| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
a Reproductive Sciences Program,
b Departments of Obstetrics and Gynecology and
c Biology, University of Michigan, Ann Arbor, Michigan 48130-0404
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONTHE SEARCH FOR METABOLIC...LEPTIN AS A METABOLIC...LEPTIN AS A METABOLIC...REFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR METABOLIC...LEPTIN AS A METABOLIC...LEPTIN AS A METABOLIC...REFERENCES |
|---|
Puberty is the time in life when mature gametes are first produced and reproductive activity is initiated. In most species, external indications of this transition into adulthood include gradual changes in behavior and body appearance. These changes reflect a chain of events originating in the brain: increasing production of sex steroids by the gonads in response to the increasing secretion of gonadotropins from the anterior pituitary gland, which, in turn, is being driven by the increased secretion of GnRH from the hypothalamus. Exactly when this cascade of hormones begins to increase is determined by a variety of signals routed through the brain to the neuroendocrine mechanisms that control GnRH secretion. Some of these signals originate internally and relate to growth whereas others are external and provide information about the individual's environment.
Perhaps the most important and contemporary issue in understanding puberty is determining how the brain knows when the body has reached the appropriate size to begin high-frequency GnRH secretion. This is based on the consideration that living organisms are endowed with the ability to sense nutritional state and to regulate their reproductive development and activity accordingly. Inadequate nutrition retards growth and delays sexual maturation; high nutrition and rapid growth advance maturation. During adulthood, alterations in nutrition may similarly depress or enhance reproductive activity. Neuroendocrine research on the metabolic regulation of puberty and adult reproductive function is of fundamental importance in view of our limited understanding of the mechanistic links between somatic metabolism and the neural/humoral control of reproduction. Recent advances in the field of ingestive behavior have provided new models and technologies for studying the metabolic regulation of appetite. By adapting these approaches to the study of reproduction, we may be able to identify metabolic changes that could serve to regulate GnRH secretion. The metabolic regulation of GnRH secretion during development and during adulthood has been an important clinical issue that is only now beginning to be addressed experimentally.
Puberty Is More Dependent upon Size Than Age
We face many fundamental questions about how the brain recognizes how well developed the body is so that it can begin the high-level GnRH secretion at the appropriate stage of development. Such questions emanate from the recognition that the timing of puberty is more closely associated with size than with age. Figure 1 shows the timing of one of the key indices for puberty in the human female (menarche—first menstruation). It is evident that whereas the age at menarche has been decreasing in Western society, size at menarche, based on body weight, has remained virtually unchanged. The most salient explanation given for this is that through better nutrition, growth has become maximized and young women achieve a comparable size at a younger age. These and other observations prompted the early consideration that puberty occurs once a critical weight is achieved. This notion has received considerable attention over the years and has been extended from "critical weight" to "critical level of fatness" to "critical level of a metabolic signal(s)." Our current concepts about what this signal(s) may be provide the focus of this review.
|
In order that we might convince ourselves that central mechanisms timing puberty are sensitive to a critical level of metabolic signal, we have noted that the frequency of LH secretion, a reflection of GnRH secretion, is more highly associated with body size than age in the developing sheep [1]; more direct measurement of GnRH in the pituitary portal circulation of rapidly growing and slowly growing lambs confirms this (Fig. 2). In lambs made to grow slowly through low nutrition, the frequency of GnRH release is much reduced compared to that in those fed ad libitum. This slow frequency of pulses can be changed dramatically and rapidly by increasing the level of nutrition [2].
|
|
THE SEARCH FOR METABOLIC SIGNALS REGULATING THE ONSET AND MAINTENANCE OF REPRODUCTIVE FUNCTION |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR METABOLIC...LEPTIN AS A METABOLIC...LEPTIN AS A METABOLIC...REFERENCES |
|---|
|
With the foregoing considerations in mind about growth and the control of GnRH secretion, we should be able to attack, at least conceptually, the problem of identifying which peripheral signals relate information about somatic development to the brain. One widely used approach to altering growth (alluded to above) is to alter the level of nutrition (Fig. 2). While this approach can be useful, by its very nature it has limitations in the developing individual because one cannot separate growth-induced signals from those induced exclusively by nutrition. Thus, to understand the nutritional component, we must turn to the adult, which is somatically mature; i.e., growth per se is not a factor. If we could better understand how energy metabolism regulates GnRH secretion in the adult, perhaps we could progress more rapidly in understanding the relationship among growth, metabolism, and production of high-frequency GnRH pulses during development.
