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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 72-79
Copyright © 2001 by The Endocrine Society

From the Clinical Research Centers

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

J. D. Veldhuis, S. M. Pincus2, M. C. Garcia-Rudaz3, M. G. Ropelato, M. E. Escobar and M. Barontini4

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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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{alpha}-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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE POLYCYSTIC ovarian syndrome (PCOS) is the most common reproductive endocrinopathy in young women (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). However, the primary pathophysiological mechanisms underlying this disorder remain enigmatic (4, 5, 12). Reproductive manifestations include peripubertal onset of oligo- or anovulation, hyperandrogenism, reduced fertility, and increased fetal wastage (3). Associated metabolic features comprise insulin resistance, dyslipidemia, and premature atherosclerosis (3).

From a neuroendocrine perspective, patients with PCOS typically exhibit an accelerated frequency and/or high amplitude of pulsatile LH release (1, 2, 4, 6, 7, 8, 9, 11, 13, 14), whether assessed by bioassay, RIA, immunoradiometric assay, or immunofluorometry (2, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16). The absolute amplitude of LH pulses in PCOS is influenced by cohort selection, mode of assay, and an inverse relationship between LH production and adiposity (4, 11, 15). Hypersecretion of LH in PCOS (5, 8, 17) probably contributes to inordinate androgen output (18, 19, 20), because the latter is relieved significantly by administration of a GnRH antagonist or down-regulating GnRH agonist (10, 19, 21, 22, 23). Hyperinsulinism appears to amplify excessive thecal-interstitial cell steroidogenesis further in vitro (24, 25, 26) and in vivo (27, 28, 29, 30, 31).

The present work tests the neurointegrative hypothesis that PCOS pathophysiology is marked by disrupted feedback control within the hypothalamo-pituitary-gonadal axis. In principle, corroborating this postulate would require simultaneous quantitation of time-varying hypothalamic GnRH drive, pituitary LH production, ovarian androgen secretion, and androgen-dependent negative feedback on GnRH and LH release (32). As such multisite monitoring is prohibitive clinically, here we implement an indirect strategy to appraise within-axis feedback regulation in PCOS via a novel scale-invariant regularity metric, approximate entropy (ApEn) (33, 34). This statistic provides a sensitive ensemble measure of signaling interactions in network-like numerical or biological systems (2, 35, 36, 37, 38, 39, 40).

In extension of the foregoing single variable concept, an analogous bivariate statistic, cross-ApEn, quantitates the pattern synchrony of bihormonal time series (35). For example, cross-ApEn detects marked uncoupling of paired profiles of LH secretion and nocturnal penile tumescence (NPT) oscillations as well as the conjoint outflow of LH and FSH, LH and PRL, LH and testosterone, and ACTH and cortisol in healthy aging individuals (35, 41, 42). Mechanistically, therefore, an elevation of (single hormone) ApEn would highlight altered control of the corresponding secretory gland, whereas an increase in (two-hormone) cross-ApEn would underscore disruption of the matching interglandular pathway (34, 35, 37, 39, 42, 43, 44, 45, 46, 47, 48). The present study uses this analytical framework to compare the network level control of LH, testosterone, and androstenedione secretion in adolescents with PCOS and matched controls.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical protocol

Study subject characteristics are given in Table 1Go. As described previously, each girl provided institutionally approved written informed assent and parental consent before participation (4). PCOS was defined by clinical (acne and Ferriman-Gallwey hirsutism score, >=9) and biochemical hyperandrogenism (an elevated morning serum concentration of testosterone or androstenedione) with peripubertal onset of oligo- or amenorrhea in a euthyroid, euprolactinemic, and otherwise healthy individual. Adolescents with PCOS (n = 12; mean ± SEM chronological age, 16.4 ± 0.57 yr) and eumenorrheic late pubertal girls of comparable age (n = 10; age, 16.5 ± 0.45 yr) were studied contemporaneously throughout the year. Postmenarchal ages (years) were similar at 4.8 ± 0.39 (PCOS) and 4.0 ± 0.36 (control; P = NS). Girls with PCOS who were anovulatory (n = 4) were sampled at a random time. The other eight patients with PCOS and all controls were studied in the early follicular phase of the menstrual cycle. Blood was sampled at 20-min intervals for 12 h overnight (1900–0700 h). Concentrations of LH, testosterone, and androstenedione were measured in each serum sample (below). Bioactive LH, insulin, sex hormone-binding globulin, estrone, estradiol, 17{alpha}-hydroxyprogesterone, and FSH were assayed as previously reported (4).


