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In female mammals reproduction is highly sensitive to the food supply. During lean times, females suspend reproductive attempts in favor of maintaining processes necessary for survival; fertility is restored once the food supply is again abundant. Nearly all aspects of reproduction are affected, including puberty, adult ovulatory cycles, and reproductive behaviors. Work with experimental animals reveals that caloric restriction inhibits release of luteinizing hormone (LH) and female sexual behavior via similar, although separate, processes. The primary metabolic event affecting LH release as well as female sexual behavior is the short-term (minute-to-minute, hour-to-hour) availability of oxidizable metabolic fuels, rather than any aspect of body size or composition (e.g., body fat content). Metabolic fuel availability is detected in the hindbrain and perhaps in peripheral tissues. Metabolic information is then transmitted synaptically from the visceral hindbrain to the forebrain effector circuits. In the forebrain, signaling via corticotropin-releasing hormone receptors appears to be crucial for inhibition of both LH secretion and female sexual behavior. [ABSTRACT FROM AUTHOR]

When previously sedentary men and women follow exercise training programs with ad libitum feeding, men lose body fat, but women do not. The purpose of this study was to evaluate whether this observation could be related to sex differences in the way energy-regulating hormones and appetite perception respond to exercise. Eighteen (9 men, 9 women) overweight/obese individuals completed four bouts of exercise with energy added to the baseline diet to maintain energy balance (BAL), and four bouts without energy added to induce energy deficit (DEF). Concentrations of acylated ghrelin, insulin, and leptin, as well as appetite ratings were measured in response to a meal after a no-exercise baseline and both exercise conditions. In men, acylated ghrelin area under the curve (AUC) was not different between conditions. In women, acylated ghrelin AUC was higher after DEF (+32%) and BAL (+25%), and the change from baseline was higher than men (P < 0.05). In men, insulin AUC was reduced (-17%) after DEF (P < 0.05), but not BAL. In women, insulin AUC was lower (P < 0.05) after DEF (-28%) and BAL (-15%). Leptin concentrations were not different across conditions in either sex. In men, but not in women, appetite was inhibited after BAL relative to DEF. The results indicate that, in women, exercise altered energy-regulating hormones in a direction expected to stimulate energy intake, regardless of energy status. In men, the response to exercise was abolished when energy balance was maintained. The data are consistent with the paradigm that mechanisms to maintain body fat are more effective in women.

Purpose of Review: To summarize the physiological bases of infertility during undernutrition., Recent Findings: When energy expenditure consistently exceeds intake, survival receives temporary priority over fertility, and reproduction is deferred until conditions are more favorable. This nutritional infertility is due to inhibition of both gonadotropin-releasing hormone secretion and copulatory behaviors. Recent work has focused on the nature of the metabolic signals to the brain, detection of these signals, and the neural circuitry involved. This work is reviewed and summarized., Summary: It was once erroneously believed that female mammals had to maintain a particular body fat content to remain fertile. We now know that the primary metabolic factor is short-term availability of glucose and fatty acids for oxidation. Metabolic fuel availability is detected in the caudal hindbrain and possibly elsewhere. This information is relayed to the forebrain via projections containing catecholamines and neuropeptide-Y, where they activate corticotropin-releasing hormone neurons. Acting as a neurotransmitter, this hormone inhibits gonadotropin-releasing hormone secretion and estrous behavior. Conversely, corticotropin-releasing hormone antagonists reverse the effects of food deprivation on both measures, indicating that corticotropin-releasing hormone is vital in the nutritional suppression of reproduction. Leptin may modulate reproductive responses to changes in short-term fuel availability.

Caloric deprivation inhibits reproduction, including copulatory behaviors, in female mammals. Decreases in metabolic fuel availability are detected in the hindbrain, and this information is relayed to the forebrain circuits controlling estrous behavior by neuropeptide Y (NPY) projections. In the forebrain, the nutritional inhibition of estrous behavior appears to be mediated by corticotropin-releasing factor (CRF) or urocortin-signaling systems. Intracerebroventricular (ICV) infusion of the CRF antagonist, astressin, prevents the suppression of lordosis by food deprivation and by NPY treatment in Syrian hamsters. These experiments sought to determine which CRF receptor type(s) is involved. ICV infusion of the CRF receptor subtype CRFR2-selective agonists urocortin 2 and 3 (UCN2, UCN3) inhibited sexual receptivity in hormone-primed, ovariectomized hamsters. Furthermore, the CRFR2-selective antagonist, astressin 2B, prevented the inhibition of estrous behavior by UCN2 and by NPY, consistent with a role for CRFR2. On the other hand, astressin 2B did not prevent the inhibition of behavior induced by 48-h food deprivation or ICV administration of CRF, a mixed CRFR1 and CRFR2 agonist, suggesting that activation of CRFR1 signaling is sufficient to inhibit sexual receptivity in hamsters. Although administration of CRFR1-selective antagonists (NBI-27914 and CP-154,526) failed to reverse the inhibition of receptivity by CRF treatment, we could not confirm their biological effectiveness in hamsters. The most parsimonious interpretation of these findings is that, although NPY inhibits estrous behavior via downstream CRFR2 signaling, food deprivation may exert its inhibition via both CRFR1 and CRFR2 and that redundant neuropeptide systems may be involved.

Natural selection has linked the physiological controls of energy balance and fertility such that reproduction is deferred during lean times, particularly in female mammals. In this way, an energetically costly process is confined to periods when sufficient food is available to support pregnancy and lactation. Even in the face of abundance, nutritional infertility ensues if energy intake fails to keep pace with expenditure. A working hypothesis is proposed in which any activity or condition that limits the availability of oxidizable fuels (e.g., undereating, excessive energy expenditure, diabetes mellitus) can inhibit both gonadotropin-releasing hormone (GnRH)/luteinizing hormone secretion and female copulatory behaviors. Decreases in metabolic fuel availability appear to be detected by cells in the caudal hindbrain. Hindbrain neurons producing neuropeptide Y (NPY) and catecholamines (CA) then project to the forebrain where they contact GnRH neurons both directly and also indirectly via corticotropin-releasing hormone (CRH) neurons to inhibit GnRH secretion. In the case of estrous behavior, the best available evidence suggests that the inhibitory NPY/CA system acts primarily via CRH or urocortin projections to various forebrain loci that control sexual receptivity. Disruption of these signaling processes allows normal reproduction to proceed in the face of energetic deficits, indicating that the circuitry responds to energy deficits and that no signal is necessary to indicate that there is an adequate energy supply. While there is a large body of evidence to support this hypothesis, the data do not exclude nutritional inhibition of reproduction by other pathways and processes, and the full story will undoubtedly be more complex than this.

Of the various environmental factors influencing reproduction, food availability plays a particularly significant role, and an insufficient supply of oxidizable metabolic fuels inhibits reproduction in female mammals. When ovariectomized, steroid-primed hamsters are food deprived for 48 h, estrous behavior is suppressed. However, the specific neuroendocrine alterations that mediate the suppression of estrous behavior are unknown. Several conditions that inhibit female sexual behavior are thought to be associated with altered neuropeptide Y (NPY) activity in the brain. Intracerebroventricular (ICV) infusion of NPY inhibits estrous behavior in ovariectomized steroid-primed rats and hamsters. Furthermore, food-deprived rats have an increase in NPY mRNA in the arcuate nucleus (ARC) of the hypothalamus. Unlike rats, studies in Syrian hamsters have failed to detect any alterations in ARC NPY mRNA following food deprivation. Here we show that ARC NPY immunoreactivity and mRNA is increased in food-deprived hamsters but not in hamsters given other metabolic challenges that inhibit estrous behavior. These findings support the hypothesis that NPY contribute to, but not be critical for, the nutritional inhibition of sexual receptivity.

