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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 8 3772-3778
Copyright © 2001 by The Endocrine Society

Other Original Articles

Disruption of the Synchronous Secretion of Leptin, LH, and Ovarian Androgens in Nonobese Adolescents with the Polycystic Ovarian Syndrome

J. D. Veldhuis, S. M. Pincus, M. C. Garcia-Rudaz, M. G. Ropelato, M. E. Escobar and M. Barontini

Division of Endocrinology (J.D.V.), Department of Internal Medicine, General Clinical Research Center and Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908; (S.M.P.), Guilford, Connecticut 06437; and Centro de Investigaciones Endocrinologicas (CEDIE) (M.C. G.-R., M.G.R., M.E.E., M.B.), Hospital de Niños "R. Gutierrez," 1425 Buenos Aires, Argentina

Address all correspondence and requests for reprints to: J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, University of Virginia School of Medicine, P.O. Box 800202, Charlottesville, Virginia 22908-0202. E-mail: JDV{at}virginia.edu

Abstract

The present study probes putative disruption of hypothalamic control of multihormone outflow in polycystic ovarian syndrome by quantitating the joint synchrony of leptin and LH release in adolescents with this syndrome and eumenorrheic controls. To this end, hyperandrogenemic oligo- or anovulatory patients with polycystic ovarian syndrome (n = 11) and healthy girls (n = 9) underwent overnight blood sampling every 20 min for 12 h to monitor simultaneous secretion of leptin (immuno-radiometric assay), LH (immunofluorometry), and androstenedione and T (RIA). Synchronicity of paired leptin-LH, leptin-androstenedione, and leptin-T profiles was appraised by two independent bivariate statistics; viz., lag-specific cross-correlation analysis and pattern-sensitive cross-approximate entropy. The study groups were comparable in chronological and postmenarchal age, body mass index, fasting plasma insulin/glucose ratios, and serum E2 concentrations. Overnight mean (± SEM) serum leptin concentrations were not distinguishable in the two study groups at 30 ± 4.8 (polycystic ovarian syndrome) and 32 ± 7.4 µg/liter (control). 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 (polycystic ovarian syndrome) vs. 0.42 ± 0.06 ng/ml (P < 0.0001). Cross-correlation analysis shows that healthy adolescents maintained a positive relationship between leptin and LH release, wherein the latter lagged by 20 min (P < 0.01). No such association emerged in girls with polycystic ovarian syndrome. In eumenorrheic volunteers, leptin and androstenedione concentrations also covaried in a lag-specific manner (0.0001 < P < 0.01), but this linkage was disrupted in patients with polycystic ovarian syndrome. Anovulatory adolescents further failed to sustain normal time-lagged coupling between leptin and T (P < 0.01). Approximate entropy calculations revealed erosion of 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 polycystic ovarian syndrome.

In summary, hyperandrogenemic nonobese adolescents with oligo- or anovulatory polycystic ovarian syndrome manifest: 1) abrogation of the regularity of monohormonal leptin secretory patterns, despite normal mean serum leptin concentrations; 2) loss of the bihormonal synchrony between leptin and LH release; and 3) attenuation of coordinate leptin and androstenedione as well as leptin and T output. In ensemble, polycystic ovarian syndrome pathophysiology 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 adulthood is not known.

LEPTIN IS A signaling peptide produced in fat cells, which supervises neuroendocrine adaptations to altered nutritional status (1, 2, 3, 4, 5, 6, 7). Leptin receptors are expressed in various hypothalamic nuclei and in the rodent mediate feedback from adipose tissue on appetite, thermoregulatory, reproductive, somatotropic, thyrotropic, and corticotropic regulatory centers (8, 9, 10). Leptin secretion is modulated by total fat cell mass, sex steroids, GH, glucocorticoids, insulin, and sympathetic activity (11, 12, 13, 14, 15). Mutations of the genes encoding leptin or its receptor are accompanied by obesity and disruption of neuroendocrine function (8, 9), such as hypogonadotropic hypogonadism (2, 8, 9, 16, 17).

