Grid1 regulates the onset of puberty in female rats.

The study aimed to investigate the effect of Grid1, encoding the glutamate ionotropic receptor delta type subunit 1 (GluD1), on puberty onset in female rats. Grid1 mRNA and protein expression was detected in the hypothalamus of female rats at prepuberty and puberty. The levels of Grid1 mRNA in the hypothalamus, the fluorescence intensity in the arcuate nucleus and paraventricular nucleus of the prepubertal rats was significantly lower than pubertal. Additionally, the expression of Grid1 was suppressed in primary hypothalamus cells and prepubertal rat. Finally, investigated the effect of Grid1 knockdown on puberty onset and reproductive performance. Treatment of hypothalamic neurons with LV-Grid1 decreased the level of Grid1 and Rfrp-3 (encoding RFamide-related peptide 3) mRNA expression, but increased the Gnrh (encoding gonadotropin-releasing hormone) mRNA levels. After an ICV injection, the time for the rat vaginal opening occurred earlier. Moreover, Gnrh mRNA expression was increased, whereas Rfrp-3 mRNA expression was decreased in the hypothalamus. The concentration of progesterone (P4) in the serum was significantly decreased compare with control group. Ovary hematoxylin-eosin staining revealed that the LV-Grid1 group mainly contained primary and secondary follicles. The reproductive performance of the rats was not affected by the Grid1 knockdown. Therefore, Grid1 may affect the onset of puberty in female rats by regulating the levels of Gnrh, and Rfrp-3 in the hypothalamus, as well as the concentrations of P4, but not reproduction performance.

Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

SCOPE: The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. METHODS AND RESULTS: Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60 mg kg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60 mg kg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. CONCLUSIONS: Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60 mg kg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.

Early life adversity accelerates hypothalamic drive of pubertal timing in female rats with associated enhanced acoustic startle.

Early life adversity in the form of childhood maltreatment in humans or as modeled by maternal separation (MS) in rodents is often associated with an earlier emergence of puberty in females. Earlier pubertal initiation is an example of accelerated biological aging and predicts later risk for anxiety in women, especially in populations exposed to early life trauma. Here we investigated external pubertal markers as well as hypothalamic gene expression of pubertal regulators kisspeptin and gonadotropin-releasing hormone, to determine a biological substrate for MS-induced accelerated puberty. We further investigated a mechanism by which developmental stress might regulate pubertal timing. As kisspeptin and gonadotropin-releasing hormone secretion are typically inhibited by corticotropin releasing hormone at its receptor CRH-R1, we hypothesized that MS induces a downregulation of Crhr1 gene transcription in a cell-specific manner. Finally, we explored the association between pubertal timing and anxiety-like behavior in an acoustic startle paradigm, to drive future preclinical research linking accelerated puberty and anxiety. We replicated previous findings that MS leads to earlier puberty in females but not males, and found expression of kisspeptin and gonadotropin-releasing hormone mRNA to be prematurely increased in MS females. RNAscope confirmed increased expression of these genes, and further revealed that kisspeptin-expressing neurons in females were less likely to express Crhr1 after MS. Early puberty was associated with higher acoustic startle magnitude in females. Taken together, these findings indicate precocial maturation of central pubertal timing mechanisms after MS, as well as a potential role of CRH-R1 in these effects and an association with a translational measure of anxiety.

Postweaning Social Isolation Alters Puberty Onset by Suppressing Electrical Activity of Arcuate Kisspeptin Neurons.

INTRODUCTION: Postweaning social isolation (PWSI) in rodents is an advanced psychosocial stress model in early life. Some psychosocial stress, such as restrain and isolation, disrupts reproductive physiology in young and adult periods. Mechanisms of early-life stress effects on central regulation of reproduction need to be elucidated. We have investigated the effects of PWSI on function of arcuate kisspeptin (ARCKISS1) neurons by using electrophysiological techniques combining with monitoring of puberty onset and estrous cycle in male and female Kiss1-Cre mice. METHODS: Female mice were monitored for puberty onset with vaginal opening examination during social isolation. After isolation, the estrous cycle of female mice was monitored with vaginal cytology. Anxiety-like behavior of mice was determined by an elevated plus maze test. Effects of PWSI on electrophysiology of ARCKISS1 neurons were investigated by the patch clamp method after intracranial injection of AAV-GFP virus into arcuate nucleus of Kiss1-Cre mice after the isolation period. RESULTS: We found that both male and female isolated mice showed anxiety-like behavior. PWSI caused delay in vaginal opening and extension in estrous cycle length. Spontaneous-firing rates of ARCKISS1 neurons were significantly lower in the isolated male and female mice. The peak amplitude of inhibitory postsynaptic currents to ARCKISS1 neurons was higher in the isolated mice, while frequency of excitatory postsynaptic currents was higher in group-housed mice. CONCLUSION: These findings demonstrate that PWSI alters pre- and postpubertal reproductive physiology through metabolic and electrophysiological pathways.

Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra's seminal work.

An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.

Pubertal exposure to dietary advanced glycation end products disrupts ductal morphogenesis and induces atypical hyperplasia in the mammary gland.

BACKGROUND: Advanced glycation end products (AGEs) are reactive metabolites intrinsically linked with modern dietary patterns. Processed foods, and those high in sugar, protein and fat, often contain high levels of AGEs. Increased AGE levels are associated with increased breast cancer risk, however their significance has been largely overlooked due to a lack of direct cause-and-effect relationship. METHODS: To address this knowledge gap, FVB/n mice were fed regular, low AGE, and high AGE diets from 3 weeks of age and mammary glands harvested during puberty (7 weeks) or adulthood (12 weeks and 7 months) to determine the effects upon mammary gland development. At endpoint mammary glands were harvested and assessed histologically (n ≥ 4). Immunohistochemistry and immunofluorescence were used to assess cellular proliferation and stromal fibroblast and macrophage recruitment. The Kruskal-Wallis test were used to compare continuous outcomes among groups. Mammary epithelial cell migration and invasion in response to AGE-mediated fibroblast activation was determined in two-compartment co-culture models. In vitro experiments were performed in triplicate. The nonparametric Wilcoxon rank sum test was used to compare differences between groups. RESULTS: Histological analysis revealed the high AGE diet delayed ductal elongation, increased primary branching, as well as increased terminal end bud number and size. The high AGE diet also led to increased recruitment and proliferation of stromal cells to abnormal structures that persisted into adulthood. Atypical hyperplasia was observed in the high AGE fed mice. Ex vivo fibroblasts from mice fed dietary-AGEs retain an activated phenotype and promoted epithelial migration and invasion of non-transformed immortalized and tumor-derived mammary epithelial cells. Mechanistically, we found that the receptor for AGE (RAGE) is required for AGE-mediated increases in epithelial cell migration and invasion. CONCLUSIONS: We observed a disruption in mammary gland development when mice were fed a diet high in AGEs. Further, both epithelial and stromal cell populations were impacted by the high AGE diet in the mammary gland. Educational, interventional, and pharmacological strategies to reduce AGEs associated with diet may be viewed as novel disease preventive and/or therapeutic initiatives during puberty.

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty.

BACKGROUND: Puberty marks the end of childhood and achieve sexual maturation and fertility. The role of hypothalamic proteins in regulating puberty onset is unclear. We performed a comprehensive differential proteomics and phosphoproteomics analysis in prepubertal and pubertal goats to determine the roles of hypothalamic proteins and phosphoproteins during the onset of puberty. RESULTS: We used peptide and posttranslational modifications peptide quantification and statistical analyses, and identified 69 differentially expressed proteins from 5,057 proteins and 576 differentially expressed phosphopeptides from 1574 phosphorylated proteins. Combined proteomic and phosphoproteomics, 759 correlated proteins were identified, of which 5 were differentially expressed only at the protein level, and 201 were only differentially expressed at the phosphoprotein level. Pathway enrichment analyses revealed that the majority of correlated proteins were associated with glycolysis/gluconeogenesis, Fc gamma R-mediated phagocytosis, focal adhesion, GABAergic synapse, and Rap1 signaling pathway. These pathways are related to cell proliferation, neurocyte migration, and promoting the release of gonadotropin-releasing hormone in the hypothalamus. CTNNB1 occupied important locations in the protein-protein interaction network and is involved in focal adhesion. CONCLUSION: The results demonstrate that the proteins differentially expression only at the protein level or only differentially expressed at the phosphoprotein level and their related signalling pathways are crucial in regulating puberty in goats. These differentially expressed proteins and phosphorylated proteins may constitute the proteomic backgrounds between the two different stages.