Food deprivation and similar metabolic challenges inhibit estrous behavior in female Syrian hamsters. The relevant metabolic cues appear to be detected in the hindbrain, and this information is then relayed synaptically to the forebrain circuits controlling estrous behavior. Neuropeptide Y (NPY) may be one of the neuropeptides/neurotransmitters serving this function. Infusion of NPY or the Y2/Y5 agonist, peptide YY3-36 (PYY3-36), into the lateral ventricles rapidly inhibits estrous behavior in ovariectomized, steroid-primed hamsters. This experiment sought to determine the neural loci where NPY acts to inhibit estrous behavior. Steroid-primed animals received infusions of artificial cerebrospinal fluid (aCSF) vehicle, 0.024 nmol PYY3-36 and 0.24 nmol PYY3-36 in separate tests 30 min prior to testing for sexual receptivity. Infusion of 0.24 nmol, but not 0.024 nmol, of PYY3-36 reduced lordosis duration when infused into the paraventricular nucleus of the hypothalamus (PVN), the caudal part of the medial preoptic area (MPO), the anterior hypothalamus (AH) or the lateral ventricles. Placements in the ventromedial hypothalamus (VMH), the arcuate nucleus (ARC) and the fourth ventricle were generally without effect. These data suggest that increased endogenous release of NPY into the caudal MPO-AH-PVN continuum during food deprivation could contribute to the observed inhibition of sexual receptivity. The possible contributions of other neuropeptides and neural estrogen receptors to this action of NPY are discussed.

Acute food deprivation or chronic food restriction suppresses reproduction in female mammals. Although a link between undernutrition and ovarian function is well established in rats, a similar link with reproductive behavior in this species is yet to be described. Therefore, we compared the display of estrous behaviors induced by exogenous steroid hormone treatment in ovariectomized fed and fasted rats. In addition, estrogen receptor-alpha immunoreactivity (ERIR) was measured in fed and fasted animals to determine whether changes in behavior were associated with changes in the number of detectable ERIR-containing cells in several brain regions. Fasting for 74 h decreased lordosis quotients (LQ) and lordosis ratings (LR) in ovariectomized, steroid-primed rats. The number of detectable ERIR cells decreased after a 74-h fast in the mid-region of the arcuate (ARC), paraventricular (PVN) and ventromedial nuclei of the hypothalamus (VMH) and the ventral bed nucleus of the stria terminalis (BST) but did not change in a number of other areas examined. Taken together, these data demonstrate that, similar to the effect on the reproductive-endocrine axis, food deprivation for 74 h suppresses steroid-induced display of lordosis in adult, female rats. Furthermore, this suppression in sexual receptivity is associated with a decrease in ERIR in a number of areas, including the VMH, a region of the hypothalamus known to be critical for the display of reproductive behaviors in female rats., (Copyright 2002 Elsevier Science Inc.)

Several conditions that inhibit female sexual behavior are thought to be associated with altered corticotropin-releasing hormone (CRH) activity in the brain. The present experiments examined the hypothesis that endogenous CRH receptor signaling mediates the inhibition of estrous behavior by undernutrition and in other instances of sexual dysfunction. Intracerebroventricular (ICV) infusion of CRH or urocortin inhibited estrous behavior in ovariectomized steroid-primed hamsters. Conversely, ICV infusion of the CRH receptor antagonist astressin prevented the suppression of estrous behavior by food deprivation or by ICV administration of neuropeptide Y. Astressin treatment also induced sexual receptivity in nonresponders, animals that do not normally come into heat when treated with hormones, and this effect persisted in subsequent weekly tests in the absence of any further astressin treatment. Activation of the hypothalamo-pituitary-adrenocortical axis was neither necessary nor sufficient to inhibit estrous behavior, indicating that this phenomenon is due to other central actions of CRH receptor agonists. This is the first direct evidence that CRH receptor signaling may be a final common pathway by which undernutrition and other conditions inhibit female sexual behavior.

Estradiol and progesterone (P) induce female mammalian reproductive behaviors, which are, in turn, sensitive to food availability. When ovariectomized, steroid-primed hamsters are food deprived for 48 h, estrous behavior is suppressed. While this suppression of estrous behavior may be due to alterations in neural steroid receptor levels, it is also possible that decreased levels of circulating estradiol could be involved in mediating this suppression. Ovariectomized Syrian hamsters given varying doses of estradiol benzoate (EB) and P were tested to determine whether increasing doses of sex steroids would overcome the suppressive effects of food deprivation on estrous behavior. As expected, lordosis duration decreased in food-deprived animals. Increasing the levels of EB, but not P, increased lordosis duration in the food-deprived animals so that animals who were given 20 microg of EB had lordosis durations significantly longer than food-deprived hamsters that received 1.5 microg and 2.5 microg EB. Following an injection of 2.5 microg of EB, food-deprived hamsters actually had higher circulating levels of estradiol than ad libitum-fed animals. Therefore, increasing circulating levels of estradiol can increase lordosis durations in fasted animals; however, the suppression of estrous behavior occurs despite increased circulating estradiol levels in ovariectomized, steroid-treated animals. The most parsimonious explanation for this phenomenon is a deprivation-induced reduction in neural responsiveness to estradiol., ((c) 2002 Elsevier Science (USA).)

Central injections of neuropeptide Y (NPY) increase food intake in Syrian hamsters; however, the effect of NPY on sexual behavior in hamsters is not known nor are the receptor subtypes involved in feeding and sexual behaviors. We demonstrate that NPY inhibits lordosis duration in a dose-related fashion after lateral ventricular injection in ovariectomized, steroid-primed Syrian hamsters. Under the same conditions, we compared the effect of two receptor-differentiating agonists derived from peptide YY (PYY), PYY-(3-36) and [Leu(31),Pro(34)]PYY, on lordosis duration and food intake. PYY-(3-36) produced a 91% reduction in lordosis duration at 0.24 nmol. [Leu(31),Pro(34)]PYY was less potent, producing a reduction in lordosis duration (66%) only at 2.4 nmol. These results suggest NPY effects on estrous behavior are principally mediated by Y2 receptors. PYY-(3-36) and [Leu(31),Pro(34)]PYY stimulated comparable dose-related increases in total food intake (2 h), suggesting Y5 receptors are involved in feeding. The significance of different NPY receptor subtypes controlling estrous and feeding behavior is highlighted by results on expression of Fos immunoreactivity (Fos-IR) elicited by either PYY-(3-36) or [Leu(31),Pro(34)]PYY at a dose of each that differentiated between the two behaviors. Some differences were seen in the distribution of Fos-IR produced by the two peptides. Overall, however, the patterns of expression were similar. Our behavioral and anatomic results suggest that NPY-containing pathways controlling estrous and feeding behavior innervate similar nuclei, with the divergence in pathways controlling the separate behaviors characterized by linkage to different NPY receptor subtypes.

