Paradoxical down-regulation and desensitization of beta(2)-adrenoceptors by exogenous progesterone in female asthmatics

We have demonstrated previously that exogenous progesterone, but not estrogen, up-regulated lymphocyte beta(2)-adrenoceptors (beta(2)-AR) when given during the follicular phase in healthy women. Female asthmatics exhibit loss of the cyclical pattern of beta(2)-AR regulation seen in healthy women, in that there is no luteal phase rise in beta(2)-AR. It has been postulated that abnormal cyclical regulation of beta(2)-AR might be a possible mechanism for premenstrual asthma. In this study, we were interested to see how exogenous female sex-steroid hormones altered beta(2)-AR regulation in female asthmatics during the follicular phase, when endogenous hormone levels are normally low. Seven nonsmoking female subjects with mild asthma, with a mean (SEM) age of 26 (2) years and FEV1 of 94.7% (6.4) of predicted, completed this randomized, double-blind, crossover study. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1 to 6). They were randomized to receive single oral doses of either ethinyl estradiol (ethinyloestradiol), 50 mu g, or medroxyprogesterone, 10 mg. Lymphocyte beta(2)-AR parameters were evaluated at baseline (T-0), 24 h (T-24), and 72 h (T-72) after ingestion. Baseline levels of progesterone and estradiol were comparable on both cycles. Receptor binding density (log Bmax; fmol/10(6) cells) decreased significantly after progesterone but not after estrogen at T-24: amounting to a 1.34-fold mean difference (95% confidence interval [CI], 1.01 to 1.78) between T-24 vs T-0 with progesterone. Comparing Bmax for progesterone with estrogen at T-24 amounted to a 1.25-fold significant difference (95% CI, 1.00 to 1.56). This was associated with a trend (p=0.06) toward a lower cyclic-adenosine monophosphate (AMP) response to isoproterenol hydrochloride (isoprenaline) 10(-4) M (Emax) at T-24 vs T-0 with progesterone. Receptor binding affinity (Kd) was not altered by either treatment. These results show that exogenous progesterone, but not estrogen, given curing the follicular phase, decreased beta(2)-AR density and cyclic-AMP response in female asthmatics, in contrast to the previously observed up-regulating effect of progesterone seen in healthy women. This paradoxical effect of progesterone in female asthmatics suggests an abnormal regulation of beta(2)-AR and might be a possible mechanism for premenstrual asthma when progesterone levels are high during this period of the cycle.