T group.

Conclusion: Our data show for the first time that men with T2D and HH are more insulin resistant than those with normal T, and insulin resistance is reversed following T replacement.

 

[Michael Scally MD]

Klinefelter Syndrome [1 In Every 500]: It Is Never Too Late To Diagnose An Easily Missed Chromosomal Disorder! [Abstract #912]
http://am.aace.com/sites/all//files/2013_abstract_book_nocover.pdf

Objective: To describe a case of Klinefelter Syndrome diagnosed at age 63, and review the literature.

Case Presentation: A 63 year old male was admitted to the hospital for chest pain. He had mild mental retardation and a history of deep vein thrombosis, pulmonary embolism, s/p Inferior vena cava filter placement, and chronic venous stasis. Endocrinology consultation was obtained because of acromegaloid features.

The patient did not shave regularly because of slow facial hair growth and never had sexual intercourse. He was unmarried and had no biological children. He had eunuchoid body proportions. Height was 6’9”, leg to height ratio 0.59, torso to height ratio 0.44, and arm-span to height ratio 1.059. He appeared to have a speech impediment, with prominent gynecomastia, small testes (< 1 cm in length bilaterally), and sparse axillary, facial, and pubic hair.

Laboratory evaluation revealed total testosterone level of 11 ng/dl [300-720 ng/dl] with free testosterone 1 pg/ml [47-244], LH 17 mIU/ml (1.2-10.8), FSH 48 mIU/ml(0.7- 10.8), prolactin 13.4 ng/ml [2.5-17.4] and IGF-1=199 ng/ ml (50-255), Pituitary MRI was normal. A karyotype of 47, XXY confirmed the clinical suspicion of Klinefelter Syndrome. The diagnosis was discussed with the patient and he received appropriate counseling.

Discussion: Klinefelter syndrome (47,XXY), the most common sex chromosome aneuploidy disorder in males, is caused by the presence of an extra X chromosome. It occurs in 1 in every 500 males in the general population. 3% of infertile males have Klinefelter syndrome and it is a frequent cause of hypogonadism. Features include small testes, increased arm span and lower extremity length, gynecomastia, developmental delay, speech and language deficits, behavioral issues, learning disabilities, and infertility. About 10% of affected males are diagnosed prenatally, 25% at puberty and another 25% in late adulthood. Amazingly, almost two-thirds of affected individuals are never diagnosed. Of those diagnosed, fully 12% are found in the sixth decade of life, like our patient. Often the diagnosis is made fortuitously as a result of unrelated medical evaluations or hospital admissions.

Conclusion: In the appropriate clinical setting, a high index of suspicion should be maintained by health care professionals for the presence of Klinefelter Syndrome. Small testes, low testosterone, and elevated gonadotropins (hypergonadotropic hypogonadism) should prompt further clinical investigation for the disorder. Since the manifestations of the syndrome are often variable, a karyotype analysis should be ordered for confirmation. Early diagnosis and management is essential for minimizing morbidity and enhancing quality of life.

 

[Michael Scally MD]

Tuberculous Epididymitis: An Unexpected Finding During Evaluation Of Male Hypogonadism [Abstract #918]
http://am.aace.com/sites/all//files/2013_abstract_book_nocover.pdf

Objective: Endocrinologists rely primarily on biochemical data to determine the etiology of male hypogonadism, and because of this may be tempted to defer the genital exam due to patient or physician discomfort. We present the case of 52 year-old man with low testosterone who was found on exam to have a scrotal mass, leading to the important diagnosis of extrapulmonary tuberculosis.

Case Presentation: A 52 year-old man had complained of fatigue and low libido to his primary care physician. He was found to have low testosterone and was started on testosterone gel. When this did not improve his symptoms, he sought endocrine consultation.

