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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1362
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1632-1638
Copyright © 2005 by The Endocrine Society

Experimentally Induced Androgen Depletion Accentuates Ethnicity-Related Contrasts in Luteinizing Hormone Secretion in Asian and Caucasian Men

Johannes D. Veldhuis, Anthony Bae, Ronald S. Swerdloff, Ali Iranmanesh and Christina Wang

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Department of Internal Medicine and General Clinical Research Center (A.B., R.S.S., C.W.), Harbor-University of California at Los Angeles Medical Center, Torrance, California 90509; and Endocrine Service, Medical Section (A.I.), Salem Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The basis for ethnicity-related distinctions in gonadotropin secretion are unknown but may have important populational and physiological implications. In male contraceptive trials, exogenous testosterone and progestins suppress spermatogenesis to a greater degree in Asian than Caucasian men. In addition, iv infusion of testosterone inhibits LH release more in Asian than Caucasian volunteers. We test the converse postulate that experimental reduction of androgen-dependent negative feedback by way of the steroidogenic inhibitor combination ketoconazole/dexamethasone will unveil ethnicity-related mechanisms of regulated LH secretion in young men. LH release was monitored by sampling blood every 10 min for 24 h followed by immunoradiometric assay, model-free pulse detection, an entropy (regulatory) statistic, and cosine regression. Statistical comparisons revealed that healthy young Asian and Caucasian men maintain comparable baseline concentrations of LH, testosterone, estradiol, SHBG, and molar testosterone to SHBG ratios. In contrast, the two ethnic groups differ prominently in each of basal, pulsatile, entropic, and 24-h rhythmic LH adaptations to short-term androgen withdrawal. Therefore, we postulate that physiological nonuniformity of sex steroid-dependent negative feedback in particular may contribute to populational diversity in LH regulation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MUTATIONAL DISRUPTION OF genes encoding the aromatase and 5 {alpha}-reductase enzymes, LH, FSH, leptin, androgen receptor or estrogen receptor (ER), and LH ß-subunit reduce or disrupt reproductive capability overtly (1, 2, 3, 4, 5, 6). Hypothalamo-pituitary disease and systemic illness also impair GnRH and LH outflow markedly (7, 8). However, many population-based contrasts in fertility regulation remain unexplained. For example, cross-cultural male contraceptive trials have disclosed an unexpected ethnic distinction in the prevalence of inducible azoospermia in Asian and Caucasian men; i.e. administration of testosterone alone or androgen and progestin combined produces azoospermia in 70–85% of Caucasian but 95–100% of Asian volunteers (9, 10, 11, 12). Other investigations have indicated that genetic differences in germ-cell apoptosis and/or 5 {alpha}-reductase activity may contribute to the foregoing populational disparity (9, 10, 12, 13, 14, 15, 16). In complementation, heightened testosterone-dependent feedback inhibition of LH and FSH secretion in Asian compared with Caucasian individuals may play a role (17). To extend the last theme, the present study contrasts the regulatory impact of short-term androgen deprivation on LH secretion in Asian and Caucasian men. We postulated that marked pharmacological testosterone depletion would unveil relatively androgen-independent distinctions in hypothalamo-pituitary control of pulsatile, entropic (feedback-sensitive), and 24-h rhythmic LH release in healthy young Asian and Caucasian subjects (18).


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

To reduce the ethnic variability of the subjects, we selected subjects whose parents and grandparents were from the same ethnic group. Asians were recruited from subjects of Chinese, Korean, or Japanese descent in Los Angeles, California, and the Caucasian men were recruited from families of European descent in Charlottesville, Virginia. The baseline characteristics of these white men recruited in the current study from Charlottesville were similar to the white men of European descent previously studied in Los Angeles by the investigators (17, 19).

