OnLine First 2013

[Michael Scally MD]

Coombs PG, Heck M, Guhring P, Narus J, Mulhall JP. A review of outcomes of an intracavernosal injection therapy programme. BJU Int 2012;110(11):1787-91. A review of outcomes of an intracavernosal injection therapy programme - Coombs - 2012 - BJU International - Wiley Online Library

Study Type--Therapy (outcomes research)
Level of Evidence 2b.

What's known on the subject? and What does the study add?

Intracavernosal injection (ICI) therapy is an important treatment option for erectile dysfunction. However, high discontinuation rates have been reported for ICI therapy, and a risk of priapism has long been a concern. There has never been a large sample study performed with multivariate analysis to characterise outcomes of ICI therapy.

The present paper reviews ICI therapy outcomes in a very large population of men at a tertiary care Sexual Medicine Clinic over 5 years. Multivariate analysis was used to further characterise these outcomes. The present study shows that for a large percentage of our sample of patients, ICI therapy is a successful treatment strategy. And, while discontinuation rates are still high, many of those not continuing ICI therapy achieved success with phosphodiesterase inhibitors. Also, the incidence of priapism was less in the present study than previously reported.

OBJECTIVES:
* To review the outcomes, adverse events and discontinuation rates of intracavernosal injection (ICI) therapy in men with erectile dysfunction (ED) in a sexual medicine practice over a 5-year period at a tertiary referral centre.
* Since 1983, ICI has become a staple therapeutic option and high success rates have been reported. However, priapism is a significant concern and discontinuation rates are estimated to be >50%.

PATIENTS AND METHODS:
* Men presenting with ED who were enrolled in our ICI programme between September 2002 and August 2006 were followed at least annually.
* Patient demographic information, agents used, erectile function outcomes and adverse events were recorded.
* Failure was defined as the inability to have penetrative sex. Discontinuation was defined as patient declaration of such, failure to attend an annual follow-up visit or failure to call for a repeat prescription.
* Multivariable analysis was used to define predictors of failure to respond to ICI therapy, as well as predictors of discontinuation within 36 months of starting ICI in those patients responding.

RESULTS:
* In all, 1412 patients had complete data and constituted the study population. Most patients were using Trimix and 89% of Trimix users were capable of having sexual intercourse.
* Response rates were lower in pelvic radiation and diabetic patients.
* However, the discontinuation rate was significant; it was lower in men who had not undergone radical prostatectomy (RP). Of note, many RP patients discontinued ICI because of recovery of natural or phosphodiesterase type 5 inhibitor-assisted erections.

CONCLUSIONS:
* ICI therapy is associated with very high success rates even in men with high comorbidity profiles; however, the discontinuation rates, even in men who had not undergone RP, by the end of the third year are significant.
* Of note, the recorded priapism rate was extremely low (0.5%).

 

[Michael Scally MD]

Szulc P, Hofbauer LC, Rauner M, Goettsch C, Chapurlat R, Schoppet M. Serum myostatin levels are negatively associated with abdominal aortic calcification in older men: the STRAMBO study. European Journal of Endocrinology 2012;167(6):873-80. Serum myostatin levels are negatively associated with abdominal aortic calcification in older men: the STRAMBO study

Objective To assess the association between abdominal aortic calcification (AAC) and serum levels of myostatin, a negative regulator of skeletal muscle mass, which has been implicated in the development of atherosclerotic lesions in mice.

Design and Patients We assessed AAC semiquantitatively from the lateral spine scans obtained using dual energy X-ray absorptiometry in 1071 men aged 20–87 years. Serum myostatin levels were measured by an immunoassay that detects all myostatin forms.

Results Total myostatin serum levels did not differ between men with or without self-reported ischemic heart disease, hypertension, or diabetes mellitus. Total serum myostatin levels were higher in men with higher serum calcium levels and lower in men with higher serum concentrations of highly sensitive C-reactive protein. Men with AAC had lower myostatin levels compared with men without AAC. Prevalence of AAC (AAC score >0) was lower in the highest myostatin quartile compared with the three lower quartiles (P<0.05). After adjustment for confounders, odds of AAC (AAC score >0) were lower (OR=0.62; 95% confidence interval (95% CI), 0.45–0.85; P<0.005) for the fourth myostatin quartile vs the three lower quartiles combined. In the sub-analysis of 745 men aged ?60 years, the results were similar: AAC prevalence was lower in the highest myostatin quartile compared with the three lower quartiles combined (OR=0.54; 95% CI, 0.38–0.78; P<0.001).