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  		Table 1. Clinical characteristics of adolescents with PCOS and postmenarchal age-matched eumenorrheic controls

 
Assays

Serum hormone concentrations were assayed in duplicate by high sensitivity and high precision immunofluorometry (LH) or RIA (testosterone and androstenedione), exactly as described previously (4).

Assessment of monohormonal pattern regularity and bihormonal synchrony

ApEn calculation. ApEn comprises a family of translation-, model-, and scale-independent two-parameter statistics designed to compare the relative orderliness or regularity of time series (33). This univariate metric quantifies sample by sample pattern reproducibility in serial (neurohormone) measurements, and thus complements conventional pulse detection and cosinor analyses (39). ApEn is an order- and pattern-sensitive ensemble measure of the regularity of successive data. Higher ApEn denotes greater disorderliness or process randomness in the sequence, as observed for tumoral secretion of GH, ACTH, cortisol, PRL, and aldosterone (41, 49, 50, 51); for GH, LH, testosterone, ACTH, cortisol, and insulin in aging (35, 41, 52, 53); and for GH in pubertal girls and women compared with the male (37, 54).

The ApEn calculation provides a single nonnegative number that quantifies the logarithmic likelihood that runs of patterns in the data that are similar remain similar on next incremental comparison. The formal technical definition of ApEn was previously discussed (34). Briefly, for N serial observations, two input parameters, m and r, are fixed to compute ApEn from successive vector sequences, where m represents the vector length (or window size), and r is the de facto statistical tolerance width (or threshold) for testing pattern recurrence. To maintain scale invariance, normalized ApEn defines r as a percentage of the SD of each time series, e.g. 20%. In the present analyses, m is assigned a value of 1, which serves to evaluate the statistical consistency of contiguous data patterns. These ApEn parameters, ApEn (1, 20%), provide a replicable statistic with an individual ApEn SD of approximately 0.06–0.08 for many neurohormone data series of this length (36, 39).

Cross-ApEn computation

The bivariate cross-ApEn statistic quantifies the joint orderliness or pairwise synchrony of patterns in two linked data series in a lag-independent manner (see above) (38). Cross-ApEn was computed for m = 1 and r = 20% using the corresponding standardized (z-score transformed) time series, which ensures good statistical replicability. Further mathematical features of ApEn and cross-ApEn have been summarized previously (33, 35, 38, 39). Cross-ApEn analysis of neurohormone time series has been validated in various applications, e.g. paired oscillatory profiles of LH-testosterone (35), LH-FSH (42), LH-PRL (42), ACTH-cortisol (41)], and LH-nocturnal penile tumescence (42).

Cross-correlation analysis

Cross-correlation analysis quantitates the strength of the simple linear relationship (if any) between successively time-lagged measurements in two paired and equally spaced time series (55, 56). Procedurally, one computes successive lag-specific Pearson’s correlation coefficients or r values. Cross-correlation is performed for paired data values considered simultaneously (zero time lag) and at various time lags defined by multiples of the sampling interval (55). For example, hormone concentrations in time series A are compared pairwise with those of series B measured simultaneously (zero lag), later (positive lag) and earlier (negative lag). Error estimates of the cross-correlation r values were propagated from the pooled intrasample variances, based on the total series length (N) and the number of lag units (k) considered (56). We appraised the overall statistical significance of group r values at any given lag time via the one-sample Kolmogorov-Smirnov statistic applied to the null hypothesis that the z-score distribution of r values is random normal with zero mean and unit SD (55).

Complementarity of cross-ApEn and cross-correlation analyses

Information gained from the foregoing statistical techniques is complementary. Specifically, cross-ApEn quantifies the degree of lag-independent (and nonlinear) pattern synchrony, and cross-correlation analysis monitors the strength of lag-specific (and linear) correlations between paired time series (35, 39, 55).