Elevated leptin secretion in obesity is associated with altered LH production (3, 4, 5, 6, 15, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29). Accordingly, coexistent adiposity may confound the facile interpretation of any pathophysiological linkage between leptin and LH secretion in reproductive diseases accompanied by obesity, such as a significant subset of patients with polycystic ovarian syndrome (PCOS) (18, 19, 21, 30, 31, 32, 33, 34, 35, 36, 37, 38). Indeed, little is known about leptin-LH coupling in nonobese individuals with PCOS (39). This issue may be especially significant in PCOS, wherein clinical evidence points to alterations in both leptin and gonadotropin secretion (40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52). Accordingly, the present study appraises the simultaneous output of leptin and LH in nonobese adolescents with PCOS and eumenorrheic controls matched for body mass index.

Materials and Methods

Clinical protocol

Volunteers provided institutionally approved individual assent and parental consent before participation. PCOS was defined by clinical androgen excess (acne and Ferriman-Gallway hirsutism score >= 9), biochemical hyperandrogenism (an elevated morning serum concentration of T or androstenedione), and peripubertal onset of oligo- or amenorrhea without disease of the thyroid, PRL, or adrenal axes (53). Adolescents with PCOS (n = 11) and eumenorrheic late-pubertal girls (n = 9) were of comparable chronological as well as postmenarchal ages: Table 1Go. Anovulatory patients with PCOS (n = 4) were sampled at a random time, whereas oligoovulatory patients and normal controls were studied within 3–5 days of bleeding. To monitor multiple hormone release, blood was withdrawn at 20-min intervals for 12 h overnight (1900–0700 h clocktime). Although 20-min sampling was required to limit total blood loss, a higher frequency of blood sampling may detect more subordinate variations in hormone outflow.


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  		Table 1. Clinical characteristics of oligo- and anovulatory adolescents with PCOS and eumenorrheic controls

 
Assays

Concentrations of LH, leptin, T, and androstenedione were measured in each serum sample using either immunofluorometry (LH) or RIA (both androgens) (40, 41, 42). Leptin was quantitated by immuno-radiometric assay with an assay sensitivity of 0.1 µg/liter and median intra and interassay coefficients of variation of 1.2% and 3.5% (23). Insulin, SHBG, estrone, E2, dehydroepiandrosterone-sulfate, 17{alpha}-hydroxyprogesterone, and FSH were assayed fasting in overnight serum pools, as described previously (40, 41, 42).

Assessment of monohormonal pattern regularity and bihormonal secretory synchrony

a) Approximate entropy (ApEn) calculation. ApEn comprises a family of translation-, model-, and scale-independent regularity statistics designed to compare the relative orderliness of time series (54, 55). Univariate ApEn quantifies pattern reproducibility in serial measurements and thus complements conventional pulse detection and cosinor analyses (54, 55, 56, 57). Higher ApEn values denote greater disorderliness of secretory patterns, as observed for pituitary tumoral production of GH, ACTH, and PRL and (58, 59, 60); the secretion of GH, LH, T, ACTH, cortisol, and insulin in aging (57, 59, 61); and GH release in women and pubertal girls compared with men and boys (62, 63).

To compute ApEn for N serial observations, two input parameters, m and r, are fixed where m represents the pattern-comparison window size and r the de facto statistical tolerance for testing pattern recurrence. Normalized ApEn defines r as a percentage of the intersample SD of each time series, e.g. 20–35%, thereby maintaining scale invariance (62, 64). In the present analysis, m was assigned a value of 1, which serves to evaluate the statistical consistency of contiguous (sample-by-sample) data patterns. The parameter r was set to 35% as appropriate for shorter time series (65). The foregoing ApEn parameters, designated by ApEn (1,35%), provide a replicable ApEn statistic with an approximate SD of 0.06–0.08 (62, 64, 66). A normalized ratio of observed-to-random ApEn was calculated for each time series as the mean ratio of observed to random ApEn values calculated by shuffling the original data series times 1000 times (65).

