Neuroendocrine Control of Reproduction in Teleost Fish: Concepts and Controversies

During the teleost radiation, extensive development of the direct innervation mode of hypothalamo-pituitary communication was accompanied by loss of the median eminence typical of mammals. Cells secreting follicle-stimulating hormone and luteinizing hormone cells are directly innervated, distinct populations in the anterior pituitary. So far, ∼20 stimulatory and ∼10 inhibitory neuropeptides, 3 amines, and 3 amino acid neurotransmitters are implicated in the control of reproduction. Positive and negative sex steroid feedback loops operate in both sexes. Gene mutation models in zebrafish and medaka now challenge our general understanding of vertebrate neuropeptidergic control. New reproductive neuropeptides are emerging. These include but are not limited to nesfatin 1, neurokinin B, and the secretoneurins. A generalized model for the neuroendocrine control of reproduction is proposed. Hopefully, this will serve as a research framework on diverse species to help explain the evolution of neuroendocrine control and lead to the discovery of new hormones with novel applications. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Kisspeptin, Neurokinin B, and Dynorphin Expression during Pubertal Development in Female Sheep

The neural mechanisms underlying increases in gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion that drive puberty onset are unknown. Neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin, i.e., KNDy neurons, are important as kisspeptin and NKB are stimulatory, and dynorphin inhibitory, to GnRH secretion. Given this, we hypothesized that kisspeptin and NKB expression would increase, but that dynorphin expression would decrease, with puberty. We collected blood and hypothalamic tissue from ovariectomized lambs implanted with estradiol at five, six, seven, eight (puberty), and ten months of age. Mean LH values and LH pulse frequency were the lowest at five to seven months, intermediate at eight months, and highest at ten months. Kisspeptin and NKB immunopositive cell numbers did not change with age. Numbers of cells expressing mRNA for kisspeptin, NKB, or dynorphin were similar at five, eight, and ten months of age. Age did not affect mRNA expression per cell for kisspeptin or NKB, but dynorphin mRNA expression per cell was elevated at ten months versus five months. Thus, neither KNDy protein nor mRNA expression changed in a predictable manner during pubertal development. These data raise the possibility that KNDy neurons, while critical, may await other inputs for the initiation of puberty.

Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction

Increasing evidence accumulated during the past two decades has demonstrated that the then-novel kisspeptin, which was discovered in 2001, the known neuropeptides neurokinin B and dynorphin A, which were discovered in 1983 and 1979, respectively, and their G-protein-coupled receptors, serve as key molecules that control reproduction in mammals. The present review provides a brief historical background and a summary of our recent understanding of the roles of hypothalamic neurons expressing kisspeptin, neurokinin B, and dynorphin A, referred to as KNDy neurons, in the central mechanism underlying gonadotropin-releasing hormone (GnRH) pulse generation and subsequent tonic gonadotropin release that controls mammalian reproduction.

Short-term regular moderate exercise improved male hypothalamic-pituitary-gonadal axis function via the reduction of hypothalamic neurokinin B expression in adult rats

Introduction: In the arcuate nucleus, kisspeptin, neurokinin-B and pro-dynorphin (KNDy) neurons control the function of gonadotropin-releasing hormone (GnRH) neurons. Early investigations indicated that exercise with various intensities affects luteinizing hormone (LH) and testosterone (T) in different ways. Meanwhile the molecular mechanisms underlying its function not yet been fully understood. Accordingly, the present study evaluated the role of alterations in the levels of KNDy mRNA upstream of GnRH neurons in conveying the effects of various short-term exercise intensities on the male hypothermic-pituitary-gonadal (HPG) axis. Methods: Twenty-one adult Wistar rats were randomly divided into 3 groups: control, one-month regular moderate exercise (ME) and one-month regular intensive exercise (IE). In ME (22m/min) and IE (35m/min) groups, the rats were treated 5 days a week for 60min each day. Finally, we assessed serum levels of LH and T using the ELIZA technique and KNDy and Gnrh mRNA expression by the real-time PCR method. Results: The results revealed that in ME group the expression of Nkb was reduced and the expression of Gnrh mRNA and the LH and T serum levels were increased. However, intensive exercise did not change the serum levels of LH and T or the relative expression of kiss1, Nkb, Pdyn and Gnrh genes. Conclusion: The results suggested that monthly moderate exercise improved male reproductive axis function, while intensive exercise did not have an adverse effect on the reproductive axis. These various effects on the male HPG axis may be propagated by the change in hypothalamic Nkb gene expression.

P–597 Placental expression of neurokinin B and its receptor NK3R is increased in women with polycystic ovary syndrome: results of a preliminary study

Study question Is the placental expression of neurokinin B (NKB) and its receptors NK1R, NK2R and NK3R affected by the polycystic ovary syndrome (PCOS)? Summary answer: The placental expression of NKB and NK3R is increased in PCOS, while the expression of NK1R and NK2R is not affected. What is known already: Women with PCOS are at increased risk of pregnancy complications and poor pregnancy outcomes. Defective placentation is among the proposed mechanisms involved. Altered NKB placental expression has been associated with several conditions characterized by placental dysfunction, such as pre-eclampsia and intra-uterine growth retardation. To our knowledge, the expression of NKB and its receptors has not been studied in placental tissue of women with PCOS. Study design, size, duration This was a single-center, prospective, case-control study. Women with PCOS according to the Rotterdam criteria (cases) and healthy pregnant women (controls) were enrolled at first prenatal visit and followed until delivery. Only women with spontaneous conception and singleton, uncomplicated, term pregnancies (10 PCOS and 10 controls) were included in the final analysis. All participants provided informed consent. Participants/materials, setting, methods At delivery, placental specimens were collected and immediately submerged in RNAlater solution. Samples were stored at –20oC until analysis. The mRNA expression of NKB, NK1R, NK2R and NK3R was quantified by real-time PCR (RT-PCR). The relative mRNA expression was estimated by the ΔΔCT method, using β-actin as reference (housekeeping gene). Statistical analysis was performed using SPSS 25.0, and the level of statistical significance was set at 0.05 (two-sided). Main results and the role of chance The placental mRNA expression of NKB and NK3R was significantly higher in PCOS women versus controls (2.4-fold, p < 0.05 for NKB and 7-fold, p < 0.05 for NK3R). No significant alterations were observed in the mRNA expression of NK1R and NK2R between the two groups. There was no statistically significant difference regarding age, BMI, caesarian section frequency, offspring sex and birth weight between women with PCOS and controls. The placental expression of NKB and its receptors was correlated neither with maternal age and BMI, nor with offspring birth weight. Limitations, reasons for caution The main limitation of this study is the small sample size. Expanding the number of participants is the necessary next step, in order to corroborate our preliminary findings. Furthermore, correlations between the placental expression of NKB, NK1R, NK2R, NK3R and maternal sex steroids, glucose and insulin levels should be sought. Wider implications of the findings: The present study is the first to demonstrate increased placental expression of NKB and its receptor NK3R in women with PCOS. These findings support a potential role for NKB as a mediator of placental alterations characterizing PCOS. Trial registration number Not applicable