Statistical analysis

An unpaired two-tailed Student’s t test with unequal variance was applied to compare 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.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1Go illustrates simultaneous overnight profiles of serum concentrations of LH, testosterone, and androstenedione measured in samples collected every 20 min for 12 h in one eumenorrheic (control) adolescent girl and a comparably aged patient with PCOS. Figure 2Go shows the dispersion of the mean (12-h overnight) serum concentrations of LH, testosterone, and androstenedione for all 28 subjects. Each measure was elevated in patients with PCOS compared with controls (P = 0.0002 to P = 0.0016). LH concentrations were also higher in PCOS patients, when assessed by Leydig cell bioassay; viz. at 52 ± 11 (PCOS) vs. 25 ± 4.1 IU/L (controls; P = 0.027). Fasting serum insulin and estradiol concentrations were comparable in the two groups, whereas levels of estrone and 17{alpha}-hydroxyprogesterone were higher and sex hormone-binding globulin levels were lower in PCOS adolescents (Table 1Go).



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  		Figure 1. Illustrative simultaneous 12-h profiles of serum LH, testosterone, and androstenedione concentrations monitored by sampling blood every 20 min overnight in a healthy eumenorrheic girl (control, left panels) and an age-matched hyperandrogenemic adolescent with PCOS (right panels). Serum concentrations of LH and androgen were measured by immunofluorometric assay and RIA, respectively (see Materials and Methods). The vertical error bars associated with each sample measurement represent the within-assay dose-dependent SDs. To convert testosterone or androstenedione concentrations (nanograms per mL) to nanomoles per L, multiply by 3.49 or 3.47, respectively.

 


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  		Figure 2. Mean (overnight) serum concentrations of LH (international units per L), testosterone (nanograms per mL), and androstenedione (nanograms per mL) in 10 postmenarchal age-matched eumenorrheic girls (controls) and 12 oligo- or amenorrheic adolescent patients with PCOS. Data are the group mean ± SEM. To convert testosterone or androstenedione concentrations (nanograms per mL) to nanomoles per L, multiply by 3.49 or 3.47, respectively.

 
To quantitate the regularity of monohormonal secretory patterns, we calculated ApEn for each of the LH (upper panel), testosterone (middle panel), and androstenedione (bottom panel) profiles (Fig. 3Go). Mean ApEn was significantly elevated in PCOS patients compared with controls in the case of overnight serum LH (P = 0.009) and androstenedione (P = 0.010), but not testosterone, profiles. Elevated ApEn identifies more disorderly release patterns of both LH and androstenedione in PCOS.



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  		Figure 3. ApEn (1, 20%) analysis of repetitively sampled overnight serum LH (upper panel), testosterone (middle panel), and androstenedione (bottom panel) concentration profiles in healthy adolescent girls (controls; left; n = 10) or patients with PCOS (right; n = 12). Higher ApEn values denote more disorderly or irregular patterns of hormone release. Data are the mean ± SEM.

 
To appraise bihormonal synchrony, we computed cross-ApEn for each hormone pair (Fig. 4Go). Cross-ApEn was significantly higher in PCOS adolescents than controls for all three paired series, viz. LH-testosterone (P = 0.0055), LH-androstenedione (P = 0.0076), and testosterone-androstenedione (P = 0.014). These findings denote consistent loss of two-hormone secretory synchrony.



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  		Figure 4. Cross-ApEn (1, 20%) quantitation of the joint synchrony of paired 12-h serum LH and testosterone (top panel), LH and androstenedione (middle panel), and testosterone and androstenedione (bottom panel) concentration profiles in age-matched normal pubertal girls (controls; n = 10) compared with identically studied patients with PCOS (n = 12). Data are the mean ± SEM.

 
Cross-correlation analysis was applied to evaluate bivariate (time-lagged) linear relationships. As summarized in Fig. 5AGo, in eumenorrheic controls, serum LH and testosterone concentrations correlated positively at a 20-min testosterone time lag (P = 0.024). This relationship was not evident in PCOS patients. In normal girls, serum LH and androstenedione concentrations likewise correlated positively at time lags of 0 and 20 min (10-3 < P < 10-2). The strength of this association was reduced in the PCOS group (Fig. 5BGo). Healthy girls further exhibited strongly positive cross- correlations between testosterone and androstenedione concentrations across a range of time lags; viz. zero (P < 10-4), a 20-min positive time lag (wherein changes in testosterone preceded those in androstenedione by 20 min; P < 10-3), and a negative time lag (wherein testosterone changes followed those in androstenedione by 20–100 min; 10-4 < P < 10-2; Fig. 5CGo). In contrast, patients with PCOS exhibited interandrogen linkages only at 0- and -20-min time lags. Unexpectedly, healthy adolescents also manifested a strongly negative biandrogen cross-correlation, wherein the serum testosterone concentration rose (or fell) 160, 180, and 220 min before the androstenedione concentration fell (or rose) reciprocally (10-3 < P < 10-2). This negative feedback-like relationship was not detectable in patients with PCOS.