Search for Metabolic Signals Regulating Reproductive Activity in the Adult
In the adult, an acute increase in reproductive activity can be induced by a short-term increase in nutrition. This phenomenon, termed "flushing," was originally described as a method to increase the twinning rate in sheep by providing high-calorie foodstuffs at least one reproductive cycle before breeding (see review [3]). Because this feeding method has no effect in well-fed animals and does not augment ovulation rate beyond that found in well-fed animals, it would suggest that those individuals in which flushing is effective are not being maintained under optimum reproductive conditions, presumably for economic reasons. This "flushing effect" can also be observed experimentally in the very short term as an increase in LH pulse frequency after high calorie intake in diet-restricted animals, indicating that even short-term changes in level of nutrition can markedly influence reproductive function in some species. This is illustrated in Figure 4 for the monkey, in which a day of fasting markedly reduces pulsatile LH secretion [4]. The high-level secretion rapidly returns upon refeeding the solid diet. The simple explanation that the stomach relays information to the brain by a neural pathway reflecting a change in volume was ruled out by providing saline to extend the stomach [5]. Similarly, milk, but not water, produces an abrupt return to high LH pulse frequency in the short-term (28-h) fasted lamb [2]. Therefore, an alternative explanation has been proposed, namely that nutritional factors or hormones function to regulate GnRH secretion. In the search for such a nutritional signal, researchers have encountered the stress axis. For example, in the above experiment, because fasted monkeys become agitated [6], it was unclear if stress played an important role in the depression of LH pulse frequency. This was determined not to be the case since gastric infusion of a nutrient mixture of amino acids and glucose into agitated, fasted monkeys restored high LH pulse frequency without changing behavior [5]. Other evidence that activation of the hypothalamo-hypophyseal-adrenal axis (HPA) is not responsible for the fasting-induced suppression of LH secretion is that infusion of "stress" levels of cortisol does not depress LH [7]. Conversely, in the rat, it is clear that fasting suppresses LH pulse frequency by activating the HPA axis because administration of a corticotropin-releasing hormone (CRH) antagonist can reverse the hypogonadotropism arising from 48-h food deprivation [8].
|
Using these and many other models in a variety of species, an increasing number of laboratories have become interested in how nutritional cues regulate reproductive function in the adult. Their findings are contained in a number of well-written reviews. Cameron's studies in the adult rhesus monkey have led her to conclude that calories, regardless of their source (fat, carbohydrates, or protein), are important in the regulation of LH secretion [9] and that these changes can produce changes in LH secretion very rapidly, within hours (Fig. 4). Studies from the laboratories of Wade and Schneider [10, 11] in the Syrian hamster have furthered this concept, providing critical evidence that oxidizable metabolic fuels can regulate estrous cyclicity and that central sensors might play a role. Metabolic hormones regulating fuel availability may be important, as evidenced by the findings of Martin [3], in which central insulin increases the secretion of LH. Our own work [12] suggests a role for glucose availability as a metabolic signal. Evidence for peripheral sensing of metabolic signals has emerged from the studies of Cagampang et al. [13] in the rat. Maeda and Tsukamura [14] have began to link the adrenal axis, particularly hypothalamic CRH neurons, with the reproductive axis to delineate a pathway for "nutritional stress."
Search for Metabolic Signals Timing Puberty
Information continually evolving from studies in the adult has provided vigor to studies of sexual maturation. At this time, using all of the available information in both the adult and developing individual, hypotheses need to be developed to explain how the pubertal rise in GnRH secretion occurs at a particular stage of growth. They would include the following elements: 1) a changing energy metabolism with growth necessitated by a changing soma; 2) increasing energy reserves (fat); 3) blood-borne signals reflecting changing energy metabolism and energy reserves. These considerations are based on the work of Kennedy and Mitra [15] 35 years ago, which yielded the contemporary hypothesis that the timing of puberty is ultimately based on energetics. They believed that the first transition between an infertile and fertile state (puberty) is tightly coupled to a change in somatic metabolism. At the heart of their hypothesis is the decrease in rate of metabolism that occurs during growth to maintain a stable core temperature when the rate of increase of the body mass (increase in heat production) exceeds the rate of the increase of surface area (heat dissipation). According to their view, once growth was sufficient as reflected by appropriate changes in energy balance, the reproductive system would become active. Their hypothesis considered that the brain might somehow detect the decrease in basal metabolic rate.
The Kennedy and Mitra concept remains valuable and needs to be evaluated further in the context of energy partitioning ([16], Fig. 5). It is generally accepted that developmental changes in metabolic state occur in response to changes in nutrient partitioning as the animal grows. With growth, less energy is expended for maintenance of basal metabolism per unit of body mass. This energy surfeit could be sensed by the brain through metabolites or metabolic hormones to signal high-level GnRH secretion. From this perspective, the search for growth-related signals timing the transition into adulthood has focused on metabolites associated with changes in energy requirements necessitated by the increase in somatic size. The metabolic signals that could serve as the molecular links between growth and reproduction remain elusive. Steiner et al. [17] proposed that glucose, insulin, or amino acids could serve as a blood-borne substance(s) to provide information about increasing body size during development to increase GnRH secretion. Although they attained only tantalizing proof for their hypothesis, it still remains highly attractive. In this respect, our own laboratory has begun to accumulate evidence that glucose availability is important.