Food deprivation inhibits estrous behavior in several species of rodents, but little is known about the neurotransmitter systems mediating this phenomenon. We determined whether partial blockade of opioid receptors by continuous infusion of naltrexone and/or acute peripheral injection of cholecystokinin (CCK) administration would overcome the suppressive effects of food deprivation on estrous behavior in Syrian hamsters. Contrary to expectation, naltrexone produced a slight suppression of estrous behavior, and systemic CCK administration had no effect. This dose of naltrexone was sufficient to reduce in vivo binding of [(3)H]naloxone in the brain, and both compounds affected other parameters such as food intake and body weight gain. Thus, the doses of CCK and naltrexone that were used were physiologically effective. These findings suggest that neither peripheral CCK nor opioid systems are likely to play a major role in the suppression of hamster estrous behavior by food deprivation.

The "adipostat hypothesis" refers to the idea that circulating hormone concentrations reflect levels of body adiposity and act as signals to control food intake and reproduction. Implicit in the adipostatic hypothesis are the following two assumptions: 1) plasma levels of adipostatic hormones accurately reflect body fat content and 2) decreased plasma concentrations of adipostatic hormones necessarily result in increased food intake and inhibited reproductive processes. The present experiments are designed to test these assumptions. Fat and lean Syrian hamsters were either fasted for 12, 24, 36, or 48 h or allowed ad libitum access to food. Contrary to the first assumption, plasma leptin and insulin levels in fat hamsters dropped dramatically by 12 h after the start of a fast, with no significant change in body fat content and no postfast hyperphagia. Lean hamsters showed anestrus after a 48-h fast but not after a 24-h fast. Contrary to the second assumption of the lipostatic hypothesis, lean hamsters fasted for 24 h and then refed for the next 24 h had leptin levels that were not significantly elevated compared with those of 48-h-fasted hamsters. Thus, in adult female Syrian hamsters, plasma leptin concentrations do not accurately reflect body fat content under all conditions; normal estrous cyclicity does not necessarily require plasma leptin concentrations higher than those of fasted hamsters; and decreased plasma leptin levels do not result in increased food intake.

Two experiments examined the effects of 72-h exposure to reduced environmental temperature (5 degrees C) on steroid-induced estrous behavior and neural estrogen-receptor immunoreactivity (ERIR) in ovariectomized Syrian hamsters. Cold exposure significantly inhibited sexual receptivity induced by sequential injections of estradiol benzoate (2.5 microg) and progesterone (500 microg), but only if the animals were not permitted to overeat (limited to 110% of ad lib intake at 22 degrees C). The suppression of sexual receptivity was accompanied by decreases in the number of detectable ERIR cells in the ventromedial hypothalamus (VMH) and by increases in the number of ERIR cells in the medial preoptic area (mPOA). The cold-induced decreases in estrous behavior and in VMH ERIR cells were prevented by lesions of the area postrema (AP), but AP lesions did not prevent the increases in mPOA ERIR cells. Thus, cold exposure mimics the effects of treatment with metabolic inhibitors, experimental diabetes, food deprivation, and insulin-induced fattening on these endpoints. These findings are consistent with the hypothesis that dwelling in the cold affects reproduction indirectly via its actions on metabolic fuel availability, rather than by acting directly on neuroendocrine processes.

Food deprivation inhibits ovulatory cycles and estrous behavior in Syrian hamsters. Lesions of the area postrema (AP) prevented the suppression of estrous behavior in food-deprived hamsters, but they did not prevent the suppression of estrous cyclicity or the increase in running-wheel activity caused by food deprivation. Food deprivation or treatment with pharmacological inhibitors of glycolysis and fatty acid oxidation decreased estrogen-receptor immunoreactivity (ERIR) in the ventromedial hypothalamus (VMH), increased ERIR in the arcuate nucleus (Arc) and the posterior parvicellular paraventricular nucleus (PaPo), but had no effect on ERIR in the posterodorsal medial amygdala or the anterior parvicellular paraventricular nucleus. Lesions of the AP prevented the food deprivation-induced decrease in VMH ERIR and the increase in Arc ERIR, but they did not prevent the increase in ERIR in the PaPo. Thus, whatever physiological cues are produced by food deprivation, an intact AP is required for their transmission to the neural circuits controlling estrous behavior, VMH ERIR, and Arc ERIR. The AP is not essential for transmission of this information to the neural circuits controlling estrous cyclicity, running-wheel activity, or PaPo ERIR.

Excessive diversion of metabolic fuels away from oxidation and into adipose tissue storage depots, such as underfeeding or extraordinary levels of energy expenditure, can induce nutritional infertility. Treatment with pharmacological doses of insulin reduces metabolic fuel availability and suppresses both ovulatory cyclicity and pulsatile luteinizing hormone release in females of several mammalian species, but little attention has been paid to the effects of insulin treatments on reproductive behaviors. Ovariectomized Syrian hamsters were injected with long-acting insulin every 12 h for 72 h and were prevented from overeating by limiting their intake to approximately 110% of pretreatment levels. When given estradiol and progesterone, insulin-treated hamsters exhibited significantly reduced levels of sexual receptivity compared with saline-treated controls. This insulin-induced inhibition of estrous behavior was prevented by lesions of the area postrema. Insulin treatments also caused changes in the number of detectable estrogen receptor immunoreactive cells in the hypothalamus and preoptic area. Therefore, insulin-induced repartitioning of metabolic fuels induces changes in estrous behavior and neural estrogen receptors that are indistinguishable from those caused by food deprivation, cold exposure, or treatment with metabolic inhibitors.

Food deprivation decreases fertility in female mammals in part by inhibiting sexual behaviors. Genetically obese ob/ob mice, like food-deprived wild-type animals, are also infertile; treatment of ob/ob mice with leptin, the adipocyte-derived protein that they lack, corrects some of their reproductive deficiencies. We tested the hypothesis that leptin treatment would prevent the suppression of sexual receptivity that is caused by food deprivation in female Syrian hamsters. Instead, we found that treatment with murine leptin facilitated female sexual behavior in ad libitum-fed hamsters, but not in food-deprived animals. In food-deprived hamsters, leptin treatment actually intensified the inhibition of lordosis. Food deprivation decreased detectable estrogen receptor immunoreactivity (ERIR) in the ventromedial hypothalamus (VMH), but the leptin-induced changes in female sexual behavior were not accompanied by parallel changes in VMH ERIR. Thus leptin facilitates estrous behavior in hamsters, but it does not overcome the lordosis-inhibiting metabolic cues produced by acute food deprivation. Because circulating leptin levels are directly related to body fat content, an implication of these findings is that elevated levels of adipose tissue could have a positive influence on sexual responsiveness.

