scholarly journals Neurokinin B Regulates Gonadotropin Secretion, Ovarian Follicle Growth, and the Timing of Ovulation in Healthy Women

2017 ◽  
Vol 103 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Karolina Skorupskaite ◽  
Jyothis T George ◽  
Johannes D Veldhuis ◽  
Richard A Anderson
Keyword(s):  
Ovarian Follicle ◽  
Follicle Development ◽  
Follicle Growth ◽  
Duration Of Treatment ◽  
Neurokinin B ◽  
Gonadotropin Secretion ◽  
Lh Surge ◽  
Healthy Women ◽  
Follicle Diameter ◽  
Lh Secretion

Abstract Context Neurokinin B (NKB) is obligate for human puberty, but its role in adult female gonadotropin secretion and ovarian follicle growth is unknown. Objective To investigate antagonism of NKB on pulsatile gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion and ovarian follicle development in healthy women. Design Open investigation of the effects of a neurokinin-3 receptor (NK3R) antagonist (NK3Ra) vs a no-treatment control cycle. Setting Clinical research facility. Patients or other participants Healthy women with regular menses (n = 13). Intervention(s) NK3Ra MLE4901 40 mg taken orally twice daily from cycle day 5 to 6 for 7 days. Main outcome measure(s) LH secretion, ovarian follicle growth, and timing of ovulation. Results NK3Ra administration reduced basal LH secretion without a change in pulse frequency and delayed the LH surge by 7 days, the duration of treatment [mean cycle day ± standard error of the mean (SEM), 22 ± 1 days vs 15 ± 1 days in control cycles; P = 0.0006]. Follicle growth (mean diameter at the end of administration of NK3Ra administration ± SEM, 9.3 ± 0.4 mm vs 15.1 ± 0.9 mm in control cycles; P < 0.0001) and rising estradiol concentrations (mean ± SEM, 166 ± 29 pmol/L vs 446 ± 86 pmol/L in control cycles; P < 0.0001) were prevented. After treatment, follicle development resumed and normal preovulatory follicle diameter and estradiol concentrations were demonstrated. Postovulatory progesterone rise was similarly delayed (peak cycle day, 30 ± 2 vs 22 ± 1; P = 0.002) and cycle length was prolonged (35 ± 1 days vs 29 ± 1 days in control cycles; P = 0.0003) but luteal progesterone excretion was unaffected by the NK3Ra (LH surge day +7 mean urinary progesterone levels ± SEM, 58 ± 10 pmol/mol vs 48±7 pmol/mol creatinine in control cycles; nonsignificant). Conclusion These data demonstrate the involvement of NKB-NK3R signaling in the physiological regulation of GnRH/LH secretion, determining normal follicle development in women.

scholarly journals KNDy Neurons Modulate the Magnitude of the Steroid-Induced Luteinizing Hormone Surges in Ovariectomized Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4200-4213 ◽  
Author(s):  
Cleyde V. Helena ◽  
Natalia Toporikova ◽  
Bruna Kalil ◽  
Andrea M. Stathopoulos ◽  
Veronika V. Pogrebna ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Arcuate Nucleus ◽  
Ovariectomized Rats ◽  
Neurokinin B ◽  
Lh Surge ◽  
Neuronal Populations ◽  
Lh Release ◽  
Positive And Negative Feedback ◽  
Kndy Neurons ◽  
Lh Secretion