Maternal cafeteria diet influences kisspeptin (Kiss1), kisspeptin receptor(Gpr54), and sirtuin (Sirt1) genes, hormonal and metabolic profiles, and reproductive functions in rat offspring in a sex-specific manner†.

Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal axis. KP acts together with dynorphin A (encoded by Pdyn) and neurokinin B (encoded by Tac2) to regulate reproduction. KP is crucial for the onset of puberty and is under the control of sirtuin (encoded by Sirt1). We hypothesize that the maternal cafeteria (CAF) diet has adverse effects on the offspring's hormonal, metabolic, and reproductive functions due to sex-specific alterations in the expression of Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 in the hypothalamus, and Kiss1, Gpr54, and Sirt1 in the liver. Rats were fed a CAF diet before pregnancy, during pregnancy, and during lactation. The vaginal opening was monitored. Offspring were sacrificed in three age points: PND 30, PND 35, and PND 60 (females) and PND 40, PND 45, and PND 60 (males). Their metabolic and hormonal status was assessed. mRNA for Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 were measured by real-time PCR in the hypothalamus and/or livers. We found that CAF offspring had lower weight and altered body composition; increased cholesterol and triglyceride levels, sex-specific changes in glucose and insulin levels; sex-dependent changes in Sirt1/Kiss1 mRNA ratio in the hypothalamus; sex-specific alterations in Kiss1 and Sirt1 mRNA in the liver with more diversity in males; and a delayed puberty onset in females. We concluded that the mother's CAF diet leads to sex-specific alterations in metabolic and reproductive outcomes via Kiss1/Gpr54 and Sirt1 systems in offspring.

Review: Early and late determinants of puberty in ruminants and the role of nutrition.

This article reviews the scientific literature on puberty with a focus on ruminants and draws inference, where appropriate, from recent findings in transgenic mouse models and human pathology. Early genetic determinants of puberty have been discovered in humans suffering from hypogonadotropic hypogonadism or central precocious puberty. Transgenic mouse models selected on the basis of the causative defective genes helped in discovering the cellular and molecular mechanisms involved. Most of the genes found are involved in the development of neuroendocrine networks during embryo development and early postnatal life. Notwithstanding that the development of neuroendocrine networks takes place early in puberty, a delay or acceleration in the development of Gonadotropin Releasing Hormone (GnRH) neurons has an impact on puberty onset inducing a delay or an advance, respectively. Among the genes discovered in humans and laboratory models, only a few of them displayed polymorphisms associated with advanced sexual maturity, but also marbling, growth traits and callipygian conformation. This could be related to the fact that rather than puberty onset, most research monitored sexual maturity. Sexual maturity occurs after puberty onset and involves factors regulating the maturation of gonads and in the expression of sexual behaviour. The association with growth and metabolic traits is not surprising since nutrition is the major environmental factor that will act on late genetic determinants of puberty onset. However, a recent hypothesis emerged suggesting that it is the postnatal activation of the GnRH neuronal network that induces the acceleration of growth and weight gain. Hence, nutritional factors need the activation of GnRH neurons first before acting on late genetic determinants. Moreover, nutritional factors can also affect the epigenetic landscape of parental gamete's genome with the consequence of specific methylation of genes involved in GnRH neuron development in the embryo. Season is another important regulator of puberty onset in seasonal small ruminants and appears to involve the same mechanisms that are involved in seasonal transition in adults. The social environment is also an underestimated factor affecting puberty onset in domestic ruminants, most research studies focused on olfactory cues, but the genetic basis has not heretofore been adequately tackled by the scientific community. Additionally, there is some evidence to suggest transgenerational effects exist, in that nutritional and social cues to which parents were exposed, could affect the epigenetic landscape of parental gametes resulting in the epigenetic regulation of early genetic determinants of puberty onset in their offspring.

Knockdown of lncRNA Meg3 delays the onset of puberty in female rats.