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  		Figure 5. Median (±absolute range) cross-correlation r ({rho}) values (y-axis) plotted against various lag times (x-axis, time in minutes separating the successively correlated serum hormone concentrations) in 10 healthy adolescent girls (controls; upper panels) compared with data from 12 patients with PCOS (lower panels). Cross-correlation analysis was applied to paired overnight serum concentration profiles of LH-testosterone (A), LH-androstenedione (B), and testosterone-androstenedione (C). P values at various time lags reflect the statistical significance of the group of correlation coefficients at this lag (see Materials and Methods). A positive time lag (right side of each subpanel) denotes that changes in the first-named hormone lead those of the second by the indicated time lag (and, conversely, for a negative time lag).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present clinical investigation documents prominent disruption of the unihormonal orderliness of and the bihormonal joint synchrony among LH, testosterone, and androstenedione secretion in adolescent girls with PCOS. From a single hormone perspective (ApEn analysis), the individual patterns of LH and androstenedione release were consistently more irregular in patients with PCOS than in healthy controls. From a two-hormone perspective (cross-ApEn analysis), the synchronous secretion of each pair of LH and testosterone, LH and androstenedione, and testosterone and androstenedione was uncoupled in girls with PCOS. These data establish unequivocal deterioration of orderly uniglandular output and of coordinate bihormonal secretion in adolescents with PCOS compared with eumenorrheic controls of comparable chronological and postmenarchal age, body mass index, and fasting serum insulin and estradiol concentrations.

Based on simple reductionistic mathematical models as well as more recent interventional clinical studies (see introduction and Materials and Methods), loss of monohormonal regularity and bihormonal synchrony in PCOS identify defective feedforward and/or feedback control in the hypothalamo-pituitary-ovarian axis. Disorderly release (elevated ApEn) of LH and androstenedione profiles individually points to impaired regulation of the GnRH-gonadotrope unit and the thecal-interstitial compartment, respectively. In analogy, consistently elevated cross-ApEn values quantify deterioration of coupling between LH and androstenedione, LH and testosterone, and testosterone and androstenedione secretion. In particular, asynchrony of both the LH-androstenedione and LH-testosterone pairs would localize a pathway defect to LH-dependent feedforward control of ovarian androgen secretion. In addition, elevated LH-androgen cross-ApEn values are consistent with altered androgen negative feedback regulation of GnRH/LH output. Cross ApEn calculations do not separate these two pathophysiologies explicitly, ascomputed cross-ApEn values in the present analysis were statistically comparable for the feedforward and feedback pairs (not shown). Indeed, such symmetry of cross-ApEn calculations (e.g. LH-testosterone and testosterone-LH) suggests bidirectional pathway failure, i.e. combined interruption of LH’s feedforward on testosterone and, conversely, of testosterone’s feedback on GHRH/LH secretion.

The complementary analytical technique of cross-correlation analysis revealed impaired time-lagged colinear LH-testosterone feedforward coupling and a blunted LH-androstenedione feedforward relationship in patients with PCOS compared with eumenorrheic controls. Thus, bihormonal synchrony loss in adolescents with PCOS was demonstrable by model-distinct cross-ApEn and cross-correlation analyses.

Cross-correlation analysis also disclosed an unexpectedly negative and time-delayed linkage between testosterone and androstenedione secretion in healthy girls. This inverse (feedback-like) interandrogen relationship disappeared entirely in patients with PCOS. Whether abrogation of such a negative linkage reflects disruption of adrenal-ovarian or intraovarian control in PCOS is not known. In either circumstance, abolition of interandrogen synchrony marks a previously unrecognized signaling pathophysiology in PCOS.

