OnLine First 2013

Paduch DA, Bolyakov A, Polzer PK, Watts SD. Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies. BJU Int 2013;111(2):334-43. Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies - Paduch - 2013 - BJU International

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Disorders of ejaculation and orgasm are common, even in men with only mild erectile dysfunction (ED). Treatment with the phosphodiesterase type-5 inhibitor tadalafil was associated with improvements in ejaculatory and orgasmic function. Patients with residual ejaculatory or orgasmic dysfunction experience reduced sexual satisfaction. These findings need to be corroborated in further clinical trials involving men without ED.

OBJECTIVES: To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED). To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction.

PATIENTS AND METHODS: Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated. EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively. Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5. Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10.

RESULTS: A total of 3581 randomized subjects were studied. Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata. In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001). Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement. Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction. Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD.

CONCLUSIONS: Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction. Proportions of subjects reporting improved ejaculatory or orgasmic function were approximately twofold higher with tadalafil than with placebo. These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).
 
Thvilum M, Brandt F, Almind D, Christensen K, Hegedus L, Brix TH. Excess Mortality in Patients Diagnosed With Hypothyroidism: A Nationwide Cohort Study of Singletons and Twins. Journal of Clinical Endocrinology & Metabolism. Excess Mortality in Patients Diagnosed With Hypothyroidism: A Nationwide Cohort Study of Singletons and Twins

Background: Although hypothyroidism is associated with increased morbidity, an association with increased mortality is still debated. Our objective was to investigate, at a nationwide level, whether a diagnosis of hypothyroidism influences mortality.

Methods: In an observational cohort study from January 1, 1978 until December 31, 2008 using record-linkage data from nationwide Danish health registers, 3587 singletons and 682 twins diagnosed with hypothyroidism were identified. Hypothyroid individuals were matched 1:4 with nonhypothyroid controls with respect to age and gender and followed over a mean period of 5.6 years (range 0–30 years). The hazard ratio (HR) for mortality was calculated using Cox regression analyses. Comorbidity was evaluated using the Charlson score (CS).

Results: In singletons with hypothyroidism, the mortality risk was increased (HR 1.52; 95% confidence interval [CI]: 1.41–1.65). Although the effect attenuated, hypothyroidism remained associated with increased mortality when evaluating subjects with a CS = 0 (HR 1.23; 95% CI: 1.05–1.44). In twin pairs discordant for hypothyroidism, the hypothyroid twin had excess mortality compared with the corresponding euthyroid cotwin (HR 1.40; 95% CI 0.95–2.05). However, after stratifying for zygosity, hypothyroidism was associated with excess mortality in dizygotic twin pairs (HR 1.61; 95% CI 1.00–2.58), whereas the association attenuated in monozygotic pairs (HR 1.06; 95% CI 0.55–2.05).
Conclusions: Hypothyroidism is associated with an excess mortality of around 50%, which to some degree is explained by comorbidity. In addition, the finding of an association between hypothyroidism and mortality within disease discordant dizygotic but not monozygotic twin pairs indicates that the association between hypothyroidism and mortality is also influenced by genetic confounding.
 
Hussain R, Ghoumari AM, Bielecki B, et al. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain 2013;136(1):132-46. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination

Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens.

Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery.

After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5?-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells.

Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7?-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair.

These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.
 
A Klinefelter Variant with Morbid Obesity

Kim Y, Kim WJ, Huh JH, et al. A 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2),Y Klinefelter Variant with Morbid Obesity. Yonsei Med J 2013;54(2):538-40. :: YMJ :: Yonsei Medical Journal

Klinefelter syndrome is the most common type of genetic cause of hypogonadism. This syndrome is characterized by the presence of 1 or more extra X chromosomes. Phenotype manifestations of this syndrome are small testes, fibrosis of the seminiferous tubules, inability to produce sperm, gynecomastia, tall stature, decrease of serum testosterone and increases of luteinizing hormone and follicle stimulating hormone. Most patients with Klinefelter syndrome are tall, with slender body compositions, and reports of obesity are rare.