Physical exam demonstrated a firm right scrotal mass. An ultrasound demonstrated a 2.5 centimeter extra-testicular mass inferior to the right testicle. Orchiectomy was recommended as malignancy could not be excluded. Pathology demonstrated necrotizing granulomas of the epididymis and spermatic cord with fibrosis. AFB and fungal stain of the tissue was negative. The patient was referred to infectious disease and an interferon gamma release assay was positive for tuberculosis (TB). He denied systemic symptoms of TB and had no prior history of TB, though he did live in India until age 20. A chest X-ray (CXR) was negative. The patient was diagnosed with tuberculous epididymitis (TBE) and started on therapy with isoniazid, rifampin and pyrazinamide. Due to uncertainty about his diagnosis of testosterone deficiency, testosterone gel was withdrawn and his gonadal axis reevaluated. He was diagnosed with hypogonadotrophic hypogonadism. Prolactin was minimally elevated and pituitary MRI was normal. He was started on therapy with intramuscular testosterone.

Discussion: Extrapulmonary involvement is seen in ~20% of patients with TB, with the genitourinary system, most commonly the kidneys, representing a common site of involvement. TBE is seen in < 10% of patients. Patients with TBE may be asymptomatic or can present with a variety of symptoms including painful scrotal swelling. The differential diagnosis often includes malignancy. Diagnosis is made by biopsy or surgical pathology, with supporting tests including PCR, interferon gamma release assays, and ultrasound. CXR to exclude pulmonary involvement should always be performed. TBE is treated with standard multidrug anti-TB regimens.

Conclusion: Our case demonstrates the importance of performing a genital exam in patients with male hypogonadism. The genital exam can demonstrate significant findings that may be related (e.g. small testes in Klinefelter’s syndrome) or unrelated (e.g. masses, hernia, varicocele) to the testosterone deficiency.

 

[Michael Scally MD]

De Ryck I, Van Laeken D, Apers L, Colebunders R. Erectile Dysfunction, Testosterone Deficiency, and Risk of Coronary Heart Disease in a Cohort of Men Living with HIV in Belgium. The Journal of Sexual Medicine. Erectile Dysfunction, Testosterone Deficiency, and Risk of Coronary Heart Disease in a Cohort of Men Living with HIV in Belgium - De Ryck - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Erectile dysfunction (ED) is more prevalent in men living with HIV (MLHIV) when compared with age-matched HIV-negative men. This may be related to a premature decline in testosterone levels. In the general population, ED has been associated with an increased risk for coronary heart disease (CHD).

Aim The aim of this study is to determine the prevalence of ED, testosterone deficiency, and risk of CHD in a cohort of young to middle-aged MLHIV in Belgium.

Methods A cross-sectional, observational study among 244 MLHIV attending the outpatient clinic of the Institute of Tropical Medicine in Antwerp.

Main Outcome Measures The short version of the international index of erectile function (IIEF-5) questionnaire diagnosed ED (cutoff score ?21). The 10-year risk score for CHD was calculated. In a subset of men reporting ED, the calculated free testosterone (CFT) was determined using Vermeulen's formula. Testosterone deficiency was defined as CFT <0.22?nmol/L.

Results One hundred fifty-one men (61.9%) self-reported ED (median IIEF-5 score: 16 [interquartile range (IQR) 12–19]). In multivariate analysis, only increasing age, but none of the HIV-related parameters, nor any of the individual cardiovascular-risk related parameters, was statistically significantly associated with ED. Eighteen out of the 49 (36.7%) men with ED who received a blood test to assess testosterone levels were diagnosed with testosterone deficiency. The 10-year risk of CHD in the cohort was 4.3% (IQR 3.6–5.7) and was significantly higher in men with ED (5.1%, IQR 4.4–6.6) compared with men without ED (3.1%, IQR 2.5–4.2).

Conclusions This study showed that ED and testosterone deficiency are highly prevalent in young to middle-aged MLHIV and that ED might be associated with an increased risk of CHD. Therefore, healthcare professionals should screen for clinical ED and should consider testing for underlying testosterone deficiency. A clinical diagnosis of ED should trigger a full evaluation of the patient's cardiovascular risk factors, even at younger age.

 

[Michael Scally MD]

Capogrosso P, Colicchia M, Ventimiglia E, et al. One Patient Out of Four with Newly Diagnosed Erectile Dysfunction Is a Young Man—Worrisome Picture from the Everyday Clinical Practice. The Journal of Sexual Medicine. One Patient Out of Four with Newly Diagnosed Erectile Dysfunction Is a Young Man&mdash;Worrisome Picture from the Everyday Clinical Practice - Capogrosso - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Erectile dysfunction (ED) is a common complaint in men over 40 years of age, and prevalence rates increase throughout the aging period. Prevalence and risk factors of ED among young men have been scantly analyzed.