Conclusions In older men, total myostatin serum levels are inversely correlated with AAC. Further studies are needed to investigate mechanisms underlying this association and to assess utility of myostatin as a cardiovascular marker.

 

[Michael Scally MD]

Highlights
? Activin A, follistatin, and myostatin were studied in aging muscle and bone.
? Myostatin levels increased with age in muscle and bone marrow.
? Myostatin decreased proliferation of aged muscle and bone cells.


Bowser M, Herberg S, Arounleut P, et al. Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells. Exp Gerontol 2013;48(2):290-7. ScienceDirect.com - Experimental Gerontology - Effects of the activin A–myostatin–follistatin system on aging bone and muscle progenitor cells

The activin A-myostatin-follistatin system is thought to play an important role in the regulation of muscle and bone mass throughout growth, development, and aging; however, the effects of these ligands on progenitor cell proliferation and differentiation in muscle and bone are not well understood. In addition, age-associated changes in the relative expression of these factors in musculoskeletal tissues have not been described.

We therefore examined changes in protein levels of activin A, follistatin, and myostatin (GDF-8) in both muscle and bone with age in C57BL6 mice using ELISA. We then investigated the effects of activin A, myostatin and follistatin on the proliferation and differentiation of primary myoblasts and mouse bone marrow stromal cells (BMSCs) in vitro.

Myostatin levels and the myostatin:follistatin ratio increased with age in the primarily slow-twitch mouse soleus muscle, whereas the pattern was reversed with age in the fast-twitch extensor digitorum longus muscle. Myostatin levels and the myostatin:follistatin ratio increased significantly (+75%) in mouse bone marrow with age, as did activin A levels (+17%).

Follistatin increased the proliferation of primary myoblasts from both young and aged mice, whereas myostatin increased proliferation of younger myoblasts but decreased proliferation of older myoblasts. Myostatin reduced proliferation of both young and aged BMSCs in a dose-dependent fashion, and activin A increased mineralization in both young and aged BMSCs.

Together these data suggest that aging in mice is accompanied by changes in the expression of activin A and myostatin, as well as changes in the response of bone and muscle progenitor cells to these factors. Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice.

 

[Michael Scally MD]

Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proceedings of the National Academy of Sciences. Genomic responses in mouse models poorly mimic human inflammatory diseases

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

 

[Michael Scally MD]

Oldknow KJ, Seebacher J, Goswami T, et al. Follistatin-Like 3 (FSTL3) Mediated Silencing of Transforming Growth Factor ? (TGF?) Signaling Is Essential for Testicular Aging and Regulating Testis Size. Endocrinology. Follistatin-like 3 (FSTL3) Mediated Silencing of Transforming Growth Factor ? (TGF?) Signaling Is Essential for Testicular Aging and Regulating Testis Size

Follistatin-like 3 (FSTL3) is a glycoprotein that binds and inhibits the action of TGF? ligands such as activin. The roles played by FSTL3 and activin signaling in organ development and homeostasis are not fully understood. The authors show mice deficient in FSTL3 develop markedly enlarged testes that are also delayed in their age-related regression. These FSTL3 knockout mice exhibit increased Sertoli cell numbers, allowing for increased spermatogenesis but otherwise showing normal testicular function. The data show that FSTL3 deletion leads to increased AKT signaling and SIRT1 expression in the testis. This demonstrates a cross-talk between TGF? ligand and AKT signaling and leads to a potential mechanism for increased cellular survival and antiaging. The findings identify crucial roles for FSTL3 in limiting testis organ size and promoting age-related testicular regression.

 

[Michael Scally MD]

Lue Y, Wang C, Lydon JP, Leung A, Li J, Swerdloff RS. Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents. Andrology 2013;1(2):308-17. Functional role of progestin and the progesterone receptor in the suppression of spermatogenesis in rodents - Lue - 2013 - Andrology - Wiley Online Library

Synthetic progestins such as levonorgestrel (LNG) are used in combination with testosterone (T) in male contraceptive clinical trials to suppress gonadotropins secretion, but whether progestins have additional direct effects on the testis are not known. This study aimed to examine the effect of a potent progestin, (LNG), alone or in combination with testosterone (T) on spermatogenesis in adult rats, and to evaluate the functional role of the progesterone receptors (PRs) in the testis.