We report the case of a 35-yr-old man with hypogonadism and morbid obesity and diabetes mellitus. He had gynecomastia, small testes and penis, very sparse body hair and his body mass index was 44.85. He did not report experiencing broken voice and was able to have erections. We conducted a chromosome study. His genotype was 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2). In this case, the patient was diagnosed as Klinefelter syndrome. He showed rare phenotypes like morbid obesity and average height and the phenotype may be caused by the karyotype and the excess number of X chromosome. Further studies of the relationship between chromosomes and phenotype are warranted.
 
Gong Y, Xiao H, Bai J, et al. Association between sex hormone levels and abnormal metabolism in a population of elderly Chinese men. Aging Male. An Error Occurred Setting Your User Cookie

Objective: Low testosterone levels may be a signal of poor health. This study aimed to investigate the effects of age and abnormal metabolism on sex hormones in Chinese male.

Methods: Three hundred and thirty-seven elder men were enrolled into this single-center, cross-sectional study, and their sex hormone levels and metabolic parameters were assessed.

Results: Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex-hormone-binding globulin (SHBG) concentrations increased with age, while free testosterone index (FTI), testosterone secretion index (TSI), estradiol (E2)/SHBG and progestin (PROG) decreased. Abnormal metabolisms were related to androgen indices (TT, FT, BT, FTI, TSI, T/E2), SHBG and E2/SHBG even after adjusting by age and macrovascular disease. Obesity and overweight, hyperglycemia and dyslipidemia were the most important abnormal metabolism that related to decreased androgen indices. Including SHBG in the stepwise regression increased the explanation effect of TT and BT by 32.7% and 28.5%, respectively, and all metabolic indices were excluded. Abnormal metabolism indies (BMI and PBG) were correlated to the decrease in SHBG levels, while age and LH was positively correlated to SHBG levels.

Conclusions: Age and abnormal metabolism were independently important factors associated with the sex hormone levels in elderly Chinese men, which were all mediated by SHBG.
 
Harslof T, Frost M, Nielsen TL, et al. Polymorphisms of Muscle Genes Are Associated with Bone Mass and Incident Osteoporotic Fractures in Caucasians. Calcif Tissue Int. Polymorphisms of Muscle Genes Are Associated with Bone Mass and Incident Osteoporotic Fractures in Caucasians - Online First - Springer

The interaction between muscle and bone is complex. The aim of this study was to investigate if variations in the muscle genes myostatin (MSTN), its receptor (ACVR2B), myogenin (MYOG), and myoD1 (MYOD1) were associated with fracture risk, bone mineral density (BMD), bone mineral content (BMC), and lean body mass. We analyzed two independent cohorts: the Danish Osteoporosis Prevention Study (DOPS), comprising 2,016 perimenopausal women treated with hormone therapy or not and followed for 10 years, and the Odense Androgen Study (OAS), a cross-sectional, population-based study on 783 men aged 20-29 years. Nine tag SNPs in the four genes were investigated. In the DOPS, individuals homozygous for the variant allele of the MSTN SNP rs7570532 had an increased risk of any osteoporotic fracture, with an HR of 1.82 (95 % CI 1.15-2.90, p = 0.01), and of nonvertebral osteoporotic fracture, with an HR of 2.02 (95 % CI 1.20-3.41, p = 0.01). The same allele was associated with increased bone loss (BMC) at the total hip of 4.1 versus 0.5 % in individuals either heterozygous or homozygous for the common allele (p = 0.006), a reduced 10-year growth in bone area at the total hip of 0.4 versus 2.2 and 2.3 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.01), and a nonsignificantly increased 10-year loss of total-hip BMD of 4.4 versus 2.7 and 2.9 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.08). This study is the first to demonstrate an association between a variant in MSTN and fracture risk and bone loss. Further studies are needed to confirm the findings.
 