Kisspeptin is the most potent stimulator of LH release. There are two kisspeptin neuronal populations in the rodent brain: in the anteroventral periventricular nucleus (AVPV) and in the arcuate nucleus. The arcuate neurons coexpress kisspeptin, neurokinin B, and dynorphin and are called KNDy neurons. Because estradiol increases kisspeptin expression in the AVPV whereas it inhibits KNDy neurons, AVPV and KNDy neurons have been postulated to mediate the positive and negative feedback effects of estradiol on LH secretion, respectively. Yet the role of KNDy neurons during the positive feedback is not clear. In this study, ovariectomized rats were microinjected bilaterally into the arcuate nucleus with a saporin-conjugated neurokinin B receptor agonist for targeted ablation of approximately 70% of KNDy neurons. In oil-treated animals, ablation of KNDy neurons impaired the rise in LH after ovariectomy and kisspeptin content in both populations. In estradiol-treated animals, KNDy ablation did not influence the negative feedback of steroids during the morning. Surprisingly, KNDy ablation increased the steroid-induced LH surges, accompanied by an increase of kisspeptin content in the AVPV. This increase seems to be due to lack of dynorphin input from KNDy neurons to the AVPV as the following: 1) microinjections of a dynorphin antagonist into the AVPV significantly increased the LH surge in estradiol-treated rats, similar to KNDy ablation, and 2) intra-AVPV microinjections of dynorphin in KNDy-ablated rats restored LH surge levels. Our results suggest that KNDy neurons provide inhibition to AVPV kisspeptin neurons through dynorphin and thus regulate the amplitude of the steroid-induced LH surges.

Cystic ovaries in intermittently-suckled sows: follicle growth and endocrine profiles

2014 ◽  
Vol 26 (3) ◽  
pp. 462 ◽  
Author(s):  
R. Gerritsen ◽  
B. F. A. Laurenssen ◽  
W. Hazeleger ◽  
P. Langendijk ◽  
B. Kemp ◽  
...  
Keyword(s):  
Follicle Development ◽  
Follicle Growth ◽  
Lh Surge ◽  
Lactating Sows ◽  
Endocrine Profiles ◽  
Follicle Size

This paper presents follicle development and hormone profiles for sows with normal ovulation or cystic follicles during an intermittent-suckling (IS) regime that started at Day 14 of lactation. Sows were subjected to separation from their piglets during blocks of 6 h or 12 h. In total, 8 out of 52 sows developed cystic follicles; either full cystic ovaries (n = 6) or partial ovulation (n = 2). Increase in follicle size of these sows was similar to that of normal ovulating sows until pre-ovulatory size at Day 5 after the start of separation, but from then on became larger (P < 0.05). LH surge was smaller or absent in sows that developed (partially) cystic ovaries (0.4 ± 0.1 vs 3.6 ± 0.3 ng mL–1; P < 0.01). Peak levels of oestradiol (E2) were similar but high E2 levels persisted in sows that developed (partly) cystic ovaries and duration of oestrus tended to be longer. The risk of developing (partly) cystic ovaries was higher when IS occurred in blocks of 6 h versus 12 h (33 vs 10%). In conclusion, the appearance of cystic ovaries at approximately Day 20 of ongoing lactation was related to an insufficient LH surge, as is also the case in non-lactating sows.

The earliest stages of folliculogenesis in vitro

Reproduction ◽  
2002 ◽  
pp. 185-202 ◽  
Author(s):  
JE Smitz ◽  
RG Cortvrindt
Keyword(s):  
Ovarian Tissue ◽  
Ovarian Follicle ◽  
Mammalian Species ◽  
Follicle Development ◽  
Follicle Growth ◽  
Follicle Culture ◽  
In Vitro Techniques ◽  
Suitable Material ◽  
Culture Systems

In recent years several follicle culture systems have been pioneered in different mammalian species for studying ovarian folliculogenesis and culturing immature oocytes. Applications of these in vitro techniques include fertility preservation for humans, conservation of rare animals and development of oocyte banks for research purposes. Immature female gametes in the ovarian cortex can be cryopreserved for later use if culture techniques are available afterwards to promote growth and maturation. This review focuses on biochemical and biophysical factors related to oocyte culture in mice, the only animal in which live offspring have been produced after folliculogenesis in vitro. The advantage of using mice for these studies is that, in parallel to development of follicle culture systems, essential knowledge on folliculogenesis can be obtained from knockout mouse models. Recent experiments in mice stressed the principal role of the oocyte in follicle development and the strict timing of the biological processes underlying oogenesis in vitro. In large domestic animals and humans, study of oocyte culture is confounded by the constitutively prolonged nature of ovarian follicle development. In humans, only some aspects of follicle development have been studied because of the limited availability of suitable material for experimentation, technical difficulties related to manipulation of very small structures and lack of knowledge on physiological regulation of the early stages of follicle growth. Only a few reports describe ovarian follicular growth in vitro. In this review, relevant information on hormonal and growth factor regulation of the earliest stages of follicle growth in mammals is reviewed. Techniques are becoming available for the precise isolation of distinct classes of follicle and powerful molecular biology techniques can be used in studies of ovarian tissue culture.

