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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 80-89
Copyright © 2001 by The Endocrine Society

From the Clinical Research Centers

Developmentally Delimited Emergence of More Orderly Luteinizing Hormone and Testosterone Secretion during Late Prepuberty in Boys1

J. D. Veldhuis, S. M. Pincus2, R. Mitamura, K. Yano, N. Suzuki, Y. Ito, Y. Makita and A. Okuno

Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center, University of Virginia School of Medicine (J.D.V.), Charlottesville, Virginia 22908-0202; and Department of Pediatrics, Asahikawa Medical College (R.M., K.Y., N.S., Y.I., Y.M., A.O.), Asahikawa 078-8510, Japan

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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To quantitate changing feedback control in the GnRH-LH/FSH-testosterone axis in male puberty, we here quantitate the orderliness of hormone release patterns using the regularity (pattern-sensitive) statistic, approximate entropy (ApEn), in 46 eugonadal boys representing 6 genitally defined stages of normal puberty. ApEn is a single variable, model-free, and scale-independent barometer of coordinate signaling or integrative regulation within a coupled neuroendocrine axis. Accordingly, we quantitated ApEn of LH profiles obtained by immunofluorometric assay of sera sampled every 20 min for 24 h. LH ApEn declined remarkably between early prepuberty (genital stage I-A: mean bone age, 4.6 ± 1.6 yr; testis volume, <3 mL for at least 3 succeeding yr) and late prepuberty (genital stage I-C: bone age, 8.7 ± 1.8 yr; testis volume, <3 mL for up to 1 yr thereafter; P = 0.00019), which indicates the acquisition of more regular LH release patterns in late prepuberty. Maximal LH orderliness occurred in puberty stage II (bone age, 10.7 ± 1.0 yr; testis volume, 2.8 ± 0.4 mL). The LH secretory process was more disorderly in mid- and later puberty (Tanner stages III and IV). Transpubertal variations in testosterone ApEn manifested a similar tempo, i.e. the greatest regularity of testosterone secretion (lowest ApEn) emerged in Tanner genital stage II (P < 10-7), with less orderly patterns evident both earlier and later in sexual development. In contrast, FSH ApEn values remained invariant of pubertal status. Analysis of bihormonal coupling using the theoretically related bivariate cross-ApEn statistic disclosed maximal 2-hormone synchrony for LH and testosterone secretion in genital stage II (P = 0.031), with relative deterioration of coordinate LH and testosterone release patterns both before and after. LH and FSH release became maximally synchronous at the end of prepuberty (genital stage I-C; P = 0.029), and FSH and testosterone synchrony peaked in pubertal stage III (P = 0.037). As mean 24-h serum concentrations of LH, FSH, and testosterone rose transpubertally by 35-fold (LH), 68-fold (FSH), and 70-fold (testosterone), respectively, we infer that pubertal developmental stage per se rather than level of hormone output dictates coordinate GnRH-LH/FSH-testosterone secretion.

In summary, in eugonadal boys, the regularity of 24-h LH and testosterone secretory patterns undergoes well defined pubertal stage-specific control. No sexually developmentally delimited regulation is inferable for FSH. The concept of temporally biphasic puberty-dependent variations in neurohormone secretory regularity contrasts with the unidirectional rise in daily hormone output. Accordingly, we infer that late prepuberty and early puberty (Tanner genital stages IC and II) embody a physiologically unique sexual developmental window, marked by transiently enhanced LH and testosterone feedback stability in boys. Whether analogous plasticity of hypothalamo-pituitary-gonadal interactions unfolds during female adolescence is not known.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NEUROENDOCRINE AXES operate physiologically as interactive ensembles of key regulatory glands (1). In the case of the male reproductive axis, hypothalamic neurons generate bursts of GnRH secretion, which drive corresponding pulses of LH release (2, 3, 4, 5, 6). Elevated LH concentrations in the circulation evoke time-lagged testosterone secretion by gonadal Leydig cells (7, 8, 9, 10, 11, 12, 13, 14). Bioavailable testosterone, in turn, feeds back negatively on the hypothalamo-pituitary unit to restrain GnRH and LH output (15, 16, 17, 18, 19, 20, 21, 22, 23, 24). Although this multiglandular system is highly interactive, nearly all clinical investigations have appraised only one regulatory site in isolation, thereby limiting insights into the dynamic control of within-axis homeostasis (1, 2). However, assessing interactions among all feedforward and feedback linkages simultaneously would be a formidable experimental and analytical undertaking, because interglandular coupling is governed via multiple, time-delayed, saturable, and nonlinear dose-response interfaces (6). Moreover, some feedback and feedforward signals are not readily observable in the undisturbed individual; e.g. hypothalamic GnRH’s (positive) feedforward on LH and testosterone’s (negative) feedback on GnRH and LH secretion. As a recently validated alternative technique to monitor the integration of combined feedforward and/or feedback signals, here we apply the validated regularity measure, approximate entropy (ApEn), as a quantitative barometer of coordinate hormone secretion within the pubertal male GnRH-LH/FSH-testosterone axis.

