1 rhythm under rigorously controlled conditions of light exposure, and, Minireview Melatonin and human puberty: Current perspectives.

Transcription

1 I JPineal Res 1993;15: Prinred in the United States of Americu--all rights resewed Copvright 0 Munksgaard. I993 Journal of Pineal Research ISSN Minireview Melatonin and human puberty: Current perspectives Cavallo A. Melatonin and human puberty: Current perspectives. J. Pineal Res. 1993: 15: Abstract: Many studies of melatonin in human puberty are difficult to interpret in light of methodological considerations such as the use of single blood samples collected either during the day or at night; a small number of observations; the failure to include the temporal characteristics of melatonin secretion; the definition of puberty by the use of broad clinical features without use of hormonal markers of puberty; the lack of control for the actual duration and intensity of light exposure during the days preceding the study; and the cross sectional nature of most studies. The few studies that have examined the plasma melatonin rhythm in humans by multiple blood sampling overnight or over suggest that normal pubertal development (as well as normal ovarian function) are not linked to alterations in the plasma melatonin profile. There is, however, some evidence to suggest that disorders of the hypothalamic-pituitary-gonadal axis (delayed puberty, precocious puberty, hypothalamic amenorrhea) may be linked to altered plasma melatonin profile, at least in some cases. These findings, taken together with strong evidence for the role of the pineal gland in the reproductive function of other vertebrate species, render unlikely the inference that the pineal gland has no role in the development and function of the human reproductive axis. Thus, one may speculate that a pineal-puberty relation does exist in humans and that the research techniques applied to date have been inadequate to uncover this relation. Greater knowledge might be gained from studies of melatonin metabolism during growth and pubertal maturation, from longitudinal studies of the melatonin 1 rhythm under rigorously controlled conditions of light exposure, and, perhaps, from the development of research strategies to explore the human melatonin receptor in vivo. Anita Cavallo Department of Pediatrics, University of Cincinnati College of Medicine, Children's Hospital Medical Center, Cincinnati, OH U S A Key words: human-melatonin-pinealpuberty-reproductive axis Address reprint requests to Anita Cavallo, MI., Division of General Pediatrics, Children's Hospital Medical Center, Elland and Bethesda Avenues, Cincinnati, OH , U.S.A. Received March 26, 1993; accepted May 26, Introduction The pineal gland of seasonal breeders transduces information about the external environment, particularly light, into a chemical messenger, melatonin, thereby modulating biological rhythms [Reiter, 1991; Cassone, 1990; Lang, Among these rhythms, reproductive activity has been widely researched and strongly linked to pineal activity in seasonal breeders [Reiter 1980; Cardinali, ; Tamarkin et al., Following the development of radioimmunoassays for melatonin in the 1970s, many studies were conducted to investigate the role of the human pineal gland, particularly regarding the development and activity of the reproductive axis. In 1984, a tantalizing editorial announced to the scientific community that the mystery of puberty had been solved, reporting confirmation of the nearly 100- year-old hypothesis that the pineal gland and its hormone melatonin suppressed puberty [Kolata, Nearly a decade has elapsed since that editorial was published and researchers continue to debate this hypothesis, while results and conclusions remain controversial. The purpose of the present report is to provide a review of the main studies of melatonin secretion in human puberty with emphasis on certain methodological issues that 115

2 Cavallo TABLE 1. Studies of plasma melatonin in human puberty: Normal subjects Results Investigators Subjects Sampling time Daytime concentrations Silman et al. 51 healthy boys and (1979) girls, years; all stages of puberty Lenko et al. 79 girls, 83 boys, (1982) healthy, 9-16 years; all stages of puberty Nocturnal concentrations or hr profiles Arendt Normal children; six (1978) prepubertal, three pubertal Fevre et al. Four normal pubertal (1978) boys, years Ehrenkranz et al. Boys with constitutional (1982) short stature, eight prepubertal, 9-13 years and seven pubertal, years; five normal adult males Waldhauser et al. 38 boys, 20 girls, 1-18 (1984) years; hospitalized in a pediatric or otolaryngological unit Attanasio et al. (1 985) Cavallo (1 992) Normal children, 21 girls, 17 boys, 1-18 years hospitalized for minor illness or diagnostic evaluations; all stages of puberty Normal children, 