|
|
LEPTIN AS A METABOLIC SIGNAL FOR THE MAINTENANCE OF REPRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR METABOLIC...LEPTIN AS A METABOLIC...LEPTIN AS A METABOLIC...REFERENCES |
|---|
The demographic studies of Frisch (see review [18]) kindled an interest in fatness as an important index for initiation of reproductive activity. She found a receptive clinical audience because a certain degree of fatness is associated with menarche as well as maintenance of reproductive cycles in women [19]. This association was found to be useful clinically, but scientifically her studies were unable to provide either any causality between fatness and reproduction or any acceptable neuroendocrine mechanism for how the brain is able to detect how fat the body is in order to increase GnRH secretion. At that time, there was nothing known to be produced by fat that could be a candidate for a signal to be detected by the brain. In lieu of this, Frisch suggested an indirect linkage by proposing that achieving greater fatness increased fertility through greater conversion of androgens to estrogens by fat tissue [20]. However, this was never considered to be a viable mechanism in terms of neuroendocrine control. Gradually increasing estrogen concentrations would not be able to stimulate tonic GnRH secretion in order to develop a preovulatory follicle that would then produce its own, massive rise of estrogen to trigger the preovulatory GnRH surge. Rather, a slowly increasing concentration of estrogen from an extraovarian source, if sufficient, would most likely reduce tonic GnRH secretion through its inhibitory feedback actions. Despite the lack of a tenable mechanism, her work provides a highly useful launch-point for the recent interest in fat and fertility, and the possibility that fat may produce something that the brain can monitor to assess somatic energetics.
Neuroendocrine Actions of Leptin on GnRH Secretion
The original clinical and pharmaceutical interest in leptin was to control appetite and obesity, and in the past 3 years, literally hundreds of papers have appeared on leptin activity and its gene regulation. Leptin is a 16-kDa protein produced by white adipocytes [21], and is considered to be a modulator of feeding behavior [22]. In this regard, high concentrations of leptin suppress appetite. Conversely, in the absence of the protein (e.g., ob/ob mouse, which cannot produce leptin) or in the absence of its receptor (e.g., db/db mouse, which cannot respond to leptin), hyperphagia, leading to obesity, occurs [23]. Studies measuring the protein reinforced this contention in view of the positive correlation between the release and synthesis of leptin and the body mass index or the percentage of body fat in the human female [24]. It was of comparatively minor interest for most reproductive scientists that the ob/ob or db/db mutants were basically infertile until 1996, when Chehab et al. [25] found that leptin injections into adult ob/ob mice restored their reproductive capacity. This watershed finding provided a novel mechanistic bridge between fatness and fertility. Since this discovery, the possibility that leptin may serve as a molecular intermediary to link metabolism and reproduction has attracted the attention of many reproductive scientists. However, to date, only a handful of reports have focused on neuroendocrinology, or on the control of GnRH secretion by leptin in a physiological setting. Barash et al. [26] found that in ob/ob mice, leptin administration increases basal LH levels. Using wild-type mice, Ahima et al. [27] found that fasting suppressed peripheral leptin concentrations, basal LH concentrations, and estrous cyclicity; such deficits could be prevented by exogenous leptin. Peripheral leptin treatment is likely to produce central modulation of GnRH secretion, on the basis of our recent finding that leptin can alter LH pulse frequency [28]. As shown in Figure 6 for the adult rat, LH pulse frequency is reduced during a 48-h fast, when leptin secretion is likewise suppressed. Such fasting-induced suppression of LH secretion is prevented by peripheral administration of leptin. Studies from other workers also suggest that leptin could act within the brain to influence GnRH secretion during fasting. When central leptin action is blunted (intracerebroventricular [icv] treatment with leptin antibody) in the fed rat, estrous cyclicity and pulsatile LH secretion cease [29]. In vitro, GnRH release from hypothalamic explants in leptin-free medium is lower than that in its presence [30]. However, a cautious evaluation as to the central action of leptin is needed, because in vivo, icv leptin treatment only partially restored basal LH secretion in the fasted rat [31].