b) Cross-correlation analysis.Cross-correlation analysis quantitates the strength of the simple linear relationship (if any) between successively paired measurements in two equally spaced time series considered at various relative lag times (67, 68). This statistic evaluates Pearson’s correlation coefficients, or r values, for the matched series viewed simultaneously (zero time lag) and at various integral time lags. Error estimates for each cross-correlation r value were propagated from the pooled sample variances corrected for total series length and the number of lag units considered (68). The overall statistical significance of group r values at any given lag interval was tested via the one-sample Kolmogorov-Smirnov statistic of the null hypothesis that the corresponding z score distribution of observed r values is random normal with zero mean and unit SD (67).

c) Cross-ApEn computation. Cross-ApEn is the bivariate analog of the ApEn statistic (above). This metric quantifies the joint synchrony of patterns in paired hormone series using standardized (z-score transformed) data (57, 59, 69). The cross-ApEn ratio (observed-to-randomly shuffled series, above) was used to normalize cross-ApEn for each hormone pair.

d) Complementarity of cross-ApEn and cross-correlation analyses. The foregoing statistical techniques are complementary, since cross-correlation analysis monitors the strength of linear lag-specific correlations and cross-ApEn quantifies the degree of lag-independent pattern synchrony between paired time series (56, 57).

Statistical analysis

An unpaired two-tailed t test with unequal variance was applied to compare log-transformed ApEn and cross-ApEn values in the two study groups. P < 0.05 was construed as statistically significant. Data are presented as the mean ± SEM. Multiple linear regression analyses were not performed in view of the small group sizes.

Results

Figure 1Go illustrates serum leptin and LH concentration profiles in 3 of 9 normal girls and 3 of 11 PCOS patients, each of whom underwent repetitive blood sampling at 20-min intervals for 12 h overnight. Mean (and integrated) serum leptin concentrations were comparable in the two study groups at respectively 32 ± 7.4 µg/liter (and 23,090 ± 5,300 µg/liter·min) [control], and 30 ± 4.8 ng/liter (and 21,700 ± 3,500 µg/liter·min) [PCOS]. In adolescents with PCOS, mean serum concentrations of LH, androstenedione, T, and estrone were elevated, SHBG suppressed, and insulin, insulin/glucose ratios, E2, and GH normal: Table 1Go. Chronological and postmenarchal ages, body mass indices and fasting serum insulin concentrations were comparable in the two groups (Table 1Go).



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  		Figure 1. Illustrative 12-h profiles of serum leptin and LH concentrations measured by RIA and immunofluorometry, respectively, in blood sampled at 20-min intervals overnight in the fasting state in three eumenorrheic healthy adolescents (control) and three hyperandrogenemic oligo- or anovulatory patients with PCOS. The study groups were comparable in chronological and postmenarchal ages, body mass indices, and fasting serum insulin concentrations. Vertical bars associated with the data points denote within-assay sample SDs (Materials and Methods).

 
Healthy adolescents exhibited a strongly positive cross-correlation between overnight sample-by-sample leptin and LH release at a 20-min LH lag time (i.e. leptin release preceded that of LH by 20 min) (P < 0.01), as illustrated in Fig. 2Go. This relationship was absent in girls with PCOS. Normal girls also maintained positive leptin-androstenedione cross-correlations over a range of androstenedione lags of 100–140 min (0.0001 < P < 0.01): Fig. 3AGo. In contrast, patients with PCOS developed a negative cross-correlation between leptin and androstenedione and only at a leptin lag interval of 140 min (P < 0.001). Leptin-T cross-correlations were negative in both cohorts: Fig. 3BGo. However, whereas normal adolescents sustained a broad window of leptin lag of -20 to + 100 min (wherein changes in leptin followed those of T, < 0.0001 < P < 0.01), whereas PCOS patients showed a restricted leptin lag intervals of +40 and +60 min (0.001 < P < 0.01).