Each participant provided written informed consent, approved by the corresponding local Institutional Review Board. Volunteers were healthy, ambulatory, community-dwelling, and unmedicated young men. In 26 Caucasian subjects, the age range was 18–33 yr, and the body mass index was 20–27 kg/m2; and in eight Asian individuals (one of whom was U.S.-born), the age range was 19–33 yr, and the body mass index was 19.5–26.5 kg/m2. Subjects were studied identically at the two institutions. Fifteen Caucasian enrollees (in Virginia) and eight Asian enrollees (in California) were assigned prospectively within the centers to receive placebo, and 11 other Caucasian and the same eight Asian subjects were assigned to receive drug, with 1 month intervening (below). For recruitment reasons, the larger Caucasian control group (n = 26) was studied in Virginia to achieve maximal statistical power, and the Asian cohort was studied in California (n = 8). Recruitment of 26 Caucasians was achieved by randomizing subjects to a single [control vs. ketoconazole (KTCZ)/dexamethasone (DEX)] admission each. This strategy is readily accommodated statistically.

Entry criteria included a normal medical history (including fertility, libido, and potentia), physical examination (including male habitus and testis size), and fasting (0800 h) screening biochemical measurements of hematological, hepatic, renal, metabolic, and endocrine function (T4, TSH, testosterone, estradiol, SHBG, GH, IGF-I, LH, FSH, and prolactin concentrations). Exclusion criteria were: recent exposure to glucocorticoids or sex-steroid hormones; weight loss or gain (>2 kg in 1 month); transmeridian travel (more than three time zones traversed in the preceding 7 d); concomitant psychotropic drug treatment; alcohol or drug abuse; systemic, hypothalamo-pituitary or neuropsychiatric disease; 2-fold or greater elevation of liver enzymes; AIDS; concurrent use of any prescription medications; and acute or chronic organic illness.

Androgen deprivation was achieved by combined oral administration of KTCZ (1000 mg loading dose and 400 mg four times daily) and DEX (0.75 mg twice daily) for 5 d (20, 21, 22). Intensive blood sampling was performed on the fifth day of continued placebo or drug exposure.

Sampling procedure

Subjects were admitted to the General Clinical Research Center on the evening of the fourth day of placebo or drug intervention to allow overnight adaptation to the unit. Meals were provided at 0800, 1200, and 1700 h. Ambulation was permitted to the lavatory. Smoking and caffeinated beverages were disallowed. At 0800 h, at least 1 h after placement of a forearm venous catheter, blood samples (2.0 ml) were withdrawn every 10 min for 24 h. Samples were allowed to clot in glass tubes for 1–2 h at room temperature. Serum was frozen at 4 C until assay.

Hormone assays

Serum LH concentrations were measured in duplicate in all 145 samples in each subject via a robotics-automated, two-site monoclonal immunoradiometric assay (IRMA) (Nichols Diagnostics Institute, San Juan Capistrano, CA) (23, 24). Sensitivity is 0.2 IU/liter (First International Reference Preparation), and cross-reactivity is less than 0.3% for FSH, TSH, free {alpha}-, and free LH ß-subunits. Intraassay coefficients of variation were 4.7–6.5% (range), and interassay coefficients of variation were 5.4–7.8% in the present determinations. Measurements in the LH IRMA correlate well (r = +0.975) with those of in vitro rat Leydig-cell bioassay (25, 26). Aliquots of serum (0.05 ml) were pooled across 24 h for other hormone determinations. Testosterone and estradiol were quantitated by coated-tube and double-antibody RIA, respectively, and SHBG, FSH, prolactin, and TSH were measured by IRMA, as reported earlier (20, 22, 26).

Cluster analysis

Cluster analysis was used as a model-free method of discrete peak detection, given uncertainty about possible ethnicity-related differences in secretory-burst waveform (7, 27). Conservative (<5.0% false-positive rate) test cluster sizes of two for the putative nadir and one for the presumptive peak were used in conjunction with (pooled-variance) t-statistic thresholds of 2.0 to detect significant upstrokes and downstrokes in the LH concentration time series (26). Quantitative features of pulsatile release were defined as: maximal peak height, the highest LH concentration (IU/liter) attained within a pulse; interpeak nadir, the mean pre- and postpeak LH concentration; incremental amplitude (IU/liter), the algebraic difference between the pulse maximum and preceding nadir; integrated LH peak (IU/liter x minute), the area of the LH pulse above the mean of the pre- and postpeak nadir; frequency, number of peaks enumerated over 24 h; and interpeak interval, the mean time (minutes) separating consecutive peak maxima.