This study investigated how lncRNA Meg3 affects the onset of puberty in female rats. We determined Meg3 expression in the hypothalamus-pituitary-ovary axis of female rats at the infancy, prepubertal, pubertal, and adult life stages, using quantitative reverse transcription polymerase chain reaction (qRT-PCR). We also assessed the effects of Meg3 knockdown on the expression levels of puberty-related genes and Wnt/ß-catenin proteins in the hypothalamus, time of puberty onset, levels of reproductive genes and hormones, and ovarian morphology in female rats. Meg3 expression in the ovary varied significantly between prepuberty and puberty (P < 0.01). Meg3 knockdown decreased the expression of Gnrh, and Kiss1 mRNA (P < 0.05) and increased the expression of Wnt (P < 0.01) and ß-catenin proteins (P < 0.05) in the hypothalamic cells. Onset of puberty in Meg3 knockdown rats was delayed compared to the control group (P < 0.05). Meg3 knockdown decreased Gnrh mRNA levels (P < 0.05) and increased Rfrp-3 mRNA levels (P < 0.05) in the hypothalamus. The serum concentrations of progesterone (P4) and estradiol (E2) of Meg3 knockdown rats were lower than those in the control animals (P < 0.05). Higher longitudinal diameter and ovary weight were found in Meg3 knockdown rats (P < 0.05). These findings suggest that Meg3 regulates the expression of Gnrh, Kiss-1 mRNA and Wnt/ß-catenin proteins in the hypothalamic cells, and Gnrh, Rfrp-3 mRNA of the hypothalamus and the serum concentration of P4 and E2, and its knockdown delays the onset of puberty in female rats.

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats.

Introduction: Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats. Design: Female rats were exposed to KTZ or DES during perinatal (DES 3-6-12µg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48µg/kg.d; KTZ 3-12-48mg/kg.d). Results: Ex vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted "Creb signaling in Neurons" and "IGF-1 signaling" among the most downregulated pathways by all doses of KTZ and DES before puberty, and "PPARg" as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood. Conclusion: nRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation.

Development of social recognition ability in female rats: Effect of pubertal ovarian hormones.

The ability to recognize previously encountered conspecifics is crucial for social interaction. This social recognition ability is well characterized in adult rodents of both sexes but remains largely unexplored in juveniles. Using the social discrimination test of social recognition with short intervals (30 min and 1 h), we first found that juvenile female rats do not display a difference in investigation directed toward a novel vs. familiar stimulus rat. Using the social discrimination test with a 30-minute interval, we then showed that social recognition is established by the time of adolescence in female rats. Based on these findings, we hypothesized that social recognition is dependent on the initiation of ovarian hormone release during puberty. To test this, we ovariectomized females prior to puberty and found that prepubertal ovariectomy prevented the development of social recognition ability in adulthood. Administration of estradiol benzoate, 48 h prior to testing, to juvenile females or prepubertally ovariectomized adult females did not restore social recognition, suggesting that ovarian hormones organize the neural circuitry regulating this behavior during adolescence. These findings provide the first evidence of an effect of pubertal development on social recognition ability in female rats and highlight the importance of considering sex and age when interpreting results from behavioral paradigms initially designed for use in adult males.

Prenatal restraint stress downregulates the hypothalamic kisspeptidergic system transcripts genes, reduces the estrogen plasma levels, delayed the onset of puberty, and reduced the sexual behavior intensity in female rats.

AIMS: This study investigated the possible relationships between the expression of the Kiss1 and Gpr54 gene expressions and the pituitary-gonadal hormones with the female onset of puberty and sexual behavior. The Kiss1 and Gpr54 gene expressions were examined because they are critical to controlling the hypothalamic activation of GnRH neurons and, in turn, the pituitary-gonadal hormones related to the early onset of puberty and sexual behavior. Further, it was evaluated that the pituitary and gonadal hormones involved in the vaginal opening and the expression of sexual behavior. METHODS: Pregnant rats exposed to PRS from gestation days 17 to 20 were evaluated for maternal and open-field behaviors. The maternal behavior was analyzed because it may alter brain sexual organization affecting the pups development. It was observed in female pups the physical and development and, in adult age, the open-field behavior, the anxiety-like behavior, the estrous cycle, the sexual behavior, the serum FSH, LH, estrogen, progesterone, and testosterone levels, and the gene expression of kisspeptin protein (Kiss1) and Gpr54 in the hypothalamus. RESULTS: the maternal and open-field behaviors were unaffected. In the F1 generation, PRS reduced weight at weaning, delayed the day of the vaginal opening and reduced the intensity of lordosis, the estrogen levels, and the Kiss1 and Gpr54 gene expression. These effects were attributed to hypothalamic kisspeptidergic system downregulation of transcripts genes and the reduced estrogen levels affected by the PRS.