ApEn monitors the strength and complexity of internodal communication in feedback-adaptive systems (25, 26, 27, 28, 29, 30). This metric quantifies the relative orderliness of serial neurohormone measurements over time, wherein higher ApEn values denote greater subpattern irregularity or higher process randomness. Earlier analyses have shown that ApEn identifies greater secretory irregularity in various contexts, e.g. tumoral vs. normal hormone time series (31, 32, 33, 34); production of GH in the female compared with male (35, 36, 37); secretion of ACTH, GH, LH, and insulin in aging (38, 39, 40, 41, 42); and output of insulin in patients with pre-type II diabetes mellitus (43). ApEn quantifies a continuum of sexually dimorphic GH secretory profiles in intact, prepubertally castrated and GnRH-agonist down-regulated male and female animals (37). Analogously, in healthy boys, ApEn unveils more disorderly patterns of GH secretion in mid- to late puberty just before the attainment of peak height velocity, thereby probably signifying an adaptation in GH-insulin-like growth factor I neuroregulation at this developmental time (44).

The thesis that the relative regularity of subordinate (nonpulsatile) patterns of hormone secretion mirrors feedback and/or feedforward adaptations within the corresponding neuroendocrine axis (30, 45) is supported by an array of pertinent recent clinical experiments. Thus, either withdrawal or imposition of an axis-specific feedforward (e.g. GnRH or GHRH) or feedback (e.g. testosterone, estradiol, L-T4, cortisol, or insulin-like growth factor I) signal modulates corresponding ApEn of LH, FSH, GH, ACTH, and TSH secretion markedly (6, 7, 31, 35, 46, 47). According to these interventional studies, statistical quantitation of pattern regularity of serial neurohormone output can identify altered integrative control in an autoregulated axis. In the case of the male GnRH-LH/FSH-testosterone axis, biomathematical modeling affirms this expectation more expressly, wherein vivid changes in LH and testosterone ApEn can be driven by a controlled variation in the time-lagged and dose-responsive interconnections of this axis (6, 48).

The present study exploits the foregoing perspective to test the hypothesis that successive pubertal developmental stages embody changing internodal or network level adaptations in the male GnRH-LH/FSH-testosterone axis. This postulate is consistent with indirect clinical data pointing to transpubertal variations in the sensitivity of the GnRH-LH/FSH secretory unit to sex steroid hormone negative feedback and in the relative concordance of LH and FSH or LH and testosterone secretion (1, 2, 49, 50, 51, 52, 53, 54, 55, 56). Accordingly, the present studies compare the single hormone pattern regularity and the joint (two-hormone) synchrony of 24-h LH, FSH, and testosterone secretion in eugonadal boys in six different genital phases of normal sexual development, viz. three prepubertal substages of Tanner stage I and each of Tanner pubertal stages II, III, and IV (49).


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

An earlier study reported cosinor analysis and peak detection of the 24-h time series of serum LH, FSH, and testosterone concentrations reanalyzed here (49). No ApEn analysis has been described previously in any of these subjects. The study was approved by the local ethics committee. Parents provided written consent, and the children gave assent to participate. Forty-six healthy boys were studied at individually documented radiographic bone ages [Tanner and Whitehouse (57)], which ranged from a mean ± SEM of 4.6 ± 1.6 to 16 ± 2.1 yr. The genital stages, as defined by Tanner (58), included I (n = 32 boys), II (n = 5), III (n = 5), and IV (n = 4). Prepubertal genital stage I (mean testicular volume, <3 mL) was subdivided further based on Prader orchidometry as follows: I-A, puberty not attained until at least 3 yr after the sampling study (n = 15); I-B, puberty evident 1–3 yr after sampling (n = 10); and I-C, puberty manifested within 1 yr (n = 7). All subjects were either normal (n = 33) or GH-treated (n = 13) boys, who were followed longitudinally at 1- to 3-month intervals for an absolute range of 1–20 yr (mean, 4.7 yr). Each boy progressed through pubertal development normally (49).

Blood was sampled every 20 min for duplicate assay of serial serum LH and FSH concentrations by ultrasensitive time-resolved immunofluorometry (Delfia, Pharmacia Wallac, Inc., Turku, Finland), and hourly for testosterone assay by RIA (49).

Analysis of pattern regularity: ApEn and cross-ApEn

ApEn comprises a class of translation-, model-, and scale-independent statistics designed to assess the relative orderliness or regularity of subpatterns in short and noisy time series (25). ApEn quantifies the serial subpattern reproducibility of successive measurements and thus provides insights that are readily distinguishable from those of Fourier analysis or pulse detection algorithms (59). The ApEn calculation provides a single nonnegative number, which is an ensemble estimate of process randomness, wherein larger ApEn values denote greater relative irregularity and vice versa. Technically, ApEn quantifies the negative logarithm of the summed conditional likelihoods that runs of patterns in the data that are similar remain similar on next incremental comparison (60). The formal mathematical definition of ApEn is reviewed in detail in other publications (59, 61).

