Disruption of the synchronous secretion of leptin, LH, and ovarian androgens in nonobese adolescents with the polycystic ovarian syndrome

The present study probes putative disruption of hypothalamic control of mul tihormone outflow in polycystic ovarian syndrome by quantitating the joint synchrony of leptin and LH release in adolescents with this syndrome and eu menorrheic controls. To this end, hyperandrogenemic oligo- or anovulatory p atients with polycystic ovarian syndrome (n = 11) and healthy girls (n = 9) underwent overnight blood sampling every 20 min for 12 h to monitor simult aneous secretion of leptin (immuno-radiometric assay), LH (immunofluorometr y), and androstenedione and T (RIA). Synchronicity of paired leptin-LH, lep tin-androstenedione, and leptin-T profiles was appraised by two independent bivariate statistics; viz., lag-specific cross-correlation analysis and pa ttern-sensitive cross-approximate entropy. The study groups were comparable in chronological and postmenarchal age, body mass index, fasting plasma in sulin/glucose ratios, and serum E2 concentrations. Overnight mean (+/- SEM) serum leptin concentrations were not distinguishable in the two study grou ps at 30 +/- 4.8 (polycystic ovarian syndrome) and 32 +/- 7.4 mug/liter (co ntrol). Serum LH concentrations were elevated at 9.5 +/- 1.4 in girls with polycystic ovarian syndrome vs. 2.8 +/- 0.36 IU/liter in healthy subjects ( P = 0.0015), androstenedione at 2.8 +/- 0.30 (polycystic ovarian syndrome) vs. 1.2 +/- 0.11 ng/ml (control) (P = 0.0002), and T at 1.56 +/- 0.29 (poly cystic ovarian syndrome) vs. 0.42 +/- 0.06 ng(ml (P < 0.0001). Cross-correl ation analysis shows that healthy adolescents maintained a positive relatio nship between leptin and LH release, wherein the latter lagged by 20 min (P < 0.01). No such association emerged in girls with polycystic ovarian synd rome. In eumenorrheic volunteers, leptin and androstenedione concentrations also covaried in a lag-specific manner (0.0001 < P < 0.01), but this linka ge was disrupted in patients with polycystic ovarian syndrome. Anovulatory adolescents further failed to sustain normal time-lagged coupling between l eptin and T (P < 0.01). Approximate entropy calculations revealed erosion o f orderly patterns of leptin release in polycystic ovarian syndrome (P = 0. 012 vs. control). Cross-entropy analysis of two-hormone pattern regularity disclosed marked disruption of leptin and LH (P = 0.0099), androstenedione and leptin (P = 0.0075) and T-leptin (P = 0.019) synchrony in girls with po lycystic ovarian syndrome. In summary, hyperandrogenemic nonobese adolescents with oligo- or anovulato ry polycystic ovarian syndrome manifest: 1) abrogation of the regularity of monohormonal leptin secretory patterns, despite normal mean serum leptin c oncentrations; 2) loss of the bihormonal synchrony between leptin and LH re lease; and 3) attenuation of coordinate leptin and androstenedione as well as leptin and T output. In ensemble, polycystic ovarian syndrome pathophysi ology in lean adolescents is marked by vivid impairment of the synchronous outflow of leptin, LH and androgens. Whether analogous disruption of leptin -gonadal axis integration is ameliorated by therapy and/or persists into ad ulthood is not known.