Friday, August 1, 2014

Testosterone, Social Distance and Inter-Male Competition Shape Parochial Altruism in Human Males

Diekhof EK, Wittmer S, Reimers L. Does competition really bring out the worst? Testosterone, social distance and inter-male competition shape parochial altruism in human males. PLoS One 2014;9(7):e98977.   

Parochial altruism, defined as increased ingroup favoritism and heightened outgroup hostility, is a widespread feature of human societies that affects altruistic cooperation and punishment behavior, particularly in intergroup conflicts. Humans tend to protect fellow group members and fight against outsiders, even at substantial costs for themselves.

Testosterone modulates responses to competition and social threat, but its exact role in the context of parochial altruism remains controversial. Here, we investigated how testosterone influences altruistic punishment tendencies in the presence of an intergroup competition.

Fifty male soccer fans played an ultimatum game (UG), in which they faced anonymous proposers that could either be a fan of the same soccer team (ingroup) or were fans of other teams (outgroups) that differed in the degree of social distance and enmity to the ingroup. The UG was played in two contexts with varying degrees of intergroup rivalry.

Our data show that unfair offers were rejected more frequently than fair proposals and the frequency of altruistic punishment increased with increasing social distance to the outgroups. Adding an intergroup competition led to a further escalation of outgroup hostility and reduced punishment of unfair ingroup members.

High testosterone levels were associated with a relatively increased ingroup favoritism and also a change towards enhanced outgroup hostility in the intergroup competition. High testosterone concentrations further predicted increased proposer generosity in interactions with the ingroup.

Altogether, a significant relation between testosterone and parochial altruism could be demonstrated, but only in the presence of an intergroup competition. In human males, testosterone may promote group coherence in the face of external threat, even against the urge to selfishly maximize personal reward.

In that way, our observation refutes the view that testosterone generally promotes antisocial behaviors and aggressive responses, but underlines its rather specific role in the fine-tuning of male social cognition.

Injectable Testosterone Undecanoate for the Treatment of Hypogonadism

Corona G, Maseroli E, Maggi M. Injectable testosterone undecanoate for the treatment of hypogonadism. Expert Opin Pharmacother 2014:1-24.   

Introduction: Injectable testosterone undecanoate (TU) is a long-acting testosterone (T) formulation available for the treatment of male hypogonadism (HG) since 2003.

Areas covered: The efficacy and safety of injectable TU are assessed, as obtained by meta-analyzing available evidence. An extensive Medline, Embase and Cochrane search was performed. All uncontrolled and placebo-controlled randomized clinical trials (RCTs), evaluating the effect of injectable TU on different outcomes, were included. Of the 98 retrieved articles, 33 were included in the study. Among those, 11 were placebo-controlled RCTs. Injectable TU was significantly associated with a reduction of fat mass and HbA1c in both controlled and uncontrolled trials, in particular when hypogonadal subjects were enrolled. Similar results were observed for the improvement of erectile function. In addition, TU ameliorated several other outcomes, including blood pressure, lipid profile, waist circumference and body mass index in uncontrolled studies, but these data were not confirmed in placebo-controlled trials. The treatment was well tolerated and no risk of prostate cancer or cardiovascular disease was observed.

Expert opinion: Injectable TU is a safe and effective treatment for male HG. The possibility of a therapeutic intervention just four to five times per year frees the patient, at least partially, from having a chronic condition, thus maintaining a positive, active role in self-caring.

Testosterone Therapy and Mortality Risk

Eisenberg ML, Li S, Herder D, Lamb DJ, Lipshultz LI. Testosterone therapy and mortality risk. Int J Impot Res.   

Recent data suggest an increased risk of cardiovascular events and mortality in men on testosterone therapy (TT). To date, there are no long-term, prospective studies to determine safety. In such cases, retrospective observational studies can be helpful.

We examined our patient database to determine whether TT altered the risk of all-cause mortality in men. We queried our hormone database for all men with a serum testosterone level and then examined charts to determine testosterone status.

In all, 509 men had charts available for review. We linked our patient records to the National Death Index to determine mortality. Of the 509 men who met inclusion criteria, 284 were on TT and 225 did not use testosterone. Age (mean 54 years) and follow-up time (mean 10 years) were similar for both groups.

In all, 19 men died-10 (4.4%) men not on TT and 9 (3.2%) men on TT. After adjusting for age and year of evaluation, there was no significant difference in the risk of death based on TT (hazard ratio 0.92, 95% confidence interval 0.36-2.35, P=1.0).

There appears to be no change in mortality risk overall for men utilizing long-term testosterone therapy.

Skeletal Myopathy in Patients with Chronic Heart Failure: Significance of Anabolic-Androgenic Hormones

Josiak K, Jankowska E, Piepoli M, Banasiak W, Ponikowski P. Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormones. Journal of Cachexia, Sarcopenia and Muscle 2014:1-10.  

In heart failure, impairment of cardiac muscle function leads to numerous neurohormonal and metabolic disorders, including an imbalance between anabolic and catabolic processes, in favour of the latter.