5-17 years; 30 boys, 32 girls; all stages of puberty girls boys Two samples: min intervals for 3-hr intervals for Two samples: hr intervals from 2100 to 0600 and single sample 1200 I-hr samples by constant withdrawal from 1800 to 0800 No change with puberty No changes in plasma melatonin in girls No changes in plasma melatonin by sex or pubertal stage No change in plasma melatonin between pubertal and prepubertal children Nocturnal increase in LH and melatonin with a positive correlation between both hormones No difference in concentration or timing of plasma melatonin among groups No change in duration of nocturnal melatonin surge or time of peak with puberty; wide individual variation in melatonin concentrations Change present with puberty Boys in stage 1 have higher plasma melatonin than all other stages Plasma melatonin decreases as a function of pubertal stage. Inverse correlation between nocturnal melatonin and LH concentrations Decline in 0300 melatonin concentration with age and pubertal stage from infancy to stage 5 Decline in nocturnal melatonin peak with age and pubertal stage, but no significant relation with pubertal stage remained with age covaried will be helpful to consider in the interpretation of results. Review of published studies of human puberty Tables 1 and 2 summarize the subject population, sampling time, and results of studies of plasma melatonin concentrations in normal children and children with disorders of puberty, respectively. Table 3 summarizes studies of urinary excretion of 116 melatonin or its metabolites in relation to human puberty. As shown in these tables, results have been conflicting. For example, in a study of normal children ages to 14 years, Silman et al. [ reported lower plasma melatonin concentrations during the day in pubertal boys than in prepubertal boys, but this group difference was not found in the girls (Table 1). These investigators explained the sex difference in the results by the fact that girls tend to

3 Melatonin and human puberty TABLE 2. Studies of plasma melatonin in human puberty: Disorders of puberty Results No change Change present Investigators Subjects Sampling time with puberty with puberty Daytime concentrations Cohen et al. 33 boys, years, (1982) with delayed puberty; 26 control subjects Nocturnal concentrations or 12- Drofiles Ehrenkranz et al. (1982) Tamarkin et al. (1 982) Attanasio et al. (1 983) Waldhauser et al. (1991) Berga et al. (1 989) Cavallo (1991) Five girls, i-7 years, and two boys, 4-7 years, with 14 girls and 12 boys with exogenous obesity; nine girls and seven boys with Prader-Willi syndrome Girls, 3-7 years: three idiopathic precocious puberty, one precocious adrenarche, one precocious thelarche; four boys, years, with delayed puberty; age-matched controls 51 girls and five boys with central ; 337 normal controls years Eight girls, years, with central before and after treatment with GnRH agonist 41 children, 5-17 years, 25 with constitutional delay, 11 with hypopituitarism, and five with hr intervals for 2-hr intervals for 3-hr intervals from 2100 to 0600 and single sample min intervals from 1800 to 0900 I-hr samples by constant withdrawal from 2000 to 0800 No differences from prepubertal boys with constitutional short stature (see Table 1) No variations in plasma melatonin as a function of pubertal stage, weight, or delayed puberty No difference in melatonin in at ages 5-7 years or 7-9 years, compared with age-matched controls No change in amplitude or duration of the nocturnal elevation before and after ovarian suppression, but wide individual variation No significant change in melatonin peak or time of peak by pubertal group or age Higher melatonin concentration in delayed puberty. Fall in melatonin between mid and late puberty Lower day-night increment in melatonin in than in age-matched controls, but higher than in pubertymatched controls. Higher day-night increment in melatonin in delayed puberty than in age-matched controls Significantly lower melatonin in at ages 1-3 years or 2-5 years, compared with age-matched controls begin puberty earlier than boys, and that a difference in melatonin concentrations between pubertal and prepubertal girls might have been present had they studied prepubertal girls younger than 11.5 years. In contrast, Lenko et al. [1982] reported no difference in plasma melatonin concentrations during the day related to sex or pubertal stage in normal boys and girls ages 9-16 years (Table 1). Waldhauser et al. [1984] reported an inverse correlation between melatonin and LH concentrations in single nocturnal blood samples of children and adolescents who seemingly had no major medical or endocrinological problems (Table 1). That report lead to the belief that the mystery of puberty had been solved [Kolata, Interestingly, in a subsequent study, Waldhauser et al. [1988] de- 117