In comparison with a low dose of LNG treatment in adult rats for 4 weeks, T and T + LNG treatment decreased testicular sperm count to 64.1 and 40.2% of control levels respectively. LNG induced germ cell apoptosis at stages I-IV and XII-XIV; T increased apoptosis at stages VII-VIII; LNG + T treatment induced greater germ cell apoptosis at a wider range of seminiferous epithelial stages.

RT-PCR and Western Blots showed that PR was present in testes and up-regulated during suppression of spermatogenesis induced by testicular hormonal deprivation. PR knockout (PRKO) mice had larger testes, greater sperm production, increased numbers of Sertoli and Leydig cells. Suppression of gonadotropin and intratesticular T by GnRH-antagonist treatment induced PR promoter driven LacZ expression in Leydig cells of PRKO mice. This suggests that GnRH-antagonist treatment while inducing germ cell apoptosis also up-regulates PR.

We conclude that
(i) LNG + T induced greater suppression of spermatogenesis through increase in germ cell apoptosis involving a wider range of seminiferous epithelial stages than either treatment alone,
(ii) up-regulation of PR was associated with inhibition of spermatogenesis,
(iii) PR knockout mice showed increased sperm production suggesting that testicular PR activated events play a physiological and pharmacological inhibitory role in the testis.

These data support the hypothesis that in addition to its known suppressive effects on gonadotropins, progestins may have direct inhibitory actions on the testis.

 

[Michael Scally MD]

Sankako MK, Garcia PC, Piffer RC, Dallaqua B, Damasceno DC, Pereira OC. Possible mechanism by which zinc protects the testicular function of rats exposed to cigarette smoke. Pharmacol Rep 2012;64(6):1537-46. http://www.if-pan.krakow.pl/pjp/pdf/2012/6_1537.pdf

Background: The aim of this study was to evaluate the changes in testicular function of rats due to cigarette smoke exposure and the possible mechanism by which zinc protects against these alterations.

Methods: MaleWistar rats (60 days old) were randomly divided into 3 groups: control (G1, n = 10); exposed to cigarette smoke (G2, n = 10; 20 cigarettes/day/9 weeks) and exposed to cigarette smoke and supplemented with zinc (G3, n = 8; 20 cigarettes/day/9 weeks; 20 mg/kg zinc chloride daily for 9 weeks, by gavage). After the treatment period, the animals were euthanized, and materials were collected for analyses.

Results: G2 rats showed a reduction in body mass; impaired sperm concentration, motility, morphology and vitality; and increased malonaldehyde and thiol group levels and superoxide dismutase activity as compared to G1. Zinc prevented the reduction of sperm concentration and the excessive increase of lipid peroxidation and induced an increase in plasma testosterone levels, wet weight of testis and thiol group concentration.

Conclusions: Exposure to cigarette smoke led to harmful effects on testicular function at least partially due to the exacerbation of oxidative stress. Supplementary zinc had an important modulator/protector effect on certain parameters. The mechanism of zinc protection can be through an increase of SH concentration. Thus, zinc supplementation may be a promising addition to conventional treatments for male infertility related to smoking.

 

[Michael Scally MD]

Lee JW, Ha YS, Park SC, Seo IY, Lee HS. Orgasmic Headache Treated with Nimodipine. The Journal of Sexual Medicine. Orgasmic Headache Treated with Nimodipine - Lee - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. Orgasmic headache (OH) is a sudden and severe headache that occurs at the time of or shortly after an orgasm.

Aim. We present the case of typical primary headache associated with sexual activity, especially during an orgasmic period.

Methods. A 34-year-old man complained of sudden and severe headache during sexual activity, or orgasmic period, for 2 months. The headache developed abruptly with an orgasm and then decreased shortly over a period of 4?8 hours. Results. Magnetic resonance angiography revealed severe spasm of the M1 segment of both the middle cerebral arteries. He was treated with oral nimodipine (30?mg every 8 hours), which alleviated the headache and prevented its recurrence.

Conclusions. We postulated a pathophysiological relationship between OH and migraine, especially with respect to vasoconstriction, and believe that in such cases, nimodipine may be an effective therapy.

