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Prepubertal Administration of Estradiol Valerate Disrupts Cyclicity and Leads to Cystic Ovarian Morphology during Adult Life in the Rat: Role of Sympathetic Innervation

Department of Physiology (A.R., M.A.G.), Faculty of Medicine at Riberao-Preto, Universidade de Sao Paulo, RP 14090-900 Sao Paulo, Brazil; Department of Pediatrics and the Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department Biochemistry and Molecular Biology (H.E.L.), Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago-1, Chile

Address all correspondence and requests for reprints to: Hernán E. Lara, Ph.D., Laboratory of Neurobiochemistry, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, P.O. Box 233, Santiago-1, Chile. E-mail: hlara{at}ll.ciq.uchile.cl.

Administration of estradiol valerate (EV) to adult rats leads to anovulation and cystic ovarian morphology. Sympathetic ovarian nerve denervation (SONX) overcomes this disruption. In this study, we determined whether EV administration to juvenile rats prevents achievement of reproductive competence, disrupts cyclicity, and whether this programming is facilitated via activation of the sympathetic nerve input to the ovary. Prepubertal rats were administered 2 mg EV in corn oil or corn oil alone. One half of the animals from each group underwent SONX on d 71 of life. Rats were euthanized on d 91 for determination of serum gonadotropins, progesterone, 4 androstenedione, and estradiol concentrations, ovarian norepinephrine (NE), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) activities and ovarian dynamics. Results revealed that EV administration during juvenile period advanced pubertal onset, suppressed circulating LH, FSH, and 4 androstenedione, increased ovarian NE, estradiol, and 3ß-HSD activities, disrupted ovarian dynamics evidenced as absent corpus luteum and presence of ovarian cysts and culminated in anovulation. SONX restored cyclicity in these animals, normalized LH, estradiol, ovarian 3ß-HSD activities, and ovarian dynamics as evidenced by the disappearance of ovarian cysts and appearance of corpus luteum and restored corpus luteum function. These findings provide evidence that EV exposure during juvenile life leads to long-lasting deleterious reproductive consequences via activation of the sympathetic ovarian nerve.

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