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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2852
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3246-3252
Copyright © 2007 by The Endocrine Society

Impact of Fatness, Fitness, and Ethnicity on the Relationship of Nocturnal Ghrelin to 24-Hour Luteinizing Hormone Concentrations in Adolescent Girls

J. Z. Kasa-Vubu, A. Rosenthal, E. G. Murdock and K. B. Welch

Department of Pediatrics (J.Z.K.-V., A.R., E.G.M.), and Center for Statistical Consultation and Research (K.B.W.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Josephine Z. Kasa-Vubu, M.D, M.S., Department of Pediatrics, University ofMichigan Medical Center, Ann Arbor, Michigan 48019-0718. E-mail: jzkv{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Ghrelin is related to energy balance that regulates food intake.

Objective: The aim was to explore whether ghrelin would be linked to differences in fitness in adolescent girls, whose menstrual cycles are sensitive to changes in energy balance.

Methods: A total of 72 girls, ages 14–21 yr, including five with amenorrhea, were studied in the follicular phase. LH was sampled every 10 min over 24-h, and ghrelin was measured hourly between 2300 and 0300 h. Body composition was measured by dual x-ray absorptiometry. Fitness was characterized by reported frequency of exercise per week and by maximal oxygen consumption with "high" vs. "low" fitness groups defined from maximal oxygen consumption norms for this population. Data were analyzed with SAS software (SAS Institute Inc., Cary, NC).

Results: Ghrelin was related to percent body fat (P = 0.038; R2 0.07), weekly exercise (P = 0.032; R2 0.07), and 24-h mean LH (P = 0.002; R2 0.13). The ghrelin relationship with LH was more pronounced in the low-fitness group. In multiple regression models, 24-h LH was an independent predictor of ghrelin after adjusting for percent body fat, fitness, exercise, or age. Ghrelin was higher in Caucasian girls than in African-American girls after adjusting for covariates at 0200 h (P = 0.017).

Conclusions: Twenty-four-hour LH is an independent predictor of nighttime ghrelin concentrations in postpubertal adolescent girls. Diverging patterns in ghrelin may reflect differences in exercise patterns and/or may be influenced by ethnicity. These data introduce ghrelin as a biomarker of individual differences in energy balance during the menstrual cycle and across ethnicities.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN IS KNOWN for its GH secretagogue properties and is involved in a wide array of endocrine and nonendocrine functions, including food intake and energy balance. Circulating ghrelin is constitutively lower in obese individuals and increases after sustained weight loss, thus appearing to function as an adiposity signal (1). In animal models, the administration of ghrelin stimulates appetite and decreases locomotor behavior, which in turn promotes weight gain (2).

The drive of the GnRH pulse generator initiates puberty (3), and energy balance plays an important role in the modulation of reproductive function, particularly in the young female (4). Because leptin, another marker of energy balance, plays a permissive role in the maturation and maintenance of reproductive competency in females, the more recently discovered ghrelin has also been explored as a potential index of reproductive function, mostly at the gonadal level (5, 6). Despite these preliminary reports linking ghrelin to reproductive competency, little is known about the potential impact of the menstrual cycle on its concentrations.

Control of the menstrual cycle in the immediate postpubertal period is vulnerable to changes in energy balance, such as those induced by intense physical conditioning (7). While the effects of deficient energy stores on the menstrual cycle become more apparent with advanced fitness (8, 9, 10), there is a wide range of threshold in weight and activity levels at which menstrual disturbances can occur (11, 12), particularly in the luteal phase of the cycle (13, 14). Although these differences in threshold have remained elusive, recent developments in the understanding of appetite regulation have shed new light on possible mechanisms responsible for modulating energy balance and reproductive function.

Leptin, which increases during puberty, was the first hormone linking fat stores to reproductive function (15). Short-term fasting decreases leptin concentrations before any evidence of weight loss (16), and energy deprived young women with exercise-induced amenorrhea have lower leptin levels than cyclic women of similar weight (9). In contrast, patterns of ghrelin secretion diverge from leptin and appear to be regulated by different mechanisms. Ghrelin levels gradually decrease with puberty (17) and are suppressed after meal consumption. The proposed mechanism for ghrelin suppression after a meal is that it is mediated by insulin sensitivity (18). In addition to meal-associated changes, ghrelin concentrations spontaneously peak at night without any relationship to a meal. This nighttime pattern of ghrelin is preserved across the weight spectrum (1) but is poorly explained.

