Androgens induce relaxation of contractile activity in pregnant human myometrium at term: a nongenomic action on L-type calcium channels.
It has long been accepted that progesterone regulates uterine contractile activity. However, little is known about the role of androgens in female physiology, and their importance and biological function on myometrial contractility so far have received limited attention. In this work, we examined the direct effect of androgens on the contractile activity of the isolated human myometrium. Myometrial biopsies were obtained, with consent, from pregnant women undergoing elective cesarean section at term. Each androgen tested (dehydroepiandrosterone, testosterone, 5alpha- and 5beta-dihydrotestosterone, androsterone, or androstanediol) caused a concentration-dependent inhibition of spontaneous contractile activity; a relaxing effect of these androgens was also observed on the contractions induced by high potassium (KCl) solution. Interestingly, nonpregnant myometrium was also sensitive to androgen-induced relaxation. 5beta-Dihydrotestosterone (5beta-DHT) was dramatically more potent than the other androgens in inducing myometrial relaxation in all preparations. Relaxation response to androgens had very rapid time courses and was affected by neither the specific antiandrogen (flutamide) nor inhibitors of protein synthesis (cycloheximide) and transcription (actinomycin D), implying that androgens act through a nongenomic mechanism. Importantly, 5beta-DHT significantly reduced the increase in intracellular calcium concentration associated with exposure to KCl in human myometrial smooth-muscle cells loaded with Fura-2-AM. The blockade of l-type calcium channels seems to be involved in the nongenomic relaxing action of androgens. These observations demonstrate that androgens may play a crucial role in maintaining pregnancy.
Perusquía
Mercedes
M
Departamento de Biología Celular y Fisiología, Universidad Nacional Autónoma de México, México. perusqui@servidor.unam.mx
Navarrete
Erika
E
Jasso-Kamel
Jaime
J
Montaño
Luis M
LM
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology* / Q000502:physiology; D015114:Androstenediol / Q000378:metabolism / Q000494:pharmacology; D000738:Androsterone / Q000494:pharmacology / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D003687:Dehydroepiandrosterone / Q000494:pharmacology / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology; D014590:Uterine Contraction / Q000187:drug effects* / Q000502:physiology
D000726:Androgen Antagonists; D000728:Androgens; D020746:Calcium Channels, L-Type; D011500:Protein Synthesis Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D003687:Dehydroepiandrosterone; D005485:Flutamide; D015114:Androstenediol; D000738:Androsterone