|
Direct vs. Indirect Action of Leptin
While many investigators have assumed that leptin acts within the brain to affect the secretion of GnRH, the mechanism is not clear. The simplest possibility is that the fat-derived hormone regulates GnRH activity directly. This is problematic because it is difficult experimentally to change levels of leptin without altering many other nutritional factors which could be involved in the modulation of reproduction as well. Little attention has yet been paid to the possibility that leptin may act indirectly or at least in concert with other metabolic signals. For example, it has been reported that leptin may regulate insulin-stimulated glucose uptake, one of the factors regulating glucose availability. Glucose availability itself is thought to be a metabolic signal according to several lines of evidence indicating that variation in glucose availability can provide information for the control of GnRH secretion. First, glucose serves as a primary metabolic fuel for both the soma and brain. Second, that glucose availability could serve as a metabolic signal has long been considered by workers studying appetite control [32]. Third, pioneering work in the Syrian hamster has shown that oxidizable metabolic fuels, such as glucose, may be important in regulating estrous cyclicity [33]. In both the sheep [34] and rat [35], there is strong evidence that glucose availability may be a regulator of LH secretion. Fourth, dietary restriction slows growth and reduces peripheral glucose and insulin concentrations; in lambs so treated, the ontogeny of high-frequency LH pulses is delayed [36]. Fifth, insulin modulates LH secretion when infused into adult male sheep [37] or diabetic male lambs [38]. Sixth, recent work by our laboratory indicates that the insulin: glucose ratio is greater in postpubertal lambs than in prepubertal lambs (see following section).
Other evidence has become available to suggest that leptin action may work through changes in glucose availability. A recent study from Schneider's group on the Syrian hamster [39] reveals that the positive influence of leptin on estrous cyclicity during fasting is inhibited by the competitive glucose antagonist (2DG). This finding raises the possibility that the underlying mechanism for leptin's ability to restore reproductive activity during fasting is due to its ability to improve glucose availability. A similar conclusion was reached in a related study in which exogenous leptin treatment could not restore LH secretion in individuals whose LH secretion was impaired by reduced glucose availability (2DG treatment; Fig. 7, unpublished results). Perhaps leptin acts centrally at a glucosensor to stimulate glucose uptake. It is well documented that insulin increases glucose transport into cells through recruitment of the insulin-dependent glucose transporter (GLUT4 [40]). It would be interesting if GLUT4 transporters were also recruited by leptin, thereby providing a mechanism for the sensitivity to insulin to be increased by leptin [41]. Of keen interest would be the finding that such regulation occurred in the area postrema, a hindbrain circumventricular organ that is thought to serve as an important glucose detector for the regulation of GnRH secretion [42, 43]. Perhaps further studies in the ob/ob mouse would be useful in unraveling the relationship between leptin action and glucose availability. It would be of interest to know how, in this leptin-deficient model, the altered insulin secretion/action [23] contributes to the infertile condition. For example, it is possible that reduced glucose availability due to insulin resistance in these mice is due to the lack of leptin-induced insulin receptors or GLUT4 transporters in the area postrema.
|
Finally, in addition to the leptin-glucosensor interrelationship, it is possible to postulate that leptin counteracts a central suppressive pathway to GnRH secretion that is activated by reduced glucose availability. Fasting [27] and glucoprivation by 2DG [44] are known to be stressors as shown by increased corticosterone levels. Of the stimulated stress axis, CRH is reported [8] to be involved in the fasting-induced suppression of pulsatile LH secretion. Interestingly, one of the documented physiological roles of leptin is to reduce the stress response. Hypoglycemic stress-induced augmentation of CRH release from hypothalamic tissue in vitro is decreased by leptin [45].
From the above discussion, several models could be proposed as to how leptin could modulate GnRH secretion (Fig. 8). In the first, leptin could regulate GnRH neural activities independently of other nutritional factors (independent regulation). Evidence for the presence of leptin receptors in the hypothalamus [46] and the capability of leptin to stimulate GnRH release from hypothalamic explants in vitro [30] would contribute to this proposed model. However, this model may be too simple in view of the consideration that changes in metabolic fuels can also serve as metabolic signals. As pointed out by Wade and Schneider [47], inhibitors of metabolic fuel oxidization suppress reproductive function long before changes in fat stores, the source of leptin, can occur. Further, although a glucose antagonist can begin to depress endogenous leptin within 30 min (unpublished results), leptin replacement cannot prevent the depression in LH (GnRH) secretion (Fig. 7). Therefore, it is apparent that leptin's action on GnRH secretion can be modified by another putative metabolic signal, glucose availability. This raises the consideration that leptin works in concert with one or more metabolic signals. Thus, in the second model, we postulate that information on both leptin and other metabolic signals, such as glucose availability, is converged within some central integrator to regulate GnRH neuronal activity (converged regulation). This model provides the possibility that fatness (reserve energy) determines the threshold of glucose availability (current energy) that will allow for high-level GnRH secretion. However, no experimental evidence supporting this hypothesis is available yet. In the last model, we put emphasis on cascade regulation, in which leptin-induced changes in glucose availability play an ultimate role in dictating information to GnRH neurons. In this model, leptin would interact with pathways regulating glucose availability, perhaps by increasing insulin action through regulating glucose transporters at the glucodetectors, which relay information to the GnRH neurosecretory system.
|
|
LEPTIN AS A METABOLIC SIGNAL TIMING PUBERTY |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR METABOLIC...LEPTIN AS A METABOLIC...LEPTIN AS A METABOLIC...REFERENCES |
|---|
Criteria for a Metabolic Signal Timing Puberty
At least two major criteria must be satisfied to qualify a substance as an important blood-borne metabolic signal timing the pubertal increase in GnRH secretion: 1) the circulating substance must be quantitatively different for the sexually immature and the sexually mature individual, and must increase/decrease during growth; 2) the substance, when administered, must lead to a change in GnRH secretion such that agonism (or antagonism) advances (or delays) the pubertal GnRH rise. The focus is on the production of high-level GnRH secretion, for this will initiate the downstream events that lead to early gonadal activation, as demonstrated repeatedly in a variety of species.