Cluster analysis was validated earlier by comparing the concordance of analytically predicted LH peaks with independently identified: 1) GnRH pulses in hypothalamo-pituitary portal venous blood in ovariectomized sheep; 2) mediobasal hypothalamic multiunit electrical activity in the gonadectomized rhesus monkey; 3) LH pulses evoked by bolus iv infusion of GnRH in men with idiopathic hypogonadotropism; 4) iv pulses of recombinant human LH infused after leuprolide-induced down-regulation; and 5) mathematically simulated LH pulse trains (7, 27, 28, 29, 30). The foregoing data sets establish nominal discriminative indices (sensitivity, specificity, and positive accuracy) of 87–93% for LH peak identification under the present sampling conditions.

Approximate entropy analysis

The approximate entropy statistic (ApEn) was used as a model-free measure of the relative orderliness (pattern reproducibility) of the subpatterns of LH release (31, 32, 33, 34). This regularity metric provides a sensitive barometer of changing feedback control (32, 35, 36). Technically, ApEn is computed as the sum of the negative logarithms of algebraic probabilities that observed subpatterns (of vector length m) within a time series of length N recur on next (m+ 1) incremental comparison within a given tolerance range r. ApEn analysis is validated for neurohormone profiles of N ≥ 60 samples under parameter choices of m = 1 (window length) and r = 20% (threshold) of the overall time-series SD (37). Setting r as a percentage of the individual series SD confers a normalized ApEn statistic that is concentration-independent. To compare pattern regularity among subjects, a set of surrogate (null) ApEn values was computed identically after randomly shuffling each observed (original) LH time series 1000 times without replacement (35, 36). The resultant distribution of null ApEn allows computation of a mean and SD of empirically random ApEn for each LH time series. Thereby, ApEn is expressed as a standard-deviate score (number of SD values removed from empirically mean random). ApEn has high sensitivity (>90%) and specificity (>90%) to distinguish pattern regularity changes due to altered feedback control of GH, prolactin, ACTH, and cortisol secretion in pathological and physiological states; GH release by gender; insulin time series among normal, prediabetic, young, and older volunteers; and LH, testosterone, GH, insulin, ACTH, and cortisol profiles in aging individuals (34, 35, 38).

Cosine regression

The 24-h rhythmicity of LH concentrations was quantitated by cosinor analysis, as described earlier (39). This procedure entails regression of a cosine function of 1440-min periodicity on each 10-min time series. Ninety-five percent statistical confidence intervals were determined for the fitted amplitude (50% of the nadir-zenith difference), mesor (cosine mean), and acrophase (clocktime of maximum) (40).

Statistical analysis

LH parameters were analyzed by way of a mixed-effects linear model. The model included two classification variables: one to differentiate between subjects in Charlottesville and Los Angeles, and the second to identify the two interventions (placebo and KTCZ/DEX). The variance-covariance matrix was created to account for the fact that volunteers received both interventions in Los Angeles and one intervention in Charlottesville, thereby allowing for intrasubject correlations in the former circumstance (41). The test is a two-sided linear contrast of means with an overall type I error rate of 0.05 (PROC MIXED procedure in SAS; SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go summarizes mean (24-h pooled serum) concentrations of testosterone, estradiol, SHBG, and the molar testosterone to SHBG ratio in relation to intervention and ethnicity. None of the foregoing measures differed significantly by ethnicity in either the placebo or KTCZ/DEX condition. Administration of KTCZ/DEX reduced the mean concentration of testosterone and the molar ratio of testosterone to SHBG markedly and equivalently in Asian and Caucasian volunteers (both P < 0.001). SHBG and estradiol concentrations did not change, and cortisol concentrations were undetectable in both study groups (<2 µg/dl).



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  		FIG. 1. Serum concentrations of testosterone, estradiol, and SHBG and the molar testosterone to SHBG ratio in Caucasian men (Caucasian: n = 8 placebo; n = 11 KTCZ/DEX) and Asian men (Asian: n = 8 placebo; n = 8 KTCZ/DEX). Data are the mean ± SEM, based on 24-h pooled sera collected in each subject. P values reflect nested-ANOVA estimates. Means with different (unshared) superscripts differ significantly.