ApEn is a family of statistics with members defined by the parameters N, m, and r (below). For any given data series containing N observations, two input parameters, m and r, are defined, where m represents the vector sequence of hormone subpatterns, and r denotes the tolerance for testing pattern recurrence. To maintain scale invariance, r is defined as a percentage of the between-sample series SD for each analysis (e.g. 20%), and m is assigned a value of 1 or 2 denoting consecutive vectors 1 or 2 data points in length. For the present data series, we calculated ApEn values with r = 20% and m = 1, and hence use the designation ApEn (1, 20%). This parameter set provides a sensitive, valid, and statistically well replicated ApEn metric for assessing hormone time series of this length (36, 37, 45).

To quantify the joint pattern synchrony (conditional regularity) of paired time series, we used cross-ApEn, as introduced by Pincus and Singer in definition 5 of Ref. 62 . Cross-ApEn is used to compare sequence patterns in two separate, but parallel, time series (29, 63). The statistical definition is analogous to that of ApEn, except that calculations are applied pairwise to the standardized (z-score transformed) time series. In the present study we applied cross-ApEn using m = 1 and r = 20%. These cross-ApEn parameters ensure good statistical replicability for the data lengths studied here. Further mathematical discussion of cross-ApEn and comparison with bivariate spectral and cross-correlation assessments is given in the appendix of Ref. 29 .

Statistical analysis

One-way ANOVA was applied after logarithmic transformation to evaluate contrasts among ApEn or cross-ApEn values across the six independently sampled study groups. Duncan’s new multiple range test was used to separate means post-hoc. P < 0.05 was construed as statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
As highlighted in Fig. 1Go (top), ApEn of 24-h serum LH concentration-time series exhibited marked stage of puberty dependence (P = 0.00019). The highest LH ApEn value occurred in late puberty at Tanner genital stage IV. This denotes maximal disorderliness of 24-h serum LH concentration profiles at this time. The nadir LH ApEn value emerged in early pubertal genital stage II. This minimum identifies the time of the most regular pattern of LH secretion across puberty. LH ApEn was significantly higher in prepuberty genital stage I-A compared with prepuberty stage I-C or puberty stage II. Thus, inferentially, ApEn values for LH fall from early prepuberty to later prepuberty, and then increase in pubertal stages III and IV.



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  		Figure 1. ApEn (1, 20%) analysis of frequently sampled profiles of serum LH (top) and FSH (bottom) concentrations measured by time-resolved immunofluorometric assay. Blood was collected at 20-min intervals for 24 h in each of 46 eugonadal boys. Data are the mean ± SEM in each genital pubertal stage (see Materials and Methods). ANOVA predicted P values of 0.00019 for LH and of more than 0.05 (NS) for FSH. Unshared alphabetic superscripts denote significantly different means.

 
In contrast to LH ApEn, the regularity of 24-h serum FSH concentration profiles was invariant of pubertal stage (Fig. 1Go, bottom). This stability of ApEn values occurred despite a 68-fold rise in the daily mean serum FSH concentration.

Transpubertal contrasts in testosterone ApEn are summarized in Fig. 2Go. Testosterone ApEn generally varied in parallel with LH ApEn, inasmuch as 1) the nadir also occurred at Tanner genital stage II (P < 10-7 compared with stages I-A, I-B, I-C, and IV); 2) testosterone ApEn was lower in genital stage I-C than I-A; and 3) testosterone ApEn rose in late puberty.



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  		Figure 2. Impact of pubertal stage on the ApEn of 24-h serum testosterone concentration profiles in 46 boys. Data are presented otherwise as described in Fig. 1Go.

 
Subanalysis of the 33 non-GH-treated boys (see Materials and Methods) corroborated the above pubertal evolution of LH ApEn (P = 0.0022) as well as testosterone ApEn (P < 10-6), with unchanging values of FSH ApEn (Table 1Go).


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  		Table 1. Subanalysis of pubertal contrasts in ApEn and X-ApEn in 33 normal boys without concomitant GH replacement

 
Analysis of two-hormone pattern synchrony using the cross-ApEn statistic disclosed significant pubertal variations in the coordinate release of LH and FSH (P = 0.029), LH and testosterone (P = 0.031), and FSH and testosterone (P = 0.037; Fig. 3Go, A–C). Bivariate contrasts also emerged in subanalysis of the non-GH-treated cohort (Table 1Go). Maximal synchrony (minimal cross-ApEn) of LH and FSH secretory patterns occurred in genital stage I-C, maximal LH-testosterone synchrony emerged at pubertal stage II, and, maximal FSH-testosterone synchrony was evident in genital stage III. For all three of the foregoing cross-ApEn assessments, pubertal stage I-C manifested significantly lower cross-ApEn values than stage I-A or I-B. Cross-ApEn of paired LH and FSH as well as paired FSH and testosterone rose in late puberty.