Metabolic energy availability has profound effects on reproduction in a wide variety of species. We have been studying the effects of fasting on estrous cycles in Syrian hamsters as a model system for metabolic control of reproduction. In previous experiments, a 48-h period of fasting inhibited estrous cycles in lean, but not fat, hamsters. In fat hamsters the effects of fasting may have been offset by the presence of high circulating levels of free fatty acids mobilized from lipids in adipose tissue. Consistent with this idea fat hamsters treated with the inhibitor of fatty acid oxidation methyl palmoxirate (MP) showed fasting-induced anestrus. Experiment 1 was designed to examine whether vagally transmitted signals are critical for the inhibitory effects of fasting and MP treatment. Lean or fat hamsters that had received bilateral subdiaphragmatic vagotomy or sham surgery were fasted and treated with MP or vehicle. In vagotomized and sham-operated hamsters, estrous cycles were inhibited in lean fasted hamsters and in fat fasted hamsters treated with MP, but not in fat fasted hamsters treated with vehicle. Thus the results of experiment 1 indicated that vagally transmitted signals about peripheral fatty acid availability are not critical for the effects of these particular metabolic challenges on estrous cycles in Syrian hamsters. In experiment 2, hamsters without food were allowed to ingest pure glucose or fructose solutions or vegetable shortening. One-half of each group was treated with an inhibitor of glucose utilization, 2-deoxy-D-glucose (2-DG), or vehicle. If ingestion of fructose or shortening, but not glucose, had protected hamsters from 2-DG-induced anestrus, this might have indicated that peripheral fuel availability is critical for anestrus. On the contrary, 2-DG treatment induced anestrus regardless of the type of fuel ingested. Neither experiment yielded results that implicated changes in peripheral fuel availability as a critical signal in metabolic control of estrous cycles.

Two experiments investigated short-term food deprivation effects on neuroendocrine processes influenced by estrogen. These studies were prompted by prior work indicating that food deprivation increased the number of immunocytochemically identified cells containing estradiol receptors in the medial preoptic area of ovariectomized female hamsters. Presumably, this is one way that changes in metabolic fuel availability might alter the responsiveness of one or more systems to estradiol. The purpose of this study was to investigate two effects of estradiol that might be affected by food deprivation; these were 1) the positive feedback effects of estradiol on the luteinizing hormone (LH) surge, and 2) the facilitating effects of estradiol on locomotor activity. In Experiment 1, ovariectomized hamsters were administered estradiol, before or after 48 h of food deprivation. Two days after hormone treatment, blood was obtained by cardiac puncture, once in the morning (1100 h) and twice during the afternoon (1600-1800 h). These times were chosen to best characterize the magnitude of the LH surge. Food deprivation enhanced the amplitude of the LH surge in response to estradiol when this treatment preceded, but not when it followed, the administration of estradiol. However, there was variability in the dose of estradiol at which this effect of food deprivation occurred. In Experiment 2, the locomotor (running wheel) activity of two groups of gonadally intact female hamsters was quantified; one group was tested during the early (days 1 + 2; low estradiol) part of the estrous cycle, and the other group was tested during the late (days 3 + 4; high estradiol part of the estrous cycle. In both groups, testing was performed first under ad lib feeding conditions and again during 48 h of food deprivation. On average, the days 3 + 4 group was more active than the days 1 + 2 group, reflecting their differing levels of endogenous estradiol. Food deprivation significantly increased locomotor activity, independently of the stage of the estrous cycle during which it was imposed. These results are discussed in terms of the influence that altered estradiol receptor expression in the medial preoptic area might play in generating the effects we observed following short-term food deprivation.

Food deprivation, as well as treatment with metabolic inhibitors, suppress steroid hormone-induced estrous behavior in ovariectomized (OVX) Syrian hamsters. Previous work indicates that 48 h of food deprivation decreases the number of detectable estrogen receptor immunoreactive (ERIR) cells in the ventromedial hypothalamus (VMH) and the area just lateral to it (VLH), increases the number of ERIR cells in the medial preoptic area (MPO), and has no effect on the number of ERIR cells in the nucleus of the solitary tract in OVX hamsters. The present study examined the effects of food deprivation on neural progestin receptor binding using an in vitro binding assay and on progestin receptor immunoreactivity (PRIR) in estradiol-primed, OVX hamsters. Parallel behavior tests for sexual behavior were also performed in both experiments. OVX hamsters received 2.5 micrograms estradiol benzoate and were fed ad libitum or food deprived at the same time. Forty-eight hours later, animals were killed in preparation for the immunocytochemistry or progestin receptor assay. Binding assays indicated that 48-h food deprivation decreased progestin receptor levels in the preoptic area and had no effect in the mediobasal hypothalamus, an area that includes the VMH and the arcuate nucleus (ARH). Immunocytochemical analysis confirmed these findings. Food deprivation caused a decrease in sexual receptivity and in the number of detectable PRIR cells in the MPO and medial amygdala but had no effect on the number of detectable PRIR cells in the VMH/VLH, the ARH, or the anteroventral periventricular nucleus. These results suggest that food deprivation modulates progestin receptor binding and PRIR in a site-specific manner. In addition, the effects of food deprivation on neural ERIR and PRIR are significantly different.

In female mammals, reproduction is extremely sensitive to the availability of oxidizable metabolic fuels. When food intake is limited or when an inordinate fraction of the available energy is diverted to other uses such as exercise or fattening, reproductive attempts are suspended in favor of processes necessary for individual survival. Both reproductive physiology and sexual behaviors are influenced by food availability. Nutritional effects on reproductive physiology are mediated by changes in the activity of gonadotropin-releasing hormone (GnRH) neurons in the forebrain, whereas the suppression of sexual behaviors appears to be due, at least in part, to decreases in estrogen receptor in the ventromedial hypothalamus. Work using pharmacological inhibitors of glucose and fatty acid oxidation indicates that reproductive physiology and behavior respond to short-term (minute-to-minute or hour-to-hour) changes in metabolic fuel oxidation, rather than to any aspect of body size or composition (e.g., body fat content or fat-to-lean ratio). These metabolic cues seem to be detected in the viscera (most likely in the liver) and in the caudal hindbrain (probably in the area postrema). This metabolic information is then transmitted to the GnRH-secreting or estradiol-binding effector neurons in the forebrain. There is no evidence to date for direct detection of metabolic cues by these forebrain effector neurons. This metabolic fuels hypothesis is consistent with a large body of evidence and seems to account for the infertility that is seen in a number of situations, including famine, eating disorders, excessive exercise, cold exposure, lactation, some types of obesity, and poorly controlled diabetes mellitus.

To investigate the relationship between energy demand, ovarian hormones and behavioral thermoregulation, we measured nestbuilding of female Syrian hamsters (Mesocricetus auratus) under conditions where energy demand and circulating ovarian hormone levels varied. Hamsters increased nestbuilding under conditions of chronically elevated estradiol and progesterone levels (late gestation; ovariectomized animals treated with estradiol +/- progesterone) and increased energy demand (late gestation or cold exposure). When hormone treatments were withdrawn, hamsters gained weight and reduced nestbuilding activity. Nestbuilding was not affected by lactation (characterized by low ovarian steroid levels and high energy demand) or by estrous cycle phase (characterized by relatively transient changes in ovarian steroid levels and subtle changes in energy demand). Thus, nestbuilding in Syrian hamsters was responsive to increased energy demand from cold exposure, late gestation, and to ovarian hormones. However, during lactation and estrous cycles, nestbuilding did not always change predictably according to known changes in energy expenditure and steroid hormone levels. Thus, levels of nestbuilding are influenced by factors in addition to ovarian hormones and energy expenditure under some circumstances.