Because the postpubertal years represent a period of heightened susceptibility to changes in energy balance (4), we sought to explore whether nighttime ghrelin could be linked to differences in fitness status in adolescent girls and young women of reproductive age. We further investigated whether these potential differences would be affected by the menstrual cycle. Using integrated 24-h gonadotropin concentrations as a surrogate measure for reproductive function, we hypothesized that ghrelin concentrations would be related to LH secretion in adolescent girls in the follicular phase of the cycle, across the weight and fitness spectra.

For this pilot study, we elected to measure ghrelin during the expected time of a nighttime increase. We have previously shown that GH secretion is elevated at night, and is influenced by fitness and fatness status in adolescent girls (19). Because ghrelin is a known GH secretagogue, we postulated that its nighttime window would reflect changes in energy balance in a fashion that would be removed from the immediate impact of meals, and might also reflect patterns and relationships characteristic of late puberty.


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

The protocol was approved by the institutional review board of the University of Michigan Health System. A total of 72 healthy adolescents, ages 14–21 yr with body mass indices (BMIs) ranging from lean to overweight (based on growth charts issued by the National Institute for Health Statistics), were studied a minimum of 2 yr after menarche as part of a study on fitness and weight control. Young women and adolescent girls were recruited from local university campuses and high schools, and were enrolled after signing an institutional review board-approved consent form. An additional signature was required from one parent or legal guardian for all participants under 18 yr of age. All participants were healthy and taking no medications. Individuals who had used any hormonal method of birth control or reported a significant weight loss (more than 10%) within the last year were excluded. The participants reported a wide range of patterns for physical activity. The types of sports favored were diverse, and included in-line skating, snowboarding, diving, biking, resistance training, jogging, skiing, belly dancing, ice hockey, kung fu, swimming, hip-hop dancing, Pilates, cheerleading, walking, and exercise videotapes.

Experimental design

We evaluated fitness in two ways. First, all participants were asked how many times a week they voluntarily exercised for at least 1 h, at recruitment. Second, we chose to include maximal oxygen consumption (VO2max) as a surrogate assessment of fitness because it measures cardiorespiratory fitness, which is lower in youth who have low levels of physical activity and high levels of sedentary behavior (20). Maximal aerobic capacity was determined by a treadmill test following the Bruce protocol (21). Based on published norms for VO2max in the adolescent population, a cutoff of 41 ml/kg·min, or the average for postpubertal girls (22), was selected to differentiate between a "high fitness" group (VO2max greater or equal to 41 ml/kg·min) and a "low fitness" group (VO2max less than 41 ml/kg·min). Relative body fat was obtained by dual x-ray absorptiometry using a total body scanner (model DPX-L; Lunar Radiation Corp., Madison, WI) (23). A measure of thyroid-stimulating hormone was used to confirm normal thyroid function in all participants. Pregnancy was excluded by serum measurement of human chorionic gonadotropin.

At recruitment, all girls were asked about their menstrual cycle. Girls who reported cycling on a monthly basis (within 21–35 d) were allocated to the cycling group. Because of the imprecision inherent to the reporting of menstrual cycle length at this young age (24), all participants had to wait until the onset of a cycle subsequent to their enrollment to be eligible for blood sampling. Because irregular menses can occur sporadically in this age group and can be associated with college life, girls who reported no menses for at least 6 months were considered amenorrheic and were also recruited but analyzed separately. Deliberate dieting, hirsutism, and/or a medical history compatible with androgen excess were criteria for exclusion. All participants were admitted to the General Clinical Research Center (GCRC) of the University of Michigan within the first 12 d of the cycle. The follicular phase of the cycle was further confirmed by serum progesterone, which was measured on the night preceding the study and before proceeding with sample collection. Because they could not report a cycle, girls with amenorrhea were admitted at any time, and with the provision that the prestudy progesterone had to be at a follicular phase level to proceed with data collection. This strategy allowed us to target consistently the follicular phase of the cycle. Admission to the GCRC was scheduled on the night before the study to allow for acclimatization. By 0700 h on the day of the study, an iv catheter was inserted in the forearm, and blood was sampled every 10 min for 24 h. All meals were served at standard times for breakfast, lunch, and dinner, with a bedtime snack scheduled at 2100 h as the last meal of the day. Ghrelin was measured in discrete hourly samples between 2300 and 0300 h inclusive, to coincide with the nighttime peak of the hormone and to bypass the variability associated with meals (1). Leptin was measured on all hourly samples for 24 h. LH was measured every 10 min to account for rapid pulsatility. To document sensitivity to insulin, fasting glucose and insulin were measured concomitantly from three consecutive fasting samples drawn 10 min apart and averaged to a single value. Adiponectin, as an additional index of insulin resistance (25), was measured on one fasting sample. To characterize the sex-steroid milieu, estradiol, testosterone, and SHBG were measured. To estimate average daily caloric intake and relative contributions of macronutrients for each participant, a 3-d food diary was mailed in advance, completed prospectively, and its contents were analyzed after a direct interview with the staff of the GCRC Nutrition core at admission.