It is intuitively obvious that peripheral concentrations of the putative puberty signal must be different for the sexually immature individual with reduced GnRH secretion and the adult with high GnRH secretion. Whether the candidate substance increases or decreases is not an important issue as long as it clearly changes. It could be argued that instead of a change in concentrations during growth and development, the sensitivity of the sensor for the substance could change. This would not provide a compelling argument for the candidate puberty-inducing substance being a signal. Instead, the substance would be considered to be permissive, and one must then determine what causes the change in sensitivity. Finally, for the first criterion to be met, in addition to a directional change, the substance would need to achieve adult concentrations in a manner that is temporally meaningful to the initiation of puberty. For example, if peripheral concentrations of the substance exhibited a pronounced change long before the time of puberty, the importance of the substance would be questionable.
The criterion that the substance must induce puberty opens complex, if not instructive, discussion. A seemingly simple approach would be to determine whether an appropriate dose of the candidate substance could prematurely produce high-level GnRH secretion to initiate the downstream events that lead to early gonadal activation. However, extreme caution must be taken to ensure clearly that the test individuals are in an optimal growth trajectory (growing as fast as possible). Advancing puberty during suboptimal growth may simply mean that the putative signal is permissive and serves only as a nutritional signal. While such nutritional signals may be important as gating mechanisms to growth and development, they would not constitute a true puberty signal. For this second criterion to be met, the substance would need to be able to induce high GnRH secretion well before the earliest time that it occurs naturally under optimum growth. Finally, and of importance, is the consideration that even if an important puberty signal(s) were identified, it is reasonable to assume that it would not be effective at earlier and earlier stages of development. This would lead to the consideration that multiple sequential signals may be involved during sexual maturation and that a developmental block exists for the proximate signal to work at some early stage. Perhaps this stage relates to the development of neural pathways that would support the information pathway leading to the metabolic control of GnRH secretion (Fig. 9, stage I). Once such systems are in place then metabolic cues may assume an important role (Fig. 9, stage II). Lastly, there could be instances when a known puberty-inducing metabolic signal simply is ineffective (Fig. 9, stage III). This may be due to other signals relating information about the individual's external environment (see the next section for expansion of this consideration of multiple signals).
|
Multiple Signals Timing Puberty
Before any discussion about puberty signals is brought to at least temporary closure, one must consider other known signals timing onset of reproductive activity and how they might relate to growth/metabolic signals. This is for both practical and theoretical reasons. Practically—for species living in their natural environment, external signals relating to time of year are important for timing puberty. This constitutes virtually all species, except the human being and a few domesticated animals. Similarly, many species use social signals as well, even our domesticated species. Theoretically—we must eventually understand how puberty can be timed so that the individual can begin reproduction not only at the appropriate body size (growth cues), but in the appropriate season (photoperiod cues, plant factors), and in the appropriate social setting (social cues) as well.
Figure 10 provides an interesting example of multiple signals timing puberty; specifically, it shows how an environmental cue, photoperiod, interacts with yet unknown growth cues to time the initiation of reproductive cycles in female lambs. Two facts emerge: 1) photoperiod cues, not growth cues, time puberty under conditions of optimal nutrition; 2) growth times puberty when growth occurs under an optimal photoperiod. In this study, the young female sheep were all born at the same time of year (spring) and were raised outside in natural photoperiod. Females of this species require a decreasing day length to attain puberty, a finding clearly demonstrated by using artificial photoperiods [48]. Growth rates were altered by changing the amount of food available. In this study, some females (group A, controls) were well fed from birth; they grew rapidly, and first ovulations (puberty) occurred at a typical age of about 30 wk in autumn when day lengths were decreasing. The three other groups (B, C, D) were placed on a restricted diet for varying periods after weaning. The onset of reproductive cycles was delayed in such growth-retarded females despite their having experienced the appropriate decreasing photoperiod for initiation of ovulations. Puberty did not occur because metabolic cues did not provide the message to the brain that energy balance and energy reserves were appropriate to initiate high-frequency GnRH secretion. Additional food was then provided to these females when they were older to induce growth during the short days of the autumn and winter breeding season (groups B and C). Reproductive cycles began at a smaller body size, (ca., 35 kg) than they did for the younger, but rapidly growing, females (i.e., group A controls, 45 kg). An important point can be raised here. Perhaps the normally growing females (group A) had already achieved the appropriate metabolic state and stage of growth for puberty much earlier in the year (August), but day lengths were too long at those younger ages (i.e., 25 wk) to produce high-level GnRH secretion. Later in the year (October), when day length became much shorter, reproductive cycles could be initiated (i.e., 30 wk of age). In the last group of lambs (D) the phase of rapid growth was induced at a much older age and during the spring anestrous season. These lambs remained anovulatory despite their growth well beyond the normal size required to initiate reproductive cycles. However, these females maintained sexual quiescence because of the long days of summer, until they experienced the decreasing day lengths of autumn. Then reproductive cycles began.