Gaskins AJ, Mendiola J, Afeiche M, Jorgensen N, Swan SH, Chavarro JE. Physical activity and television watching in relation to semen quality in young men. British Journal of Sports Medicine. Physical activity and television watching in relation to semen quality in young men -- Gaskins et al. -- British Journal of Sports Medicine

Background Semen quality appears to have declined over the past decades but reasons for this decline are unresolved. The concurrent increase in sedentary behaviour may be a contributing factor. The objective of this study was to evaluate the relationship of physical activity and television (TV) watching with sperm parameters in a population of young, healthy men.

Methods Men aged 18–22 years (n=189) from the Rochester Young Men's Study (2009–2010) participated in this analysis. Physical activity (h/week of moderate and vigorous exercise) and TV watching (h/week of TV, video or DVD watching) over the past 3 months were assessed via questionnaire. Semen quality was assessed by sperm concentration, motility, morphology and total sperm count.

Results Sperm concentration and total sperm count were directly related to physical activity after multivariable adjustment (p-trend=0.01 and 0.04); men in the highest quartile of moderate-to-vigorous activity (?15 h/week) had 73% (95% CI 15% to 160%) higher sperm concentration than men in the lowest quartile (<5 h/week). TV watching was inversely associated with sperm concentration and total sperm count in multivariable analyses (p-trend=0.05 and 0.06); men in the highest quartile of TV watching (>20 h/week) had 44% (95% CI 15 to 63%) lower sperm concentration than men in the lowest quartile (0 h/week). These measures of physical and leisure time activities were not significantly associated with sperm motility or morphology.

Conclusions In this population of healthy men, higher moderate-to-vigorous activity and less TV watching were significantly associated with higher total sperm count and sperm concentration.
 
Banks E, Joshy G, Abhayaratna WP, et al. Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality: A Prospective Cohort Study. PLoS Med 2013;10(1):e1001372. PLOS Medicine: Erectile Dysfunction Severity as a Risk Marker for Cardiovascular Disease Hospitalisation and All-Cause Mortality: A Prospective Cohort Study

Background - Erectile dysfunction is an emerging risk marker for future cardiovascular disease (CVD) events; however, evidence on dose response and specific CVD outcomes is limited. This study investigates the relationship between severity of erectile dysfunction and specific CVD outcomes.

Methods and Findings - We conducted a prospective population-based Australian study (the 45 and Up Study) linking questionnaire data from 2006–2009 with hospitalisation and death data to 30 June and 31 Dec 2010 respectively for 95,038 men aged ?45 y. Cox proportional hazards models were used to examine the relationship of reported severity of erectile dysfunction to all-cause mortality and first CVD-related hospitalisation since baseline in men with and without previous CVD, adjusting for age, smoking, alcohol consumption, marital status, income, education, physical activity, body mass index, diabetes, and hypertension and/or hypercholesterolaemia treatment. There were 7,855 incident admissions for CVD and 2,304 deaths during follow-up (mean time from recruitment, 2.2 y for CVD admission and 2.8 y for mortality). Risks of CVD and death increased steadily with severity of erectile dysfunction. Among men without previous CVD, those with severe versus no erectile dysfunction had significantly increased risks of ischaemic heart disease (adjusted relative risk [RR] = 1.60, 95% CI 1.31–1.95), heart failure (8.00, 2.64–24.2), peripheral vascular disease (1.92, 1.12–3.29), “other” CVD (1.26, 1.05–1.51), all CVD combined (1.35, 1.19–1.53), and all-cause mortality (1.93, 1.52–2.44). For men with previous CVD, corresponding RRs (95% CI) were 1.70 (1.46–1.98), 4.40 (2.64–7.33), 2.46 (1.63–3.70), 1.40 (1.21–1.63), 1.64 (1.48–1.81), and 2.37 (1.87–3.01), respectively. Among men without previous CVD, RRs of more specific CVDs increased significantly with severe versus no erectile dysfunction, including acute myocardial infarction (1.66, 1.22–2.26), atrioventricular and left bundle branch block (6.62, 1.86–23.56), and (peripheral) atherosclerosis (2.47, 1.18–5.15), with no significant difference in risk for conditions such as primary hypertension (0.61, 0.16–2.35) and intracerebral haemorrhage (0.78, 0.20–2.97).