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  		Figure 3. Cross-ApEn (X-ApEn) analyses of paired LH and testosterone (A) and paired FSH and testosterone (B) time series. Data encompass six clinically defined genital stages of puberty in 46 eugonadal boys, each sampled every 20 min for assay of LH and FSH by immunofluorometry and at hourly intervals for later measurement of serum total testosterone concentrations by ultrasensitive RIA. Cross-ApEn values of bivariate LH and FSH time series (C) reflect 20-min sampled time series. Data are presented otherwise as defined in Fig. 1Go.

 
Figure 4Go depicts a scatterplot of the 46 individual testosterone ApEn and the natural logarithm of the corresponding mean (24-h) serum testosterone concentration values. By simple linear regression, within the developmental window defined by the four pubertal stages I-A through II (inclusive), testosterone ApEn correlated negatively with its cognate concentration. In later stages of puberty (stages II–IV), this relationship was inverted, wherein ApEn of testosterone correlated positively with its concentration. ApEn of LH and cross-ApEn of LH-testosterone behaved analogously, but less prominently (not shown).



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  		Figure 4. A, Linear regression analyses of the relationship between ApEn of each 24-h testosterone profile (y-axis) and the corresponding natural logarithm of the mean serum testosterone concentration (x-axis) in each of 46 eugonadal pubertal boys. Two regression lines are plotted: one for the prepubertal stage range I-A to II inclusive (continuous line), and the other for the later pubertal stage range II to IV inclusive (dotted line). Tanner pubertal stage II data thus overlap in the regressions, as testosterone ApEn values are at their minimum in this developmental window. B, Analogous simple quadratic plot of the relationships between cross-ApEn (X-ApEn) of LH-testosterone and the natural logarithm of the mean serum LH (top) and testosterone (bottom) concentrations.

 
Figure 5Go illustrates a typical LH, FSH, and testosterone profile and ApEn value for each of the six substages of male pubertal progression evaluated here.





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  		Figure 5. Illustrative 24-h profiles of serum LH, FSH, and testosterone concentrations (A–C) in individual boys studied at their indicated stages in puberty. The corresponding LH ApEn values are noted.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although neuroendocrine axes operate physiologically as interconnected feedforward and feedback ensembles rather than as individual glands secreting in isolation, little is known about the pathophysiology and developmental control of such network-like functions (1, 6, 13, 29, 63). Here, to quantitate possible adaptive changes in the GnRH-LH/FSH-testosterone axis transpubertally in boys, we used a recently developed, model-independent, and scale-invariant regularity statistic, ApEn, and its bivariate analog, cross-ApEn. Thereby, we could monitor putative feedback and feedforward alterations in the maturing male gonadal axis quantitatively. To this end, we quantified both single variable regularity and two-hormone synchrony in 46 eugonadal boys with bone ages ranging from 4.6–16 yr, and with sexually developmental status spanning six genitally defined stages of puberty (62). This analysis documented that ApEn values of LH and testosterone profiles decline as LH and testosterone concentrations rise in early prepuberty and puberty (Tanner stages I-A, I-B, I-C, and II). ApEn then increases progressively across mid- and later puberty (Tanner stages II, III, and IV) as mean hormone values continue to increase. Thus, the pattern orderliness of LH and testosterone secretion, as quantified by ApEn, shows strongly biphasic and clearly developmentally delimited regulation in male puberty. This pubertal stage specificity also emerges for changes in the joint synchrony of LH and testosterone release. In contrast, FSH ApEn exhibits no such variations across puberty.

ApEn quantitates the relative orderliness or reproducibility of subordinate (nonpulsatile) secretory patterns in neurohormone time series; these regularity features are believed to mirror feedforward and feedback adjustments driven by (patho-) physiological changes in interglandular communication (see introduction). ApEn is largely model free and scale invariant, and thus complementary to and readily distinguishable from conventional pulse detection or 24-h rhythmicity analyses (27, 64, 65, 66). The model-independent nature of ApEn is important, inasmuch as no a priori models exist of the expected time evolution of GnRH-LH/FSH-testosterone network behavior across puberty. The scale-invariant property of ApEn also is relevant here, as 24-h mean serum concentrations of LH, FSH, and testosterone rose by 35-fold (LH), 68-fold (FSH), and 70-fold (testosterone), respectively, across the six successive stages of eugonadal puberty. Indeed, regression analysis of testosterone ApEn values against mean (24-h) testosterone concentrations documented complete dissociation between the biphasic evolution of ApEn values and the unidirectional rise in androgen concentrations.