Two experiments evaluated the combined effects of food deprivation and runningwheel access on estrous cycles and estrous behavior of female hamsters. In experiment 1, food deprivation on days 1 and 2 of the estrous cycle disrupted the next expected ovulation, and this effect was more, rather than less, robust in females allowed to exercise in running wheels while they were deprived. In experiment 2, a similar protocol was used except the females were ovariectomized and received sequential injections of estradiol benzoate (EB; 5 micrograms) and progesterone (P; 200 micrograms) separated by 48 h to induce lordosis, which was tested 4-5 after P. Food deprivation concomitant with hormonal treatment diminished lordosis durations, but this effect was significant only among the females that were permitted to run in activity wheels. Previous findings demonstrated that access to running wheels attenuated the inhibitory effects of short photoperiod exposure on hamster estrous cycles. In contrast, the present results indicate that this same manipulation exaggerates rather than diminishes the inhibitory effects of food deprivation on estrous cycles and hormone-induced behavioral estrus.

Decreases in metabolic fuel utilization caused by food deprivation, diabetes, or treatment with metabolic inhibitors have been shown to suppress steroid-induced estrous behavior in ovariectomized Syrian hamsters. These same manipulations also caused a decrease in the number of detectable estrogen-receptor immunoreactive (ERIR) cells in the ventromedial hypothalamus (VMH) and the adjacent area lateral to it (VLH) in ovariectomized hamsters. Forty-eight hours of food deprivation or treatment with pharmacological blockers of glycolysis (2-deoxy-D-glucose) and fatty acid oxidation (methyl palmoxirate) decreased the number of detectable ERIR cells in the VMH/VLH. However, neither inhibitor given alone was sufficient to affect the number of detectable ERIR cells in the VMH/VLH, even when given in much higher doses. Therefore, the number of ERIR cells in the VMH/VLH, like steroid-induced estrous behavior, responds only to a combination of glucoprivation and lipoprivation and not to either alone. The effects of metabolic fuel restriction are not due to a general suppression of neural ERIR, because food deprivation or treatment with 2-deoxy-D-glucose and methyl palmoxirate actually increased the number of detectable ERIR cells in the medial preoptic area (mPOA) and had no effect in the nucleus of the solitary tract. Lesions destroying the area postrema (AP) prevented the decrease in ERIR cells in the VMH/VLH and the inhibition of estrous behavior caused by fuel restriction. However, AP lesions did not alter the effects of metabolic inhibitors on ERIR in the mPOA. On the other hand, subdiaphragmatic vagotomy abolished the effects of metabolic inhibitors on mPOA ERIR, but did not affect either lordosis or VMH/VLH ERIR. These results suggest that the suppression of estrous behavior induced by metabolic fuel restriction is at least in part due to a decrease in the number of ERIR neurons in the VMH/VLH. In addition, the estrogen-sensitive neurons in the VMH/VLH and mPOA receive metabolic cues via different neural pathways. The AP, but not vagus nerves, is required for ERIR neurons in the VMH/VLH to detect fuel availability; the vagus nerves, but not the AP, are necessary for estrogen-binding neurons in the mPOA to detect visceral information.

The distribution of estrogen-receptor containing cells in the preoptic area, hypothalamus and amygdala of female Syrian hamster brain was studied by immunocytochemical methods. Dense populations of estrogen-receptor immunoreactive (ER-IR) cells were found in the medial preoptic area, the bed nucleus of the stria terminalis, amygdala, ventral and lateral parts of the hypothalamus, and the arcuate nucleus. Injection of estradiol caused a decrease in estrogen-receptor immunoreactivity (ERIR) containing cells within one hour, a decrease that may reflect a change in the ability of the occupied estrogen receptor to bind the particular antibody (H222) used rather than down-regulation of the estrogen receptor. Our findings on the distribution of estrogen-receptor containing cells in these areas using an immunocytochemical technique are consistent with and extend the findings of others using autoradiographic and in vitro binding techniques to study estrogen receptor distribution in hamster brain.

ICI 182,780 is one of a new class of steroidal antiestrogens that differs from nonsteroidal antiestrogens, such as tamoxifen, in a number of respects. 1) It is bound by estrogen receptors with a high affinity, similar to that for estradiol. 2) It is a "pure" antiestrogen in that it does not mimic any of the effects of estradiol. 3) This class of antiestrogens does not seem to be bound by antiestrogen binding sites. 4) ICI 182,780 may not be active in the brain after peripheral administration. Indeed, ICI 182,780 blocked in vivo cell nuclear binding of [3H]estradiol in uterus, pituitary, and adipose tissue but not in hypothalamus-preoptic area. In vitro, ICI 182,780 competed for binding by neural estrogen receptors with an affinity comparable with that for estradiol. When given to ovariectomized rats, ICI 182,780 did not mimic any of the actions of estradiol. Instead, ICI 182,780 treatment completely blocked the uterotrophic effects of estradiol and attenuated the actions of estradiol on linear growth, carcass fat content, fat pad weight, and sexual receptivity. Treatment with ICI 182,780 also attenuated the estrogenic effects of tamoxifen on food intake, body weight and composition, linear growth, and uterine weight. These findings support the concept that, in addition to its actions in the brain, estradiol can act peripherally to modulate regulatory behaviors, energy balance, and estrous behavior. They are also consistent with the hypothesis that nonsteroidal antiestrogens, such as tamoxifen, affect energy balance via estrogen receptors, rather than antiestrogen binding sites.

Three experiments examined the effects of ICI 182,780, a steroidal "pure" antiestrogen that is thought to be active peripherally but not in the brain when given systemically, on energy balance, estrous behavior, and in vivo cell nuclear binding of [3H]estradiol in Syrian hamsters. Pretreatment with ICI 182,780 reduced in vivo uptake of [3H]estradiol in uterus but not in pooled hypothalamus-preoptic area. Ovariectomized Syrian hamsters were treated with estradiol benzoate (EB, 5 micrograms/day), ICI 182,780 (250 micrograms/day), or both EB and ICI 182,780 for 4 wk. Estradiol treatment caused significant decreases in food intake, body weight and fat content, and linear growth. Given alone, ICI 182,780 had no effect on these measures. When they were given concurrently, ICI 182,780 attenuated the effects of estradiol on body weight, growth, and fat content but not on food intake. Treatment with ICI 182,780 significantly diminished estrous behavior induced with either EB plus progesterone or with EB alone. These findings support the hypothesis that, in addition to its actions in the brain, estradiol acts peripherally to modulate estrous behavior and energy balance.

During pregnancy or after experimental manipulations of ovarian hormone levels, Syrian hamsters exhibit changes in energy balance and body fat content without modifying their food intake. The present experiments determined whether fluctuations in voluntary exercise play a role in these changes in energy balance, as they appear to do in other species. As expected, pregnant hamsters maintained a constant level of food intake and lost approximately 40% of their body fat. These animals did not show the abrupt decrease in activity after mating that is seen in rats. Instead, they maintained their high, premating level of running wheel activity until the last 3 days of pregnancy. Similarly, ovariectomy and replacement therapy with estradiol or estradiol+progesterone caused substantial changes in energy balance in the absence of significant changes in food intake or running wheel activity. These findings indicate that, unlike rats, Syrian hamsters do not exhibit substantial changes in voluntary exercise during pregnancy or in response to manipulations of ovarian steroid levels. Therefore, neither changes in food intake nor in voluntary exercise play any important role in the pregnancy- or steroid-induced changes in energy balance in Syrian hamsters.