Assays

Plasma samples were stored at –70 C until assayed. Plasma LH concentrations were measured using a chemiluminescent enzyme immunometric assay for use with the Immulite Automated Analyzer (Immulite; Diagnostic Product Corp., Los Angeles, CA). LH assay sensitivity was 0.1 mU/ml, intraassay and interassay coefficients of variation (CVs) were 4.0% and 5.0%, respectively. Leptin, ghrelin, and adiponectin were measured using specific reagents from Linco Research (St. Charles, MO). Leptin assay sensitivity was 0.5 mg/ml, and had intraassay and interassay CVs of 4.5% and 6.6%, respectively. The ghrelin assay used a RIA kit designed for the measure of total ghrelin, with a sensitivity of 93 pg/ml, intraassay and interassay CVs of 5.8% and 8.5%, respectively. Adiponectin assay had a sensitivity of 1 ng/ml, intraassay CV at 2.3%, and interassay CVs 15.5% at 22 ng/ml and 10.2% at 75 ng/ml.

Analysis

The participants were allocated to either a high (VO2max greater or equal than 41 mg/kg·min) or a low (VO2max less than 41 mg/kg·min) fitness group. Girls with amenorrhea were allocated to a third category, regardless of fitness status. Nighttime ghrelin was calculated as the average value measured at 2300, 2400, 0100, 0200, and 0300 h, and was the primary outcome. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). An {alpha}-level of 0.05 was selected to indicate statistical significance.

Regression analysis with individual predictors

The relationships between the dependent variable, nighttime ghrelin, and the independent variables, including BMI, percent body fat, diet, day of the cycle, VO2max, and 24-h LH, were first analyzed using linear regression.

Regression analysis with multiple predictors

Subsequently, multiple regression models were constructed for the dependent variable nighttime ghrelin and the independent variables that had shown a significant relationship with ghrelin by simple linear regression.

Repeated measures analysis of covariance (ANCOVA)

Repeated measures ANCOVA was applied on the log-transformed hourly ghrelin values for the cycling participants using time, ethnicity (African-American, Asian-American, and Caucasian), and their interaction as predictors, with 24-h LH as the covariate. Post hoc tests were performed to compare the LH-adjusted mean ghrelin values of African-Americans and Asian-Americans with those of Caucasian participants at each time point.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subjects’ characteristics

The subject characteristics by fitness status are described in Table 1Go. There were five girls with amenorrhea who are represented separately. Of these five, four had fitness levels compatible with the high-fitness group, and one was a college freshman that had been a competitive high school track runner and stopped exercising regularly after the start of the school year.


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  		TABLE 1. Subjects’ characteristics by menstrual status and fitness levels (n = 72)

 
Of a total of 72 girls, 13 were African-Americans, seven Asian-Americans, and 52 Caucasians. Table 2Go compares the characteristics among African-American, Asian-American, and Caucasian subgroups.


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  		TABLE 2. Subjects’ characteristics by ethnic groups in subjects with a menstrual cycle (n = 67)

 
There was a wide range of exercise patterns reported by the participants, including regular activity year-round (40 girls, one to seven sessions a week), seasonal activity (15 girls, zero to seven sessions a week), sporadic (nine girls, zero to four sessions a week), and rare (eight girls, zero session a week). Weekly sessions of exercise recorded reflect the frequency reported by each girl at the time of enrollment. Girls with higher fitness had a lower BMI, lower percent body fat, fasting insulin, and leptin. They reported roughly twice as many sessions of exercise per week than their counterparts with lower fitness. Although there was no difference in the average day of the cycle, the progesterone levels were lower in the more active girls than in their more sedentary counterparts.

Regression analysis with individual predictors

As shown in Table 3Go, nighttime ghrelin was significantly related to percent body fat, day of the menstrual cycle, weekly exercise, and 24-h LH concentration for cycling participants. There was a nonsignificant negative relationship between nighttime ghrelin and BMI, and a marginally significant positive relationship with VO2max.


