Non-Genomic Actions of Testosterone Metabolites on Uterine Contractility in Rats

Background: Sex hormones play crucial functions in the body via the genomic and non-genomic pathways. 5α- and 5β-dihydrotestosterone (5α- and 5β-DHT) are 5-reduced testosterone metabolites. We aimed to investigate the non-genomic effect of 5α- and 5β-DHT on uterine muscle contractility in vitro and in vivo for non-pregnant and 22-day-pregnant rats. Methods: The rapid in vitro action of 5α-DHT and 5β-DHT (10^-9-10^-3 M) on KCl (25 mM)-stimulated contractions was examined in an organ bath in the presence of several blockers and after endometrium removal. The actions of DHTs (10^-4 M) and nifedipine (10^-7 M) were also examined in contractions stimulated by KCl (40 mM) with a cumulative addition of CaCl2 (3-120 mM). Plasma DHT levels were measured by ELISA after a single intraperitoneal (i.p.) administration of DHT (10 mg/kg), and kinetic curves were obtained. The in vivo relaxing action of DHTs was detected by strain-gauge sensors. The animals received 5α- or 5β-DHT alone (3/10/30/100/300 mg/kg i.p.) or with flutamide (100 mg/kg i.p.). Results: DHT showed concentration-dependent relaxation of uterine muscle in vitro, with a higher potency observed for 5β-DHT. Among the blockers used, G15 and L-NAME reduced the potency of 5α-DHT in pregnant rats only. Both DHTs inhibited the contraction-increasing effect of CaCl₂, proving their Ca²⁺ inhibiting effects. DHTs had similar c_max and t_max values in both non-pregnant and pregnant rats. DHT plasma levels before and 30 min after administration were proportional to the administered doses. Their single doses (30/100/300 mg/kg) elicited a flutamide-resistant uterine relaxing effect in vivo. Conclusions: DHTs or their analogs are candidates for further studies in the human uterus to establish their potential to treat conditions associated with uterine hyperactivity.