Guest editorial

Beyond hormonal action: are oestrogens effective free radical scavengers?

Pulmonary effects of ozone (O₃) inhalation have been comprehensively studied, but little is known about its extrapulmonary consequences, particularly in the reproductive tract. Thus, the effects of an acute O₃ exposure on the contractile response of the pregnant rat uterus were evaluated. Nonpregnant and pregnant (5, 10, and 18 days of gestation) rats were exposed to air or O₃ (3 ppm) for1 h, and uterine strips isolated from these animals were studied 16–18 h later. Contractile responses to acetylcholine (ACh) and oxytocin (OT) were evaluated with respect to three parameters (area under the curve, amplitude, and frequency). O₃ did not modify the sensitivity (−log EC₅₀) to either agonist at any pregnancy stage, but induced a statistically significant increase in all maximum responses to OT at gestational day 5, and increased the maximum response (area under the curve) to ACh at pregnancy days 5 and 10. Our results suggest that O₃ inhalation can produce abnormal contractility in the pregnant uterus, and identify the need for further investigation of this issue.

Interactions of 27 steroids, among them 17 derivatives such as ethers, sulfates and amidosulfonates derived from 17β- and 17α-estradiol, from testosterone and α- and β-dihydrotesosterone and from dehydroepiandrosterone with rat liver microsomal cytochromes P450 (P450) were investigated in vitro by assessing binding to P450 and effects on P450 mediated monooxygenase functions as measured by different model reactions: ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD) and ethylmorphine N-demethylation (EMND). With the exception of 17α-estradiol-3-dimethylamidosulfonate, estrone, its -3-methylether and -3-amidosulfonate and testosterone, all other steroids displayed type I or reverse type I binding to P450. All steroids inhibited EROD activity in micromolar concentrations. An additional strong inhibition of ECOD and EMND activities was only demonstrated for the androgens and progestins. Estriol, estrone and mestranol displayed less inhibitory actions on the model reactions than estradiol. No major differences in comparison to the parent compounds were noted with the other derivatives. The only exceptions were 17β-(8,9-dehydro-14α,15α-methylene)estradiol, which displayed stronger effects than estradiol, and dehydroepiandrosterone-3-sulfate, which was less effective than dehydroepiandrosterone. Possible antioxidant properties of the steroids were examined by the stimulated lipid peroxidation (LPO), H₂O₂ production, and lucigenin (LC) and luminol (LM) amplified chemiluminescence (CL) using rat liver microsomes. Additionally, the influence on rat whole blood chemiluminescence (WB-CL) was assessed. All the estrogens, but not their methylethers and amidosulfonates inhibited LPO in micromolar concentrations. The effects on the other oxidase model reactions or on WB-CL were less distinct. Only ethinylestradiol and 17β-(8,9-dehydro-14α,15α-methylene)estradiol displayed a strong inhibitory action on all model reactions. With the exception of dehydroepiandrosterone-3-sulfate, which in general had only weak effects, the androgen and progestin derivatives, in contrast, strongly decreased H₂O₂ formation and LM- and LC-CL, but were mostly ineffective on LPO and WB-CL.

Recent studies in several animal models have suggested that estrogen, given for the short term, may protect ischemic myocardium. Our objective was to test the effect of exogenous estradiol on the development of myocardial necrosis. Twenty minutes before coronary occlusion, rabbits were given an IV bolus of either 17β-estradiol, a form of the hormone that stimulates the estrogen receptor (10 μg) or 17α-estradiol, a natural form of the hormone lacking estrogenic effects (1 mg), or vehicle. Regional myocardial blood flow (RMBF) was measured after treatment and during occlusion and reperfusion, and heart rate and blood pressure were monitored throughout. All rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Estradiol levels were 6 ± 2 pg/ml in untreated rabbits, 392 ± 78 pg/ml in rabbits given 17β-estradiol, and 413 ± 68 pg/ml in rabbits given 17α-estradiol. The size of the ischemic region was similar in all groups, but rabbits treated with 17β-estradiol developed significantly less necrosis than did control rabbits (0.33 ± 0.04 vs 0.53 ± 0.05 of the area at risk; p < 0.05), whereas rabbits treated with 17α-estradiol did not (0.43 ± 0.03; p = NS vs control group). Heart rate, systemic pressure, and RMBF were comparable among groups throughout the protocol. In conclusion, 17β-estradiol exerts a protective effect on ischemic myocardium, reducing infarct size. This beneficial effect is not associated with an increase in myocardial blood flow or alteration in hemodynamics. Because 17α-estradiol did not affect infarct size, the cardioprotective effect of 17β-estradiol is probably receptor mediated.