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 cmax and tmax 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.