Conventional neurohormone pulsatility determinations yield important complementary insights into the frequency and amplitude modulation of an axis output (2, 67, 68, 69, 70). The complementarity of pulsatility and regularity (ApEn) measures is illustrated here, inasmuch as discrete peak detection analysis of the present data had revealed a simple unidirectional (rather than developmentally biphasic) rise in LH peak amplitude across puberty (49). Likewise, the 24-h rhythmicities of LH, FSH, and testosterone profiles in these boys exhibited unidirectional amplitude enhancement in puberty. There was no evidence of a delimited pubertal window of altered regulation of either pulsatile or nyctohemeral LH secretion. Therefore, the present quantitation of developmentally biphasic control of the pattern regularity of LH, testosterone, and FSH secretion across puberty offers a qualitative perspective beyond that of conventional pulsatility and rhythmicity analyses.

The 24-h rhythmicity of endocrine signals is explicated by diurnal control of underlying secretory pulse amplitude (ACTH) and/or frequency (GH, PRL, TSH, LH, and FSH) (71). How pattern orderliness and circadian modulatory mechanisms might be linked, if at all, is not known (13, 30, 35). Indeed, in the case of the somatotropic axis, changes in the pattern regularity of GH secretion are readily distinguishable from those of 24-h rhythmicity (31, 35, 36, 38). The present analysis unveils a further divergence between 24-h cosine amplitude modulation, which is unidirectional (49), and entropy control, which is bidirectional, across male puberty.

Regularity analysis also unmasked a prominent distinction between the neuroregulation of LH and FSH secretion in puberty. First, FSH ApEn values did not differ significantly among the six different clinical stages of puberty. Secondly, FSH ApEn was higher than LH ApEn in 43 of 46 boys (P < 10-10). More irregular patterns of FSH than LH release are also quantifyable in the jugular circulation of sheep and in peripheral blood in young men and women (39, 40, 72). The within-subject contrast in FSH and LH ApEn values wanes in healthy older men, and disappears in estrogen-deficient postmenopausal women (39, 40). The prominent LH-FSH ApEn difference observed here was sustained transpubertally, suggesting that this bihormonal contrast is not attributable to the changing sex steroid hormone milieu per se. Thus, we can infer that LH and FSH secretory distinctions are evident before the onset of male puberty and endure into young adulthood before then declining with age.

Based on biological and mathematical considerations (13, 27, 64, 73, 74), the maximal quantifiable regularity of LH and testosterone secretion in early puberty could reflect increases in the number and/or strength of feedback signals that integrate the GnRH-LH/FSH-testosterone axis. The precise nature of such dynamic adaptations across puberty is not known. Primary considerations would include altered GnRH inputs to gonadotropes, changes in LH and/or testosterone feedback or feedforward, and adaptations in GnRH neuronal synaptology and intrapituitary and/or intragonadal regulation (1, 2, 13). In particular, we reason that interglandular (two-variable) feedback and feedforward control vary across puberty, based upon the prominent changes in LH and testosterone joint synchrony. Thus, LH’s drive of testosterone and testosterone’s restraint of GnRH/LH release probably evolve transpubertally. In the adult reproductive years, cross-ApEn of LH-testosterone also rises further with increasing age (29, 39, 40). Therefore, from a broader perspective, the GnRH-LH-testosterone axis behaves as a dynamically controlled network throughout the full male reproductive life span. Testing this prediction definitively will require longitudinal observations in the same individual. Corresponding clinical studies will be needed to explore neuroregulatory evolution during female pubertal maturation and postpubertal aging.


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


   Footnotes
 
1 This work was supported in part by NIH Grant MO1-RR-00847 to the General Clinical Research Center of the University of Virginia Health Sciences Center. Back

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

Received June 20, 2000.

Revised September 25, 2000.