Aim Assessing sociodemographic and clinical characteristics of young men (defined as ?40 years) seeking first medical help for new onset ED as their primary sexual disorder.

Methods Complete sociodemographic and clinical data from 439 consecutive patients were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF).

Main Outcome Measure Descriptive statistics tested sociodemographic and clinical differences between ED patients ?40 years and >40 years.

Results New onset ED as the primary disorder was found in 114 (26%) men ?40 years (mean [standard deviation [SD]] age: 32.4 [6.0]; range: 17–40 years). Patients ?40 years had a lower rate of comorbid conditions (CCI?=?0 in 90.4% vs. 58.3%; ?2, 39.12; P?<?0.001), a lower mean body mass index value (P?=?0.005), and a higher mean circulating total testosterone level (P?=?0.005) as compared with those >40 years. Younger ED patients more frequently showed habit of cigarette smoking and use of illicit drug, as compared with older men (all P???0.02). Premature ejaculation was more comorbid in younger men, whereas Peyronie's disease was prevalent in the older group (all P?=?0.03). At IIEF, severe ED rates were found in 48.8% younger men and 40% older men, respectively (P?>?0.05). Similarly, rates of mild, mild-to-moderate, and moderate ED were not significantly different between the two groups.

Conclusions This exploratory analysis showed that one in four patients seeking first medical help for new onset ED was younger than 40 years. Almost half of the young men suffered from severe ED, with comparable rates in older patients. Overall, younger men differed from older individuals in terms of both clinical and sociodemographic parameters.

 

[Michael Scally MD]

Male Androgen Deficiency (MAD) Screening Questionnaire: A Simplified Tool to Identify Hypogonadal Men [Abstract: 1391]
http://www.aua2013.org/abstracts/archive/printabstracts.cfm?id=1391

Introduction and Objectives - To identify which patient factors might be useful in developing a simplified hypogonadal screening questionnaire.

Methods - 5073 men with a median age of 62 years (IQ 54-69) were identified who participated in Prostate Awareness Week in 2010 and 2011 and had serum testosterone (T) determinations and completed an extensive screening questionnaire which included life style habits, coexisting diseases and body mass index (BMI, by height and weight). Significant associations were determined by test for variance (ANOVA) for mean T and by chi-square (Pearson) for hypogonadal state (T<300 ng/dL). The effect of multiple variables on T levels were determined by linear regression. Highly significant variables (p<0.001) were used to construct the questionnaire model.

Results - The median T and BMI were 349 ng/dL (IQ 251-349) and 27.0 kg/m2 (IQ 24.4-30.5). 1952 men (38.5%) were identified with a T level <300 ng/dL. Caucasian men had lower mean T (371.9 ng/dL) compared to African-American men (406.6 ng/dL, p<0.001).

Men who never smoked had lower T than current smokers (377.4 vs 418, p<0.001). Men who exercised 5 or more than times per week had T levels of 391.9 ng/dL compared to 360.4 ng/dL for men who did not exercise (p<0.001). Men who considered themselves overweight by 30 lbs. had T of 293.3 ng/dL compared to 421.8 ng/dL for those of normal weight (p<0.001). On multivariate analysis only high BMI (p<0.001), type 2 diabetes (p<0.001) and being overweight (p<0.001) remained significant.

The MAD screening questionnaire was built on the significant variables which were dichotomized for the analysis. BMI and the question on degree obesity were highly correlated (AUC 0.827. p<0.001). The most predictive model for identifying HS was a positive response to overweight (20 lbs or more) +diabetes +erectile dysfunction which identified 62.6% (132/221) with T<300 (p<0.001). For patients without AODM the best model included overweight+ HD+ED which identified 54.3% (p<0.001).

Conclusions - We have identified health factors which can be used with a high degree of predictability to screen for HS. The MAD screening questionnaire, which includes queries on AODM, obesity, heart disease and ED can be easily introduced into practice.