GnRH Neuron Excitability and Action Potential Properties Change with Development But Are Not Affected by Prenatal Androgen Exposure.

Gonadotropin-releasing hormone (GnRH) neurons produce the final output from the brain to control pituitary gonadotropin secretion and thus regulate reproduction. Disruptions to gonadotropin secretion contribute to infertility, including polycystic ovary syndrome (PCOS) and idiopathic hypogonadotropic hypogonadism. PCOS is the leading cause of infertility in women and symptoms resembling PCOS are observed in girls at or near the time of pubertal onset, suggesting that alterations to the system likely occurred by that developmental period. Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in PCOS, including altered time of puberty, disrupted reproductive cycles, increased circulating levels of testosterone, and altered gonadotropin secretion patterns. We tested the hypotheses that the intrinsic properties of GnRH neurons change with puberty and with PNA treatment. Whole-cell current-clamp recordings were made from GnRH neurons in brain slices from control and PNA females before puberty at three weeks of age and in adulthood to measure GnRH neuron excitability and action potential (AP) properties. GnRH neurons from adult females were more excitable and required less current to initiate action potential firing compared with three-week-old females. Further, the afterhyperpolarization (AHP) potential of the first spike was larger and its peak was delayed in adulthood. These results indicate development, not PNA, is a primary driver of changes to GnRH neuron intrinsic properties and suggest there may be developmentally-induced changes to voltage-gated ion channels in GnRH neurons that alter how these cells respond to synaptic input.

Impact of Physiologically Relevant Genistein Exposure at Different Time Windows on Puberty Onset and Neuroendocrine Function in Female Rats.

SCOPE: Puberty timing, critical for adulthood wellbeing, is influenced by the environment, life-style, and diets. However, differential puberty-interfering effects of soy and soy isoflavone are observed in both epidemiological and toxicological studies. Additionally, their impact on neuroendocrine function at various pre-pubertal developmental windows is unclear. METHODS AND RESULTS: This study investigates the effect of genistein, a typical soy isoflavone, at neonatal, lactational, and post-weaning stages on the time of vaginal opening and determines the levels of neuroendocrine factors in female rats using immunofluorescence, immunochemistry, and enzyme-linked immunosorbent assays. A physiologically relevant dosage (10 mg kg-1 ) is used to resemble human exposure. The results show that genistein exposure at lactational stage significantly accelerates vaginal opening time, marginally increases hypothalamic gonadotropin-releasing hormone (GnRH) secretion, significantly enhances kisspeptin receptor expression, and markedly elevates blood levels of GnRH, luteinizing hormone, and follicle-stimulating hormone, while neonatal and post-weaning exposures do not induce significant alternations. CONCLUSION: Lactational stage may be an important window for genistein to impact reproductive development and neuroendocrine regulations.

Daily GnRH agonist treatment effectively delayed puberty in female rats without long-term effects on sexual behavior or estrous cyclicity.

The present study examined the long-term effects of suppressing puberty with a GnRH agonist on reproductive physiology and behavior in female rats. We have recently reported that administration of the GnRH agonist leuprolide acetate (25 µg/kg) daily between postnatal day (PD) 25-50 delayed puberty and disrupted the development of copulatory behavior and sexual motivation in male rats. However, pilot data from our lab suggest that this low dose of leuprolide acetate (25 µg/kg) was not high enough to significantly delay puberty in female rats. Therefore, we injected female Long-Evans rats with leuprolide acetate at a higher dose (50 µg/kg) or 0.9% sterile saline, daily , starting on PD 25 and ending on PD 50. Vaginal opening was monitored daily starting on PD 30 for signs of pubertal onset and first estrous cycle. In addition, we measured estrous cyclicity starting approximately 2 weeks after the last injection of leuprolide (∼PD 64). Immediately after monitoring estrous cyclicity, the female rats were mated on their first day in behavioral estrus using the partner-preference paradigm, with and without physical contact (PD 95-110). We found that this dose of leuprolide (50 µg/kg) significantly delayed puberty; however, neither estrous cyclicity nor sexual motivation was significantly affected by periadolescent exposure to leuprolide. Together with our findings in male rats, these results add to our understanding of the developmental effects of chemically suppressing puberty in rats.