 
Figure 2Go summarizes 24-h mean and integrated LH concentrations. Values were independent of ethnicity in the placebo setting and rose comparably (P < 0.001) in the two cohorts given KTCZ/DEX. Pulse analyses in subjects assigned to placebo intervention revealed that Asian compared with Caucasian volunteers maintain: 1) a higher daily LH peak frequency (P = 0.019) and reciprocally lower mean LH interpeak interval (P = 0.034) (Fig. 3AGo); 2) smaller incremental LH peak amplitude (difference between peak maximum and preceding nadir, P < 0.01); 3) reduced LH peak area (integrated LH peak size above mean flanking nadir LH concentrations; P = 0.034) (Fig. 3BGo); 4) elevated maximal LH peak height (P = 0.003) and interpulse (valley) nadir (P < 0.01) LH concentrations; and 5) diminished fractional LH peak amplitude (percentage ratio of the peak maximum to preceding nadir; P = 0.002) (Fig. 3CGo). Accordingly, feedback-intact Asian compared with Caucasian men generate more frequent and incrementally smaller LH pulses, which are superimposed on elevated nadir LH concentrations.



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  		FIG. 2. Mean (top) and integrated (bottom) serum LH concentrations are presented as described in the legend of Fig. 1Go.

 


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  		FIG. 3. Frequency (panel A) and amplitude-specific properties of pulsatile LH release (panels B and C) in Asian and Caucasian men studied under eugonadal (placebo) or androgen-deprived (KTCZ/DEX) conditions. Measures are based on model-free, discrete peak-detection analysis (see Subjects and Methods). The statistical format is defined in Fig. 1Go.

 
The KTCZ/DEX intervention accentuated observed ethnicity-related differences and unveiled other regulatory contrasts, despite comparable mean LH concentrations. In particular, Asian unlike Caucasian subjects responded to withdrawal of androgen feedback with: 1) no additional rise in LH peak frequency or decline in interpeak interval (Fig. 3AGo); 2) no significant increase in incremental LH peak amplitude or peak area (Fig. 3BGo); 3) no additional elevation of nadir LH concentrations; and 4) no additional augmentation of maximal and fractional LH peak height (Fig. 3CGo).

ApEn analysis was applied to quantitate the orderliness of LH release, which is a measure of feedback adaptations in an ensemble axis (see Subjects and Methods). In the closed-loop (placebo) setting, LH ApEn estimates did not differ by ethnicity. In contrast, in the low-feedback (KTCZ/DEX) context, ApEn standard-deviate scores (SD values removed from empirically mean random ApEn) averaged 4.1 ± 0.89 and 8.0 ± 0.97 in Asian and Caucasian volunteers, respectively (P = 0.004) (Fig. 4Go). The foregoing distinction signifies less regular patterns of LH release in Asian than Caucasian men during androgen depletion.



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  		FIG. 4. Impact of ethnicity and testosterone depletion on the orderliness (regularity) of LH secretion patterns, as quantitated by the ApEn. Data are given as the number of SD values that an individual ApEn value is removed from empirically mean random ApEn (defined by the statistical distribution of ApEn values derived from 1000 randomly shuffled versions of the cognate series). Thus, lower absolute ApEn SD values in Asian than Caucasian subjects denote reduced orderliness (greater relative randomness) of the LH release process due putatively to lesser feedback activity. Data are presented otherwise, as described in the legend of Fig. 1Go.

 
Measures of 24-h rhythmic LH release in the placebo setting did not differ in the two ethnic groups. However, during KTCZ/DEX administration, the LH mesor (mean concentration about which the predicted cosine function oscillates) was higher in Asian than Caucasian individuals (P < 0.001) (Fig. 5Go). Neither androgen withdrawal nor ethnicity influenced the amplitude (one-half the difference between the zenith and nadir) or acrophase (clocktime of maximum) of the daily LH rhythm.