|
Thus, in the foregoing example, it is clear that photoperiod cues and growth-related cues serve as codeterminants timing the initiation of reproductive cycles through timing the expression of the high-frequency GnRH pulses. It is also evident that from an experimental strategy, one must be able to recognize when each signal is important to the regulation of high-frequency GnRH pulses. For example, growth signal(s) can be overridden by external signals, e.g., photoperiod. Experimentally, in the female lamb, administration of the putative metabolic/growth signal at an early age simply could not induce puberty during an inhibitory photoperiod. But, against the background of a stimulatory photoperiod, such a signal could be highly effective. A myriad of species use multiple cues to time puberty, and the next chapter in our understanding of growth-related signals will necessitate unraveling how the brain integrates and prioritizes these vastly different cues.
Is Leptin a Metabolic Signal Timing Puberty?
In view of our two fundamental criteria for a substance involved in the timing of puberty, we will eventually be able to determine whether leptin is the unique peripheral signal, is an important signal, is but one of a constellation of signals, or is not such a signal. However, at present, whether leptin plays a role regulating the pubertal increase in GnRH secretion remains highly controversial. It is not clear if peripheral levels of this hormone change in a meaningful way during development because there is no uniform consensus about the growth-related changes in circulating leptin among various species. This variation could be due to the condition of samples in retrospective studies and to the great differences between the current assays for leptin; many heterologous assays are used. In the human, peripheral leptin concentrations differ among studies [49–51]. In the monkey, circulating leptin does not increase during puberty [52, 53]. In the mouse, serum leptin concentrations peak during early development, after which they decline during the time of puberty [54]. Only a single study in the rat reports a progressive rise in peripheral leptin during puberty [55]. The ability of leptin to induce precocious puberty has been studied only in rodents due to the practical limitations of the supply of the hormone and the longer developmental time span of other species. Thus far, two studies have appeared in which giving leptin has advanced the time of puberty to an earlier age than it would normally occur [56, 57]; this was the case in one of the two experiments reported in the former article [56]. In other studies, exogenous leptin has been found to induce puberty in nutritionally growth-retarded individuals [55, 58]. As a cautionary note, administration of leptin suppresses food intake, and hence may block the action of other metabolic substances that act as important signals for the timing of puberty (see Discussion below). The next article by Steiner and coworkers [59] discusses in greater detail some of our current understanding of the status of leptin as a putative signal for timing the transition into adulthood. Overall, our present understanding is that leptin may at least be a permissive signal. In this regard, the lack of puberty, and lifetime infertility in the genetically obese human are reported to have their etiology in a defective leptin receptor [60].
Hypothesis
If leptin were found to be an important metabolic signal, albeit permissive, how could we explain its interaction with other metabolic cues also thought to be involved with the timing of puberty? This is illustrated in Figure 11. Such candidate signals include glucose availability and insulin-like growth factor I (IGF-I). Glucose availability could be increased to time puberty in several ways—an increase in peripheral concentrations of glucose, an increase in transport of glucose into cells, or an increase in glucose metabolism. Of these possibilities, there is some evidence for the transport mechanism. In both the monkey [17] and sheep (unpublished results), insulin increases during development. A concomitant increase in peripheral leptin would reinforce the uptake of glucose by the possible action of leptin on an insulin-dependent transporter (GLUT4?). According to this hypothesis, both leptin and glucose availability would serve as codeterminants for the timing of puberty. They may also be two of a constellation of signals. In this respect, Ojeda and Urbanski [61] propose that IGF-I, which is a trophic factor mediating the physiological effects of growth hormone and is progonadotropic [62], is a signal timing puberty. IGF-I does satisfy the aforementioned criteria for a metabolic signal. First, plasma concentrations of IGF-I increase notably during the onset of puberty in the rodent [63], primate [64], and sheep [65]. Second, icv injection of the hormone in the prepubertal female rat advances puberty and acutely increases plasma LH levels [66]. However, it is not known if antagonizing IGF-1 can delay/prevent the onset of puberty. It could be proposed that leptin might stimulate IGF-I, but the one study thus far conducted does not support this contention. Central leptin treatment cannot restore circulating IGF-I concentrations in fasting rats, although it can prevent the suppression of growth hormone secretion [67]. In order to understand if there is indeed any regulation of IGF-I by leptin, we need to determine the importance of the presence of peripheral, rather than central, leptin for growth hormone to exert its stimulatory effect on IGF-I secretion. Until such data become available, we can only speculate that leptin may time puberty through its triggering of IGF-I secretion as well as through its effect on increasing glucose availability.