 

[Michael Scally MD]

Leeners B, Kruger THC, Brody S, Schmidlin S, Naegeli E, Egli M. The Quality of Sexual Experience in Women Correlates with Post-Orgasmic Prolactin Surges: Results from an Experimental Prototype Study. The Journal of Sexual Medicine. The Quality of Sexual Experience in Women Correlates with Post-Orgasmic Prolactin Surges: Results from an Experimental Prototype Study - Leeners - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Sexual intercourse, orgasm, and sexual satisfaction are associated with well-being and improved quality of life. The pituitary hormone prolactin (PRL) may have an important role in regulating (and thus indexing) sexual satiety and satisfaction.

Aim Physiological indices to quantify the quality and resulting satisfaction from female orgasm would be valuable. Therefore we aim to validate associations of orgasm-induced PRL surges with women's orgasm quality and subsequent sexual satisfaction. Methods In a prospective study, with a pre-post, single-blinded, cross-over design in a naturalistic field setting, we analyzed the correlation of women's post-orgasmic serum PRL surges following sexual intercourse with women's perceived quality of orgasm and resulting sexual satisfaction, as measured by a questionnaire.

Main Outcome Measures PRL levels prior to and following penile-vaginal intercourse with and without orgasm, and scores from the Acute Sexual Experience Scale (ASES) on quality of orgasm and sexual satisfaction.

Results An analysis of variance of the blood samples in nine women indicated large magnitude, significant effects of intercourse orgasm on PRL levels (P?=?0.004, eta squared?=?0.78), as well as an interaction with the effect of multiple orgasms (P?=?0.008, eta squared?=?0.80). PRL post/pre ratios and arithmetic difference correlated strongly with orgasm quality (r?=?0.85, P?=?0.016, and r?=?0.69, P?=?0.08) and sexual satisfaction (r?=?0.75, P?=?0.05 and r?=?0.77, P?=?0.045).

Conclusion Women's intercourse orgasm induced PRL surges are strongly related to the quality of orgasm and subsequent sexual satisfaction. This implies that post-orgasmic PRL surges are an objective index of orgasm and orgasm quality. PRL might be used in future studies on basic research as well as a treatment target in sexual disorders in women.

 

[Michael Scally MD]

Upadhyaya SK, Sharma A, Rai DK, Thawani V. Anabolic androgenic steroids in delayed diagnosis of tuberculosis. J Pharmacol Pharmacother 2012;3(4):345-7. Anabolic androgenic steroids in delayed diagnosis of tuberculosis

This is the first case report depicting masking of symptoms of intestinal tuberculosis by anabolic androgenic steroids (AAS) causing delay in diagnosis which lead to a major surgery. Negative tuberculosis skin test (TST) probably due to immunomodulating effects of AAS also contributed to the delay. Patient also had early dependence on AAS and rapid growth of scrotal sebaceous cysts, findings of which have not yet been reported.

 

[Michael Scally MD]

[Free Full-Text At Link]

Buysse DJ. Insomnia. JAMA.2013;309(7):706-716. JAMA Network | JAMA | InsomniaInsomnia

Importance - Insomnia is one of the most prevalent health concerns in the population and in clinical practice. Clinicians may be reluctant to address insomnia because of its many potential causes, unfamiliarity with behavioral treatments, and concerns about pharmacologic treatments.

Objective - To review the assessment, diagnosis, and treatment of insomnia in adults.
Evidence Review Systematic review to identify and summarize previously published quantitative reviews (meta-analyses) of behavioral and pharmacologic treatments for insomnia.

Findings - Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, accompanied by symptoms such as irritability or fatigue during wakefulness.

The prevalence of insomnia disorder is approximately 10% to 20%, with approximately 50% having a chronic course. Insomnia is a risk factor for impaired function, development of other medical and mental disorders, and increased health care costs.

The etiology and pathophysiology of insomnia involve genetic, environmental, behavioral, and physiological factors culminating in hyperarousal. The diagnosis of insomnia is established by a thorough history of sleep behaviors, medical and psychiatric problems, and medications, supplemented by a prospective record of sleep patterns (sleep diary).

Quantitative literature reviews (meta-analyses) support the efficacy of behavioral, cognitive, and pharmacologic interventions for insomnia. Brief behavioral interventions and Internet-based cognitive-behavioral therapy both show promise for use in primary care settings. Among pharmacologic interventions, the most evidence exists for benzodiazepine receptor agonist drugs, although persistent concerns focus on their safety relative to modest efficacy. Behavioral treatments should be used whenever possible, and medications should be limited to the lowest necessary dose and shortest necessary duration.

