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Disruption of the Joint Synchrony of Luteinizing Hormone, Testosterone, and Androstenedione Secretion in Adolescents with Polycystic Ovarian Syndrome¹

Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center and National Science Foundation Center for Biological Timing, University of Virginia Health System (J.D.V.), Charlottesville, Virginia 22908; Centro de Investigaciones Endocrinologicas, Hospital de Niños R. Gutierrez (M.C.G.-R., M.G.R., M.E.E., M.B.), Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu

The present study explores the postulate that the polycystic ovarian syndrome (PCOS) is marked by failure of physiological feedforward and feedback signaling between pituitary LH and ovarian androgens. To this end, we appraised the 3-fold simultaneous overnight release of LH (assayed by high precision immunofluorometry), testosterone (RIA), and androstenedione (RIA) in 12 an- or oligoovulatory adolescents with PCOS (mean ± SEM age, 16.4 ± 0.47 yr) and 10 eumenorrheic girls (age, 16.5 ± 0.45 yr). Gynecological (postmenarchal) ages (years) were also comparable at 4.8 ± 0.39 (PCOS) and 4.0 ± 3.6 (control; P = NS). Body mass index and fasting serum insulin and estradiol concentrations were indistinguishable in the two study cohorts. Mean overnight serum concentrations of LH (assayed by both immunofluorometry and Leydig cell bioassay), testosterone, androstenedione, and 17-hydroxyprogesterone were each elevated significantly in patients with PCOS (all P 0.027). The bivariate cross-approximate entropy (cross-ApEn) statistic was used as a sensitive barometer of altered within-axis feedback. This scale-invariant metric is designed to quantitate the joint synchrony of putatively linked (neurohormone) time series in a lag-independent pattern-sensitive manner. Here, we applied cross-ApEn to the coupled release of LH and testosterone, LH and androstenedione, and testosterone and androstenedione. Statistical comparisons of the two adolescent study cohorts unveiled consistently elevated cross-ApEn in patients with PCOS, denoting disruption of the pairwise synchrony of LH and testosterone (P = 0.0055), LH and androstenedione (P = 0.0076), and testosterone and androstenedione (P = 0.014) secretion. As an analytically distinct technique to monitor coordinate hormone release, we also applied cross-correlation analysis with variable lag. This appraisal revealed that adolescents with PCOS further exhibit 1) loss of rapid feedforward coupling between LH and testosterone output, 2) erosion of the time-lagged positive linkages between LH and androstenedione secretion, and 3) attenuation of the coordinate relationship between testosterone and androstenedione release.

In summary, based on complementary, but independent, statistical tools, the present two-variable analyses unmask vivid deterioration of the joint synchrony of LH-testosterone, LH-androstenedione, and testosterone-androstenedione secretion in adolescents with PCOS. The multiplicity of the bihormonal coupling defects points to impaired feedforward and feedback signaling interfaces among the hypothalamus, pituitary gland, and ovary. Disruption of interandrogen synchrony also identifies pathophysiological dissociation of testosterone and androstenedione cosecretion. Whether presumptive failure of integrative hypothalamo-pituitary-gonadal control emerges prepubertally in girls at risk for PCOS or persists in adults with PCOS is not known.

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