 

[Michael Scally MD]

Cochran A, Thuet W, Holt B, Faraklas I, Smout RJ, Horn SD. The impact of oxandrolone on length of stay following major burn injury: A clinical practice evaluation. Burns. ScienceDirect.com - Burns - The impact of oxandrolone on length of stay following major burn injury: A clinical practice evaluation

INTRODUCTION: The anabolic agent oxandrolone (OX) has been found to decrease length of stay (LOS) following 20-60% total body surface area (TBSA) burn injury. This study uses the Comprehensive Severity Index (CSI) to control for severity of illness and explores the relationship between OX and LOS in a more broadly selected sample of burn patients and a natural practice setting.

METHODS: A practice-based evidence study was conducted at a single regional burn center. Maximum severity of illness (MCSIC) was measured using a burn-specific version of CSI. Data on 167 consecutive surviving patients with TBSA>/=15% were analyzed using case-control matching for MCSIC, TBSA, and age. Thirty-eight patients received OX.

RESULTS: Median patient age for the entire patient sample was 42.7 years. Using a 1:1 match based upon MCSIC, TBSA, then age, mean LOS for patients who received OX was 33.6 days, as opposed to 43.4 days for those who were not managed with OX (p=0.03). If patients were matched >1:1 for controls: cases, mean LOS was 40.9 days (controls) versus 31.6 days (cases).

CONCLUSIONS: OX is associated with shorter LOS after controlling for MCSIC, TBSA, and age. Future comparative effectiveness studies should better define which patients derive the greatest benefits from receipt of OX during their recovery from major burn injury.

 

[Michael Scally MD]

Albert O, Desdoits-Lethimonier C, Lesne L, et al. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro

STUDY QUESTION: Do mild analgesics affect the endocrine system of the human adult testis?

SUMMARY ANSWER: Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro.

WHAT IS KNOWN ALREADY: Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line.

STUDY DESIGN, SIZE, DURATION: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10-4 or 10-5 M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10-5 M ketoconazole, used as an anti-androgenic reference molecule, was also assessed.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods.

MAIN RESULTS AND THE ROLE OF CHANCE: The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play.

LIMITATIONS, REASONS FOR CAUTION: Our studies were performed in vitro.

WIDER IMPLICATIONS OF THE FINDINGS: We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.

STUDY FUNDING/COMPETING INTEREST(S): This work was funded by Inserm (Institut national de la sante et de la recherche medicale), EHESP (Ecole des Hautes Etudes en Sante Publique), Ministere de l'Enseignement Superieur et de la Recherche, Region Bretagne and Agence Nationale de securite du medicament et des produits de sante (IMPACTESTIS, Project no. AAP-2012-037). The authors declare they have no competing interests, be it financial, personal or professional.

 

[Michael Scally MD]

Afeiche M, Williams PL, Mendiola J, et al. Dairy food intake in relation to semen quality and reproductive hormone levels among physically active young men. Human Reproduction. Dairy food intake in relation to semen quality and reproductive hormone levels among physically active young men

STUDY QUESTION Is increased consumption of dairy foods associated with lower semen quality?

SUMMARY ANSWER We found that intake of full-fat dairy was inversely related to sperm motility and morphology. These associations were driven primarily by intake of cheese and were independent of overall dietary patterns.

WHAT IS KNOWN ALREADY It has been suggested that environmental estrogens could be responsible for the putative secular decline in sperm counts. Dairy foods contain large amounts of estrogens. While some studies have suggested dairy as a possible contributing factor for decreased semen quality, this finding has not been consistent across studies.

STUDY DESIGN, SIZE, DURATION The Rochester Young Men's Study (n= 189) was a cross-sectional study conducted between 2009 and 2010 at the University of Rochester.

PARTICIPANTS/MATERIALS, SETTING, METHODS Men aged 18–22 years were included in this analysis. Diet was assessed via food frequency questionnaire. Linear regression was used to analyze the relation between dairy intake and conventional semen quality parameters (total sperm count, sperm concentration, progressive motility, morphology and ejaculate volume) adjusting for age, abstinence time, race, smoking status, body mass index, recruitment period, moderate-to-intense exercise, TV watching and total calorie intake.