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  		Figure 2. Median and absolute range of cross-correlation coefficients (r, values) plotted against various lag times (intervals in min separating the successively paired serum hormone concentrations) in a group of 9 normal girls (control, upper panels) and 11 patients with PCOS (lower panels). Cross-correlation analysis was applied to overnight simultaneous profiles of serum leptin and LH concentrations. P values at various time lags reflect the statistical significance of the group correlation coefficients under a null hypothesis of purely chance associations between the two hormones (Materials and Methods). A positive time lag (right side of each subpanel) denotes that a change in the concentration of the first-named hormone precedes that of the second by the indicated time lag (and, conversely, for a negative time lag).

 


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  		Figure 3. Median and range of cross-correlation coefficients for serum androstenedione-leptin (A) and T-leptin (B) concentration profiles in 9 control (upper) and 11 PCOS patients (lower). Data are presented as defined in the legend of Fig. 2Go.

 
The univariate ApEn statistic was used to quantitate pattern regularity of leptin secretion: Fig. 4Go. In eumenorrheic girls, the mean ApEn ratio for leptin profiles was 0.865 ± 0.046 (P < 0.005 vs. random); in PCOS patients, this value rose to 1.016 ± 0.017 (P = NS vs. randomly shuffled leptin series, and P = 0.012 vs. healthy controls). These findings establish highly irregular patterns of monohormonal leptin release in PCOS.



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  		Figure 4. Approximate entropy [ApEn (1,35%)] ratios quantifying the regularity of overnight serum leptin concentration profiles in individual healthy adolescent girls (controls, left, n = 9) and patients with PCOS (right, n = 11). ApEn ratios below unity denote more orderly patterns of hormone release, and conversely. Numerical values are the group mean ± SEM.

 
ApEn ratios for LH (P = 0.015), androstenedione (P = 0.004) and T (P = 0.0019) were also elevated in PCOS patients, denoting marked loss of orderliness: Fig. 5Go.



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  		Figure 5. ApEn (1,35%) ratios of LH, androstenedione, and T time series in individual normal and PCOS adolescents. Data are presented as defined in Fig. 4Go.

 
The bivariate cross-ApEn ratio was applied to quantify joint (two-hormone) pattern synchrony. Cross-ApEn ratios for leptin and LH (P = 0.0099), leptin and androstenedione (P = 0.0075), and leptin and T (P = 0.019) were elevated in patients with PCOS: Fig. 6Go. These contrasts identify significant marked erosion of bivariate synchrony.



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  		Figure 6. Cross-approximate entropy [cross-ApEn (1,35%)] ratios quantitating the joint synchrony of paired 12-h leptin and LH (A), leptin and androstenedione (B), and leptin and T (C) release in normal pubertal girls (controls, n = 9) compared with patients with PCOS (n = 11). See legend of Fig. 4Go for data presentation.

 
Anovulatory and oligoovulatory patients did not differ in any of the foregoing measures.

Discussion

The present investigation compares patterns of monohormonal leptin and bihormonal (coordinate) leptin-LH, leptin-androstenedione, and leptin-T release in nonobese hyperandrogenemic oligo- and anovulatory adolescents with PCOS and eumenorrheic girls of comparable age, body mass index, and fasting serum insulin concentrations. From a univariate perspective, the patterns of overnight leptin release were markedly irregular in PCOS. From a bivariate perspective, the coordinate release of leptin and LH, leptin and androstenedione, and leptin and T was disrupted in this disorder, denoting disruption of leptin-gonadal axis coupling.

Healthy adolescent girls maintained orderly patterns of leptin secretion, as quantitated objectively by the ApEn statistic (56, 58, 65). The latter metric provides a sensitive and objective index of alterations in within- and between-axis feedback control (57, 62, 65). ApEn quantitation differs from pulse detection and cosinor analysis by discriminating degrees of subpattern reproducibility on a sample-by-sample basis independently of pulse enumeration or rhythm assessments (55, 57, 58, 59, 61, 64). In the present study, application of the ApEn statistic unveiled profound disruption of leptin pattern regularity in adolescent with PCOS. In fact, mean observed ApEn ratios for leptin in PCOS were statistically indistinguishable from randomly shuffled data series.