|
In view of the foregoing, we are left with the possibility that a number of circulating substances reflecting the status of energy metabolism may serve a metabolic signals timing puberty. Importantly, and regardless of the exact details, if a particular metabolic state typical of the adult must be achieved to support high-level GnRH secretion, then the metabolic control of the timing of puberty would not be a unique developmental phenomenon. Puberty would simply be the time when this metabolic state is first attained. This would provide an alternative explanation to the idea that the timing of puberty is signaled by the first appearance of a unique adult somatic substance. The validity of this concept remains to be determined. It rests on comparative studies between sexually immature and sexually mature individuals, to identify important metabolic signals and then to assess their relative efficacy in regulating GnRH secretion at each stage of the life cycle.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 Correspondence: Douglas L. Foster, Room 1101, 300 North Ingalls Building, Ann Arbor, MI 48109–0404. FAX: 734 763 0247; dlfoster{at}umich.edu
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR METABOLIC...LEPTIN AS A METABOLIC...LEPTIN AS A METABOLIC...REFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  P. K. Chelikani, D. J. Ambrose, D. H. Keisler, and J. J. Kennelly Effects of dietary energy and protein density on plasma concentrations of leptin and metabolic hormones in dairy heifers J Dairy Sci, April 1, 2009; 92(4): 1430 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E Buyken, N. Karaolis-Danckert, and T. Remer Association of prepubertal body composition in healthy girls and boys with the timing of early and late pubertal markers Am. J. Clinical Nutrition, January 1, 2009; 89(1): 221 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Wilson and B. Kinkead Gene-Environment Interactions, Not Neonatal Growth Hormone Deficiency, Time Puberty in Female Rhesus Monkeys Biol Reprod, April 1, 2008; 78(4): 736 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. Bonjour and T. Chevalley Pubertal Timing, Peak Bone Mass and Fragility Fracture Risk IBMS BoneKEy, February 1, 2007; 4(2): 30 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The ESHRE Capri Workshop Group Nutrition and reproduction in women Hum. Reprod. Update, May 1, 2006; 12(3): 193 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Salvi, E. Castillo, M.-J. Voirol, M. Glauser, J.-P. Rey, R. C. Gaillard, P. Vollenweider, and F. P. Pralong Gonadotropin-Releasing Hormone-Expressing Neurons Immortalized Conditionally Are Activated by Insulin: Implication of the Mitogen-Activated Protein Kinase Pathway Endocrinology, February 1, 2006; 147(2): 816 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J P Ebling The neuroendocrine timing of puberty Reproduction, June 1, 2005; 129(6): 675 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Menet, P. Vuillez, D. Bonn, A. Senser, and P. Pevet Conflicting effects of exercise on the establishment of a short-photoperiod phenotype in Syrian hamster Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R234 - R242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. N. Wade and J. E. Jones Neuroendocrinology of nutritional infertility Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1277 - R1296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.E. Wilson, K. Chikazawa, J. Fisher, D. Mook, and K.G. Gould Reduced Growth Hormone Secretion Prolongs Puberty But Does Not Delay the Developmental Increase in Luteinizing Hormone in the Absence of Gonadal Negative Feedback Biol Reprod, August 1, 2004; 71(2): 588 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.N. Maciel, D.A. Zieba, M. Amstalden, D.H. Keisler, J.P. Neves, and G.L. Williams Leptin Prevents Fasting-Mediated Reductions in Pulsatile Secretion of Luteinizing Hormone and Enhances Its Gonadotropin-Releasing Hormone-Mediated Release in Heifers Biol Reprod, January 1, 2004; 70(1): 229 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Ehrhardt, P. L. Greenwood, A. W. Bell, and Y. R. Boisclair Plasma Leptin Is Regulated Predominantly by Nutrition in Preruminant Lambs J. Nutr., December 1, 2003; 133(12): 4196 - 4201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-S. Parent, G. Teilmann, A. Juul, N. E. Skakkebaek, J. Toppari, and J.