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  		TABLE 3. Regression analysis with individual predictors for nighttime ghrelin in all participants with a menstrual cycle (n = 67)

 
Nighttime ghrelin and menstrual cycle day or LH concentrations by fitness status

The relationship between nighttime ghrelin and 24-h LH concentration was considered separately for participants by fitness status. There was a significant positive relationship between LH and nighttime ghrelin in the low-fitness group (P = 0.0013; R2 = 0.24). In contrast, the relationship between LH and ghrelin in the high-fitness group was not significant (P = 0.15; R2 = 0.08), suggesting that the LH-ghrelin relationship is weaker with higher fitness status. Although the sample size was smaller in the high-fitness group, a power analysis suggested that there was 74% power to detect a relationship of the same magnitude as seen in the low-fitness group.

Regression analysis with multiple predictors

We performed a multiple regression analysis using predictors that were found to be significant in individual regression analyses. Day of the cycle and 24-h LH were highly correlated (Pearson coefficient 0.48; P < 0.0001), and when both 24-h LH and day of the menstrual cycle were combined in a regression model, only LH remained significant (P = 0.02; R2 = 0.14). Thus, we chose to include 24-h LH in our multiple regression model. There was also a strong correlation between weekly exercise and VO2max (Pearson coefficient 0.54; P < 0.0001). However, when the two variables were included in a regression model, both lost significance (P = 0.18 and P = 0.43, respectively). We developed models for each of these predictors. The significant results of the multiple regression analyses are represented in Table 4Go. The most parsimonious model (model C) included weekly exercise and 24-h LH. The addition of percent body fat modestly increased the R2 from 0.22–0.24. The addition of age was not statistically significant, and it did not improve the R2 value.


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  		TABLE 4. Regression analysis with multiple predictors for nighttime ghrelin in all participants with a menstrual cycle (n = 67)

 
Repeated measures ANCOVA analysis and ethnicity

The mean nighttime ghrelin patterns at each hour by ethnic group (Caucasian, African-American, and Asian-American) are represented in Fig. 1Go. Post hoc comparison of means (adjusted for 24-h LH and weekly exercise) showed that there was no statistical difference between Asian-Americans and Caucasians, whereas African-Americans had a distinct pattern from the two other groups, with significantly lower values than Caucasians at 0200 h.


Figure 1
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  		FIG. 1. Average ghrelin on hourly samples collected at between 2300 and 0300 h in African-American, Asian-American, and Caucasian girls. Average ghrelin concentrations per time point per ethnic group with SE bars. *, P < 0.05, Statistically significant between African-American and Caucasian girls at 0200 h (P = 0.017) after adjusting for 24-h LH, weekly exercise, and age.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To our knowledge, there has been no study delineating a link between ghrelin and the menstrual cycle during late puberty. Clues of a potential relationship between ghrelin and the female reproductive cycle have recently emerged. Ghrelin was up-regulated 5-fold in the central nervous system of female mice during the estrous cycle, a high-estrogen state (26). We did not find a relationship between estradiol and ghrelin in our participants, but our estradiol values were derived from a single sample instead of integrated estradiol concentrations over a longer period of time (27), which could have provided additional information. Ghrelin concentrations have been sexually dimorphic in a clinical study with adults (28). Although GH concentrations were only slightly higher in women than men, ghrelin concentrations in women were 3-fold higher. Because our data indicate that LH is a predictor of ghrelin concentration in adolescent females, we propose that the gonadotropin milieu of the menstrual cycle is likely to account, in part, for differences in ghrelin between men and women.

Because ghrelin has been shown to decrease during puberty, the positive relationship that we found between LH concentrations and this orexigenic factor represents a paradox that needs to be further explored. From the start to the end of puberty, the reproductive system in females undergoes a striking transformation (29) with superimposed positive and negative feedback mechanisms modulating gonadotropin secretion. For example, gonadotropins and inhibins increase during puberty. At the start of the pubertal transformation, there is a positive correlation between FSH and inhibin concentrations, however, at the end of puberty, the correlations are negative (29). Thus, depending on the window of time selected during puberty or the menstrual cycle, cross-sectional analyses could reflect relationships that are seemingly contradictory to the overall positive trend for both inhibin and FSH. Estradiol exemplifies another sequence of seemingly contradictory relationships as puberty progresses toward the establishment of the menstrual cycle. During puberty, estradiol and gonadotropin concentrations are increasing; however, depending on the phase of the menstrual cycle, estradiol exerts either a negative or positive effect of gonadotropin secretion, and the mechanisms of this bimodal action are still under investigation (30). Our findings suggest that the hormonal milieu of the menstrual cycle modulates ghrelin concentrations. This novel concept opens new possibilities for research on the role of ghrelin in late puberty.