These disorders cause loss of muscle mass with structural and functional changes within the skeletal muscles, known as skeletal myopathy.

This phenomenon constitutes an important mechanism that participates in the pathogenesis of chronic heart failure. both its clinical symptoms and the progression of the disease.

Attempts to reverse the above-mentioned pathologic processes by exploiting the anabolic action of androgenic hormones could provide a potentially attractive treatment option.

The current concepts of anabolic androgen deficiency and resultant skeletal myopathy in patients with heart failure are reviewed, and the potential role of anabolic-androgenic hormones as an emerging therapeutic option for targeting heart failure is discussed.

The Muscle Hypothesis in Heart Failure: Pathogenesis of Skeletal Myopathy

Mechanisms of Action of Anabolic Hormones on Skeletal Muscles 
AR - Androgen Receptor, UPS - Ubiquitin-Proteasome System

Thursday, July 31, 2014

FGF5 Is a Crucial Regulator of Hair Length

The length of your eyelashes probably differs from the length of the hair on your head—and unlike your hair, your eyelashes can never reach your shoulders.

What controls how long hair can get?

To find out, Higgins et al. studied people with a rare disorder called familial trichomegaly, who have very long eyelashes and longer hair on the arms. They found that these people had a mutation in the gene that encodes fibroblast growth factor 5 (FGF5).

When human hair follicles produce FGF5, they stop growing hair.

FGF5 underlies trichomegaly and is a crucial regulator of hair growth in humans.

Targeting FGF5 could potentially control the growth and rest phases of hair follicles, preventing unwanted hair from sprouting or growing longer lashes and locks.

Higgins CA, Petukhova L, Harel S, et al. FGF5 is a crucial regulator of hair length in humans. Proc Natl Acad Sci USA. 2014;111(29):10648-53.   

Mechanisms that regulate the growth of eyelashes have remained obscure. We ascertained two families from Pakistan who presented with familial trichomegaly, or extreme eyelash growth.

Using a combination of whole exome sequencing and homozygosity mapping, we identified distinct pathogenic mutations within fibroblast growth factor 5 (FGF5) that underlie the disorder. Subsequent sequencing of this gene in several additional trichomegaly families identified an additional mutation in FGF5.

We further demonstrated that hair fibers from forearms of these patients were significantly longer than hairs from control individuals, with an increased proportion in the growth phase, anagen.

Using hair follicle organ cultures, we show that FGF5 induces regression of the human hair follicle.

We have identified FGF5 as a crucial regulator of hair growth in humans for the first time, to our knowledge, and uncovered a therapeutic target to selectively regulate eyelash growth.

Application Site Affects the Pharmacokinetics of Topical Testosterone Applied to the Axilla Compared With the Inner Arm

Davis SR, Evans AM, Humberstone A. Application Site Affects the Pharmacokinetics of Topical Testosterone Applied to the Axilla Compared With the Inner Arm. Clin Ther.   

PURPOSE: This study compared the pharmacokinetics of a single dose of 1% testosterone solution after application to the inner arm or the axilla as application sites for transdermal testosterone therapy.

METHODS: Healthy, not pregnant, premenopausal women, 18 to 45 years of age with a body mass index of 20 to 28 kg/m2 were enrolled into a single-center, open-label, randomized, 2-way crossover study. Serum total testosterone (TT), free testosterone (fT), and sex hormone binding globulin concentrations were measured. Pharmacokinetic parameters determined from serum TT and fT included area under the serum concentration versus time curve from time zero (pre-dose) until 72 hours post-dose (AUC0-72), Cmax, and Tmax. Descriptive statistics were performed on serum concentrations of TT and fT for each site. ANOVA was performed on AUC0-72 and Cmax.

FINDINGS: A single-dose application of 1% testosterone solution to the inner arm and the axilla produced clear increases in TT and fT. Slower and lower increases in TT and fT were observed after treatment to the inner arm. Based on baseline-corrected AUC versus time curves, the bioavailability of 1% testosterone solution was increased 2-fold for the axilla compared with the inner arm.

IMPLICATIONS: The absorption of a 1% testosterone solution was significantly greater after application to the axilla than to the inner arm.

A Novel Finasteride 0.25% Topical Solution for Androgenetic Alopecia

Caserini M, Radicioni M, Leuratti C, Annoni O, Palmieri R. A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers. Int J Clin Pharmacol Ther.   

Objective: Finasteride, a selective inhibitor of type 2 5-alpha reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT.

Methods: 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined.

Results: After multiple doses, mean (+/- SD) finasteride Cmax and AUC00-t corresponded to 0.46 +/- 0.28 ng/mL and 6.64 +/- 7.50 ng/mL x h for the topical solution and to 6.86 +/- 1.78 ng/mL and 57.93 +/- 29.38 ng/mL x h for the tablet. Plasma DHT was reduced by ~ 68 - 75% with the topical solution and by ~ 62 - 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred.

Conclusions: A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride formulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).