Ovariectomized Syrian hamsters were treated with estradiol benzoate (5 micrograms/day for 4 wk), tamoxifen (500 micrograms/day), an antiestrogen that competes with estradiol for central and peripheral estrogen receptors, or both estradiol benzoate and tamoxifen. As expected, estradiol treatment caused significant decreases in body weight and fat content without affecting food intake. Given alone, tamoxifen had no effect on body weight or composition, but when given concurrently, tamoxifen significantly attenuated the effects of estradiol. These results stand in contrast to findings in rats where nonsteroidal antiestrogens, including tamoxifen, mimic the effects of estradiol on body weight and energy metabolism and are completely devoid of any antiestrogenic actions. As in rats, tamoxifen was a potent inhibitor of estrous behavior, whether induced with estradiol alone or with sequential treatment with estradiol and progesterone. Again, as in rats, tamoxifen acted as an antagonist and a weak estrogen agonist on uterine weight. These findings support the notion that the relative agonistic and antagonistic actions of tamoxifen, and other antiestrogens, vary with species and with the estrogen-sensitive endpoint being investigated.

Treatment of ovariectomized rats with the nonsteroidal antiestrogen tamoxifen mimicked the effects of estradiol and caused significant decreases in food intake and body weight. The decreases in body weight were reflected mainly in a decreased body fat content, although tamoxifen treatment did suppress linear growth too. Similar to the effects of estradiol, tamoxifen decreased parametrial white adipose tissue wet weight and lipoprotein lipase activity. When given concurrently with estradiol, tamoxifen showed no evidence of antiestrogenic activity on any of these measures. As reported previously, tamoxifen acted as a partial agonist/antagonist for uterine weight. The effective dose of tamoxifen for suppression of food intake, body weight, and body fat content fell between 10 and 50 micrograms/day. Therefore, tamoxifen behaves like other nonsteroidal antiestrogens and mimics but fails to antagonize the actions of estradiol on many aspects of physiological and behavioral regulation of energy balance.

Previous results supported the notion that estrous cycles in Syrian hamsters are responsive to the general availability of metabolic fuels, rather than to either fatty acid or glucose availability per se. To test this idea, we monitored estrous cycles in hamsters that were fed ad libitum and treated with a range of doses of 2-deoxy-D-glucose (2-DG), an inhibitor of glucose utilization. Hamsters treated with 2-DG at doses ranging from 750-1,250 mg/kg showed normal estrous cycles, but higher doses (1,750 or 2,000 mg/kg) induced anestrus. While it is clear from these data that estrous cycles are affected by glucoprivation, it is not clear whether they are responsive to decreased fatty acid availability. Groups of hamsters were fed ad libitum and treated with a range of doses of methyl palmoxirate (MP), an inhibitor of fatty acid utilization. Some of the hamsters that received the highest doses became torpid and thus were not tested for lordosis. None of the euthermic, MP-treated hamsters became anestrous. Other experiments examined the role of glucose availability in fasted hamsters. Hamsters with a high body fat content were protected from fasting-induced anestrus. In contrast, fat food-deprived hamsters treated with low doses of 2-DG (750 mg/kg) became anestrous. Thus fatty acids mobilized from adipose tissue did not prevent fasting-induced anestrus when glucose utilization was blocked. One interpretation is that during fasting fatty acid utilization spares glucose for other tissues involved in the control of estrous cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

The availability of oxidizable metabolic fuels affects reproductive physiology and behaviors in female mammals. In Syrian hamsters, 48 h of food deprivation is sufficient to suppress secretion of gonadotropins and ovarian steroids and to prevent the occurrence of ovulation and estrous behavior. These experiments attempted to determine whether the deprivation-induced suppression of lordosis is entirely due to the disruption of ovarian steroid secretion or whether there are also changes in behavioral responsiveness to estradiol and/or progesterone (P). Estrous behavior was induced in ovariectomized hamsters with sequential injections of 5 micrograms of estradiol benzoate (EB) and 200 micrograms P. Food deprivation for 48 h, either before or just after EB treatment, significantly suppressed the amount of time females spent in lordosis during a 5-min test with a sexually experienced male. Treatment with an inhibitor of glycolysis (2-deoxy-D-glucose) in combination with an inhibitor of fatty acid oxidation (methyl palmoxirate) for 48 h mimicked the effects of food deprivation and suppressed the amount of time spent in lordosis after treatment with EB+P. Given alone, neither metabolic inhibitor had an effect on lordosis. These findings indicate that suppression of hamster estrous behavior by metabolic fuel deprivation is at least in part due to a reduced responsiveness to estradiol and/or progesterone. Furthermore, estrous behavior is responsive to metabolic fuels in general. This is unlike hamster ovulatory cycles, which are primarily responsive to glucose availability.

In female mammals, reproduction is sensitive to the availability of metabolic fuels, and food deprivation has been shown to suppress pulsatile LH secretion, attenuate the preovulatory LH surge, and prevent ovulation. It has been suggested that food deprivation impairs fertility by reducing the secretion of GnRH by GnRH-producing neurons in the forebrain. A series of experiments tested this hypothesis by examining the effects of estrous cycles and manipulations of metabolic fuel availability on the expression of Fos-like proteins (Fos-IR) in GnRH-immunoreactive (GnRH-IR) neurons in the forebrain of Syrian hamsters. GnRH-IR neurons were detected in several areas, including the diagonal band of Broca (DBB), medial septum (MS), rostral medial preoptic area (mPOA), and caudal POA. In the more rostral regions (DBB and MS/mPOA), GnRH-IR neurons expressed Fos-IR almost exclusively on day 4 of the cycle, just after the preovulatory LH surge. However, in the caudal POA, GnRH-IR neurons expressed Fos-IR across the entire cycle, including days 1-3, when LH secretion is pulsatile. Food deprivation on days 1 and 2 of the cycle, which attenuates the LH surge and blocks ovulation in hamsters, significantly reduced the proportion of GnRH-IR neurons that expressed Fos-IR on days 2 and 4 (caudal POA) or only on day 4 (DBB and MS/mPOA). Suppression of fuel availability with insulin or 2-deoxy-D-glucose on day 1 of the cycle mimicked the effects of food deprivation and reduced the proportion of caudal POA GnRH-IR neurons that expressed Fos-IR. The results of these experiments suggest that in Syrian hamsters, there are separate populations of GnRH-IR neurons associated with pulsatile and surge modes of LH secretion. In addition, the fact that manipulations of metabolic fuel availability cause changes in the expression of Fos-IR in both populations of GnRH-IR neurons provides strong support for the hypothesis that nutritional infertility is due in part to decreased GnRH secretion.

