Ovarian Steroidal Response to Gonadotropins and ,&Adrenergic Stimulation Is Enhanced in Polycystic Ovary Syndrome: Role of Sympathetic Innervation*

Experimental induction of a polycystic ovarian syndrome (PCOS) in rodents by the administration of a single dose of estradiol valerate (EV) results in activation of the peripheral sympathetic neurons that innervate the ovary. This activation is evidenced by an increased capacity of ovarian nerve terminals to incorporate and release norepinephrine (NE), an increase in ovarian NE content, and a decrease in ovarian fl-adrenergic receptor number in the ovarian compartments receivingcatecholaminergic innervation. The present experiments were undertaken to examine the functional consequences of this enhanced sympathetic outflow to the ovary. The steroidal responses of the gland to @-adrenergic receptor stimulation and hCG were examined in uitro 60 days after EV administration, i.e. at the time when follicular cysts are well established. EV-treated rats exhibited a remarkable increase in ovarian progesterone and androgen responses to isoproterenol, a /3adrenergic receptor agonist, with no changes in estradiol responsiveness. Basal estradiol release was, however, 50-fold higher than the highest levels released from normal ovaries at any phase of the estrous cycle. The ovarian progesterone and androgen responses to hCG were enhanced in EV-treated rats, as were the responses to a combination of isoproterenol and hCG. Transection of the superior ovarian nerve (SON), which carries most of the catecholaminergic fibers innervating endocrine ovarian cells, dramatically reduced the exaggerated responses of all three steroids to both p-adrenergic and gonadotropin stimulation. SON transection also reduced the elevated levels of ovarian NE resulting from EV treatment and caused up-regulation of /3-adrenoreceptors. Most importantly, SON transection restored estrous cyclicity and ovulatory capacity. The results indicate that the increased output of ovarian steroids in PCOS is at least in part due to an enhanced responsiveness of the gland to both catecholaminergic and gonadotropin stimulation. The ability of SON transection to restore a normal response indicates that the alteration in steroid output results from a deranged activation of selective components of the noradrenergic innervation to the ovary. These findings support the concept that an alteration in the neurogenic control of the ovary contributes to the etiology of PCOS. (Endocrinology 133: 2696-2703,1993) P OLYCYSTIC ovarian syndrome (PCOS) is a complex pathophysiology characterized by ovulatory failure, amenorrhea, hyperandrogenemia, and variable levels of circulating gonadotropins (l-3). Frequently, PCOS is accompanied by obesity, hirsutism, and, in the vast majority of cases, infertility. A hallmark of PCOS is the elevation in circulating levels of androgenic hormones and their precursors (1); this excess is accompanied by moderately elevated levels of estrogen, which mainly derive from peripheral aromatization of the heightened androgen (A) levels. In spite of the progress made toward characterizing the different components of the syndrome and devising therapeutical strategies for its treatment, little is known about the primary factors that initiate the dysfunction. Although ovulatory surges of gonadotropins fail to occur in PCOS, and Received March 30, 1993. Address all correspondence and requests for reprints to: Heman E. Lara, Ph.D., Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, P.O. Box 233, Santiago, Chile. * This work was supported by grants from the Departamenyo Tecnico de Investigaciones, Universidad de Chile B 3344-9213; Fondecyt 901001 and 1931049, and the Rockefeller Foundation (to H.E.L.), and NIH Grants HD-24870, HD-18185, and RR-00163 (SRO). This is publication 1886 of the Oregon Regional Primate Research Center. t Present address: Departamento de Morfologia Experimental, Facultad de Medicina, Universidad de Chile, Santiago, Chile. the pattern of basal gonadotropin secretion is disturbed (1, 4, 5), it is unlikely that PCOS results from a primary hypothalamic defect. On the one hand, the patterns of pulsatile LH release and LH/FSH ratios of secretion are inconsistent among PCOS patients (5). On the other, the hypothalamicpituitary axis retains its responsiveness to both negative and positive feedback of estradiol (E2) (4) and can reinitiate cyclic function after appropriate therapeutic manipulations (1). Both of these observations suggest that the alterations in neuroendocrine hypothalamic function in PCOS are secondary to a defect located elsewhere. It is now clear that a major factor responsible for the acyclicity of PCOS is a tonic inhibition of gonadotropin secretion effected by the elevated circulating estrogen levels that result from the peripheral aromatization of A (for reviews, see Refs. 1 and 4). The validity of this view, which derived from clinical observations, is supported by experimental data in laboratory rodents showing the ability of estradiol valerate (EV), a long-acting estrogen, to cause acyclicity, anovulation, and formation of ovarian cysts (6, 7). These and other considerations have suggested that the primary defect underlying the etiology of PCOS may be intraovarian, a possibility that has recently redirected investigative efforts toward the study of intraovarian molecules involved in paracrine/autocrine regulation, such as insulinlike growth factor-I (for reviews, see Refs. 1 and 8). Never-