Conclusions - These findings give support for CVD risk assessment in men with erectile dysfunction who have not already undergone assessment. The utility of erectile dysfunction as a clinical risk prediction tool requires specific testing.
 
Freriks K, Sas TC, Traas MA, et al. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome. Eur J Endocrinol 2013;168(1):91-9. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome

OBJECTIVE: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment.

DESIGN AND METHODS: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition.

RESULTS: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2+/-4.9 cm, Ox 0.06 9.7+/-4.4 cm vs Pl 8.0+/-4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency.

CONCLUSION: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.
 
Gasco V, Beccuti G, Baldini C, et al. Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults. Eur J Endocrinol 2013;168(1):23-30. Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults

OBJECTIVE: Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue.

METHODS: We studied the GH response (every 15 MIN from 15 TO +120 MIN) to acylated ghrelin (1G/KG I.V. AT 0MIN) IN 78 patients with a history of pituitary disease (49 male, 29 female; age (MEANS.D.): 52.1+/-18.7 years; BMI: 26.7+/-5.3 kg/m(2)). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis.

RESULTS: The best GH cut-off to ghrelin test was 7.3 mug/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 mug/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 mug/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively.

CONCLUSIONS: Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test.
 
Bronselaer GA, Schober JM, Meyer-Bahlburg HF, T'Sjoen G, Vlietinck R, Hoebeke PB. Male circumcision decreases penile sensitivity as measured in a large cohort. BJU Int. Male circumcision decreases penile sensitivity as measured in a large cohort - Bronselaer - 2013 - BJU International - Wiley Online Library

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?:
• The sensitivity of the foreskin and its importance in erogenous sensitivity is widely debated and controversial. This is part of the actual public debate on circumcision for non-medical reason. Today some studies on the effect of circumcision on sexual function are available. However they vary widely in outcome.
• The present study shows in a large cohort of men, based on self-assessment, that the foreskin has erogenous sensitivity. It is shown that the foreskin is more sensitive than the uncircumcised glans mucosa, which means that after circumcision genital sensitivity is lost. In the debate on clitoral surgery the proven loss of sensitivity has been the strongest argument to change medical practice. In the present study there is strong evidence on the erogenous sensitivity of the foreskin. This knowledge hopefully can help doctors and patients in their decision on circumcision for non-medical reason.

OBJECTIVES:
• To test the hypothesis that sensitivity of the foreskin is a substantial part of male penile sensitivity.
• To determine the effects of male circumcision on penile sensitivity in a large sample.

SUBJECTS AND METHODS:
• The study aimed at a sample size of approximately 1000 men.
• Given the intimate nature of the questions and the intended large sample size, the authors decided to create an online survey.
• Respondents were recruited by means of leaflets and advertising.

RESULTS:
• The analysis sample consisted of 1059 uncircumcised and 310 circumcised men. For the glans penis, circumcised men reported decreased sexual pleasure and lower orgasm intensity.
• They also stated more effort was required to achieve orgasm, and a higher percentage of them experienced unusual sensations (burning, prickling, itching, or tingling and numbness of the glans penis).
• For the penile shaft a higher percentage of circumcised men described discomfort and pain, numbness and unusual sensations.
• In comparison to men circumcised before puberty, men circumcised during adolescence or later indicated less sexual pleasure at the glans penis, and a higher percentage of them reported discomfort or pain and unusual sensations at the penile shaft.

CONCLUSIONS:
• This study confirms the importance of the foreskin for penile sensitivity, overall sexual satisfaction, and penile functioning.
• Furthermore, this study shows that a higher percentage of circumcised men experience discomfort or pain and unusual sensations as compared with the uncircumcised population.
• Before circumcision without medical indication, adult men, and parents considering circumcision of their sons, should be informed of the importance of the foreskin in male sexuality.
 