MAIN RESULTS AND THE ROLE OF CHANCE Total dairy food intake was inversely related to sperm morphology (P-trend = 0.004). This association was mostly driven by intake of full-fat dairy foods. The adjusted difference (95% confidence interval) in normal sperm morphology percent was ?3.2% (?4.5 to ?1.8) between men in the upper half and those in the lower half of full-fat dairy intake (P < 0.0001), while the equivalent contrast for low-fat dairy intake was less pronounced [?1.3% (?2.7 to ?0.07; P= 0.06)]. Full-fat dairy intake was also associated with significantly lower percent progressively motile sperm (P= 0.05).

LIMITATIONS, REASONS FOR CAUTION As it was a cross-sectional study, causal inference is limited.

WIDER IMPLICATIONS OF THE FINDINGS Further research is needed to prove a causal link between a high consumption of full-fat dairy foods and detrimental effects on semen quality. If verified our findings would mean that intake of full-fat dairy foods should be considered in attempts to explain secular trends in semen quality and that men trying to have children should restrict their intake.

STUDY FUNDING/COMPETING INTEREST(S) European Union Seventh Framework Program (Environment), ‘Developmental Effects of Environment on Reproductive Health’ (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 from the National Institutes of Health. None of the authors has any conflicts of interest to declare.

 

[Michael Scally MD]

Deyo RA, Smith DH, Johnson ES, et al. Prescription opioids for back pain and use of medications for erectile dysfunction. Spine (Phila Pa 1976) 2013;38(11):909-15. Prescription Opioids for Back Pain and Use of Medications fo... : Spine

STUDY DESIGN: Cross-sectional analysis of electronic medical and pharmacy records.

OBJECTIVE: To examine associations between use of medication for erectile dysfunction or testosterone replacement and use of opioid therapy, patient age, depression, and smoking status.

SUMMARY OF BACKGROUND DATA: Males with chronic pain may experience erectile dysfunction related to depression, smoking, age, or opioid-related hypogonadism. The prevalence of this problem in back pain populations and the relative importance of several risk factors are unknown.

METHODS: We examined electronic pharmacy and medical records for males with back pain in a large group model health maintenance organization during 2004. Relevant prescriptions were considered for 6 months before and after the index visit.

RESULTS: There were 11,327 males with a diagnosis of back pain. Males who received medications for erectile dysfunction or testosterone replacement (n = 909) were significantly older than those who did not and had greater comorbidity, depression, smoking, and use of sedative-hypnotics. In logistic regressions, the long-term use of opioids was associated with greater use of medications for erectile dysfunction or testosterone replacement compared with no opioid use (odds ratio, 1.45; 95% confidence interval, 1.12-1.87, P < 0.01). Age, comorbidity, depression, and use of sedative-hypnotics were also independently associated with the use of medications for erectile dysfunction or testosterone replacement. Patients prescribed daily opioid doses of 120 mg of morphine-equivalents or more had greater use of medication for erectile dysfunction or testosterone replacement than patients without opioid use (odds ratio, 1.58; 95% confidence interval, 1.03-2.43), even with adjustment for the duration of opioid therapy.

CONCLUSION: Dose and duration of opioid use, as well as age, comorbidity, depression, and use of sedative-hypnotics, were associated with evidence of erectile dysfunction. These findings may be important in the process of decision making for the long-term use of opioids.

Level of Evidence: 4.

 

[Michael Scally MD]

Rodriguez-Tolrà J, Torremadé J, di Gregorio S, del Rio L, Franco E. Effects of testosterone treatment on bone mineral density in men with testosterone deficiency syndrome. Andrology. Effects of testosterone treatment on bone mineral density in men with testosterone deficiency syndrome - Rodriguez-Tolr[] - 2013 - Andrology - Wiley Online Library