Accepted September 29, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Veldhuis JD. 1999 Male hypothalamic-pituitary-gonadal axis. In: Yen SSC, Jaffe RB, Barbieri RL, eds. Reproductive endocrinology. Philadelphia: Saunders; 622–631.
  2. Urban RJ, Evans WS, Rogol AD, Kaiser DL, Johnson ML, Veldhuis JD. 1988 Contemporary aspects of discrete peak detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men. Endocr Rev. 9:3–37.[Medline]
  3. Terasawa E. 1995 Control of luteinizing hormone-releasing hormone pulse generation in nonhuman primates. Cell Mol Neurobiol. 15:141–164.[CrossRef][Medline]
  4. Dluzen DE, Ramirez VD. 1987 In vivo activity of the LHRH pulse generator as determined with push-pull perfusion of the anterior pituitary gland of unrestrained intact and castrate male rats. Neuroendocrinology. 45:328–332.[Medline]
  5. Clarke IJ, Cummins JT. 1982 The temporal relationship between gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology. 111:1737–1739.[Medline]
  6. Keenan DM, Veldhuis JD. 1998 A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis. Am J Physiol. 275:E157–E176.
  7. Veldhuis JD, Zwart AD, Iranmanesh A. 1997 Neuroendocrine mechanisms by which selective Leydig-cell castration unleashes increased pulsatile LH release in the human: an experimental paradigm of short-term ketoconazole-induced hypoandrogenemia and deconvolution-estimated LH secretory enhancement. Am J Physiol. 272:R464–R474.
  8. Winters SJ, Troen PE. 1986 Testosterone and estradiol are co-secreted episodically by the human testis. J Clin Invest. 78:870–872.
  9. Veldhuis JD, King JC, Urban RJ, et al. 1987 Operating characteristics of the male hypothalamo-pituitary-gonadal axis: pulsatile release of testosterone and follicle-stimulating hormone and their temporal coupling with luteinizing hormone. J Clin Endocrinol Metab. 65:929–941.
  10. Foresta C, Bordon P, Rossato M, Mioni R, Veldhuis JD. 1997 Specific linkages among luteinizing hormone, follicle stimulating hormone, and testosterone release in the peripheral blood and human spermatic vein: evidence for both positive (feed-forward) and negative (feedback) within-axis regulation. J Clin Endocrinol Metab. 82:3040–3046.[Abstract/Free Full Text]
  11. Boyar M, Finkelstein J, Kapen S, Roffwarg H, Weitzman E, Hellman L. 1973 Simultaneous episodic secretion of luteinizing hormone and testosterone during sleep in puberty. J Clin Invest. 52:11–12.
  12. Pavlou SN, Veldhuis JD, Lindner J, et al. 1990 Persistence of concordant LH, testosterone and alpha subunit pulses following LHRH antagonist administration in normal men. J Clin Endocrinol Metab. 70:1472–1478.[Abstract]
  13. Veldhuis JD. 1999 Recent insights into neuroendocrine mechanisms of aging of the human male hypothalamo-pituitary-gonadal axis. J Androl. 20:1–17.[Free Full Text]
  14. Davies TF, Platzer M. 1981 The perifused Leydig cell: system characterization and rapid gonadotropin-induced desensitization. Endocrinology. 108:1757–1762.[Medline]
  15. Marynick SP, Loriaux DL, Sherins RJ, Pita JC, Lipsett MB. 1979 Evidence that testosterone can suppress pituitary gonadotropin secretion independently of peripheral aromatization. J Clin Endocrinol Metab. 49:396–398.[Abstract]
  16. Vigersky RA, Easley RB, Loriaux DL. 1976 Effect of fluoxymesterone on the pituitary-gonadal axis: the role of testosterone-estradiol-binding globulin. J Clin Endocrinol Metab. 43:1–9.[Abstract]
  17. Santen RJ. 1975 Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in man. J Clin Invest. 56:1555–1563.
  18. Matsumoto AM, Bremner WJ. 1984 Modulation of pulsatile gonadotropin secretion by testosterone in man. J Clin Endocrinol Metab. 58:609–614.[Abstract]
  19. Winters SJ, Troen P. 1983 A reexamination of pulsatile luteinizing hormone secretion in primary testicular failure. J Clin Endocrinol Metab. 57:432–435.[Abstract]
  20. Winters SJ, Sherins RJ, Loriaux DL. 1979 Studies on the role of sex steroids in the feedback control of gonadotropin concentrations in men. III. Androgen resistance in primary gonadal failure. J Clin Endocrinol Metab. 48:553–558.[Medline]
  21. Deslypere JP, Kaufman JM, Vermeulen A. 1987 Influence of age on pulatile LH release and responsiveness of the gonadotrophs to sex hormone feedback in men. J Clin Endocrinol Metab. 64:68–73.[Abstract]
  22. Kerrigan JR, Veldhuis JD, Rogol AD. 1994 Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: evidence for a hypothalamic site of physiological androgen feedback action. Pediatr Res. 35:102–106.[Medline]
  23. Urban RJ, Davis MR, Rogol AD, Johnson ML, Veldhuis JD. 1988 Acute androgen receptor blockade increases luteinizing-hormone secretory activity in men. J Clin Endocrinol Metab. 67:1149–1155.[Abstract]
  24. Veldhuis JD, Urban RJ, Dufau ML. 1992 Evidence that androgen negative-feedback regulates hypothalamic GnRH impulse strength and the burst-like secretion of biologically active luteinizing hormone in men. J Clin Endocrinol Metab. 74:1227–1235.[Abstract]
