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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 2950-2955
Copyright © 1997 by The Endocrine Society

Special Articles

Comparison of Pulsatile Luteinizing Hormone Secretion Between Prepubertal Children and Young Adults: Evidence for a Mass/Amplitude-Dependent Difference Without Gender or Day/Night Contrasts1

Pamela A. Clark, Ali Iranmanesh, Johannes D. Veldhuis and Alan D. Rogol

The Departments of Pediatrics (P.A.C., A.D.R.), Internal Medicine (J.D.V.), Pharmacology (A.D.R.), and the National Science Foundation Center for Biological Timing (J.D.V., A.D.R.), The University of Virginia, Charlottesville, Virginia 22908; The Endocrine Section, Medical Service, Salem Virginia Medical Center (A.I.), Salem, Virginia 24153

Address all correspondence and requests for reprints to: Pamela A. Clark, M.D., University of Louisville, Department of Pediatrics, 571 South Floyd Street, Suite 439, Louisville, Kentucky 40202.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The assessment of pulsatile GnRH activity in children has become possible since the introduction of the sensitive third generation immunochemiluminescent assays, permitting detection of previously unmeasurable levels of LH and FSH. Despite this, however, studies differ with regard to pulse frequency and the presence of a diurnal variation in LH secretion in clinically prepubertal children. Discrepancies may reflect the limitations of relatively long intersampling intervals, less sensitive LH assays such as RIAs, and the use of algorithms to analyze pulsatile LH secretion, which do not account for endogenous production rates and metabolic clearance.

To address this, we studied LH secretion in 10 prepubertal children (4 boys and 6 girls, age 8.5–10.8 y) and 12 young adults (7 men and 5 women in the early follicular phase, age 18.6–32.8 y). Blood was sampled every 5 min from 2000 h to 0200 h (nighttime) and from 0800 h to 1400 h (daytime) for LH determination, using an immunochemiluminescent assay. Deconvolution analysis revealed no difference between daytime and nighttime LH secretion, including LH secretory amplitude and pulse frequency, within any of the 4 groups, permitting pooling of the data from the 2 sampling intervals for analysis. In addition, there was no difference in LH secretion or half-life between genders. Comparison of pulsatile LH secretion between children and adults revealed a marked increase in the mass and amplitude of LH secreted per burst. LH secretory burst mass rose 9.5-fold in females, increasing the mean LH concentration by nearly 13-fold and the production rate by nearly 9-fold. The trend in males was similar although less remarkable, with a 4.2-fold rise in LH secretory burst mass from childhood to adulthood. No differences in pulse frequency, interburst interval, half-life, or approximate entropy were found between prepubertal children and adults.

We conclude that the maturational change in LH secretion occurs via a highly specific mass/amplitude-dependent mechanism without significant gender or day/night differences.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE HALLMARK of puberty is a progressive increase in gonadotropin-releasing hormone (GnRH) activity, reflected by increased circulating concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (1). Early in the progression of human pubertal development the intermittent release of gonadotropins, especially LH, occurs predominately during the night, followed by an early morning rise in gonadal steroid hormone concentrations (2, 3). With further pubertal maturation, pulsatile gonadotropin secretion increases throughout the day, and gonadal steroid hormone concentrations remain relatively constant, except for fluctuations of estrogen and progesterone levels characteristic of the menstrual cycle. However, less is known about GnRH activity during childhood, because of the difficulty of detecting very low levels of gonadotropins with standard radioimmunoassays.

Previously, it was suggested that the GnRH pulse generator was under tonic inhibitory control during childhood by an undefined central mechanism (4, 5). With the advent of the more sensitive gonadotropin assays however, episodic LH secretion has been detected in prepubertal children (2, 3, 6, 7, 8, 9, 10, 11). Most of these studies have described a day/night rhythm of gonadotropin release with the major secretory episodes associated with nocturnal sleep, although many have focused on nocturnal LH release with relatively short awake sampling periods for comparison. There is also disagreement regarding the pattern of GnRH secretory activity. Some investigators have found increases in both the amplitude and frequency of LH secretory pulses with advancing pubertal age (7, 8, 10, 11, 12, 13), whereas others report only an increase in LH pulse amplitude with pulse frequency stable across pubertal stages (3, 9, 14, 15). This discrepancy may be due, in part, to several factors: 1) the relatively long sampling intervals of most of these studies (predominantly every 20 min) may have led to an underestimation of the true pulse frequency; 2) the low sensitivity of many of the LH assays, especially those done by RIA and by some immunoradiometric assays (IRMA), may have failed to detect circulating LH levels in the younger children; and 3) the use of several algorithms to analyze circulating LH concentrations that fail to account for endogenous production rates and metabolic clearance.