Azzouni F, Zeitouni N, Mohler J. Role of 5a-reductase inhibitors in androgen-stimulated skin disorders. J Drugs Dermatol 2013;12(2):e30-5. Role of 5

5alpha-reductase (5alpha-R) isozymes are ubiquitously expressed in human tissues. This enzyme family is composed of 3 members that perform several important biologic functions. 5alpha-R isozymes play an important role in benign prostate hyperplasia, prostate cancer, and androgen-stimulated skin disorders, which include androgenic alopecia, acne, and hirsutism. Discovery of 5alpha-R type 2 deficiency in 1974 sparked interest in development of pharmaceutical agents to inhibit 5alpha-R isozymes, and 2 such inhibitors are currently available for clinical use: finasteride and dutasteride. 5alpha-R inhibitors are US Food and Drug Administration (FDA)-approved for the treatment of benign prostate hyperplasia. Only finasteride is FDA-approved for treatment of male androgenic alopecia. This article reviews the pathophysiology of androgen-stimulated skin disorders and the key clinical trials using 5alpha-R inhibitors in the treatment of androgen-stimulated skin disorders.
 
Androgen Receptor Repression Of Gonadotropin-Releasing Hormone Gene Transcription Via Enhancer 1

Highlights
? AR-mediated repression of GnRH gene expression involves enhancer 1.
? AR represses GnRH enhancer 1 via interaction with the -1796/-1791 region.
? Our study provides a new mechanism involved in the repression of GnRH by androgens.


Brayman MJ, Pepa PA, Mellon PL. Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1. Mol Cell Endocrinol 2013;363(1-2):92-9. ScienceDirect.com - Molecular and Cellular Endocrinology - Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1

Gonadotropin-releasing hormone (GnRH) plays a major role in the hypothalamic-pituitary-gonadal (HPG) axis, and synthesis and secretion of GnRH are regulated by gonadal steroid hormones. Disruptions in androgen levels are involved in a number of reproductive defects, including hypogonadotropic hypogonadism and polycystic ovarian syndrome. Androgens down-regulate GnRH mRNA synthesis in vivo and in vitro via an androgen receptor (AR)-dependent mechanism. Methyltrienolone (R1881), a synthetic AR agonist, represses GnRH expression through multiple sites in the proximal promoter. In this study, we show AR also represses GnRH transcription via the major enhancer (GnRH-E1). A multimer of the -1800/-1766 region was repressed by R1881 treatment. Mutation of two bases, -1792 and -1791, resulted in decreased basal activity and a loss of AR-mediated repression. AR bound to the -1796/-1791 sequence in electrophoretic mobility shift assays, indicating a direct interaction with DNA or other transcription factors in this region. We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at -1792/-1791.
 
Gronbladh A, Johansson J, Nostl A, Nyberg F, Hallberg M. GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats. Journal of Endocrinology;216(1):31-41. GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats

GH has previously been shown to promote cognitive functions in GH-deficient rodents. In this study we report the effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone.

Male Wistar rats received nandrolone decanoate (15?mg/kg) or peanut oil every third day for 3 weeks and were subsequently treated with recombinant human GH (1.0?IU/kg) or saline for 10 consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of IGF1 were assessed and the gene expression of the GH receptors (Ghr), Igf1 and Igf2, in hippocampus and frontal cortex was analyzed.

The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone-treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared with controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated with spatial memory, the difference between GH- and steroid-treated animals was significant and administration of GH improved this parameter in the latter group.

In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by anabolic androgenic steroid.
 
Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, et al. Plasma total testosterone and incident cardiovascular events in hypertensive patients. Am J Hypertens 2013;26(3):373-81. Plasma Total Testosterone and Incident Cardiovascular Events in Hypertensive Patients

BACKGROUND Androgen deficiency confers an independent risk for cardiovascular events and total mortality. Hypertension, a major contributory factor to the development of cardiovascular disease, has also been associated with increased prevalence of low testosterone. We investigated whether low androgen concentration predicts incident major adverse cardiovascular events (MACE) in middle-aged nondiabetic hypertensive patients without clinical atherosclerosis.