Certain pathophysiological features of PCOS could mediate altered feedback control, as inferred here for LH-androgen and androgen-androgen coupling in anovulatory hyperandrogenemic adolescent girls. First, progestin-dependent negative feedback regulation of pulsatile LH secretion is blunted at least in adults with PCOS (57, 58, 59, 60). Secondly, patients with PCOS exhibit pituitary and ovarian hyperresponsiveness to an exogenous GnRH stimulus, thus highlighting excessive feedforward drive (10, 18, 32). Thirdly, loss of feedback restraint is inferable under basal conditions, as high bioavailable androgen levels fail to repress LH hypersecretion (4, 17). Fourth, administration of L-dopa/naloxone (61), antiandrogen (62, 63), or estrogen (64, 65) to patients with PCOS can elicit anomalous LH secretory responses. Lastly, two studies have described disruption of the expected diurnal rhythm of LH release in PCOS (1, 16). One or more of the foregoing mechanisms of feedback dysregulation may contribute to the pathophysiology of altered integrative control in PCOS, as quantitated here by ApEn, cross-ApEn, and cross-correlation analyses. Whether such inferred neuroregulatory defects develop in utero or emerge in early puberty is not known (12, 13, 66, 67). Moreover, precisely how the hypothalamo-pituitary unit and ovary maintain dysregulation remains uncertain (68).

Recent clinical experiments indicate that fixed iv infusions of hypothalamic-releasing peptides (e.g. GnRH, GHRH, TRH and GH-releasing peptide-2) heighten the disorderliness of cognate hormone output (52, 69, 70). If generalizable to pathophysiology, these observations would suggest that a more autonomous (less feedback-dependent) hypothalamic GnRH signal could drive disorderly LH secretion patterns in PCOS (2, 4, 6, 8, 9, 14). In turn, amplified and irregular LH output may disrupt normal ovarian androgen secretion. Attenuation of normal testosterone/androstenedione negative feedback on GnRH/LH could further disable normal integration within this axis. This 3-fold scenario in PCOS might be modulated or maintained by one or more additional pathophysiological mechanisms, such as 1) relatively unrestrained pituitary LH production, possibly exacerbated by hyperinsulinism, hyperandrogenism, hyperestrogenism, or unknown intrapituitary factors (2, 71, 72); and/or 2) heightened thecal cell steroidogenesis due to intrinsic ovarian steroidogenic defects, evidently amplified by excessive systemic LH and insulin stimulation (24, 73, 74). Additional interventional experiments will be required to elucidate the relevant roles of the foregoing presumptive feedforward and feedback defects in the pathophysiology of PCOS in adolescents and adults.

The generality of our inferences in PCOS might be limited by the young postmenarchal (4–5 yr) and chronological ages (mean, 16.5 yr) of the volunteers, the low prevalence of fasting hyperinsulinemia or obesity (body mass index, <30 kg/m2 in all but three PCOS patients), the choice of an overnight sampling regimen, and/or the ethnicity and demographics of the adolescents studied here. However, each of the foregoing clinical features was matched in the PCOS and control groups as well as timing of study across seasons and within the menstrual cycle and serum insulin and estradiol concentrations. In addition, no volunteers exhibited any (other) abnormality of hypothalamo-pituitary-gonadal or adrenal function. Therefore, to the extent that the pathophysiology of PCOS is homogeneous in this patient sample, the present analyses establish unequivocal disruption of orderly monohormonal and synchronous bihormonal secretion of LH, testosterone, and androstenedione in adolescent girls with this syndrome. Further investigations will be required to assess the persistence of these findings in adults with PCOS and to determine the exact age of onset of the inferred regulatory defects.


   Acknowledgments
 
We are grateful for the support of the nursing staff of the Division of Endocrinology of R. Gutierrez Hospital; the technical assistance of Paula Azimi, Cora Quiroga, and Ana Maria Montese; and skillful preparation of the manuscript by Patsy Craig.


   Footnotes
 
1 This work was supported in part by the Center for Biomathematical Technology, the NIH Specialized Cooperative Centers Program in Reproduction Research (U-54 HD-28934), the National Center for Research Resources-supported General Clinical Research Center (RR-00847), and Consejo Nacional de Investigaciones Cientificas y Tecnicas (PID 4202). Back

2 Present address: 990 Moose Hill Road, Guilford, Connecticut 06437. Back

3 Fellow Research at Consejo Nacional de Investigaciones Cien- tificas y Tecnicas. Back

4 Senior Investigator at Consejo Nacional de Investigaciones Cientificas y Tecnicas. Back

Received April 8, 2000.

Revised September 21, 2000.

Accepted September 29, 2000.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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