University of Virginia Charlottesville, Virginia 22908
Address correspondence and requests for reprints to: Alan D. Rogol, M.D., Ph.D., Professor of Pediatrics and Pharmacology, Box 386, Department of Pediatrics, University of Virginia Health Science Center, Charlottesville, Virginia 22908; E-mail: ADR{at}virginia.edu
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Introduction |
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After the initial explosion of interest, we have entered a period of defining the physiological role of leptin in the human. Naturally, we have focused on the energy equation, reasoning from the laws of thermodynamics that energy retained (and stored as fat) is energy intake minus energy output. The usual energy intake of our Western society has been criticized for an easy abundance of very palatable, high-fat (and thus energy dense) foods eaten in the context of diminished energy expenditure in an increasingly sedentary lifestyle (4).
We have known for some time that energy and the reproductive system are linked. It is not so simple as the original Frisch hypothesis (5), that a young woman must be above a certain cutoff weight or have her body fat above a specific level to attain menarche or to avoid secondary amenorrhea. However, even in the human it is clear that body weight, either insufficient or morbidly obese, and fertility are correlated. The data in mice are helpful in this regard. The ob/ob mouse, which makes no leptin, is morbidly obese, and has decreased energy expenditure and infertility, can attain sexual development and be fertile following weight loss induced by exogenous leptin (6). In fact, normal mice can have puberty advanced by several days with the administration of leptin (7). Leptin has multiple neuroendocrine actions that affect fertility. It may serve as a metabolic gating mechanism to determine the energy status of the organism and, if favorable, to begin the pulsatile release of GnRH with its consequent pubertal development (8).
Given these findings, what do we know about leptin, growth, and puberty in the developing child? Puberty is a time of rapid changes in body composition, complementing the explosive increase in linear growth rate. Direct measures of body composition would require a determination of the chemical composition of the various tissues; therefore, in the human we use only indirect methods of varying accuracy and precision. Although all are related to the chemical composition of the body, each has its own assumptions and limitations. Often the least laborious (e.g. bioelectrical impedance and several skin-fold thickness measurements) have the least accuracy and the greatest variability. In addition, during pubertal development the chemical composition of the body changes, for example, the degree of hydration of the fat-free mass, and limits the validity of any method across ages, stages of adolescent development, and extremes of body fatness unless all compartments are measured and any equations used account for the degree of physical maturity (9).
What are the alterations in body composition during puberty? Several recent reviews may be summarized as follows: children of both genders have similar amounts of fat before puberty, although boys may have slightly greater fat-free mass (FFM); thus, girls are relatively fatter than boys by approximately 1% at age 5 and 6% by age 10 (10). During puberty, boys accrue FFM at a much greater rate and for a longer period of time than girls. In addition, pubertal girls continue to increase the amount and percentage of body fat (11). The control of these sexually dimorphic differences in the composition of the body is virtually unknown, although sex steroid hormones and growth hormone are intimately involved (12). The interest in this subject has only been heightened by the increasingly pervasive evidence that body composition, especially the fat compartment (and its regional distribution), impact the later general health of an individual; that is, the risks for hypertension, cardiovascular disease, and type 2 diabetes mellitus are increased [the metabolic syndrome or syndrome X (13, 14)]. It seems clear that the antecedents are already present during childhood, but amplified during adolescence.
What are the data linking leptin concentrations and pubertal development? Several large studies in children have shown a strong correlation of serum leptin levels with adiposity as determined by body mass index [wt (kg)/ht2 (cm)2] (15, 16). In general, girls have higher leptin levels than boys, although some investigators note that the concentrations are indistinguishable at the same relative fat mass. As pubertal development begins in boys, or just before its onset, there is a marked relative rise in leptin levels, whether reported cross-sectionally (15, 16, 17) or longitudinally (18). Mantzoros and colleagues (18) reported a consistent rise in leptin levels in boys of normal height, weight, and weight-for-height just before a major increase in circulating testosterone concentration or an increase in testicular size. These data were consistent with the hypothesis that leptin could trigger puberty, at least in the male. Before the time of peak height velocity, the leptin concentrations had returned to prepubertal levels, even as the body mass index increased with pubertal development. Perhaps it is the marked increase in androgens or the vastly greater androgen-to-estrogen ratio that affects both the leptin levels and the changes in body compositionincreased FFM and a lower ratio of fat mass to FFM.
In girls the leptin-body composition correlation is quite different. Body fat, both relative and absolute, continues to rise as do the circulating levels of leptin (15, 16, 17). The hormonal milieu responsible remains incompletely defined, although estrogen must be a major factor, as it is in the adult. Although transport to and from the cerebrospinal spinal fluid (and brain) has been implicated, there are no compelling data that point specifically to this transport system perhaps mediated by the truncated form of the leptin receptor in the choroid plexus (19).
Our own recent data show that circulating leptin concentrations are more closely related to subcutaneous fat than to total fat, abdominal visceral fat, or energy expenditure. These data are in agreement with previous studies, which have shown that the abdominal subcutaneous fat area is more strongly correlated with the circulating leptin concentration than the abdominal visceral fat, when evaluated from the same magnetic resonance imaging slice (20). Further, we have found that, during childhood and adolescence, the subcutaneous fat depot is the one primary influence on circulating leptin concentrations, and that changes in leptin levels closely track the changes in the subcutaneous fat depot (Roemich, J. N., P. A. Clark, C. S. Mantzoros, J. S. Flier, A. Weltman, and A. D. Rogol, manuscript in preparation).
The data from the longitudinal study (see JCEM page 1091) of children with precocious puberty before, during, and after GnRH therapy are completely consistent with the data in normal children going through puberty (21). Boys had higher leptin levels just before analogue therapy and after several months following cessation than during therapy. There were no changes in leptin levels for girls with precocious puberty whether before, during, or after receiving GnRH therapy (21).
What is the message from all of this? I believe that we know more about linear growth than about other "components" of the pubertal transition. These issues are important relative to adult cardiovascular risk. With proper study of the physiology and pathophysiology of the attainment of the adult body composition, whether leptin is the major player or not, we may come to a point at which rational interventions, including diet, exercise, and even pharmacological agents, will slow and perhaps reverse the marked increase in over-fat children and adolescents (22).
Received February 4, 1998.
Accepted February 5, 1998.
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References |
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