To address these issues, we evaluated 10 prepubertal children and 12 young adults. Serial blood sampling was performed every 5 min to capture the majority of LH release episodes (16) and during 2 time windows, from 2000 h to 0200 h (nighttime), and again from 0800 h to 1400 h (daytime), to identify diurnal differences (17). Serum concentrations of LH were determined using a new ultra-sensitive immunochemiluminescent assay. Deconvolution analysis was employed to analyze LH secretion patterns and LH half-life (18). Comparisons of pulsatile LH secretory patterns and half-life then were made between daytime and nighttime, between prepubertal and adult subjects of the same gender, and between genders of similar ages.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects

We evaluated 10 prepubertal children (6 girls and 4 boys), ages 8.3 y to 10.8 y, and 12 young adults (5 women and 7 men), ages 18.6 y to 32.8 y. All participants were healthy volunteers with normal physical examinations and unremarkable medical histories. All women had regular menstrual cycles and were admitted during the early follicular phase. None of the subjects was taking any hormonal preparations or any medications known to affect pituitary hormone release. Characteristics of the subject population are summarized in Table 1Go.


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  		Table 1. Characteristics of the study population

 
Experimental design

The study was approved by the Human Investigation and the General Clinical Research Center Advisory Committees of the University of Virginia Health Sciences Center, and informed consent and assent were obtained from all subjects and their parents or guardians. All subjects were admitted to the General Clinical Research Center (GCRC) in the late afternoon. A complete physical examination was performed, including pubertal staging by the method of Tanner (19) and testicular size determined by the volumetric ellipsoids of Prader (20). A radiograph of the left hand and wrist was obtained on all children for assessment of skeletal maturation by the method of Greulich and Pyle (21). An indwelling catheter was placed in a vein of the nondominant arm. At this time blood specimens were obtained for general screening laboratory tests (complete blood count, chemistry profile) and tests of basic endocrine function (T4, TSH, prolactin, IGF-1). At 0600 h, samples were obtained for measures of cortisol and testosterone (males) or estradiol (females). Beginning at 2000 h blood (0.5 mL) was withdrawn every 5 minutes until 0200 h (nighttime), and again from 0800 h to 1400 h (daytime) for later LH determinations.

Hormonal assays

Serum LH concentrations were determined in duplicate using an immunochemiluminescent assay (Nichols Institute, San Juan Capistrano, CA). The assay was modified to improve low-end sensitivity. The assay procedure was optimized by using 200 µL of the serum sample assayed in duplicate with 200 µL of LH antibody incubated overnight on a sample rotator. This approach increased the sensitivity of the assay to 0.002–0.005 IU/L from 0.01 IU/L, claimed by the manufacturer. The chemiluminescence technology for LH determination and the methods employed to modify and validate the optimal procedure were identical to the GH chemiluminescence assay, which has been described previously (22). The lower limit of sensitivity was 0.005 IU/L, with intra- and interassay coefficients of variation of 4.4% and 12.9%, respectively. The volume requirement of this assay was 200 µL, permitting blood sampling every 5-min without exceeding a total blood volume of 7 mL/kg, even in the smallest children. Determinations of serum testosterone and estradiol concentrations were made using commercial radioimmunoassays.

LH Secretory analysis

Deconvolution analysis (23, 24) was employed to analyze pulsatile LH secretion. This algorithm estimates pulsatile hormone secretory activity and hormone half-life based on plasma hormone concentration-time series. Plasma concentrations were assumed to result from discrete secretory bursts with definable amplitudes, durations, and temporal positions, without significant interburst secretion. Circulating LH was assumed to be eliminated by subject-specific clearance kinetics and, therefore, a corresponding half-life. Secretion and elimination functions were then related by a convolution integral and estimated simultaneously by nonlinear least-squares fitting (18).

Approximate entropy (ApEn) was used as a scale- and model-invariant statistic to quantify the serial orderliness or regularity of the LH release process over the two 6-hour intervals. Here, ApEn parameters of m = 1 and r = 20% of the intraseries SD were used, as described earlier (25), to normalize ApEn for the different mean hormone concentrations expected (26).

Statistical Analysis

Results are expressed as mean ± SEM. Because most measures of hormone secretion and half-life were non-Gaussian in distribution, all data were log transformed before analysis. Daytime and nighttime values were found to be no different in any of the four primary groups by paired within-subject Student’s t test (two-tailed) comparisons, and hence, were arithmetically pooled. Comparisons among boys, girls, men, and women were made using one-way analysis of variance (ANOVA). Significance was defined as a P value less than 0.05. All statistics were performed using the Clinfo statistical package.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Representative LH profiles of girls, boys, women, and men are shown in Fig. 1Go and 2Go. Figure 1Go depicts the observed mean serum LH concentrations (discrete data points ± range of replicate samples) and calculated reconvolved curves (continuous lines). Figure 2Go shows computed LH secretion rates. The deconvolution-predicted curves in Fig. 1Go reflect LH concentration profiles generated when LH secretory episodes occur as estimated in Fig. 2Go. This provides an indication of the goodness of fit between predicted and measured hormone concentrations. Paired (within-subject) comparisons of deconvolution measures revealed no differences in LH half-life or secretory burst activity, including mass, duration, amplitude and frequency, between nighttime and daytime sampling intervals. This permitted pooling of the data from the two sampling intervals for each individual for analysis.



