BIOLOGY OF REPRODUCTION 60, 205–215 (1999)
Physiological Perspectives on Leptin as a Regulator of Reproduction:
Role in Timing Puberty1
D.L. Foster2,3,4,5 and S. Nagatani3
Reproductive Sciences Program,3 Departments of Obstetrics and Gynecology4 and Biology,5
University of Michigan, Ann Arbor, Michigan 48130-0404
ABSTRACT
How nutrition regulates reproductive activity remains a ma-
jor unsolved question of reproductive biology. Reducing the lev-
el of nutrition during adulthood can lead to infertility, primarily
through reduction of GnRH secretion. Inquiry about such a
mechanism has its roots in the search for cues timing the onset
of fertility, because the tempo of sexual maturation is much
more closely associated with body growth than with chronolog-
ical age. Growth depends on the quantity and quality of food
intake. When food availability is low, small, short-lived species
with high metabolism and reduced growth may not even attain
puberty before they die. In longer-lived species, puberty is de-
layed for months or even years until more food becomes avail-
able. To appreciate fully how the pubertal progression is timed
will require understanding how peripheral signals relating in-
formation about energy metabolism are sensed by the brain and
how such information is routed through pathways controlling
GnRH secretion. Here, we provide some background and phys-
iologic perspective on the question of whether the fat-derived
hormone leptin is the unique peripheral signal, is an important
signal, is but one of a constellation of signals, or is not a signal
timing puberty.
INTRODUCTION
General Considerations
Puberty is the time in life when mature gametes are first
produced and reproductive activity is initiated. In most spe-
cies, 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 hy-
pothalamus. 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 environ-
ment.
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 con-
sideration that living organisms are endowed with the abil-
ity to sense nutritional state and to regulate their reproduc-
tive development and activity accordingly. Inadequate nu-
trition retards growth and delays sexual maturation; high
1
This work was supported by NIH-HD-18394, NSF-INT-9603310, and
Amgen, Inc.
2
Correspondence: Douglas L. Foster, Room 1101, 300 North Ingalls
Building, Ann Arbor, MI 48109–0404. FAX: 734 763 0247;
e-mail: dlfoster@umich.edu
205
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 lim-
ited understanding of the mechanistic links between so-
matic metabolism and the neural/humoral control of repro-
duction. Recent advances in the field of ingestive behavior
have provided new models and technologies for studying
the metabolic regulation of appetite. By adapting these ap-
proaches 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 secre-
tion 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 as-
sociated 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 vir-
tually 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 ‘‘crit-
ical 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 high-
ly associated with body size than age in the developing
sheep [1]; more direct measurement of GnRH in the pitu-
itary portal circulation of rapidly growing and slowly grow-
ing lambs confirms this (Fig. 2). In lambs made to grow
slowly through low nutrition, the frequency of GnRH re-
lease is much reduced compared to that in those fed ad
libitum. This slow frequency of pulses can be changed dra-
matically and rapidly by increasing the level of nutrition
[2].
206 FOSTER AND NAGATANI

FIG. 2. Patterns of GnRH secretion in a rapidly growing (top) and in a

slowly growing (bottom) lamb. (Redrawn from [2]).

is somatically mature; i.e., growth per se is not a factor. If

FIG. 1. Age (top) and weight (bottom) at menarche in the human. (Top
redrawn from [68]; bottom redrawn from [69]).
we could better understand how energy metabolism regu-
lates GnRH secretion in the adult, perhaps we could pro-
gress more rapidly in understanding the relationship among
growth, metabolism, and production of high-frequency
GnRH pulses during development.

THE SEARCH FOR METABOLIC SIGNALS REGULATING Search for Metabolic Signals Regulating Reproductive
THE ONSET AND MAINTENANCE OF REPRODUCTIVE Activity in the Adult
FUNCTION
In the adult, an acute increase in reproductive activity
To appreciate fully how pubertal progression is timed can be induced by a short-term increase in nutrition. This
requires an understanding of how the brain senses changes phenomenon, termed ‘‘flushing,’’ was originally described
in growth, perhaps through sensing changes in energy me- as a method to increase the twinning rate in sheep by pro-
tabolism. In the adult, we are fundamentally ignorant of viding high-calorie foodstuffs at least one reproductive cy-
how nutrition modulates the reproductive neuroendocrine cle before breeding (see review [3]). Because this feeding
system, a problem that is receiving increasing attention. method has no effect in well-fed animals and does not aug-
Ironically, it is of historical interest that we have now come ment ovulation rate beyond that found in well-fed animals,
full circle because the contemporary search for how nutri-
tion and metabolism influence reproduction in the adult has
its major root in the search for cues timing puberty. In
broadest terms, we believe some of the most important un-
answered questions in all of the reproductive sciences relate
to what are the peripheral signals that convey information
about energy metabolism to the brain, where are they
sensed, and how such information is routed through path-
ways controlling GnRH secretion (Fig. 3).
