Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm

Abstract

Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5a-and 5b-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5b-DHT was more potent for relaxing KCl-induced contraction, while TES and 5a-DHT were more potent for CCh-and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K C channels. These data indicate the absence of involvement of the epithelium-, NO-and K C channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca 2C ] i increment. 5b-DHT was the most potent at decreasing KCl-induced [Ca 2C ] i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca 2C influx through L-type Ca 2C channels but additional Ca 2C entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action. Key Words" asthma " testosterone " 5a-dihydrotestosterone" 5b-dihydrotestosterone " bronchoactive steroids " airway smooth muscle

Serum estradiol concentration, estradiol-toprogesterone ratio and sputum IL-5 and IL-8 concentrations are increased in luteal phase of the menstrual cycle in perimenstrual asthma patients

“…Our study adds the key evidence of the immuno-hormonal crosstalk in the pathogenesis of PMA, which is now considered one consistent with some earlier (25,26), but not with all (27,28) studies. The association between androgens and PMA has weakly been examined yet.…”

“…Consistent with our findings, Wulfsohn et al demonstrated (28) that female asthmatic patients treated with testosterone demonstrated a 90% improvement of asthma symptoms, while Mileva et al (25) found low levels of serum testosterone in patients with severe (when compared with mild) asthma. The impact of testosterone on the function of lower airways might be explained by the results of the study by Monatano et al (26) who found that testosterone induces bronchial relaxation via blockage of calcium channels, thus relaxing airway smooth muscle and increasing the airflow. It is therefore possible that reduced serum testosterone level in PMA patients found in our study is one of the factors increasing BHR in these patients.…”

Endocrine regulation of airway contractility is overlooked

“…Androgens Androgens, such as testosterone, have an acute, non-genomic, and non-estrogenic effect on ASM activation (Kouloumenta et al 2006, Bordallo et al 2008, Montano et al 2014. The direction of the effect depends on the state of ASM activation.…”

“…The direction of the effect depends on the state of ASM activation. On one hand, androgens relax pre-contracted ASM (Kouloumenta et al 2006, Bordallo et al 2008, Montano et al 2014 and potentiate the relaxing effect of b 2 -agonists (Foster et al 1983, Bordallo et al 2008, which suggest an overall bronchodilator effect. On the other hand, in the same ASM preparations and at the same concentrations, androgens potentiate the contractile response to a spasmogen, which suggest a constrictor effect (Bordallo et al 2008).…”

“…On one hand, i.v. administration of androgens almost completely abrogates the increased lung resistance elicited by allergen challenge in sensitized animals (Montano et al 2014). Testosterone therapy is also salutary in the treatment of symptoms of women suffering from premenstrual asthma (Wulfsohn et al 1964).…”