Paradoxical down-regulation and desensitization of beta2-adrenoceptors by exogenous progesterone in female asthmatics.
We have demonstrated previously that exogenous progesterone, but not estrogen, up-regulated lymphocyte beta2-adrenoceptors (beta2-AR) when given during the follicular phase in healthy women. Female asthmatics exhibit loss of the cyclical pattern of beta2-AR regulation seen in healthy women, in that there is no luteal phase rise in beta2-AR. It has been postulated that abnormal cyclical regulation of beta2-AR might be a possible mechanism for premenstrual asthma. In this study, we were interested to see how exogenous female sex-steroid hormones altered beta2-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 microg, or medroxyprogesterone, 10 mg. Lymphocyte beta2-AR parameters were evaluated at baseline (T0), 24 h (T24), and 72 h (T72) 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 T24: amounting to a 1.34-fold mean difference (95% confidence interval [CI], 1.01 to 1.78) between T24 vs T0 with progesterone. Comparing Bmax for progesterone with estrogen at T24 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 T24 vs T0 with progesterone. Receptor binding affinity (Kd) was not altered by either treatment. These results show that exogenous progesterone, but not estrogen, given during the follicular phase, decreased beta2-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 beta2-AR and might be a possible mechanism for premenstrual asthma when progesterone levels are high during this period of the cycle.
Tan
K S
KS
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Scotland.
McFarlane
L C
LC
Lipworth
B J
BJ
D000284:Administration, Oral; D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015536:Down-Regulation; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005498:Follicular Phase; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000737:chemistry; D008525:Medroxyprogesterone / Q000008:administration & dosage / Q000494:pharmacology; D008598:Menstruation / Q000502:physiology*; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects*
D012739:Gonadal Steroid Hormones; D011943:Receptors, Adrenergic, beta; D004997:Ethinyl Estradiol; D011374:Progesterone; D008525:Medroxyprogesterone