Early juvenile but not mid-to-late prenatal nutrition controls puberty in heifers but neither impact adult reproductive function†.

Objectives were to test the hypothesis that pre- and post-natal nutrition in the bovine female, independently or interactively, affect age at puberty and functional characteristics of the estrous cycle of sexually mature offspring. Brangus and Braford (n = 97) beef cows bearing a female fetus were fed to achieve body condition scores of 7.5-8 (H, obese), 5.5-6 (M, moderate), or 3-3.5 (L, thin) by the start of the third trimester and maintained until parturition. Heifer offspring were weaned and fed to gain weight at either a high (H; 1 kg/day) or a low (L; 0.5 kg/day) rate between 4 and 8 months of age, then fed the same diet during a common feeding period until puberty, which resulted in compensatory growth of heifers in the L group. Heifers (n = 95) from the H postnatal diet reached puberty 2 months earlier (12 ± 0.4 months; P = 0.0002) than those from the L postnatal diet (14 ± 0.4 months). Estrous cycles of a subgroup of postpubertal heifers (n = 53) were synchronized to evaluate antral follicle count (AFC), rate of growth and size of the pre-ovulatory follicle, size of corpus luteum and ovary, endometrial thickness, and plasma concentrations of progesterone and estradiol-17ß (E2). Although there was a trend for postnatal H heifers to have greater AFC and plasma concentrations of E2 compared to L heifers, neither pre- nor post-natal nutrition affected any other physiological or hormonal variables, including short-term fertility. Postnatal nutritional effects on pubertal age remained the dominant observed feature.

The mechanism underlying the pubertal increase in pulsatile GnRH release in primates.

In primates, the gonatotropin-releasing hormone (GnRH) neurosecretory system, consisting of GnRH, kisspeptin, and neurokinin B neurons, is active during the neonatal/early infantile period. During the late infantile period, however, activity of the GnRH neurosecretory system becomes minimal as a result of gonadal steroid independent central inhibition, and this suppressed GnRH neurosecretory state continues throughout the prepubertal period. At the initiation of puberty, the GnRH neurosecretory system becomes active again because of the decrease in central inhibition. During the progress of puberty, kisspeptin and neurokinin B signaling to GnRH neurons further increases, resulting in the release of gonadotropins and subsequent gonadal maturation, and hence puberty. This review further discusses potential substrates of central inhibition and subsequent pubertal modification of the GnRH neurosecretory system by the pubertal increase in steroid hormones, which ensures the regulation of adult reproductive function.

The polygamous GnRH neuron: Astrocytic and tanycytic communication with a neuroendocrine neuronal population.

To ensure the survival of the species, hypothalamic neuroendocrine circuits controlling fertility, which converge onto neurons producing gonadotropin-releasing hormone (GnRH), must respond to fluctuating physiological conditions by undergoing rapid and reversible structural and functional changes. However, GnRH neurons do not act alone, but through reciprocal interactions with multiple hypothalamic cell populations, including several glial and endothelial cell types. For instance, it has long been known that in the hypothalamic median eminence, where GnRH axons terminate and release their neurohormone into the pituitary portal blood circulation, morphological plasticity displayed by distal processes of tanycytes modifies their relationship with adjacent neurons as well as the spatial properties of the neurohemal junction. These alterations not only regulate the capacity of GnRH neurons to release their neurohormone, but also the activation of discrete non-neuronal pathways that mediate feedback by peripheral hormones onto the hypothalamus. Additionally, a recent breakthrough has demonstrated that GnRH neurons themselves orchestrate the establishment of their neuroendocrine circuitry during postnatal development by recruiting an entourage of newborn astrocytes that escort them into adulthood and, via signalling through gliotransmitters such as prostaglandin E2, modulate their activity and GnRH release. Intriguingly, several environmental and behavioural toxins perturb these neuron-glia interactions and consequently, reproductive maturation and fertility. Deciphering the communication between GnRH neurons and other neural cell types constituting hypothalamic neuroendocrine circuits is thus critical both to understanding physiological processes such as puberty, oestrous cyclicity and aging, and to developing novel therapeutic strategies for dysfunctions of these processes, including the effects of endocrine disruptors.