  25. Pincus SM. 1991 Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA. 88:2297–2301.[Abstract/Free Full Text]
  26. Pincus SM, Huang WM. 1992 Approximate entropy: statistical properties and applications. Commun Stat Theory Methods. 21:3061–3077.
  27. Pincus SM. 1994 Greater signal regularity may indicate increased system isolation. Math Biosci. 122:161–181.[CrossRef][Medline]
  28. Pincus SM. 1995 Quantifying complexity and regularity of neurobiological systems. Methods Neurosci. 28:336–363.
  29. Pincus SM, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD. 1996 Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc Natl Acad Sci USA. 93:14100–14105.[Abstract/Free Full Text]
  30. Veldhuis JD, Pincus SM. 1998 Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses. Eur J Endocrinol. 138:358–362.[CrossRef][Medline]
  31. Hartman ML, Pincus SM, Johnson ML, et al. 1994 Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. J Clin Invest. 94:1277–1288.
  32. Siragy HM, Vieweg WVR, Pincus SM, Veldhuis JD. 1995 Increased disorderliness and amplified basal and pulsatile aldosterone secretion in patients with primary aldosteronism. J Clin Endocrinol Metab. 80:28–33.[Abstract]
  33. van den Berg G, Pincus SM, Veldhuis JD, Frolich M, Roelfsema F. 1997 Greater disorderliness of ACTH and cortisol release accompanies pituitary-dependent Cushing’s disease. Eur J Endocrinol. 136:394–400.[Abstract]
  34. Veldman RG, van den Berg G, Pincus SM, Frolich M, Veldhuis JD, Roelfsema F. 1999 Increased episodic release and disorderliness of prolactin secretion in both micro- and macroprolactinomas. Eur J Endocrinol. 140:192–200.[Abstract]
  35. Veldhuis JD, Metzger DL, Martha Jr PM, et al. 1997 Estrogen and testosterone, but not a non-aromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin Endocrinol Metab. 82:3414–3420.[Abstract/Free Full Text]
  36. Pincus SM, Gevers E, Robinson ICAF, et al. 1996 Females secrete growth hormone with more process irregularity than males in both human and rat. Am J Physiol. 270:E107–E115.
  37. Gevers E, Pincus SM, Robinson ICAF, Veldhuis JD. 1998 Differential orderliness of the GH release process in castrate male and female rats. Am J Physiol. 274:R437–R444.
  38. Hindmarsh PC, Dennison E, Pincus SM, et al. 1999 A sexually dimorphic pattern of growth hormone secretion in the elderly. J Clin Endocrinol Metab. 84:2679–2685.[Abstract/Free Full Text]
  39. Veldhuis JD, Iranmanesh A, Mulligan T, Pincus SM. 1999 Disruption of the young-adult synchrony between luteinizing hormone release and oscillations in follicle-stimulating hormone, prolactin, and nocturnal penile tumescence (NPT) in healthy older men. J Clin Endocrinol Metab. 84:3498–3505.[Abstract/Free Full Text]
  40. Pincus SM, Veldhuis JD, Mulligan T, Iranmanesh A, Evans WS. 1997 Effects of age on the irregularity of LH and FSH serum concentrations in women and men. Am J Physiol. 273:E989–E995.
  41. Meneilly GS, Ryan AS, Veldhuis JD, Elahi D. 1997 Increased disorderliness of basal insulin release, attenuated insulin secretory burst mass, and reduced ultradian rhythmicity of insulin secretion in older individuals. J Clin Endocrinol Metab. 82:4088–4093.[Abstract/Free Full Text]
  42. Meneilly GS, Veldhuis JD, Elahi D. 1999 Disruption of the pulsatile and entropic modes of insulin release during an unvarying glucose stimulus in elderly individuals. J Clin Endocrinol Metab. 84:1938–1943.[Abstract/Free Full Text]
  43. Schmitz O, Porksen N, Nyholm B, et al.1997 Disorderly and nonstationary insulin secretion in relatives of patients with NIDDM. Am J Physiol. 35:E218–E226.
  44. Pincus SM, Veldhuis JD, Rogol AD. 2000 Longitudinal changes in growth hormone secretory process irregularity assessed transpubertally in healthy boys. Am J Physiol. 279:E417–E424.
  45. Pincus SM, Hartman ML, Roelfsema F, Thorner MO, Veldhuis JD. 1999 Hormone pulsatility discrimination via coarse and short time sampling. Am J Physiol. 277:E948–E957.
  46. Zwart A, Iranmanesh A, Veldhuis JD. 1997 Disparate serum free testosterone concentrations and degrees of hypothalamo-pituitary-LH suppression are achieved by continuous versus pulsatile intravenous androgen replacement in men: a clinical experimental model of ketoconazole-induced reversible hypoandrogenemia with controlled testosterone add-back. J Clin Endocrinol Metab. 82:2062–2069.[Abstract/Free Full Text]
  47. Veldhuis JD, Iranmanesh A, Pincus SM. Reduction of intrinsic negative-feedback regulation of neuroendocrine axes increases the approximate entropy (serial irregularity) of the pituitary hormone release process for TSH, GH, and LH. Proc of Annual Meet of the Soc for Neurosci. 1996; 428.
  48. Veldhuis JD, Keenan DM. Neuroendocrine mechanisms underlying aging of the human male reproductive axis: novel hypothesis formulation and testing via a physiologically interlinked feedback and feedforward biomathematical construct. Proc of the 25th Annual Meet of the Am Soc of Androl. 2000; 321.