The decline in testosterone levels found in men with testosterone deficiency syndrome (TDS) is associated with a decrease in bone mineral density (BMD). To study the safety profile and efficacy of testosterone treatment on BMD in patients with TDS. In this 2-year prospective open-label study, patients were administered 50 mg of testosterone gel daily (adjustable after 3 months up to 75–100 mg or down to 25 mg) for 12 months, followed by treatment with 1000 mg of testosterone undecanoate every 2–3 months from months 12–24. Outcome measures were as follows: (i) Changes in clinical chemistry safety parameters and total testosterone, sex hormone binding globulin and calculated free testosterone (cFT) levels; (ii) Changes in Aging Males? Symptoms Scale (AMS) and International Prostate Symptom Score scores; and (iii) Changes in lumbar spine and hip BMD. A total of 50 men aged 50–65 years with TDS (AMS >26 and cFT <0.250 nmol/mL) took part in the study. There was no significant impact of testosterone on safety. Prostate-specific antigen and haematopoietic parameters increased significantly, although the changes were not clinically significant. Total and cFT increased significantly after 3 months (p < 0.001) and there were significant improvements after 3 months in AMS scores (p < 0.001). BMD improved significantly in L2–L4 (2.90 and 4.5%), total femur (0.74 and 3%) and trochanter (1.09 and 3.2%) at 12 and 24 months respectively. Testosterone treatment in men with TDS has a good safety profile, leads to significant improvement in lumbar spine and hip BMD, and improves symptoms, as assessed by the AMS questionnaire.

 

[Michael Scally MD]

Growth Hormone–Releasing Hormone Effects on Brain ?-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging

Circulating levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) decline across the life span, a condition referred to as somatopause. Most of the GH measured in plasma is produced in the pituitary, with some central nervous system tissues, such as the hippocampus, also producing GH. Several different peptides act as regulators for the GH system: 1 that is inhibitory, somatostatin, and 2 that are excitatory, ghrelin and GH-releasing hormone (GHRH).

As with GH, GHRH levels decrease with age. When given as an injectable supplement, GHRH acts on its own receptors and directly stimulates GH release and IGF-1 synthesis by the liver. Unlike extrinsic GH supplementation, GHRH administration modulates intrinsic regulatory systems and evokes a normal pulsatile pattern of GH release.

In summary, 20 weeks of GHRH administration increased brain levels of the inhibitory transmitters GABA and NAAG and decreased MI levels both in adults with MCI and in healthy older adults. These treatment-related changes are consistent with amelioration of aging- or disease-related biochemical processes in the brain. Although larger and longer-duration treatment trials are needed to confirm these preliminary findings, our pilot study provides additional evidence to support positive GHRH effects on brain function in normal and pathological aging.

Friedman SD, Baker LD, Borson S, et al. Growth Hormone–Releasing Hormone Effects on Brain ?-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging. JAMA Neurol. 2013:1-8. JAMA Network | JAMA Neurology | Growth Hormone–Releasing Hormone Effects on Brain ?-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy AgingBrain Effects of Growth Hormone–Releasing Hormone

Importance Growth hormone–releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response.

Objective To examine the neurochemical effects of GHRH in a subset of participants from the parent trial.

Design Randomized, double-blind, placebo-controlled substudy of a larger trial.

Setting Clinical research unit at the University of Washington School of Medicine.

Participants Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study.

Interventions Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention.

Main Outcomes and Measures Brain levels of glutamate, inhibitory transmitters ?-aminobutyric acid (GABA) and N -acetylaspartylglutamate (NAAG), and myo -inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 × 2 × 2-cm3 left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phosphocreatine, and NAAG was expressed as a ratio to N -acetylaspartate.

Results After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P < .04), NAAG levels were increased (P = .03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P = .002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r = 0.47; P = .001) and tended to be negatively correlated with MI (r = ?0.34; P = .06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P = .03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects.

Conclusions Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults.

 

[Michael Scally MD]

[NO] Effect of Oxandrolone on the Healing of Chronic Pressure Ulcers in Persons With Spinal Cord InjuryA

Bauman WA, Spungen AM, Collins JF, et al. The Effect of Oxandrolone on the Healing of Chronic Pressure Ulcers in Persons With Spinal Cord Injury - A Randomized Trial. Annals of Internal Medicine 2013;158(10):718-26. Annals of Internal Medicine | The Effect of Oxandrolone on the Healing of Chronic Pressure Ulcers in Persons With Spinal Cord Injury: A Randomized Trial

Background: Anabolic steroids have been reported to improve wound healing.