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 FIG. 3. Signals, sensors, and pathways, a unified view toward under-
those induced exclusively by nutrition. Thus, to understand standing how nutrition regulates the neuroendocrine control of reproduc-
the nutritional component, we must turn to the adult, which tive activity.
 LEPTIN AS PHYSIOLOGICAL SIGNAL FOR A GnRH SECRETION
it would suggest that those individuals in which flushing is
effective are not being maintained under optimum repro-
ductive 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, indicat-
ing 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 ex-
tend the stomach [5]. Similarly, milk, but not water, pro-
duces 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 fac-
tors 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 ex-
periment, because fasted monkeys become agitated [6], it
was unclear if stress played an important role in the de-
pression 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 behav-
ior [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]. Con-
versely, in the rat, it is clear that fasting suppresses LH
pulse frequency by activating the HPA axis because ad-
ministration 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 spe-
cies, an increasing number of laboratories have become in-
terested in how nutritional cues regulate reproductive func-
tion in the adult. Their findings are contained in a number
of well-written reviews. Cameron’s studies in the adult rhe-
sus monkey have led her to conclude that calories, regard-
less of their source (fat, carbohydrates, or protein), are im-
portant 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 cen-
tral sensors might play a role. Metabolic hormones regu-
lating fuel availability may be important, as evidenced by
the findings of Martin [3], in which central insulin increases
207
FIG. 4. Patterns of LH secretion in a rhe-
sus monkey on a normal day of feeding,
during a day of fasting, and during refeed-
ing. (Redrawn from [4]).
the secretion of LH. Our own work [12] suggests a role for
glucose availability as a metabolic signal. Evidence for pe-
ripheral 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, partic-
ularly 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 de-
veloped 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 hy-
pothesis 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 hy-
pothesis 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 pro-
duction) 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 par-
titioning ([16], Fig. 5). It is generally accepted that devel-
opmental 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 met-
abolic hormones to signal high-level GnRH secretion. From
this perspective, the search for growth-related signals tim-
ing the transition into adulthood has focused on metabolites
associated with changes in energy requirements necessitat-
ed 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
208 FOSTER AND NAGATANI
FIG. 5. Scheme of energy partitioning,
growth, and reproduction. Note that at a
young age, when the soma is small and
metabolic rate is high, most energy is ex-
pended for cellular maintenance and loco-
motion; any excess can be used for
growth. As the individual grows, the meta-
bolic rate decreases, the amount of energy
reserve (fat) increases, and excess energy
becomes sufficient to initiate reproductive
activity. (Redrawn from [16]).
body size during development to increase GnRH secretion.
Although they attained only tantalizing proof for their hy-
pothesis, 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
Historical Association of Fatness and Fertility
The demographic studies of Frisch (see review [18]) kin-
dled an interest in fatness as an important index for initi-
ation 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 cy-
cles in women [19]. This association was found to be useful
clinically, but scientifically her studies were unable to pro-
vide 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 in-
crease 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 in-
creasing 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 high-
ly useful launch-point for the recent interest in fat and fer-
tility, 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 pro-
duced 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 pro-
tein reinforced this contention in view of the positive cor-
relation 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 repro-
duction 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 increas-
es basal LH levels. Using wild-type mice, Ahima et al. [27]
found that fasting suppressed peripheral leptin concentra-
tions, 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 Fig-
ure 6 for the adult rat, LH pulse frequency is reduced dur-
ing a 48-h fast, when leptin secretion is likewise sup-
pressed. 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 cy-
clicity 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 need-
ed, because in vivo, icv leptin treatment only partially re-
stored 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 mech-
anism 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 fac-
tors which could be involved in the modulation of repro-
duction as well. Little attention has yet been paid to the
possibility that leptin may act indirectly or at least in con-
cert 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 sig-
nal according to several lines of evidence indicating that
variation in glucose availability can provide information for
 LEPTIN AS PHYSIOLOGICAL SIGNAL FOR A GnRH SECRETION
FIG. 6. Patterns of LH secretion in adult female rats during a 48-h fast
in the absence (left) or presence (right) of leptin replacement throughout
fasting. (Redrawn from [28]).