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  		Figure 1. Deconvolution-resolved estimates of LH secretory bursts in a prepubertal boy and girl and in a young man and woman. Observed serum LH concentrations (mean sample value ± range of replicate samples) as measured by an immunochemiluminescent assay on blood samples collected at 5-min intervals between 2000 h and 0200 h and between 0800 h and 1400 h. The continuous lines through the observed serum LH concentrations represent computer-calculated fits via multiple parameter deconvolution analysis.

 


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  		Figure 2. Calculated LH secretory profile, comprising discrete secretory episodes, corresponding to the serum LH concentration profiles in Fig. 1Go.

 
LH Secretion Patterns in Children:

Pulsatile LH secretory activity was detected in all 10 children. Clinically all were prepubertal with Tanner stage 1 breast development or testicular volumes no more than 3 mL. Although the oldest girl had an elevation of her early morning estradiol level, all of her LH secretion parameters were similar to those of the other girls, including measures of amplitude and frequency. No statistically significant differences in LH secretion or half-life were observed between the girls and boys.

LH Secretion Patterns in Adults:

No differences in LH secretion or half-life were observed between genders, i.e. women in the early follicular phase of the menstrual cycle and men. As noted above, there were no significant difference between nighttime and daytime LH secretory activity.

Comparison of Prepubertal and Adult LH Secretory Profiles:

The lack of significant differences in LH secretion between males and females of similar ages, and between nighttime and daytime sampling periods, shows that the predominant change in LH secretion is maturation-dependent. ANOVA of logarithmically transformed data revealed a sharp contrast between the mass (P < 0.000001) and amplitude (P < 0.00001) of LH secreted per burst, which completely separated the prepubertal subjects from the adults. No further separation of boy vs. girl or man vs. woman was found. Thus, there are augmented mean serum LH concentrations (P < 0.000000001) and increases in LH production (P < 0.00000001) in the adult compared to the child. LH secretory burst mass rose 9.5-fold in the females from childhood to adulthood, with concomitantly increased mean serum LH concentrations of nearly 13-fold and of the LH production rate by nearly 9-fold. Males showed a similar although less remarkable trend with a 4.2-fold increase in burst mass (man vs. boy). No significant differences between the children and adults were found for secretory event duration or frequency, interburst interval, half-life, or ApEn. Data are summarized in Table 2Go.


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  		Table 2. Serum LH concentration and deconvolution-estimated secretion parameters

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Indirect determination of endogenous GnRH activity in prepubertal children has become possible since the introduction of the sensitive third generation assays for LH and FSH. The immunochemiluminescent (ICMA) and immuno-fluorometric (IFMA) assays are 40–100 times more sensitive than traditional RIA and 10-fold more sensitive than IRMA (27, 28). ICMA and IFMA can accurately and specifically measure very low concentrations of LH with virtually no cross-reaction with free {alpha}-subunits and related molecules such as FSH and TSH (11). LH values by RIA diverge markedly from ICMA at low concentrations because of the increased sensitivity of ICMA (0.005 IU/L vs. 0.1 for RIA) (29). In addition, ICMA and IFMA more accurately characterize the low gonadotropin concentrations of children and prevent the overestimation of low hormone concentrations determined by RIA (30). However, the greater specificity of ICMA and IFMA may result in the detection of fewer pulses than with RIA; for the latter may cross-react with free {alpha}-subunits (31). Here, we have used a new ultrasensitive ICMA configured with the same antibodies employed in an earlier high-specificity IRMA (32). All samples obtained here exceeded the detectability limit of 0.005 IU/L.