4 Cavallo TABLE 3. Studies of urinary excretion of melatonin or its metabolites in human puberty - Results Sampling time and compound No change Change present Investigators Subjects measured with puberty with puberty Penny (1982) Tetsuo et al. (1 982) Sizonenko et al. (1 985) Normal children, S16 years: 88 boys, 82 girls; 16 adult males Healthy children, 3-16 years: 54 boys, 47 girls; normal adults: 14 male, six female Healthy children stages 1-5: 43 normal, 33 obese; seven delayed puberty in stage to 0800 Increased urinary Melatonin melatonin during puberty. Higher excretion in stage 2 than stage 1 of same age ( years). Lower urinary melatonin in adult males Two consecutive 24-hr No change with age in Increased nocturnal in 8-hr blocks boys or girls. No excretion in girls in 6-hydroxymelatonin relation with puberty stage to 0800 Melatonin in boys No change in melatonin excretion (ng/m2) with puberty scribed a decline in nocturnal melatonin concentrations with age in 367 subjects ages 3 days to 90 years, without any reference to a relationship of melatonin with puberty. In contrast, in studies of normal children that included multiple blood sampling over 24 h or overnight, Arendt [1978] found no differences in melatonin concentrations between six prepubertal and three pubertal normal children, and Fevre et al. [ reported a positive correlation between nocturnal melatonin and LH concentrations in four normal pubertal boys (Table I). Also using multiple blood sampling, but including a larger number of subjects, Attanasio et al. [ and Cavallo [ showed a decline in nocturnal melatonin concentrations with age and advancing pubertal stages (Table 1). Cavallo [ 19921, however, also demonstrated that, as expected, the effects of age and puberty overlapped, and no significant relationship remained between melatonin concentrations and pubertal stages when age was covaried. Conflicting results are also present among studies of children with disorders of puberty (Table 2). For example, Cohen et al. [ reported higher serum melatonin concentrations in single daytime samples in boys with delayed puberty ages years than in control boys ages 9-15 years; moreover, among the boys with delayed puberty there was a fall in melatonin concentrations between mid- and late puberty, but not between prepuberty and early or mid-puberty. Similarly, using multiple blood sampling technique, Attanasio et al. [I9831 described higher day-night increments in melatonin concentrations in four boys with delayed puberty than in age-matched controls (Table 2). The latter group also reported that the day-night increment in melatonin concentrations in four girls with precocious puberty was lower than in age-matched controls but higher than in puberty-matched controls. In a study of melatonin concentrations in single nocturnal plasma samples of 56 children with precocious puberty, Waldhauser et al. [1991] reported significantly lower concentrations in the younger girls, ages 1-3 years and 3-5 years compared with age-matched controls, but no significant difference from age-matched controls in girls with precocious puberty older than 5 years (Table 2). In addition, these investigators noted a decline in melatonin concentrations in the overall group after 1 year of GnRH agonist therapy. In contrast, other studies that used multiple blood sampling technique found no relationship between nocturnal melatonin concentrations and puberty in children with [Ehrenkranz et al., 19821, hypogonadism associated with Prader- Willi syndrome [Tamarkin et al., 19821, and in a cohort of children with precocious and delayed puberty [Cavallo, (Table 2). Moreover, Berga et al. [I9891 found no significant difference in the nocturnal melatonin profile determined by multiple blood sampling technique in eight girls with central before and after GnRH-agonist therapy that varied in duration from 6 to 16.5 months (Table 2). Likewise, studies of urinary excretion of melatonin or its metabolites during puberty have also yielded conflicting results. For example, Penny [ reported increased urinary melatonin excretion with pubertal development in a study of normal children years of age (Table 3). Interest- 118