the control of GnRH secretion. First, glucose serves as a
primary metabolic fuel for both the soma and brain. Sec-
ond, that glucose availability could serve as a metabolic
signal has long been considered by workers studying ap-
petite 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 re-
duces 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 lep-
tin action may work through changes in glucose availabil-
ity. 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 compet-
itive glucose antagonist (2DG). This finding raises the pos-
sibility that the underlying mechanism for leptin’s ability to
restore reproductive activity during fasting is due to its abil-
ity 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 in-
sulin-dependent glucose transporter (GLUT4 [40]). It
209
FIG. 7. Patterns of LH secretion in adult female rats during cellular hy-
poglycemia (induced by 2DG, a competitive glucose antagonist) in the
absence (top) or presence (bottom) of leptin replacement beginning 2 h
before treatment. (unpublished results).
would be interesting if GLUT4 transporters were also re-
cruited 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 avail-
ability. 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 pos-
sible that reduced glucose availability due to insulin resis-
tance in these mice is due to the lack of leptin-induced
insulin receptors or GLUT4 transporters in the area postre-
ma.
Finally, in addition to the leptin-glucosensor interrela-
tionship, it is possible to postulate that leptin counteracts a
central suppressive pathway to GnRH secretion that is ac-
tivated 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 fast-
ing-induced suppression of pulsatile LH secretion. Interest-
ingly, one of the documented physiological roles of leptin
is to reduce the stress response. Hypoglycemic stress-in-
210 FOSTER AND NAGATANI
FIG. 8. Models to account for the regulation of GnRH secretion by leptin
and glucose availability.
duced augmentation of CRH release from hypothalamic tis-
sue in vitro is decreased by leptin [45].
From the above discussion, several models could be pro-
posed as to how leptin could modulate GnRH secretion
(Fig. 8). In the first, leptin could regulate GnRH neural
activities independently of other nutritional factors (inde-
pendent regulation). Evidence for the presence of leptin re-
ceptors in the hypothalamus [46] and the capability of lep-
tin to stimulate GnRH release from hypothalamic explants
in vitro [30] would contribute to this proposed model. How-
ever, this model may be too simple in view of the consid-
eration 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 re-
productive function long before changes in fat stores, the
source of leptin, can occur. Further, although a glucose an-
tagonist can begin to depress endogenous leptin within 30
min (unpublished results), leptin replacement cannot pre-
vent the depression in LH (GnRH) secretion (Fig. 7).
Therefore, it is apparent that leptin’s action on GnRH se-
cretion can be modified by another putative metabolic sig-
nal, 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 secre-
tion. However, no experimental evidence supporting this
hypothesis is available yet. In the last model, we put em-
phasis on cascade regulation, in which leptin-induced
changes in glucose availability play an ultimate role in dic-
tating information to GnRH neurons. In this model, leptin
would interact with pathways regulating glucose availabil-
ity, perhaps by increasing insulin action through regulating
glucose transporters at the glucodetectors, which relay in-
formation to the GnRH neurosecretory system.
LEPTIN AS A METABOLIC SIGNAL TIMING PUBERTY
Before we can consider whether leptin might serve as a
metabolic signal, it would be important to establish the cri-
teria for such a signal. They are more or less obvious, but
some of the nuances of the criteria prove to be interesting.
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 cir-
culating 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 secre-
tion such that agonism (or antagonism) advances (or de-
lays) the pubertal GnRH rise. The focus is on the produc-
tion 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 sexu-
ally 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 develop-
ment, 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 permis-
sive, 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 tempo-
rally 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 appro-
priate dose of the candidate substance could prematurely
produce high-level GnRH secretion to initiate the down-
stream events that lead to early gonadal activation. How-
ever, 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 sig-
nal 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 impor-
tance, is the consideration that even if an important puberty
 LEPTIN AS PHYSIOLOGICAL SIGNAL FOR A GnRH SECRETION
signal(s) were identified, it is reasonable to assume that it
would not be effective at earlier and earlier stages of de-
velopment. This would lead to the consideration that mul-
tiple sequential signals may be involved during sexual mat-
uration and that a developmental block exists for the prox-
imate 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 sys-
tems are in place then metabolic cues may assume an im-
portant role (Fig. 9, stage II). Lastly, there could be instanc-
es 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 con-
sideration of multiple signals).