Despite the greater sensitivity of the new assays, data are conflicting with regard to maturational changes in LH pulse frequency and diurnal variations in its secretion. It is well documented that an increase in nocturnal LH pulse frequency occurs during puberty, typically at Tanner breast or genital stage 2–3 (33). This phenomenon appears to be lost by late puberty or early adulthood because of the feedback influence of adult levels of sex steroid hormones (28, 34, 35). This implies that adults may have LH pulse frequencies more similar to children than adolescents. However, other studies have found a small increase in nocturnal LH pulse frequency (1.8-fold) approximately 2 yr before the clinical onset of puberty (11, 36). Our prepuberal subjects did not manifest higher nighttime values, despite evidence of imminent pubertal development in some. Our oldest prepubertal girl (chronologic age 10.8 yr) had evidence of follicular activity, but was clinically Tanner stage 1 and had LH secretory parameters similar to those of the other children with no evidence of enhanced nocturnal LH release. New ultrasensitive estradiol assays (37) have shown measurable estrogen production in young girls several years before the physical changes of puberty. Whether this represents true hypothalamic-pituitary-gonadal axis activation or is the result of spontaneous follicular activity is not clear. It is also important to note that the study that found an increase in LH pulse frequency during childhood used 20-min sampling intervals, had a very short awake sampling period for comparison, and used an IFMA in which some samples were undetectable (11), which may have underestimated daytime LH secretion. To our knowledge, our study is the first to investigate GnRH activity in prepubertal children of both genders and to use an ultra-high sensitivity chemiluminescent LH assay, deconvolution analysis, and 5-min sampling intervals for 6 h during both daytime and nighttime hours. The last two issues are important, because available data indicate that both deconvolution analysis and 5-min (and even 10-min) blood sampling enhance the sensitivity and reproducibility of LH pulse detection over earlier methodologies (38, 39).

Maturational differences in mean LH concentration, amplitude of secretory bursts, and mass of LH secreted per burst observed in this study are in accord qualitatively with previous inferences (2, 3, 9, 11, 14). Control of plasma LH concentrations is mediated by 3 main variables other than the volume of distribution: 1) mass of LH secreted per burst; 2) plasma half-life; and 3) frequency of secretory episodes. The dramatic increases in LH secretory burst mass and amplitude alone accounted for the increased circulating LH concentrations in our adult subjects. The duration and frequency of secretory bursts and LH metabolic clearance (as indexed by LH half-life) remained largely constant across age groups, confirming the results of another investigation in another assay system (11). Of interest, a model-free estimate of the orderliness of the LH release process over time, namely, approximate entropy (ApEn), was statistically indistinguishable in all four groups of subjects. This indicates the specificity of the differences in LH secretory burst amplitude unveiled here.

With respect to possible gender differences in LH secretion, we observed no significant contrasts in mean serum LH concentration, secretory burst duration, mass, frequency, amplitude, or LH half-life among prepubertal girls and boys, or women and men. These findings are in accord with other studies assessing males and females of comparable ages (9, 15).

In conclusion, we have demonstrated a highly specific maturational mechanism of amplified LH secretion, which is mass/amplitude-dependent and does not manifest gender or day/night differences. The short sampling interval, equal day and night sampling periods, ultra-sensitive ICMA assay, and use of deconvolution analysis have permitted a more detailed analysis of GnRH activity among children.


   Acknowledgments
 
We wish to thank Ms. Brenda Crisso for assistance with the chemiluminescent assay, Ms. Christy Langlois and Mr. Andrew Reiss for help with data preparation, Ms. Paula Azimi for her help with deconvolution analysis, and The University of Virginia General Clinical Research Center nursing staff and core laboratory.


   Footnotes
 
1 This study was supported in part by the Genentech Foundation for Growth and Development (P.A.C.), NIH Grant RR00847 to the General Clinical Research Center of the University of Virginia, the NSF Center for Science and Technology, RCDA 1K04 (J.D.V.), HD00634 and HD28934 (NICHD), and NIH P-30 Reproductive Research Center grant (J.D.V.). Back

Received March 12, 1997.

Revised May 29, 1997.

Accepted June 6, 1997.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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J. D. Veldhuis, A. Iranmanesh, D. Naftolowitz, N. Tatham, F. Cassidy, and B. J. Carroll
Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback
J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5554 - 5563.
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G. Van den Berghe, F. Weekers, R. C. Baxter, P. Wouters, A. Iranmanesh, R. Bouillon, and J. D. Veldhuis
Five-Day Pulsatile Gonadotropin-Releasing Hormone Administration Unveils Combined Hypothalamic-Pituitary-Gonadal Defects Underlying Profound Hypoandrogenism in Men with Prolonged Critical Illness
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3217 - 3226.
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 Hum ReprodHome page
M. Bergendah and J. D. Veldhuis
Is there a physiological role for gonadotrophin oligosaccharide heterogeneity in humans?: III. Luteinizing hormone heterogeneity: a medical physiologist's perspective
Hum. Reprod., June 1, 2001; 16(6): 1058 - 1064.
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 EndocrinologyHome page
K. J. Suter, C. R. Pohl, and T. M. Plant
The Pattern and Tempo of the Pubertal Reaugmentation of Open-Loop Pulsatile Gonadotropin-Releasing Hormone Release Assessed Indirectly in the Male Rhesus Monkey (Macaca mulatta)
Endocrinology, June 1, 1998; 139(6): 2774 - 2783.
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