Conclusions and Relevance - Clinicians should recognize insomnia because of its effects on function and health. A thorough clinical history is often sufficient to identify factors that contribute to insomnia. Behavioral treatments should be used when possible. Hypnotic medications are also efficacious but must be carefully monitored for adverse effects.

 

[Michael Scally MD]

Elbornsson M, Gotherstrom G, Bosaeus I, Bengtsson B, Johannsson G, Svensson J. Fifteen years of Growth Hormone (GH) Replacement Improves Body Composition and Cardiovascular Risk Factors. European Journal of Endocrinology. Fifteen years of Growth Hormone (GH) Replacement Improves Body Composition and Cardiovascular Risk Factors

Objective: Few studies have determined the effects of more than 5-10 years of GH replacement in adults on body composition and cardiovascular risk factors.

Design/Patients: In this prospective, single-centre, open-label study, the effects of 15 years of GH replacement on body composition and cardiovascular risk factors were determined in 156 hypopituitary adults (93 men) with adult onset GH deficiency (GHD). Mean age was 50.5 (range 22-74) years at study start. Body composition was measured using dual-energy X-ray absorptiometry (DXA).

Results: The mean initial GH dose of 0.55 (SEM 0.03) mg/day was gradually lowered to 0.40 (0.01) mg/day after 15 years. The mean serum insulin-like growth factor-I (IGF-I) SD score increased from -1.53 (0.10) at baseline to 0.74 (0.13) at study end (p<0.001 vs. baseline). Lean soft tissue increased to 3% above the baseline level at study end (p<0.001). After a 9% decrease during the first year of treatment (p<0.001 vs. baseline), body fat started to increase and had returned to the baseline level after 15 years. Serum levels of total cholesterol and low density lipoprotein-cholesterol (LDL-C) decreased and serum high density lipoprotein-cholesterol (HDL-C) level increased. Fasting plasma glucose increased from 4.4 (0.1) at baseline to 4.8 (0.1) mmol/L at study end (p<0.001). However, blood HbA1c decreased from 5.0 (0.1) % to 4.6 (0.1) % (p<0.001).

Conclusions: Fifteen-year GH replacement in GHD adults induced a transient decrease in body fat and sustained improvements of lean soft tissue and serum lipid profile. Fasting plasma glucose increased whereas blood HbA1c was reduced.

 

[Michael Scally MD]

Camacho EM, Huhtaniemi IT, O'Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol 2013;168(3):445-55. Age-associated changes in hypothalamic–pituitary–testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study

OBJECTIVE: Health and lifestyle factors are associated with variations in serum testosterone levels in ageing men. However, it remains unclear how age-related changes in testosterone may be attenuated by lifestyle modifications. The objective was to investigate the longitudinal relationships between changes in health and lifestyle factors with changes in hormones of the reproductive endocrine axis in ageing men.

DESIGN: A longitudinal survey of 2736 community-dwelling men aged 40-79 years at baseline recruited from eight centres across Europe. Follow-up assessment occurred mean (+/-s.d.) 4.4+/-0.3 years later.

RESULTS: PAIRED TESTOSTERONE RESULTS WERE AVAILABLE FOR 2395 MEN. MEAN (S.D.) ANNUALISED HORMONE CHANGES WERE AS FOLLOWS: testosterone -0.1+/-0.95 nmol/l; free testosterone (FT) -3.83+/-16.8 pmol/l; sex hormone-binding globulin (SHBG) 0.56+/-2.5 nmol/l and LH 0.08+/-0.57 U/l. Weight loss was associated with a proportional increase, and weight gain a proportional decrease, in testosterone and SHBG. FT showed a curvilinear relationship to weight change; only those who gained or lost >/=15% of weight showed a significant change (in the same direction as testosterone). Smoking cessation was associated with a greater decline in testosterone than being a non-smoker, which was unrelated to weight change. Changes in number of comorbid conditions or physical activity were not associated with significant alterations in hypothalamic-pituitary-testicular (HPT) axis function.

CONCLUSIONS: Body weight and lifestyle factors influence HPT axis function in ageing. Weight loss was associated with a rise, and weight gain a fall, in testosterone, FT and SHBG. Weight management appears to be important in maintaining circulating testosterone in ageing men, and obesity-associated changes in HPT axis hormones are reversible following weight reduction.