The mechanisms that govern orderly leptin release are not known, but presumably include both systemic (neuroendocrine) and local (adipocyte) factors (see Introduction). Although detailed body compositional data were not analyzed here, the two study groups had comparable body mass indices and fasting serum insulin concentrations. Moreover, integrated (12-h) serum leptin concentrations were equivalent. Thus, the leptin secretory derangement in adolescents with PCOS is not so readily attributable to any of these factors (19, 24). Other potential mechanisms include the abnormal sex-steroid milieu in PCOS, inasmuch as androgen can suppress and estrogen stimulate leptin secretion (8, 11, 15, 27, 70). However, E2 levels were similar in the two groups studied here.

Two-hormone synchrony was assessed by statistically independent methodologies. Cross-correlation analysis showed abrogation of the normal positive time-lagged relationship between paired leptin and LH release, and cross-ApEn analysis identified significant distortion of the joint pattern synchrony of leptin and LH secretion in adolescents with PCOS. Given the different biomathematical principles underlying the foregoing measures of bihormonal coupling (57, 67), their thematically consonant predictions provide unique evidence for loss of normal leptin-LH linkages in PCOS.

Eumenorrheic controls maintained a significantly positive and consistently time-lagged linear correlation between leptin and androstenedione release and a negative time-lagged relationship between leptin and T output. Both cross-correlations were reduced in patients with PCOS. Likewise, the pattern-dependent synchrony observed in healthy girls between leptin and androstenedione as well as between leptin and T release, as quantitated by the cross-ApEn statistic, was significantly attenuated in PCOS. Thus, both analytical assessments demonstrate unequivocal erosion of coordinate leptin-androstenedione and leptin-T secretion. The precise basis for this interaxis pathophysiology in adolescents with PCOS is not yet known. However, the foregoing findings would be consistent with aberrant feedback by ovarian androgen (or its aromatized product, estrogen) on leptin secretion or anomalous feedforward by leptin on the hypothalamo-pituitary-gonadal axis (8, 9, 14, 17, 71, 72, 73). Indeed, since leptin can inhibit in vitro androgen biosynthesis by gonadal cells, and, conversely, androgens appear to suppress leptin production in vivo 119061} (13, 14, 15, 27, 74), impairment of bidirectional (leptin-androgen and androgen-leptin) communication is plausible in PCOS. Although dehydroepiandrosterone-sulfate levels were normal here, altered adrenal androgen production might contribute further to the observed leptin-androgen asynchrony (8, 70).

In summary, the present investigations delineate disruption of the orderly release of leptin and erosion of the synchrony between leptin and each of LH, androstenedione, and T secretion in nonobese adolescents with PCOS. Thereby, we establish joint dysregulation of the leptin and gonadotropin-gonadal axes despite mean euleptinemia. Whether this interaxis pathophysiology is reversible to therapeutic intervention and occurs analogously in the adult with PCOS will require further study.

Acknowledgments

We acknowledge the contribution of the nursing staff of the Division of Endocrinology of "R Gutierrez" Hospital and Mrs. Maria Gabriela Gutierrez Moyano for her excellent technical assistance.

We thank Patsy Craig for her skillful preparation of the manuscript and Paula P. Azimi for the deconvolution analysis, data management, and graphics. This focused report necessarily omits many primary references because of editorial constraints. The authors therefore acknowledge numerous colleagues who have made earlier foundational observations.

Footnotes

This work was supported in part by Grant PID-4202 from Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET). M.B. is a Senior Investigator of CONICET, Argentina, and M.C.G.-R. is a Research Fellow. This work was supported in part by NIH Grant MO-1-RR-00847 to the General Clinical Research Center of the University of Virginia Health Sciences Center, NICHD/NIH through cooperative agreement U-54 HD-28934 as part of the Specialized Cooperative Centers Program in Reproduction Research, and NIDDK/SBIR R44 DK-54104 (to S.P.). This work was supported in part by grants Carrillo-Oñativia 2000 from Ministerio de Salud de la Nacion and from Fundacion Alberto J. Roemmers.

Abbreviations: ApEn, Approximate entropy; PCOS, polycystic ovarian syndrome.

Received January 10, 2001.

Accepted April 5, 2001.

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