A complete reproductive cycle of ovulation, conception, pregnancy, and lactation is one of the most energetically expensive activities that a female mammal can undertake. A reproductive attempt at a time when calories are not sufficiently available can result in a reduced return on the maternal energetic investment or even in the death of the mother and her offspring. Numerous physiological and behavioral mechanisms link reproduction and energy metabolism. Reproductive attempts may be interrupted or deferred when food is scarce or when other physiological processes, such as thermoregulation or fattening, make extraordinary energetic demands. Food deprivation suppresses both ovulation and estrous behavior. The neural mechanisms controlling pulsatile release of gonadotropin-releasing hormone (GnRH) and, consequently, luteinizing hormone secretion and ovarian function appear to respond to minute-to-minute changes in the availability of metabolic fuels. It is not clear whether GnRH-secreting neurons are able to detect the availability of metabolic fuels directly or whether this information is relayed from detectors elsewhere in the brain. Although pregnancy is less affected by fuel availability, both lactational performance and maternal behaviors are highly responsive to the energy supply. When a reproductive attempt is made, changes in hormone secretion have dramatic effects on the partitioning and utilization of metabolic fuels. During ovulatory cycles and pregnancy, the ovarian steroids, estradiol and progesterone, induce coordinated changes in the procurement, ingestion, metabolism, storage, and expenditure of metabolic fuels. Estradiol can act in the brain to alter regulatory behaviors, such as food intake and voluntary exercise, as well as adenohypophyseal and autonomic outputs. At the same time, ovarian hormones act on peripheral tissues such as adipose tissue, muscle, and liver to influence the metabolism, partitioning and storage of metabolic fuels. During lactation, the peptide hormones, prolactin and growth hormone, rather than estradiol and progesterone, are the principal hormones controlling partitioning and utilization of metabolic fuels. The interactions between metabolic fuels and reproduction are reciprocal, redundant, and ubiquitous; both behaviors and physiological processes play vital roles. Although there are species differences in the particular physiological and behavioral mechanisms mediating nutrition-reproduction interactions, two findings are consistent across species: 1) Reproductive physiology and behaviors are sensitive to the availability of oxidizable metabolic fuels. 2) When reproductive attempts are made, ovarian hormones play a major role in the changes in ingestion, partitioning, and utilization of metabolic fuels.

Male golden-mantled ground squirrels held at 23 degrees C were fed high-fat (HF) or standard (chow) diets. In December, ambient temperature was reduced to 6 degrees C, food was removed, and frequency and duration of torpor bouts were monitored continuously by radiotelemetry. Reproductive condition and body composition were assessed upon terminal arousal in the spring. Juvenile males fed the HF diet weighed more than chow-fed controls before and throughout the hibernation season and had significantly greater lipid masses at terminal arousal. Testes masses and plasma testosterone concentrations were substantially higher in HF than in chow-fed juveniles. The accelerated reproductive development of fatter squirrels was not contingent upon increases in the total number of days spent in torpor, number of torpor bouts, or the average duration of each arousal from torpor. Access to the HF diet had no effect on body mass, adiposity, or reproductive status of adult male ground squirrels in spring. Threshold levels of white adipose tissue and associated differences in availability of metabolic fuels may be permissive for testicular growth during the hibernation season. Juveniles exceed this threshold only when fed the HF diet.

Weight gain in ovariectomized Syrian hamsters occurs without increased food intake, which suggests that metabolic efficiency may be enhanced through a reduction in energy expenditure. We examined the effect of ovariectomy on metabolic activity in brown adipose tissue and liver. Four groups of hamsters (n = 13, each) were killed 0, 2, 4, or 16 weeks following ovariectomy. Ovariectomized hamsters rapidly gained weight without overeating. Body weights stabilized after 8 weeks and remained 12-17% above sham-operated control weights for the duration of the experiment. Weight gain in the hamsters ovariectomized for 16 weeks was characterized by significant increases in retroperitoneal white adipose tissue weight and carcass lipid content. Similar trends were seen in 2-week and 4-week ovariectomized animals. There were no differences in interscapular brown adipose tissue weight, protein content, DNA content, or norepinephrine (NE) content among sham-operated and 2-, 4-, or 16-week ovariectomized hamsters, indicating that ovariectomy had no effect on brown adipose tissue growth. Similarly, there was no difference in either sympathetic nervous system activity (estimated by the rate of NE turnover) or mitochondrial GDP binding among the four groups of hamsters. In contrast, hepatic cytochrome P-450 activity was significantly reduced 2, 4, and 16 weeks after ovariectomy. These results suggest that reduced thermogenic activity in liver, but not in brown adipose tissue, could contribute to the weight gain in Syrian hamsters after ovariectomy.

Reproduction in Syrian hamsters is sensitive to the general availability of metabolic energy. For example, females often modify their litter size by cannibalism on days 1-7 postpartum, and the number of young eaten is a function of the total supply of metabolic energy as determined by both food supply and body fat content. If the level of cannibalism is a function of energy availability, it might be expected that a drop in ambient temperature would increase cannibalism, since cold acclimation demands greater energy expenditure. We found that hamsters ate significantly more of their offspring when housed at 10 compared to 22 degrees C during lactation. The effect of cold on cannibalism was attenuated in hamsters fattened prior to cold exposure and exaggerated in hamsters that were lean prior to cold exposure. Thus, the litter size maintained by Syrian hamsters is a function of the total supply of metabolic fuels as determined by energy sources, such as food supply and adipose tissue, and by energetic costs of thermoregulatory and other processes.

In Syrian hamsters, reproduction is sensitive to the availability of metabolic fuels. Estrous cycles can be interrupted by brief periods of food deprivation, by pharmacological inhibition of glycolysis and fatty acid oxidation, or by increasing energy demands for thermoregulation. We predicted that manipulations that divert an excessive portion of the metabolic fuel supply into storage also should inhibit reproduction. Redirection of metabolic fuels from oxidation to storage was accomplished by treatment with protamine zinc insulin suspension (PZI). Syrian hamsters treated with PZI and fed ad libitum increased their food intake by approximately equal to 40% and body fat stores, but there was no effect on estrous cycles. When PZI-treated hamsters were limited to approximately equal to 110% of their preinjection food intake, they still fattened, and there was a significant inhibition of estrous cyclicity. Thus, in the absence of overeating, PZI-enhanced energy storage may lead to a shortage of oxidizable metabolic fuels with the result that reproduction is inhibited in favor of processes essential for survival (e.g., cellular maintenance, thermoregulation). It is unlikely that insulin-induced anestrus is due to actions of PZI unrelated to metabolic fuel partitioning, because the hormone had no effects on estrous cyclicity in ad libitum-fed hamsters. These findings are inconsistent with the hypothesis that nutritional infertility is due to the failure to maintain a minimum body fat content and raise the possibility that the infertility associated with some types of obesity could be due in part to a disorder of macronutrient partitioning.

The effects of pregnancy and ovarian steroids on the in vivo distribution of newly synthesized fatty acids (incorporation of tritium from 3H2O into fatty acid) in Syrian hamsters (Mesocricetus auratus) were examined. During late, but not early, gestation hamsters had reduced levels of newly synthesized fatty acids in heart, liver, uterus, and white adipose tissues (parametrial and inguinal fat pads). Treatment of ovariectomized hamsters with estradiol + progesterone significantly decreased fatty acid synthesis-uptake in heart, liver, and inguinal white adipose tissue. Treatment with either estradiol or progesterone alone was without significant effect in any tissue. Pretreatment of hamsters with Triton WR-1339 (tyloxapol), an inhibitor of lipoprotein lipase activity and tissue triglyceride uptake, abolished the effects of estradiol + progesterone in white adipose tissue and heart but not in liver. Thus hamsters lose body fat during pregnancy in part because of decreased de novo lipogenesis. The effect of pregnancy on lipogenesis is mimicked by treatment with estradiol + progesterone but not by either hormone alone. Furthermore, it appears that the liver is the principal site of estradiol + progesterone action on lipogenesis in Syrian hamsters.