 

[Michael Scally MD]

Gasco V, Prodam F, Grottoli S, et al. THERAPY OF ENDOCRINE DISEASE: GH therapy in adult GH deficiency: A review of treatment schedules and the evidence for low starting doses. European Journal of Endocrinology 2013;168(3):R55-R66. THERAPY OF ENDOCRINE DISEASE: GH therapy in adult GH deficiency: A review of treatment schedules and the evidence for low starting doses

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as ‘low dose’ in the studies discussed here (?1–4?mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.

 

[Michael Scally MD]

Marchetti PM, Barth JH. Clinical biochemistry of dihydrotestosterone. Ann Clin Biochem. Clinical biochemistry of dihydrotestosterone

Dihydrotestosterone (DHT) is the most potent natural androgen in humans. There has been an increasing interest in this androgen and its role in the development of primary and secondary sexual characteristics as well as its potential roles in diseases ranging from prostate and breast cancer to Alzheimer's disease. Despite the range of pathologies shown to involve DHT there is little evidence for measurement of serum DHT in the management of these diseases. In this review we describe the physiology of DHT production and action, summarize current concepts in the role of DHT in the pathogenesis of various disorders of sexual development, compare current methods for the measurement of DHT and conclude on the clinical utility of DHT measurement. The clinical indications for the measurement of DHT in serum are: investigation of 5alpha reductase deficiency in infants with ambiguous genitalia and palpable gonads; men with delayed puberty and/or undescended testes; and to confirm the presence of active testicular tissue. Investigation is aided by the use of human chorionic gonadotrophin stimulation. Due to paucity of published data on this procedure, it is important to follow guidelines prescribed by the laboratory performing the analysis to ensure accurate interpretation.

 

[Michael Scally MD]

Denson TF, Ronay R, von Hippel W, Schira MM. Endogenous testosterone and cortisol modulate neural responses during induced anger control. Soc Neurosci 2013;8(2):165-77. An Error Occurred Setting Your User Cookie

Research with violent offenders and delinquent adolescents suggests that endogenous testosterone concentrations have the strongest positive correlations with violence among men who have low concentrations of cortisol. The present study tested the hypothesis that testosterone and cortisol would similarly interact to determine neural activation in regions supporting self-regulation in response to anger provocation. Nineteen healthy Asian male participants were insulted and asked to control their anger during functional magnetic resonance imaging (fMRI). When cortisol levels were low, testosterone positively correlated with activation in the dorsolateral prefrontal cortex (dlPFC) and thalamus, but not when cortisol levels were high. During induced anger control, functional connectivity was increased between the amygdala and a top-down prefrontal cortical control network. Moreover, the amygdala-PFC connectivity was strongest among those high in testosterone and low in cortisol. This research highlights a possible neural mechanism by which testosterone and cortisol may influence anger control.


Romero-Martinez A, Gonzalez-Bono E, Lila M, Moya-Albiol L. Testosterone/cortisol ratio in response to acute stress: A possible marker of risk for marital violence. Soc Neurosci. An Error Occurred Setting Your User Cookie

Testosterone to cortisol (T/C) ratios could be associated with feelings and expression of anger as high testosterone and low cortisol levels indicate a predisposition to violence. The basal T/C ratio has recently been proposed as a marker for proneness to social aggression; so far, however, only its value as an indicator of state anger or violence has been investigated. Given this, we aimed to establish whether the T/C ratio response to acute stress was a specific psychobiological feature in individuals with a history of violence, namely, perpetrators of intimate partner violence (IPV). T/C ratio and anger responses were compared in men jailed for IPV and controls using the Trier Social Stress Test. IPV perpetrators had higher T/C ratios than controls, during the preparation period, and 15 and 30 minutes post-task. In IPV perpetrators, high T/C ratios were linked to better self-esteem and good mental health. An increase in anger may increase proneness to violence by altering hormones and, thereby, increasing T/C ratios. The basal T/C ratio together with acute stress responses and other indicators could serve as a marker to identify men at high risk of reacting violently to their partners.

 

[Michael Scally MD]

Macaluso F, Barone R, Catanese P, et al. Do fat supplements increase physical performance? Nutrients 2013;5(2):509-24. Nutrients | Free Full-Text | Do Fat Supplements Increase Physical Performance?