Objective: To determine whether oxandrolone increases the percentage of target pressure ulcers (TPUs) that heal compared with placebo and whether healed ulcers remain closed 8 weeks after treatment.

Design: Parallel-group, placebo-controlled, randomized trial conducted from 1 August 2005 to 30 November 2008. Patients, clinical care providers, study personnel, and statisticians were blinded to treatment assignment. (ClinicalTrials.gov: NCT00101361)

Setting: 16 inpatient spinal cord injury (SCI) services at Veterans Affairs medical centers.

Patients: 1900 prescreened, 779 screened, and 212 randomly assigned inpatients with SCI and stage III or IV TPUs.

Intervention: Oxandrolone, 20 mg/d (n = 108), or placebo (n = 104) until the TPU healed or 24 weeks.

Measurements: The primary outcome was healed TPUs. The secondary outcome was the percentage of TPUs that remained healed at 8-week follow-up.

Results: 24.1% (95% CI, 16.0% to 32.1%) of TPUs in oxandrolone recipients and 29.8% (CI, 21.0% to 38.6%) in placebo recipients healed (difference, ?5.7 percentage points [CI, ?17.5 to 6.8 percentage points]; P = 0.40). At 8-week follow-up, 16.7% (CI, 9.6% to 23.7%) of oxandrolone recipients and 15.4% (CI, 8.5% to 22.3%) of placebo recipients retained a healed TPU (difference, 1.3 percentage points [CI, ?8.8 to 11.2 percentage points]; P = 0.70). No serious adverse events were related to oxandrolone. Liver enzyme levels were elevated in 32.4% (CI, 23.6% to 41.2%) of oxandrolone recipients and 2.9% (CI, 0.0% to 6.1%) of placebo recipients (P < 0.001).

Limitations: Selection of severe wounds may have reduced treatment response. Approximately one third of patients did not complete the study in the treatment and placebo groups. The study was terminated after a futility analysis showed a low probability of detecting a significant difference between the groups.

Conclusion: Oxandrolone showed no benefit over placebo for improving healing or the percentage of TPUs that remained closed after 8 weeks of treatment.

 

[Michael Scally MD]

Jasuja GK, Travison TG, Davda M, et al. Circulating Estrone Levels Are Associated Prospectively With Diabetes Risk in Men of the Framingham Heart Study. Diabetes Care. http://care.diabetesjournals.org/content/early/2013/05/14/dc12-2477.abstract

OBJECTIVE - In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS).

METHODS - Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998-2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography tandem mass spectrometry, and free estradiol and estrone were calculated.

RESULTS - In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02-1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8.

CONCLUSIONS - Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than estradiol.

 

[Michael Scally MD]

Mello PA, Naves LA, Pereira Neto A, et al. Clinical and laboratorial characterization and post-surgical follow-up of 87 patients with non-functioning pituitary macroadenomas. Arq Neuropsiquiatr 2013;71(5):307-12. http://www.scielo.br/pdf/anp/v71n5/0004-282X-anp-71-05-307.pdf

Objective: It was to assess the main characteristics of patients undergoing pituitary tumor surgery.

Method: Eighty-seven patients (44 men; 44.8+/-13 years old) were included.

Results: The main symptoms were visual alterations (87.3%), headache (70.1%), diminished libido (34.4%), galactorrhea (22.9%) and hair loss (19.5%). The axes affected were gonadotropic (72.6%), thyrotropic (48.4%) and corticotropic (38.7%), without significant changes after surgery. The average largest tumor diameter was 3.1 cm before surgery and 1.56 cm after surgery. The most frequent postoperative complications were hydro-electrolyte and acid-base disorders (12%), diabetes insipidus (9%), visual field alterations (9%), liquoric fistula (8%) and nasal obstruction (7%). The patients were affected by more than one complication.

Conclusion: Although a decrease in tumor volume was achieved through surgery, hormonal deficiencies persisted in most of the patients and new surgical approaches were necessary for dealing with tumor recurrence or persistence.