  49. Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A. 1999 Diurnal rhythms of luteinizing hormone follicle-stimulating hormone, and testosterone secretion before the onset of male puberty. J Clin Endocrinol Metab. 84:29–37.[Abstract/Free Full Text]
  50. Tanner JM, Whitehouse RH, Hughes PCR, Carter BS. 1976 Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone-deficient children. Pediatrics. 89:1000–1008.
  51. Mauras N, Rogol AD, Haymond MW, Veldhuis JD. 1996 Sex steroids, growth hormone, IGF-I: neuroendocrine and metabolic regulation in puberty. Horm Res. 45:74–80.[Medline]
  52. Marshall JC, Kelch RP. 1986 Gonadotropin-releasing hormone: role of pulsatile secretion in the regulation of reproduction. N.Engl J Med. 315:1459–1467.
  53. Valk TW, Corley KP, Kelch RP, Marshall JC. 1981 Pulsatile gonadotropin-releasing hormone in gonadotropin deficient and normal men: suppression of follicle-stimulating hormone responses by testosterone. J Clin Endocrinol Metab. 53:184–191.[Medline]
  54. Styne DM, Grumbach MM. 1986 Puberty in the male and female: its physiology and disorders. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia: Saunders; 313–384.
  55. Haavisto AM, Dunkel L, Pettersson K, Huhtaniemi I. 1990 LH measurements by in vitro bioassay and a highly sensitive immunofluorometric assay improve the distinction between boys with constitutional delay of puberty and hypogonadotropic hypogonadism. Pediatr Res. 27:211–214.[Medline]
  56. Wu FCW, Butler GE, Kelnar CJH, Huhtaniemi I, Veldhuis JD. 1996 Patterns of pulsatile luteinizing hormone secretion from childhood to adulthood in the human male: a study using deconvolution analysis and an ultrasensitive immunofluorometric assay. J Clin Endocrinol Metab. 81:1798–1805.[Abstract]
  57. Tanner JM, Whitehouse RH. 1975 A note on the bone age at which patients with true isolated growth hormone deficiency enter puberty. J Clin Endocrinol Metab. 41:788–790.[Abstract]
  58. Tanner JM, Whitehouse RH, Takaishi M. 1966 Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children 1965. Arch Dis Child. 41:613–635.
  59. Pincus SM, Goldberger AL. 1994 Physiological time-series analysis: what does regularity quantify? Am J Physiol. 266:H1643–H1656.
  60. Pincus SM, Kalman RE. 1997 Not all (possibly) "random" sequences are created equal. Proc Natl Acad Sci USA. 94:3513–3518.[Abstract/Free Full Text]
  61. Pincus SM. 1995 Approximate entropy (ApEn) as a complexity measure. Chaos. 5:110–117.[CrossRef][Medline]
  62. Pincus SM, Singer BH. 1996 Randomness and degrees of irregularity. Proc Natl Acad Sci USA. 93:2083–2088.[Abstract/Free Full Text]
  63. Roelfsema F, Pincus SM, Veldhuis JD. 1998 Patients with Cushing’s disease secrete adrenocorticotropin and cortisol jointly more asynchronously than healthy subjects. J Clin Endocrinol Metab. 83:688–692.[Abstract/Free Full Text]
  64. Kaplan DT, Furman MI, Pincus SM, Ryan SM, Lipsitz LA, Goldberger AL. 1998 Aging and the complexity of cardiovascular dynamics. Biophys J. 59:945–949.[Abstract/Free Full Text]
  65. Pincus SM, Gladstone IM, Ehrenkranz RA. 1991 A regularity statistic for medical data analysis. J Clin Monit. 7:335–345.[CrossRef][Medline]
  66. Pincus SM, Keefe DL. 1992 Quantification of hormone pulsatility via an approximate entropy algorithm. Am J Physiol. 262:E741–E754.
  67. Veldhuis JD, Moorman J, Johnson ML. 1994 Deconvolution analysis of neuroendocrine data: waveform-specific and waveform-independent methods and applications. Methods Neurosci. 20:279–325.
  68. Veldhuis JD, Johnson ML. 1992 Deconvolution analysis of hormone data. Methods Enzymol. 210:539–575.[Medline]
  69. Veldhuis JD, Carlson ML, Johnson ML. 1987 The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc Natl Acad Sci USA. 84:7686–7690.[Abstract/Free Full Text]
  70. Veldhuis JD, Johnson ML. 1986 Cluster analysis: A simple, versatile and robust algorithm for endocrine pulse detection. Am J Physiol. 250:E486–E493.
  71. Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G. 1990 Twenty-four hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab. 71:1616–1623.[Abstract]
  72. Pincus SM, Padmanabhan V, Lemon W, Randolph J, Midgley Jr AR. 1998 Follicle-stimulating hormone is secreted more irregularly than luteinizing hormone in both humans and sheep. J Clin Invest. 101:1318–1324.[Medline]
  73. Prank K, Kloppstech M, Nowlan SJ, Sejnowski TJ, Brabant G. 1996 Self-organized segmentation of time series: separating growth hormone secretion in acromegaly from normal controls. Biophys J. 70:2540–2547.[Abstract/Free Full Text]
  74. Schaefer F, Veldhuis JD, Jones J, Scharer K, Cooperative Study Group on Pubertal Development in Chronic Renal Failure. 1994 Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. J Clin Endocrinol Metab. 78:1298–1306.[Abstract]



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