Fish oil and conjugated linoleic acid (CLA) belong to a popular class of food supplements known as "fat supplements", which are claimed to reduce muscle glycogen breakdown, reduce body mass, as well as reduce muscle damage and inflammatory responses. Sport athletes consume fish oil and CLA mainly to increase lean body mass and reduce body fat. Recent evidence indicates that this kind of supplementation may have other side-effects and a new role has been identified in steroidogenensis. Preliminary findings demonstrate that fish oil and CLA may induce a physiological increase in testosterone synthesis. The aim of this review is to describe the effects of fish oil and CLA on physical performance (endurance and resistance exercise), and highlight the new results on the effects on testosterone biosynthesis. In view of these new data, we can hypothesize that fat supplements may improve the anabolic effect of exercise.

 

[Michael Scally MD]

Seccareccia E, Brodt P. The role of the insulin-like growth factor-I receptor in malignancy: An update. Growth Hormone & IGF Research 2012;22(6):193-9. ScienceDirect.com - Growth Hormone & IGF Research - The role of the insulin-like growth factor-I receptor in malignancy: An update

In the past three decades, evidence has been accumulating that the IGF-I receptor/ligand system plays an important role in malignant disease. This has led to a search for specific inhibitors of the IGF receptor for cancer therapy, revealing some predictable, but also unexpected challenges. Here we review recent data that highlight the essential role of the IGF axis in several important steps in cancer cell progression and metastasis and highlight cellular processes that have been the focus of much interest and new insight in recent years. Strategies used to target the IGF axis clinically are summarized and the obstacles encountered are discussed.


The Many Facets Of IGF Axis Involvement In Malignancy

IGF-I can activate the expression of Vascular Endothelial Growth Factor (VEGF) thereby initiating angiogenesis. Furthermore it has been demonstrated that IGF-II can act as a chemoattractant to recruit endothelial progenitor cells to ischemic sites (A).

The IGF axis participates in the induction of epithelial to mesenchymal transition (EMT) via the activation of the Snail transcription factor (TF) (B) and can activate the expression of matrix metalloproteinases (MMPs) that promote cell detachment, motility and invasion through the degradation of the extracellular matrix (ECM) (C).

In secondary sites, the IGF axis can protect tumor cells from immune response-mediated attack and enhance tumor cell survival by providing protection from apoptosis (D). Several lines of evidence suggest that the IGF axis also contributes to the maintenance of cancer stem cells (CSCs) (E).

 

[Michael Scally MD]

Aromatase Regulates Aggression

Highlights
? We measured brain aromatase expression in subordinate and dominant male African cichlid fish.
? We inhibited aromatase in dominant males and quantified behavioral and hormonal changes.
? Subordinate males have higher aromatase expression in the preoptic area.
? Inhibiting aromatase decreases aggression and circulating estradiol and increases testosterone.


Huffman LS, O'Connell LA, Hofmann HA. Aromatase regulates aggression in the African cichlid fish Astatotilapia burtoni. Physiol Behav. ScienceDirect.com - Physiology & Behavior - Aromatase regulates aggression in the African cichlid fish Astatotilapia burtoni

The roles of estrogen and androgens in male social behavior are well studied, but little is known about how these hormones contribute to behavior in a social hierarchy. Here we test the role of aromatase, the enzyme that converts testosterone into estradiol, in mediating aggression and reproductive behavior in male Astatotilapia burtoni, an African cichlid fish that displays remarkable plasticity in social behavior.

We first measured aromatase expression in subordinate and dominant males in brain regions that regulate social behavior and found that subordinate males have higher aromatase expression than dominant males in the magnocellular and gigantocellular regions of the preoptic area. Next, we functionally tested the role of aromatase in regulating behavior by intraperitoneally injecting dominant males with either saline or fadrozole (FAD), an aromatase inhibitor, and found that FAD treatment decreases aggressive, but not reproductive, behaviors compared to saline controls.

To determine the underlying physiological and molecular consequences of FAD treatment, we measured estradiol and testosterone levels from plasma and brain aromatase expression in FAD and saline treated dominant males. We found that estradiol levels decreased and testosterone levels increased in response to FAD treatment. Moreover, FAD treated males had increased aromatase expression in the gigantocellular portion of the POA, possibly a compensatory response.

Overall, our results suggest aromatase is a key enzyme that promotes aggression in A. burtoni males through actions in the preoptic area.

 

[Michael Scally MD]

Furuya K, Yamamoto N, Ohyabu Y, et al. Mechanism of the tissue-specific action of the selective androgen receptor modulator s-101479. Biol Pharm Bull 2013;36(3):442-51. https://www.jstage.jst.go.jp/article/bpb/36/3/36_b12-00885/_article

Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known.

In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation.

Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, beta-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1.

The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues.