CONCENTRATIONS of luteinizing hormone

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1 ntegrated Concentrations of Luteinizing Hormone and Puberty PETER A. LEE, LESLE P. PLOTNCK, RONALD E. STEELE, ROBERT G. THOMPSON, AND ROBERT M. BLZZARD Department of Pediatrics, the Johns Hopkins University School of Medicine, Baltimore, Maryland 2205 ABSTRACT. ntegrated serum concentrations of luteinizing hormone have been compared among 30- minute collections from 0 boys (6-8 years old) and 5 girls (5- years old). This study suggests that prepubertal as well as pubertal boys have CONCENTRATO of luteinizing hormone (LH) in early and mid-pubertal boys and girls have been reported to be increased significantly during sleep (,2). Prepubertal children, late pubertal adolescents, and postpubertal individuals, in contrast, were reported to have similar concentrations of LH during waking and sleep (,3). Our goal in the present report was to examine further the inter-relationship of the secretion of LH in the sleepwake cycle during the maturation of the hypothalamic-pituitary-gonada] axis. Materials and Methods Ten boys and five girls, 5 to 8 years old, participated in the study. All were normal. Constant blood withdrawal using a Sigma motor pump with a non-thrombogenic catheter (4) was continued for 2 to 24 hours, with subperiods of 30 minutes each. Sleep was observed and recorded. Each individual's LH values were run in a single assay. Serum LH was measured, using a modification of a double-antibody radioimmunoassay described elsewhere (5), using LER 907 as assay Received April, 975. Supported by Research Grants HD-0852, HD , and AM and by Traineeship Grant Ti-AM of the National nstitutes of Health, United States Public Health Service. Patients were studied on the Pediatric Clinical Research Unit of the Johns Hopkins Hospital, supported by Grant 5-M0-RR-0052 from the General Research Centers Program of the Division of Research Resources, National nstitutes of Health. Correspondence: Peter A. Lee, M.D., 3-0 Children's Medical Center, The Johns Hopkins Hospital, Baltimore, Maryland greater mean integrated concentrations of LH during sleep than during waking. One of two pubertal girls had greater concentrations of LH during sleep, while three prepubertal girls did not. (J Clin Endocrinol Metab 43: 68, 976) standard. The intra-assay coefficient of variation for 0 replicate samples of a serum standard having a mean of 9.7 ng/200 fx\ was 4.3%, and the inter-assay coefficient of variation was 7.%. alues of less than sensitivity in the LH assay,.6 ng/200 /Ltl sample volume, were assigned a value of 8.0 ng/ml for statistical evaluations. The stages of puberty are classified according to Tanner (6). The Student's t and paired t tests were used for statistical analysis. nformed consent was obtained for all studies. Results The integrated concentrations (C) of LH are presented in Table and in Figs., 2, and 3. The calculated means are the averages of the determined luteinizing hormone concentrations in 30-minute specimens. The total number of awake specimens after the first 2 collections after the insertion of the withdrawal apparatus was used to obtain the calculated mean C for the awake period. Early specimens were omitted to disregard the early data taken after the insertion of the pump, which might have been taken during a period of acclimatization. Four (nos. 2-5) of the five boys in stage had a significantly greater mean integrated concentration of LH during sleep than during the awake period. The averages of the calculated means for the five boys in stage were also higher (P < 0.05) during the sleep period (mean 38 ng/ml) than during the awake period (32 ng/ml). The three pubertal boys (nos. 6-8) and one postpubertal boy (no. 0) had significantly higher values during sleep than during the awake period. The mean C LH during sleep (49

2 NTEGRATED LH LEELS AND PUBERTY 69 TABLE. Comparison of mean integrated concentrations (int. cone.) oflh during sleep and while awake Pubertal Breast/ genital stage Pubic hair Age of sleep samples Calculated integrated concentration nt. cone, sleep of awake samples (LER 907, ng/ml) nt. cone, awake P value Mean ± SE Mean ± SE Male /2 6 8/2 0 0/2 2 7/2 3 4/ ± ± ± ± ± ± ± ± ± ±.7 <0.05 <0.05 Mean 38.4 ± ± /2 6 4/2 8/2 6 /2 8 5/ ± ± ± ± ± ± ± ± ±.4 5. ± 4.6 Mean 48.8 ± ± 4.0 Female /2 9 7/2 9 /2 2 /2 5/ ± ± ± ± ± ± ± ± ± ±.8 FG.. ntegrated concentrations of LH (ng/ml, LER 907) from five prepubertal (stage ) boys. Each horizontal line indicates the integrated LH level from a 30-minute collection period. The onset and termination of sleep are indicated by the clashed line and arrows. Slanted lines indicate incomplete collections. Ages in years are indicated.

3 70 LEE, PLOTNCK, STEELE, THOMPSON AND BLZZARD JCE & M 976 ol 43 No FlG. 2. ntegrated concentrations of LH (ng/ml, LER 907) from five pubertal and post-puhertal boys. Pubertal stage (6) based on both genital and pubic hair criteria, and age in years are listed. The onset and temiination of sleep are indicated by the dashed line and arrows. The collection from the 8 5/2-year-old man was discontinued before he awoke. Slanted lines indicate incomplete collections. ng/ml) from stage - boys was significantly higher than that during the awake period (39 ng/ml, P < 0.05). Although both the average awake and asleep calculated mean integrated concentrations of LH from pubertal boys were higher than comparable values in prepubertal boys, the differences were not statistically significant. The prepubertal girls (nos.,2,) had similar calculated mean C LH during the sleep and waking periods. Only two pubertal girls (nos., 5) were evaluated. One (no. ) had a significantly higher value during sleep and one (no. 5) did not. Figures -3 show that episodic release of LH, even in preadolescent males and females, is apparent. As expected, the variability and magnitude of the peaks increase with the onset of puberty. (Compare Fig. with Fig. 2 and the prepubertal with the pubertal subjects in Fig. 3). Electroencephalographic recordings were not done to correlate peaks during sleep with electrical activity or stages of sleep. Discussion Previous studies have indicated an increased secretion of LH at puberty with sleep (,2). These data were obtained using plasma concentrations which were drawn eveiy 20 minutes. While the design of the present study differs, this study corroborates the results of those prior studies of increased secretion of LH in males with sleep during pubertal development. n addition, it is sug-

4 NTEGRATED LH LEELS AND PUBERTY Fic. 3. Thirty-minute integrated concentrations of LH (ng/ml, LER 907) (horizontal lines) from 5 girls. Pubertal stage (6) based on breast development, and age in years are listed. The onset and termination of sleep are indicated by the dashed line and arrows. Slanted lines indicate incomplete collections. gested by this study that the integrated concentration in prepubertal boys during sleep may be significantly greater than the C of LH during wakefulness. Hence, the greater secretion of LH during sleep in boys may be a phenomenon which occurs during the last several prepubertal years but to a lesser degree than during puberty. Two recent reports further indicate that increased testosterone levels before (7) and during (7,8) puberty are related to sleep and increased LH levels. The limited data for prepubertal girls are not similarly suggestive. f the prepubertal levels for boys and girls were evaluated together, prepubertal LH levels were not higher during sleep than during waking. The previous studies have used frequent sampling to indicate secretory patterns, while this study reports integrated concentrations from continuous sampling. Total gonadotropin secretion can be estimated using several criteria, including integrated levels from continuous sampling, mean concentrations of samples obtained every 20 minutes (,2), or the height and number of secretory spikes (,2). All of the methods can be used to indicate changes occurring during the maturation of the hypothalamicpituitary axis. There is no evidence that any one method is better correlated with the physiologic effects of gonadotropins. t is not possible in the present study to determine whether gonadotropin secretion was affected during acclimatization to the hospital environment and the withdrawal

5 72 LEE, PLOTNCK, STEELE, THOMPSON AND BLZZARD JCE & M ol 43 pump. To decrease this problem, the first two 30-minute collections were discarded in each instance. t is noted that some of the prepubertal (stage ) boys had higher integrated concentrations of LH than some of the pubertal boys. This finding from a relatively small group of boys who are chronologically at or approaching pubertal age may not be completely unexpected. Single samplings of concentrations from such boys have been repeatedly found to overlap, and large populations have been required to show a significant increase between stages of puberty (9,0). Acknowledgments Antisera and purified hormone preparations for the LH radioimniunoassays were generously provided by the National Pituitary Agency and the National nstitute of Health. References. Boyar, R., J. Finkelstein, H. Roffwarg, S. Kapen, E. Weitzman, and L. Hellman, Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 287: 582, Boyar, R., J. W. Finkelstein, R. David, H. Roffwarg, S. Kapen, E. Weitzman, and L. Hellman, Twentyfour hour patterns of plasma luteinizing hormone and follicle-stimulating hormone in sexual precocity', N EnglJ Med 289: 282, No 3. Boyar, R., M. Perlow, L. Hellman, S. Kapen, and E. Weitzman, Twenty-four hour pattern of luteinizing hormone secretion in normal men with sleep stage recording, J Clin Endocrinol Metub 35: 73, Kowarski, A., R. G. Thompson, C. J. Migeon, and R. M. Blizzard, Determination of integrated plasma concentrations and true secretion rates of human growth hormone, J Clin Endocrinol Metab 32: 356, Odell, W. D., G. T. Ross, and P. L. Rayford, Radioimmunoassay for human luteinizing hormone, Metabolism 5: 287, Tanner, J. M., The development of the reproductive system, in Growth at Adolescence, Chapter 2, Blackwell Scientific Publications, Oxford, 962, p Parker, D. C., H. L. Judd, L. C. Rossman, and S. S. C. Yen, Pubertal sleep-wake patterns of episodic LH, FSH, and testosterone release in twin boysj Clin Endocrinol Metab 40: 099, Boyar, R. M., R. S. Rosenfeld, S. Kapen, J. W. Finkelstein, H. P. Roffwarg, E. D. Weitzman, and L. Hellman, Human puberty: Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep, 7 Clin nvest 54: 609, August, G. P., M. M. Grumbach, and S. L. Kaplan, Hormonal changes in puberty: Correlation of plasma testosterone, LH, FSH, testicular size, and bone age with male pubertal development, J Clin Endocrinol Metab 34: 39, Lee, P. A., R. B. Jaffe, and A. R. Midgley, Jr., Serum gonadotropin, testosterone, and prolactin concentrations throughout puberty in boys: A longitudinal study, J Clin Endocrinol Metab 39: 664, 974.