METHODS MACE in relation to total testosterone (TT) were analyzed with proportional hazards models in 228 male patients (mean age 56 years).

RESULTS During a mean follow-up of 44 months, 19 of 228 participants (8.3%) experienced a MACE. Compared to patients who did not experience MACE, hypertensive subjects who developed MACE had lower TT concentration (3.9+/-0.7ng/ml vs. 4.6+/-1.5ng/ml, P < 0.01) and a higher prevalence of hypogonadism (36% vs. 16%, P < 0.05). Subjects in the lowest TT tertile (<4.0ng/ml) had a statistically significant higher risk of MACE compared to those in the highest tertile (>4.9ng/ml) in multivariate Cox models adjusted for age, systolic blood pressure, and risk factors (all P < 0.05). A TT plasma level of 5.04ng/ml was associated with a negative predictive value (ability to "rule out" MACE) of 97.2%. Addition of TT to standard risk factors model yielded a net reclassification improvement of 38.8 % (P < 0.05).

CONCLUSIONS Our results show that low plasma testosterone is associated with increased risk for a MACE in hypertensive patients. Low endogenous androgen concentration improves risk prediction when added to standard risk factors and may represent a valuable biomarker of prediction of cardiovascular disease risk in these patients.
 
Kumar S, Kaur G. Intermittent fasting dietary restriction regimen negatively influences reproduction in young rats: a study of hypothalamo-hypophysial-gonadal axis. PLoS One 2013;8(1):e52416. PLOS ONE: Intermittent Fasting Dietary Restriction Regimen Negatively Influences Reproduction in Young Rats: A Study of Hypothalamo-Hypophysial-Gonadal Axis

Nutritional infertility is very common in societies where women fail to eat enough to match their energy expenditure and such females often present as clinical cases of anorexia nervosa. The cellular and molecular mechanisms that link energy balance and central regulation of reproduction are still not well understood. Peripheral hormones such as estradiol, testosterone and leptin, as well as neuropeptides like kisspeptin and neuropeptides Y (NPY) play a potential role in regulation of reproduction and energy balance with their primary target converging on the hypothalamic median eminence-arcuate region.

The present study was aimed to explore the effects of negative energy state resulting from intermittent fasting dietary restriction (IF-DR) regimen on complete hypothalamo-hypophysial-gonadal axis in Wistar strain young female and male rats. Significant changes in body weight, blood glucose, estrous cyclicity and serum estradiol, testosterone and LH level indicated the negative role of IF-DR regimen on reproduction in these young animals.

Further, it was elucidated whether serum level of metabolic hormone, leptin plays a mechanistic role in suppressing hypothalamo-hypophysial-gonadal (HPG) axis via energy regulators, kisspeptin and NPY in rats on IF-DR regimen.

We also studied the effect of IF-DR regimen on structural remodeling of GnRH axon terminals in median eminence region of hypothalamus along with the glial cell marker, GFAP and neuronal plasticity marker, PSA-NCAM using immunostaining, Western blotting and RT-PCR.

Together these data suggest that IF-DR regimen negatively influences reproduction in young animals due to its adverse effects on complete hypothalamus-hypophysial-gonadal axis and may explain underlying mechanism(s) to understand the clinical basis of nutritional infertility.
 
Raffin-Sanson ML, Oudet B, Salenave S, et al. A man with a DAX1/NR0B1 mutation, normal puberty and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up. Eur J Endocrinol. A man with a DAX1/NR0B1 mutation, normal puberty and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up

OBJECTIVE: DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism, leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia.

CASE REPORT: The proband was referred for infertility at age 32. He reported adrenal insufficiency diagnosed at age 19. Puberty started at age 13, with spontaneous virilization, growth spurt and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic-pituitary-gonadal axis with normal testosterone and inhibin B; basal and GnRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild hypogonadotropic hypogonadism and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia.

CONCLUSION: Long-term preservation of normal hypothalamic-pituitary-gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.
 