211
FIG. 9. Stages of development and re-
sponsiveness to metabolic cues timing pu-
berty. Stage I would be during early devel-
opment, when neural pathways are form-
ing and when the GnRH neurosecretory
system is not yet responsive to metabolic
signals. During stage II, GnRH neurosecre-
tion is regulated by metabolic signals.
During stage III, the response to metabolic
signals is integrated with other signals
about the environment and society; often
these externally derived signals can over-
ride those metabolic signals relating infor-
mation about the growth of the soma. (Re-
drawn from [16]).
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 be-
ing and a few domesticated animals. Similarly, many spe-
cies use social signals as well, even our domesticated spe-
cies. Theoretically—we must eventually understand how
puberty can be timed so that the individual can begin re-
production not only at the appropriate body size (growth
cues), but in the appropriate season (photoperiod cues, plant
212 FOSTER AND NAGATANI
FIG. 10. Interaction between growth and
photoperiod to time the initiation of repro-
ductive activity in the female sheep fed
different diets (see text for details). The as-
terisks denote the age and body weight for
the time of first ovulations in relation to
length of day (-—) and the time of the
adult breeding season (top). Note that pu-
berty can occur only when the appropriate
growth occurs during the appropriate time
of the year (breeding season). (Redrawn
from [48]).
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 envi-
ronmental 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 nu-
trition; 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 photoperi-
ods [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 repro-
ductive cycles was delayed in such growth-retarded females
despite their having experienced the appropriate decreasing
photoperiod for initiation of ovulations. Puberty did not oc-
cur because metabolic cues did not provide the message to
the brain that energy balance and energy reserves were ap-
propriate to initiate high-frequency GnRH secretion. Ad-
ditional 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). Re-
productive 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 (Au-
gust), 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 short-
er, 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 photo-
period cues and growth-related cues serve as codetermi-
nants 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 exam-
ple, growth signal(s) can be overridden by external signals,
e.g., photoperiod. Experimentally, in the female lamb, ad-
ministration of the putative metabolic/growth signal at an
early age simply could not induce puberty during an inhib-
itory photoperiod. But, against the background of a stim-
ulatory photoperiod, such a signal could be highly effec-
tive. 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 mean-
ingful 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, periph-
eral leptin concentrations differ among studies [49–51]. In
the monkey, circulating leptin does not increase during pu-
berty [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 pu-
 LEPTIN AS PHYSIOLOGICAL SIGNAL FOR A GnRH SECRETION
berty [55]. The ability of leptin to induce precocious pu-
berty 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 experi-
ments reported in the former article [56]. In other studies,
exogenous leptin has been found to induce puberty in nu-
tritionally growth-retarded individuals [55, 58]. As a cau-
tionary note, administration of leptin suppresses food in-
take, 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 per-
missive signal. In this regard, the lack of puberty, and life-
213
FIG. 11. Hypothesis for how metabolic
cues could interact to time puberty.
time 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 trans-
port of glucose into cells, or an increase in glucose metab-
olism. 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
214 FOSTER AND NAGATANI
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 hor-
mone and is progonadotropic [62], is a signal timing pu-
berty. IGF-I does satisfy the aforementioned criteria for a
metabolic signal. First, plasma concentrations of IGF-I in-
crease 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, al-
though 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 cen-
tral, leptin for growth hormone to exert its stimulatory ef-
fect 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 con-
cept remains to be determined. It rests on comparative stud-
ies between sexually immature and sexually mature indi-
viduals, to identify important metabolic signals and then to
assess their relative efficacy in regulating GnRH secretion
at each stage of the life cycle.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the conceptual assistance of nu-
merous colleagues seeking to define the peripheral metabolic signals that
influence the reproductive neuroendocrine system: Drs. David Bucholtz
and Robert Thompson, University of Michigan; Kei Maeda and Hiroko
Tsukamura, Nagoya University; Tomomi Tanaka, Tokyo University of Ag-
riculture and Technology; Satoshi Ohkura, Kyoto University Primate Re-
search Institute; Frank Bronson, University of Texas, Austin; Judy Cam-
eron, University of Pittsburgh and Oregon Regional Primate Center;
Duane Keisler, University of Missouri; Graeme Martin, University of
Western Australia; Robert Steiner, University of Washington; Jill Schnei-
der, Lehigh University; George Wade, University of Massachusetts, Am-
herst. We thank Ms. Juanita Pelt for her technical assistance in manuscript
preparation, and the Reproductive Sciences Program, University of Mich-
igan, for providing the framework for multidisciplinary research in repro-
ductive biology.
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