-P. Bourguignon The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration Endocr. Rev., October 1, 2003; 24(5): 668 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Wilson, J. Fisher, K. Chikazawa, R. Yoda, A. Legendre, D. Mook, and K. G. Gould Leptin Administration Increases Nocturnal Concentrations of Luteinizing Hormone and Growth Hormone in Juvenile Female Rhesus Monkeys J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4874 - 4883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bandyopadhyay, J. Chakrabarti, S. Banerjee, A.K. Pal, S.K. Goswami, B.N. Chakravarty, and S.N. Kabir Galactose toxicity in the rat as a model for premature ovarian failure: an experimental approach readdressed Hum. Reprod., October 1, 2003; 18(10): 2031 - 2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Block, J. M. Smith, R. A. Ehrhardt, M. C. Diaz, R. P. Rhoads, M. E. Van Amburgh, and Y. R. Boisclair Nutritional and Developmental Regulation of Plasma Leptin in Dairy Cattle J Dairy Sci, October 1, 2003; 86(10): 3206 - 3214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Burcelin, B. Thorens, M. Glauser, R. C. Gaillard, and F. P. Pralong Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin Endocrinology, October 1, 2003; 144(10): 4484 - 4491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Mann, A. O. K. Johnson, T. Gimpel, and V. D. Castracane Changes in Circulating Leptin, Leptin Receptor, and Gonadal Hormones from Infancy until Advanced Age in Humans J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3339 - 3345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. White, T. Nguyen, and R. D. Fernald Social regulation of gonadotropin-releasing hormone J. Exp. Biol., September 1, 2002; 205(17): 2567 - 2581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Garcia, M. Amstalden, S. W. Williams, R. L. Stanko, C. D. Morrison, D. H. Keisler, S. E. Nizielski, and G. L. Williams Serum leptin and its adipose gene expression during pubertal development, the estrous cycle, and different seasons in cattle J Anim Sci, August 1, 2002; 80(8): 2158 - 2167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. I. Williams, D. L. Helmreich, D. B. Parfitt, A. Caston-Balderrama, and J. L. Cameron Evidence for a Causal Role of Low Energy Availability in the Induction of Menstrual Cycle Disturbances during Strenuous Exercise Training J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5184 - 5193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Sisk, H. N. Richardson, P. E. Chappell, and J. E. Levine In Vivo Gonadotropin-Releasing Hormone Secretion in Female Rats during Peripubertal Development and on Proestrus Endocrinology, July 1, 2001; 142(7): 2929 - 2936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Unkila-Kallio, S. Andersson, H.A. Koistinen, S.-L. Karonen, O. Ylikorkala, and A. Tiitinen Leptin during assisted reproductive cycles: the effect of ovarian stimulation and of very early pregnancy Hum. Reprod., April 1, 2001; 16(4): 657 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Terasawa and D. L. Fernandez Neurobiological Mechanisms of the Onset of Puberty in Primates Endocr. Rev., February 1, 2001; 22(1): 111 - 151. [Abstract] [Full Text]
|
|
|
|
|
|
M. C. Henson and V. D. Castracane Leptin in Pregnancy Biol Reprod, November 1, 2000; 63(5): 1219 - 1228. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. E. Freeman, B. Kanyicska, A. Lerant, and G. Nagy Prolactin: Structure, Function, and Regulation of Secretion Physiol Rev, October 1, 2000; 80(4): 1523 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Fitzgerald and C. J. McManus Photoperiodic Versus Metabolic Signals as Determinants of Seasonal Anestrus in the Mare Biol Reprod, July 1, 2000; 63(1): 335 - 340. [Abstract] [Full Text]
|
|
|
|
|
|
I. S. Parhar, T. Soga, and Y. Sakuma Thyroid Hormone and Estrogen Regulate Brain Region-Specific Messenger Ribonucleic Acids Encoding Three Gonadotropin-Releasing Hormone Genes in Sexually Immature Male Fish, Oreochromis niloticus Endocrinology, May 1, 2000; 141(5): 1618 - 1626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Hileman, D. D. Pierroz, and J. S. Flier Leptin, Nutrition, and Reproduction: Timing Is Everything J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 804 - 807. [Full Text]
|
|
|
|
|
|
K. J. Suter, C. R. Pohl, and M. E. Wilson Circulating Concentrations of Nocturnal Leptin, Growth Hormone, and Insulin-Like Growth Factor-I Increase before the Onset of Puberty in Agonadal Male Monkeys: Potential Signals for the Initiation of Puberty J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 808 - 814. [Abstract] [Full Text]
|
|
|
|
|
|
D. R. Mann, M. A. Akinbami, K. G. Gould, and V. D. Castracane A Longitudinal Study of Leptin During Development in the Male Rhesus Monkey: The Effect of Body Composition and Season on Circulating Leptin Levels Biol Reprod, February 1, 2000; 62(2): 285 - 291. [Abstract] [Full Text]
|
|
|
|
|
|
Is Obesity an Outcome of Gonadotropin-Releasing Hormone Agonist Administration? Analysis of Growth and Body Composition in 110 Patients with Central Precocious Puberty J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4480 - 4488. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Cunningham, D. K. Clifton, and R. A. Steiner Leptin's Actions on the Reproductive Axis: Perspectives and Mechanisms Biol Reprod, February 1, 1999; 60(2): 216 - 222. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