Goto K, Shioda K, Uchida S. Effect of 2 days of intensive resistance training on appetite-related hormone and anabolic hormone responses. Clin Physiol Funct Imaging 2013;33(2):131-6. Effect of 2

This study was designed to determine endocrine responses during 2 days of strenuous resistance training. Ten healthy men performed resistance training twice a day for two successive days to induce acute fatigue (excessive physical stress). The resistance training consisted of four exercises for the lower body in the morning and seven exercises for the upper body in the afternoon. Maximal isometric and isokinetic strengths were measured from day 1 (before the training period) to day 3 (after the training period). Fasting blood samples were taken on days 1-3.

Maximal isometric and isokinetic strengths significantly decreased with two successive days of training (P<0.05), with significant increases in serum creatine phosphokinase and myoglobin concentrations (P<0.05).

Significant reductions in the fasting concentrations of serum insulin-like growth factor-1, free testosterone, insulin and high-molecular-weight adiponectin were observed on day 3 (P<0.05), whereas there were no changes in the serum cortisol concentration or the free testosterone/cortisol ratio. Plasma active ghrelin and serum leptin concentrations decreased by -20.7 +/- 2.8% and -29.6 +/- 4.1%, respectively (P<0.05).

Two days strenuous resistance training significantly affects the profiles of anabolic hormone and endocrine regulators of appetite and energy balance, such as ghrelin and leptin. The present findings suggest that decreased ghrelin and leptin concentrations might reflect excessive physical stress and may be early signs of accumulated fatigue.
 
Mazon MaJ, Zanuy S, Munoz I, Carrillo M, Gomez A. Luteinizing Hormone Plasmid Therapy Results in Long-Lasting High Circulating Lh and Increased Sperm Production in European Sea Bass (Dicentrarchus labrax). Biology of Reproduction 2013;88(2):32, 1-7. http://www.biolreprod.org/content/88/2/32.abstract

The present work aimed at evaluating the potential of intramuscular injection of a hormone-coding gene as an approach for gene therapy in fish. A plasmid containing luteinizing hormone (Lh) in a single-chain (sc) form, pCMV-scLh, was chosen as the coding gene, and sea bass was chosen as the target species. In vivo injection of pCMV-scLh in muscle of juvenile sea bass rendered plasma Lh levels higher than 50 ng/ml in 40% of the injected fish, while these Lh levels were only detected in 4% of controls. Injections performed on spermiating broodstock demonstrated that this strategy produced an active Lh able to increase sperm production without affecting its quality, in terms of density. Compared with the injection of a recombinant single-chain Lh, plasmid injection provoked longer-lasting and higher plasma Lh levels. These results show that sea bass skeletal muscle is able to uptake plasmid DNA and to secrete the encoded protein to the bloodstream. Therefore, we propose somatic gene transfer as a realistic approach for hormone therapy of dysfunctions due to low hormone levels in fish or just to synchronize spawning.
 
Xu L, Xu C, Yu C, et al. Association between Serum Growth Hormone Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. PLoS ONE 2012;7(8):e44136. PLOS ONE: Association between Serum Growth Hormone Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study

Growth hormone (GH) is an important regulator of metabolism and body composition. GH deficiency is associated with increased visceral body fat and other features of the metabolic syndrome. Here we performed a cross-sectional study to explore the association of GH levels with nonalcoholic fatty liver disease (NAFLD), which is considered to be the hepatic manifestation of the metabolic syndrome. A total of 1,667 subjects were diagnosed as NAFLD according the diagnostic criteria, and 5,479 subjects were defined as the controls. The subjects with NAFLD had significantly lower levels of serum GH than the controls. Those with low GH levels had a higher prevalence of NAFLD and the metabolic syndrome. A stepwise logistic regression analysis showed that GH levels were significantly associated with the risk factor for NAFLD (OR = 0.651, 95%CI = 0.574–0.738, P<0.001). Our results showed a significant association between lower serum GH levels and NAFLD.
 
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