In this study, age was not significantly related to ghrelin because its range was very narrow. However, the negative trend of this relationship is in agreement with previous reports. The pubertal decrease of ghrelin is consistent with the characteristic increase in adiposity seen during those years (15). Puberty is also a time when insulin levels increase (31), and ghrelin levels have been inversely related to insulin levels (18). Our findings, particularly as they relate to lower fitness and higher insulin levels in the more sedentary girls, are in agreement with these studies because the lower fitness group had the lowest ghrelin levels. A strength of our study is that it relates to potential changes in ghrelin that would occur during specific physiological windows of time, such as the follicular phase. Although girls in late puberty may overall have ghrelin levels that are lower than girls in early or midpuberty, we propose that, within the span of the menstrual cycle, ghrelin levels are related to differences in LH concentrations.

The physiological significance of the LH-ghrelin relationship is unclear. Animal models may shed some further light on potential mechanisms fueling the dialogue between energy balance and the reproductive axis. In vitro and in vivo studies in rat strongly suggest that ghrelin influences gonadotropin secretion from the pituitary in ways that can be modulated by the estrous cycle (44, 51). In sheep, the injection of ghrelin into the third cerebral ventricle inhibits LH secretion (52). Closest to human physiology is the monkey: ovariectomized animals will suppress LH secretion after the iv administration of ghrelin (53). Although these studies, performed in ovariectomized animals, showed a negative relationship between ghrelin and gonadotropin secretion, we found a positive relationship in healthy intact subjects. Ovariectomized animals are devoid of the gonadal steroid milieu, which could modulate the ghrelin-gonadotropin interaction in the intact animal. Based on the positive relationship between ghrelin and LH that we observed, we hypothesize that increasing ghrelin levels during the cycle may ultimately reach a threshold at which point they could suppress LH concentrations, perhaps at midcycle. Future in vivo experiments in intact animals or prospective human studies might provide further insight into what promises to be a very dynamic layer of the energy reproduction interface.

The nocturnal increase of ghrelin may have some potential important implications in appetite regulation and eating behavior (1, 32). However, current knowledge does not explain the significance of the nighttime increase of ghrelin, nor has it provided support for any relationship between nighttime ghrelin concentrations and appetite, late-eating behavior in particular (33), and/or the risk for obesity. Because adolescent girls experience steady weight gain even as their growth rate subsides (34), a better understanding of physiological variations of appetite could provide tools for the prevention of obesity as they enter their reproductive years.

The ethnic differences in nighttime ghrelin we found echo those of a recent report on differences in secretion dynamics between American children of African or European descent (35). This difference between two groups was thought to reflect, in part, differences in insulin resistance. We found that the patterns of nighttime ghrelin were achieved with consistently lower levels in African-American girls when compared with Caucasian girls, while Asian-American participants had an intermediate profile. Non-Caucasian females share a disproportionate burden of the obesity epidemic (36, 37), and if ethnic differences in ghrelin secretion are confirmed, it will be important for future studies to explore the potential for specific behavioral interventions. Our small numbers of African-American and Asian-American participants should be viewed as preliminary pilot results that we hope will foster randomized trials that would prospectively control for relevant covariates.

Another limitation in our study was the unequal size of the three groups. We speculate that, despite our efforts at targeting them, many high-fitness and/or amenorrheic girls did not meet inclusion criteria because they were using hormonal methods of birth control. Bearing in mind these limitations, follow-up randomized studies are needed to address fully the impact of increasing or decreasing fitness on ghrelin concentrations during the menstrual cycle.

The difference we found between girls with higher vs. lower fitness suggests that the relationship between gonadotropins and nighttime ghrelin concentrations is weaker in girls with greater cardiovascular conditioning. When we included weekly exercise in the multiple predictor’s models, we found it to be a significant predictor, independent from VO2max. This suggests that repetitive exercise or a relatively more pronounced energy deficit may have a more direct effect than cardiovascular fitness on the modulation of ghrelin concentrations (32).