5 Melatonin and human puberty ingly, in that study children in early puberty (stage 2) had higher urinary melatonin excretion than prepubertal children of similar age ( years). In contrast, Tetsuo et al. [ reported no correlation of urinary excretion of conjugated 6-hydroxymelatonin with puberty in boys, while girls who were in early puberty (stage 2) had increased excretion of this metabolite (Table 3); furthermore, there was no correlation between excretion of 6-hydroxymelatonin and age, and children and adults had similar excretion rates (expressed as mcg/day). No explanation was available for the higher excretion of 6-hydroxymelatonin in the girls in stage 2, and no follow-up studies were reported from that group. Another research group reported no change in urinary melatonin excretion during normal puberty [Sizonenko et al., (Table 3). Possible causes for the conflicting results In all likelihood, several factors account for the conflicting results described above. First, earlier studies that were based on daytime plasma melatonin concentrations, such as those reported by Lenko et al. [ 19821, Silman et al. [ 19791, and Cohen et al. [ 19821, must be interpreted cautiously because newer and more sensitive assays have demonstrated that daytime plasma melatonin concentrations are usually below the limit of assay sensitivity. Supersensitive assays that might enable studies of physiologic changes in daytime melatonin concentrations may become available in the near future [Vaughan et al., 19921, but have not been applied to date in studies of human puberty. Presently, useful information about melatonin secretion can be obtained more reliably by collecting repeated blood samples or several timed urine blocks over a 24-hr period to determine the rhythm of melatonin or its metabolites in plasma or urine. Second, because of the wide range of melatonin concentrations observed in narrow age groups or in pubertal groups, caution must be exercised in interpreting results of studies based on a small number of observations, such as those reported by Arendt [1978], Fevre et al. [1978], Ehrenkranz et al. [1982], Tamarkin et al. [1982], and Attanasio et al. [1983]. Third, melatonin secretion follows a rhythmic pattern with a gradual increase in plasma concentrations during the night, followed by a decline to low daytime levels by the next morning [Lang, Because the time of melatonin peak is variable among individuals and unpredictable [Arendt, 19781, single nocturnal samples may represent different points of the nocturnal rise and may not reflect accurately the secretory activity of the pineal gland. Therefore, the possibility of spurious results may be considered in the interpretation of studies based on single nocturnal blood samples, such as those by Waldhauser et al. [1984, 1988, Fourth, another issue to be considered is that most studies have examined plasma melatonin concentrations without regard to the other characteristics of the hormone s rhythm. In seasonal breeders, the temporal characteristics of the nocturnal melatonin rise, particularly the duration, seem to be of primary importance in the regulation of the hypothalamic-pituitary-gonadal axis [Reiter, In human physiology, the duration of the melatonin nocturnal rise also may be important as shown in patients with functional hypothalamic amenorrhea [Berga et al., Perhaps in normal puberty the temporal characteristics of the nocturnal rise are less important because Cavallo [1992] found no relationship of pubertal stages with the duration of the nocturnal rise and with the time of peak concentration in normal subjects (Table 1). That study, however, used integrated melatonin concentrations in blood samples obtained hourly by constant withdrawal; a more accurate assessment of the duration of the nocturnal rise and of the time of peak may require frequent instantaneous blood sampling, such as applied by Berga et al. [ in the small cohort of girls with (Table 2). As for the studies based on urinary excretion of melatonin or metabolites (Table 3), the results may be considered preliminary and follow-up studies are needed to verify the reported findings. Because only about 1% of melatonin is excreted in the urine and the hormone is excreted mostly in its metabolized form, very sensitive assays will be needed to determine accurately the urinary excretion of the hormone s native form. More useful at the present time may be the determination of urinary excretion of 6-hydroxymelatonin sulfate [Bojkowski et al., 1987; Sharp et al., An additional consideration of the referenced studies is that most applied the clinical criteria of puberty defined by the Tanner stages [ More accurate assessment of the maturational state of the hypothalamic-pituitary-gonadal axis requires hormonal markers of puberty that were used only in a few studies. Thus, Waldhauser et al. [1984] described an inverse relationship between melatonin and LH concentrations in single plasma samples obtained between 2300 and 0100 of children hospitalized for medical evaluations on a pediatric or an otolaryngologic unit. As discussed earlier, because of the variability in the nocturnal melatonin rhythm among individual subjects, such relationships found in single nocturnal blood samples may have been 119