Two experiments examined the role of the sympathetic nerves in estradiol-induced fat pad weight losses in ovariectomized (OVX) rats. Rats were OVX, and the retroperitoneal white adipose tissue (RWAT) was unilaterally denervated 4 wk later. After 14 days of treatment with estradiol benzoate (EB, 2 micrograms/day), the intact pads lost 23% more weight than the denervated pads. There was no effect of denervation on fat pad weight or on cytosol estrogen receptor concentration in RWAT in the animals treated with sesame oil vehicle. These data suggest that the sympathetic nerves play a role in estrogen-induced reductions in fat pad weight but not via changes in adipose tissue cytosol estrogen receptors. A second experiment examined whether estradiol-induced fat pad weight losses are accompanied by increased norepinephrine (NE) turnover, an index of sympathetic activity, in adipose tissue. Rats were OVX and treated with EB or sesame oil vehicle. NE turnover was assessed by measuring the decline of tissue NE over time after injection of alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase activity and thus NE biosynthesis. NE turnover in RWAT, but not heart, was significantly greater in animals treated with EB, suggesting that estradiol decreases fat pad weight in part by increasing sympathetic nervous system activity. It is possible that estradiol acts in the brain to regulate the activity of the sympathetic nerves to white adipose tissue and peripherally to alter adipose tissue responsiveness to catecholamines.

In the first experiment, the effects of food availability on growth and reproduction were assessed by placing male musk shrews on 3 different feeding schedules, i.e. fed ad libitum, fed 50% of the amount eaten by the ad-libitum controls or fed 25% of the amount eaten by the ad-libitum controls. After 25 days, growth and sexual maturation were significantly retarded in both of the food-restricted groups compared to the control group. In the second experiment, the combined effects of food availability and social cues were investigated in juvenile males that were either fed ad libitum (during the day) or placed on a restricted diet known to inhibit growth and reproduction. Half of these males were either housed alone or with an adult female (separated from female during the day by a wire barrier, but in full contact at night). The ad-libitum-fed males living with a female ate more food, gained more body weight and were more sexually mature than ad-libitum-fed animals living alone. Furthermore, males in the two food-restricted groups had lower body weights and were sexually immature compared with males in both of the ad-libitum-fed groups. Finally, there were little or no differences in growth and reproduction between animals in the two food-restricted groups. These results suggest that food availability is an important environmental regulator of the timing of sexual maturation, and that stimulatory social cues cannot override the inhibitory effects of an inadequate diet.

Mammalian reproduction is inhibited by food shortages, increased foraging requirements, and other factors that decrease the energy available for biological processes. Cold-induced inhibition of reproduction may result from a depletion of available metabolic energy due to the increased requirements for thermogenesis or, alternatively, from mechanisms unrelated to energy expenditure. We examined the relationship between energy availability (in the diet and the body fat stores) and cold-induced anestrus in Syrian hamsters. In experiment 1, hamsters were housed in the cold (5 degrees C) and fed diets that differed in the amount of effort required to ingest them. The number of consecutive estrous cycles was positively correlated with caloric intake and negatively correlated with body weight loss in the cold. In experiment 2, hamsters were fed these diets for several weeks, so that they differed dramatically in body weight and fat content before cold exposure. Half of each group retained the same diet during cold exposure, whereas the other half were fed a regular chow diet. The effects of body weight before cold exposure were less pronounced than the effects of caloric intake during cold exposure. In experiment 3, females were fed different diets before cold exposure, then, during cold exposure, all were fed in a manner that decreased food intake and increased the effort required to obtain food. This energetic challenge exaggerated the effect of prior body weight on the latency to cold-induced anestrus. Thus the latency to cold-induced anestrus in Syrian hamsters is primarily a function of the availability of metabolic energy.(ABSTRACT TRUNCATED AT 250 WORDS)

Rates of brain growth differed in meadow voles maintained in long (LP) or short (SP) photoperiods postnatally. At 35 days of age, brain weight was greater by 6.6% in LP males and by 4.7% in LP females as compared to their SP counterparts. Whole brain galactolipid content, an index of brain myelin, was greater by 15.6% in LP as compared to SP males. At 70 days of age, brains of LP males were 4% heavier than those of SP males. Differences attributable to photoperiod were most pronounced in midbrain and hindbrain (8% and 14%, respectively). DNA and galactolipid contents were greater by 11% and 15%, respectively, in hindbrain of LP males. Photoperiod did not affect any of these measures in diencephalon, striatum, or cerebellum. Short day lengths reduce myelination in meadow voles, presumably by decreasing proliferation rates of oligodendroglia. This is one facet of a general delay in somatic development associated with being born at the end of the normal breeding season when day lengths are decreasing or below a critical threshold.

In most adult mammals, brain weights of males exceed those of females. The role of androgens in the genesis of this sex difference was assessed in meadow voles by acute neonatal or chronic postweaning manipulation of testosterone titers. Female voles given a single injection of testosterone propionate (TP) on the second day of postnatal life had brain weights in adulthood that were indistinguishable from those of male voles and significantly heavier than those of control females. Whole brain DNA content, a measure of cell number, was not increased by neonatal TP treatment. Females treated with TP from day 19 to 70 had lower brain weights than control females and males gonadectomized at 19 days of age had greater brain weights than did intact male voles at day 70. The sex dimorphism in brain weight reflects organizational effects of testosterone during perinatal development. Beginning at weaning, and continuing through postpubertal development, testosterone decreases brain weight in both sexes. We suggest that testosterone affects brain weight by altering cell size or non-cellular components rather than cell number.

Male meadow voles kept in a long photoperiod (LP) from birth to 70 days of age have heavier brains than those kept in a short photoperiod (SP). Brain weights of male voles kept in the LP first exceeded those of SP animals at 20 days of age; differences were greatest at 35 days (5.8%) and persisted through 140 days of age (2%), although the magnitude of the difference declined progressively. Accelerated compensatory increases in brain weight were observed in voles transferred from the SP to the LP at 70 days of age. Total brain DNA content, an index of cell number, was not significantly affected by initial or final photoperiod, although it increased 7.8% within 70 days after voles were transferred from the SP to the LP. Brain weights (but not DNA content) of males exceeded those of females, but this sex difference was present only in the LP. We suggest that short day lengths retard brain development by reducing rates of myelination and possibly reducing cell size as well; this is part of a general retardation of somatic growth associated with a delayed onset of puberty that can be reversed by a stimulatory LP but, ordinarily, occurs spontaneously as voles become refractory to short day lengths.

Food deprivation inhibits ovulation and estrous behavior in golden hamsters. In experiment 1, the effects of phasic starvation (food deprivation on days 1 and 2 of the 4-day estrous cycle) depended on prior body weight and fat content. Starvation-induced anestrus, which occurs after only one cycle of phasic starvation in lean hamsters, did not occur until after three or more cycles in fat hamsters. None of the fat hamsters became anestrous until their body weights had declined to the level of lean hamsters. However, in experiment 2, we found evidence that changes in reproductive status were not signaled by any dimension of body size per se but instead by the general availability of metabolic fuels. Estrous cycles of thin hamsters were not significantly affected by food deprivation and weight loss when the hamsters were provided with either a 25% glucose solution or with vegetable shortening. In experiment 3, simultaneous pharmacological reduction of both fatty acid oxidation and glycolysis inhibited estrous cycles in hamsters fed ad libitum. Estradiol treatment restored estrous behavior, but not ovulation, in food-deprived, lean hamsters and in hamsters in which both fatty acid oxidation and glycolysis were reduced. Decreased availability of utilizable metabolic fuels may inhibit follicular development, which may in turn lead to circulating estradiol levels that are insufficient to stimulate estrous behavior.