Preventive effect of androgens against the bronchospasm in sensitized guinea pigs.

Perusquia M1, Espinoza J1, Montaño LM2. 1Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City, Mexico, 2Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico

The impact of sex based biological differences on health and disease has been recently recognized, especially in chronic diseases including asthma. Male gender has been demonstrated to be a risk factor for bronchial asthma. Changes in the androgen levels in men may be associated with the occurrence of asthma since the incidence of this disease is greater in prepuberal boys than girls, with a change to female predominance after puberty but after middle age, the prevalence increases once again in men. Recently, it has been reported that the isolated tracheal smooth muscle is a target of androgen-induced nongenomic relaxation (1,2,3). To confirm that androgen-induced relaxation is operative in vivo, testosterone (Tes) or its 5-reduced metabolites (5αα- or 5β-dihydrotestosterone; DHT) were tested in the lung resistance (RL) of ovalbumin (OVA)-sensitized animals (n≥20; adult male Hartley guinea pigs).

The anti-bronchospasmatic effect to androgens was evaluated by using the barometric plethysmography, as previously reported (3). Changes of the RL, increased by the antigen challenge to OVA (75 μμg kg-1 min-1 i.v.), were measured at different i.v., independent doses (35-350 μmol kg-1 min-1, n≥6±SDM; n=1 represents one guinea pig) of each androgen, applied 15 min before the challenge. The effect was observed during the immediate-phase response (EAR; after 4 min of the challenge) and late-phase response (LAR; from 12 min ahead) of the bronchospasm. To compare treatment vs. control we used a one-way ANOVA followed by Dunnett’s multiple comparison test.

All androgens decreased the RL increment induced by antigen challenge. Significant inhibition (p<0.05) was observed of the EAR by each androgen in a dose-dependent manner from the control (response to OVA in the absence of androgen, RL=3.80±0.54 cm H2O ml-1 s-1) or from the vehicle control (response to OVA with the equivalent volume used with androgen; DMSO 40 μl) which did not modify the RL. The difference in ED50 values, calculated from the dose-response curves for each androgen, was done using one-way ANOVA followed by Tukey multiple comparisons test, and was significantly different (p<0.05). The order of potency of androgens in decreasing RL was (μmol kg-1 min-1): 5β-DHT (76.48±4.07)>Tes (85.27±4.20)>5α-DHT (124.58±1.80). Notably, the LAR was also suppressed by each androgen at all doses tested (p<0.05).

The results strongly suggest that these androgens may have anti-asthmatic effects by preventing the bronchospasm induced by allergens. Consequently, the present finding advises that androgens, indeed, play a major role in the differences between male and female asthma which might be associated with low Tes in the childhood or deficiency in the aging male to aggravate asthma.

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(1) Kouloumenta V, Hatziefthimiou A, Paraskeva E. et al. (2006) Br J Pharmacol 149: 1083-1091.

(2) Bordallo J, de Boto MJ, Meana C. et al. (2008) Eur J Pharmacol 601: 154-162.

(3) Espinoza J, Montaño LM, Perusquía M. (2013) J Steroid Biochem Mol Biol 138: 174-182.