6 Cavallo spurious. In fact, Cavallo et al. [1992] found no relationship between the nocturnal melatonin profile assessed by multiple blood sampling and the peak LH response to LHRH in a cohort of 96 children with normal puberty and disorders of puberty. Finally, all studies of puberty in humans have been unable to control for the possible confounding effect of light on melatonin secretion [McIntyre et al., In all animal species, the duration of the daily light exposure determines the characteristics of the melatonin nocturnal rise [Reiter, Studies in laboratory animals always control rigorously the time and intensity of the light exposure. Such control can be achieved in humans placed in an experimental setting for at least 1 week in order to entrain the melatonin rhythm to a constant routine of 1ight:dark cycles. This type of protocol may not be feasible in studies of children and adolescents. Various studies in adults have demonstrated that light exposure has a profound effect on the melatonin profile. For example, bright light during the nocturnal rise causes an abrupt decline in plasma melatonin concentrations [Lewy et al., 19801, while the onset, offset, and duration of the nocturnal melatonin rise can be altered by exposure to bright light at critical times over a 24-hr period [Shanahan and Czeisler, or by altering the duration of the photoperiod [Wehr, In studies of normal puberty and pubertal disorders, Cavallo [ 1991, attempted to control for the period of darkness by maintaining the period of lights outlsleep constant for each child. The duration or the dark period did not affect the relationship between pubertal stages and melatonin nocturnal profile in normal children; however, light exposure, per se, was not measured [Cavallo, Possibly, not only the duration, but also the intensity of the light exposure during the day may explain a great portion of the variability in melatonin concentrations in the various age and pubertal groups observed virtually by all investigators. Melatonin secretory profile in adults Most studies of the pineal gland in relation to the adult human reproductive function were conducted in females, and results have also been conflicting [Berga and Yen, Applying careful methods to characterize the phases of the menstrual cycle and taking frequent blood samples to determine the melatonin secretory profile, Brzezinski et al. [ and Berga and Yen [1990] have demonstrated that the plasma melatonin profile is stable during the various phases of ovarian cycles. Augmented nocturnal melatonin secretion, however, has been re- ported in hypothalamic amenorrhea [Berga et al., 1988; Brzezinski et al., Recently Puig-Doming0 et al. [ reported striking hypermelatoninemia in a young adult male with hypothalamic hypogonadism who had been previously treated for delayed puberty. When first assessed, this patient s plasma melatonin concentrations were much higher than those reported for hypothalamic amenorrhea, and they declined gradually to the normal range over the course of several years. Interestingly, this patient achieved fertility spontaneously while the melatonin concentrations were still elevated at levels comparable to those reported for hypothalamic amenorrhea [Berga et al., 1988; Brzezinski et al., To explain fertility despite hypermelatoninemia, the authors of that case report proposed that the important feature of melatonin secretion in relation to the function of the hypothalamic-pituitary-gonadal axis is the change in amplitude or duration of the nocturnal melatonin rise, rather than the absolute values of melatonin concentrations [Puig-Doming0 et al., Longitudinal studies of normal individuals and of other cases of delayed puberty or infertility are needed to clarify this point. Conclusions Although there is some evidence that certain disorders of the human reproductive axis in children and adults may be accompanied by an altered melatonin secretory profile, the role of the human pineal in pubertal development remains speculative. Research techniques applied to date to human studies may have been inadequate to fully explore the relationship of the pineal gland with the human reproductive axis. Additional information may be gained from longitudinal studies of both normal subjects and patients with disorders of the reproductive axis. However, any study of the human melatonin rhythm ought to include strategies to account for the effects of light exposure and for possible changes of melatonin metabolism with sexual maturation and aging. Finally, new insight may be attained by studies of the pineal-reproductive relationship at the receptor level, a goal that will become feasible with the application of recently developed melatonin agonists and antagonists to human research. Acknowledgments Work by the author was supported by NICHD grant HD Literature cited ARENDT, J (1978) Melatonin assay in body fluids. J Neural Transm. Suppl. 13:

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