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  		FIG. 5. Effect of ethnicity and short-term androgen deprivation on nycthemeral (24-h rhythmic) LH release. Top, Amplitude (one-half the difference between the zenith and nadir); middle, mesor (mean value about which the hormone rhythm oscillates); and bottom, acrophase (clocktime of the diurnal maximum, ± minutes). P = NS denotes more than 0.05. Data are presented otherwise, as described in the legend of Fig. 1Go.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present clinical investigation establishes specific contrasts in androgen feedback-intact and feedback-withdrawn regulation of LH secretion in healthy young Asian and Caucasian men. Ethnicity-related distinctions encompassed all four of pulsatile, basal, entropic (pattern sensitive), and 24-h rhythmic modes of LH release. In the placebo (androgen-replete) setting, Asian volunteers maintained a significantly higher daily LH pulse frequency and lower incremental and integrated LH peak amplitude than Caucasian individuals. These differences emerged in the face of comparable (24-h mean) concentrations of LH, testosterone, estradiol, and SHBG and molar testosterone to SHBG ratios. Experimental depletion of testosterone accentuated each of the foregoing ethnic differences and disclosed additional divergent features of LH neuroregulation. In particular, Asian compared with Caucasian subjects exhibited a feedback-invariant LH pulse frequency; accentuated elevation of interpulse nadir LH concentrations; markedly lower incremental and integrated LH pulse amplitudes; more irregular (nearly random) patterns of LH release; and higher mesor (mean of 24-h rhythmic) LH concentrations.

The mechanistic basis for attenuation of LH pulse increment and area and, conversely, augmentation of nadir LH concentrations in Asian compared with Caucasian men is not immediately evident. Systemic concentrations of testosterone, SHBG, and estradiol and their molar ratios did not differ by ethnicity. However, combined reduction of incremental LH pulse amplitude and peak area would putatively signify relative diminution in endogenous GnRH drive, because GnRH-receptor antagonists and GnRH immunoneutralization rapidly suppress these specific measures of pulsatile LH release in the human and experimental animal (7, 8, 42, 43). In addition, an analysis of the GnRH dose-LH secretory-response relationship in GnRH-deficient men delineated a log-linear relationship between GnRH stimulus strength and the incremental mass of LH secreted above baseline (44). Maximal LH peak amplitude, on the other hand, would reflect both GnRH stimulation and nonpulsatile (nadir) LH release (7, 45).

The accelerated frequency of discrete LH pulses in Asian compared with Caucasian subjects would predictably augment interpeak (nadir) LH concentrations for kinetic reasons; i.e. LH decay is interrupted between successive peaks (45). Experimentally increased GnRH/LH pulse frequency also elevates interpulse nadir values and reduces incremental LH peak height (8, 46). The inverse linkage between LH pulse frequency and secretory-burst mass is illustrated in: 1) healthy older men (26, 47); 2) young men under restricted androgenic negative feedback (20, 21); and 3) patients with hypogonadotropic hypogonadism exposed to higher frequency GnRH pulses (48). For these reasons, we infer that elevated LH peak frequency in Asian compared with Caucasian men contributes to increased interpulse nadir LH concentrations. Whether other factors augment basal LH release in this setting is not known.

Two ethnic differences in the regulation of LH release were unmasked by experimental testosterone deprivation; viz., a higher 24-h rhythmic mesor and heightened irregularity (less orderly secretion patterns) of LH release in Asian than Caucasian individuals. An Asian-pertinent technical explanation of the first finding is that higher interpulse nadir LH concentrations in Asian subjects would elevate the mean value about which the 24-h cosine rhythm oscillates (39). And, a plausible interpretation of greater irregularity of LH release patterns in Asian than Caucasian individuals is less-effective, estrogen-dependent, negative feedback in the low-androgen milieu. This consideration follows, because sex steroid-negative feedback serves to maintain orderliness of the LH secretory process (20, 35). The latter empirical outcome is corroborated by a simplified biomathematical construct of reciprocal interactions among GnRH, LH, and testosterone (49). Thus, we postulate that the capability of androgen depletion to evoke more disorderly patterns of LH secretion in Asian than Caucasian men points to (in Asian subjects): 1) greater dependence of orderly GnRH/LH outflow on androgen action; and/or 2) lesser dependence of regular GnRH/LH release on estrogen-mediated, negative feedback. These nonexclusive hypotheses arise because the KTCZ/DEX regimen decreased the molar concentration ratio of testosterone to SHBG without altering that of estradiol to SHBG (22, 50).

