Regulation of ovarian function by catecholestrogens: current concepts

Development of the ovarian follicle(s) destined for ovulation appears to be a process in which antral follicles undergo a recruitment, selection and subsequent dominance phase. Several intraovarian or autocrine/paracrine regulatory mechanisms have been evoked to explain these processes. One of these potential autocrine/paracrine regulators is a catecholestrogen, 2-hydroxy-estradiol (2-OH-E2). Evidence implicating 2-OH-E2 as an autocrine/paracrine regulator of follicular function is reviewed. Studies have shown 2-OH-E2 to be present in nanomolar concentrations in fluid of human and equine follicles. In addition, the enzyme responsible for converting estradiol (E2) into 2-OH-E2, estrogen 2-hydroxylase (E-2-H), is abundant in granulosa and thecal cells (but not corpora lutea) of porcine follicles. Moreover, activity of E-2-H increases during follicular development in pigs. In vitro, the actions of 2-OH-E2 have been compared to those of E2, gonadotropins, catecholamines, and androgens. Studies indicated that the maximal stimulatory effects of 2-OH-E2 on progesterone production were comparable to those of E2 and gonadotropins, and greater than androgens or catecholamines. The effect of 2-OH-E2 was found to be significantly additive to each of the other classes of compounds at maximally effective concentrations, suggesting that the mechanism of action of 2-OH-E2 was different. The mode of action of the several stimulators of progesterone biosynthesis were examined additionally with antihormones for E2, catecholamines, and androgens. In each instance, the hormonal antagonists were able to inhibit the action of the predicted class of effector compounds. However, with the exception of the antiandrogen, hydroxyflutamide, no effects of anti-hormones on the action of 2-OH-E2 were observed. In the aggregate, these studies suggested that the action of 2-OH-E2 is mediated by a mechanism discrete from those of the other classes of hormones examined to date, and that hydroxyflutamide exhibits both antiandrogen and anticatecholestrogen activity. 2-OH-E2 can also enhance the actions of other trophic hormones, epinephrine, LH and FSH, by enhancing hormone-stimulated cAMP production. This effect on epinephrine action appears to be due to a 2-OH-E2-stimulated increase in the density of beta-adrenergic receptors. Whether 2-OH-E2 stimulates an increase in the number of LH and FSH receptors remains to be determined. The precise locus of the stimulatory effect of 2-OH-E2 alone on steroidogenesis is unclear but preliminary data would suggest that 2-OH-E2 may be stimulating side-chain cleavage enzyme activity.(ABSTRACT TRUNCATED AT 400 WORDS)