Our data were confined to the follicular phase because we anticipated that it would be the most consistent in adolescent girls whose ability to ovulate and, thus, progress to a luteal phase may not be completely established. Because luteal phase defects are more likely to occur with more intense physical conditioning (13, 14), one can speculate that girls with lower fitness would have been more likely to progress into the luteal phase, while girls with higher fitness would have been less likely to do so despite reporting a regular cycle. Whether these differences in reproductive competency are related to differences in ghrelin and/or appetite regulation across the menstrual cycle remains to be determined. Others have reported a relationship between menstrual cycle status and ghrelin concentration from a single fasting sample in adult women with or without exercise-induced amenorrhea (38). We used a simple classification of menstrual cycle in younger subjects and focused on how the drive of the reproductive axis related to a 5-h nighttime window for ghrelin. Our study suggests that, when one moves across the fitness spectrum, there is a shift in relationships between markers of energy balance, such as ghrelin, and the GnRH pulse generator, as reflected by LH concentrations.

Girls with amenorrhea were the most insulin sensitive when compared with others. They represented the high end of the fitness spectrum in our participants, except for one girl who had become sedentary, gained weight, but had still not recovered cyclicity. Although their caloric intake was slightly higher than their cyclic counterparts, this may have been insufficient for their level of physical conditioning to maintain menstrual cyclicity (29).

It was beyond the scope of our design to determine whether girls with higher fitness would be less susceptible to variations in appetite and/or eating behavior during the menstrual cycle. We were also unable to address whether ghrelin patterns, overtime and within individual subjects, during the menstrual cycle can be related to other important regulators of energy balance and appetite, such as peptide YY (35). Such studies in adolescents would further define the interface between energy balance and the activity of the GnRH pulse generator, early in the process of establishing reproductive competency.

We did not measure acylated ghrelin in our participants (39). Because total ghrelin represents a combination of circulating acylated and deacylated forms of the hormone, we cannot make conclusions about the physiological significance of these changes. Although acylated ghrelin is linked to hunger (40), both circulating forms promote adipogenesis in animal models (41), and recent reports point to metabolic effects from the presence of both forms of ghrelin in the peripheral circulation (42, 43). While the respective roles of different forms of ghrelin in the follicular phase have yet to be determined, our findings suggest that the changes in energy balance reflected by total ghrelin are modulated by the reproductive axis.

Animal studies link ghrelin to sleep-wake regulation and nighttime eating behavior (44). In addition, there are limited human data linking differences in nighttime ghrelin and/or leptin to nighttime eating behavior (33, 45), or an altered diurnal rhythm (46). It has been suggested that levels of nocturnal ghrelin could trigger hunger sensation that would disrupt sleep and promote food-seeking behavior (47). Because the nighttime increase in ghrelin can be stunted by frequent awakening, it has been proposed that the diverging patterns between night- and daytime ghrelin could either be explained by late-night snacking or decreased sleep (48). Our participants were not given access to food overnight, and all lights were turned off for the night, but quality of sleep was not monitored. Therefore, it is possible that the differences in ghrelin between subgroups could have been related to differences in sleep (49). We are aware of no reports on individual differences in the quality of sleep in youth, in relation to ghrelin.

Because the recent discoveries in appetite control are fueling vigorous research in the pharmacology of weight control, one can speculate that as ghrelin-blocking agents become available for human use, their administration could judiciously target patient-specific behavioral and neuroendocrine characteristics associated with specific eating behavior (50).

In conclusion, during the follicular phase in adolescent girls, nighttime ghrelin concentrations relate to LH concentrations, even after accounting for fatness and fitness. This indicates that nighttime ghrelin increases with the activity of the GnRH pulse generator, as reflected by LH concentrations. Bearing in mind our relatively small numbers, we observed that the ghrelin relationship with LH is strongest with lower fitness status, weakens with increased cardiovascular conditioning, and may be subject to ethnic differences.


   Acknowledgments
 
We thank the adolescent girls who participated in this study and the skilled nurses of the General Clinical Research Center of the University of Michigan. We also thank Pamela Olton for her expert technical assistance, and Vasantha Padmanabhan for her valuable feedback and support in implementing assays.


   Footnotes
 
This work was supported by 1K23DK065995 award (to J.Z.K.-V.) and General Clinical Research Center Grant M01-RR-0042. This work also used the Chemistry Laboratory of the Michigan Diabetes Research and Training Center funded by NIH5P60 DK20572 from the National Institute of Diabetes and Digestive and Kidney Diseases. Registered at Clinicaltrials.gov: NCT00441402.

Disclosure Summary: The authors have nothing to declare.

First Published Online May 15, 2007

Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass index; CV, coefficient of variation; GCRC, General Clinical Research Center; VO2max, maximal oxygen consumption.

Received December 22, 2006.

Accepted May 3, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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