Androgen inhibits transcriptional activity of the LH ß-subunit gene in vitro and in vivo (51, 52), whereas estradiol can either repress or induce LH ß-subunit gene transcription (51, 52, 53, 54, 55, 56, 57). If such principles apply in vivo in the human, then a relatively estrogen-enriched milieu associated with androgen depletion may up-regulate basal LH ß-subunit gene expression, which would secondarily increase nadir LH concentrations. The concomitant action of androgen to inhibit LH ß-subunit synthesis may account for an earlier report of accentuated suppression of pulsatile LH release in Asian than Caucasian men given graded iv infusions of testosterone (17). However, precisely why sex-steroid feedback differs by ethnicity, as revealed here, is not known. Relevant considerations would include genetic differences in expression or activity of the ER, androgen receptor, and aromatase or 5 {alpha}-reductase enzymes (1, 2, 9, 58, 59, 60).

The postulate that Asian individuals secrete relatively less GnRH per burst more frequently could reflect unequal sex-steroid feedback on hypothalamic regulatory centers. For example, GnRH neurons in the adult male rodent express both ER subtypes {alpha} (>50%) and ß (~8%) but not androgen-receptor gene transcripts (56, 57, 61, 62, 63, 64, 65). In the mouse, ER {alpha} mediates significant negative feedback on the hypothalamo-pituitary unit (3, 64). In several mammalian species, estradiol inhibits transcription of the GnRH gene in vitro and in vivo (55, 66, 67, 68, 69). Although little is known about the genetic control of ER {alpha} and ER ß in human GnRH neurons, rare male patients with an inactivating mutation of ER {alpha} or the aromatase-enzyme gene maintain 2-fold elevated LH concentrations (70, 71, 72, 73). In the case of men who harbor an aromatase defect, estradiol administration suppresses LH concentrations. In healthy men and the male rhesus monkey, experimental inhibition of aromatase activity likewise elevates LH concentrations and (in the human) stimulates pulsatile, basal, entropic, and 24-h rhythmic LH release (20, 21, 22, 50, 74). Because experimental androgen deprivation with stable estradiol concentrations unmasks the same neuroendocrine phenotype of LH dynamics, one could hypothesize that Asian men maintain less effective estrogen feedback-dependent control of GnRH/LH outflow. Given that estrogen and aromatizable androgen enforce significant negative feedback at the pituitary level also (7), the precise sites of distinguishable feedback activity are not determinable at present.

In summary, young Asian men compared with Caucasian men manifest elevated nadir LH concentrations, decreased incremental and integrated LH pulse amplitudes, and accelerated LH pulse frequency in the absence of intervention. Asian volunteers exhibit more irregular LH release and higher 24-h rhythmic mean LH concentrations during short-term testosterone withdrawal in the face of equivalent estradiol concentrations. Accordingly, unequal sex steroid-dependent negative feedback on the hypothalamo-pituitary unit provides a potential mechanism for populational diversity of LH secretion.


   Acknowledgments
 
We thank Kandace Bradford and Kris Nunez for excellent editorial assistance.


   Footnotes
 
This work was supported by a Veterans Affairs Merit Review Award (to A.I.), National Institutes of Health (NIH) Grant R01 AG23133 (to J.D.V.), General Clinical Research Center Program Grants MO100585 (to J.D.V.) and MO1 RR00425 (to A.B., R.S.S., and C.W.), and NIH Training Grant T032-DK07571 (to A.B., R.S.S., and C.W.).

First Published Online November 30, 2004

Abbreviations: ApEn, Approximate entropy statistic; DEX, dexamethasone; ER, estrogen receptor; IRMA, immunoradiometric assay; KTCZ, ketoconazole.

Received July 26, 2004.

Accepted November 22, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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