Effect of deslorelin acetate on gonadotropin secretion and ovarian follicle development in cycling mares

2001 ◽  
Vol 218 (5) ◽  
pp. 749-752 ◽  
Author(s):  
Valerie J. Farquhar ◽  
Patrick M. McCue ◽  
Terry M. Nett ◽  
Edward L. Squires
Keyword(s):  
Ovarian Follicle ◽  
Follicle Development ◽  
Gonadotropin Secretion ◽  
Ovarian Follicle Development

scholarly journals Effect of the metabolic environment at key stages of follicle development in cattle: focus on steroid biosynthesis

2012 ◽  
Vol 44 (9) ◽  
pp. 504-517 ◽  
Author(s):  
S. W. Walsh ◽  
J. P. Mehta ◽  
P. A. McGettigan ◽  
J. A. Browne ◽  
N. Forde ◽  
...  
Keyword(s):  
Luteal Phase ◽  
Ovarian Follicle ◽  
Regulatory Protein ◽  
Follicle Development ◽  
Preovulatory Follicle ◽  
Dominant Follicle ◽  
Beef Heifers ◽  
Steroid Biosynthesis ◽  
Lh Surge ◽  
Lactating Cows

Cellular mechanisms that contribute to low estradiol concentrations produced by the preovulatory ovarian follicle in cattle with a compromised metabolic status are largely unknown. To gain insight into the main metabolic mechanisms affecting preovulatory follicle function, two different animal models were used. Experiment 1 compared Holstein-Friesian nonlactating heifers ( n = 17) and lactating cows ( n = 16) at three stages of preovulatory follicle development: 1) newly selected dominant follicle in the luteal phase (Selection), 2) follicular phase before the LH surge (Differentiation), and 3) preovulatory phase after the LH surge (Luteinization). Experiment 2 compared newly selected dominant follicles in the luteal phase in beef heifers fed a diet of 1.2 times maintenance (M, n = 8) or 0.4 M ( n = 11). Lactating cows and 0.4 M beef heifers had higher concentrations of β-hydroxybutyrate, and lower concentrations of glucose, insulin, and IGF-I compared with dairy heifers and 1.2 M beef heifers, respectively. In lactating cows this altered metabolic environment was associated with reduced dominant follicle estradiol and progesterone synthesis during Differentiation and Luteinization, respectively, and in 0.4 M beef heifers with reduced dominant follicle estradiol synthesis. Using a combination of RNA sequencing, Ingenuity Pathway Analysis, and qRT-PCR validation, we identified several important molecular markers involved in steroid biosynthesis, such as the expression of steroidogenic acute regulatory protein ( STAR) within developing dominant follicles, to be downregulated by the catabolic state. Based on this, we propose that the adverse metabolic environment caused by lactation or nutritional restriction decreases preovulatory follicle function mainly by affecting cholesterol transport into the mitochondria to initiate steroidogenesis.

scholarly journals Ovarian Follicle Growth during Lactation Determines the Reproductive Performance of Weaned Sows

Animals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1012 ◽  
Author(s):  
Tania P. Lopes ◽  
Lorena Padilla ◽  
Alfonso Bolarin ◽  
Heriberto Rodriguez-Martinez ◽  
Jordi Roca
Keyword(s):  
Reproductive Performance ◽  
Post Partum ◽  
Ovarian Follicle ◽  
Transrectal Ultrasound ◽  
Great Variability ◽  
Early Lactation ◽  
Follicle Growth ◽  
Follicle Diameter ◽  
Follicular Size ◽  
Follicle Size

Factors causing variability in ovarian follicle size among weaned sows are not well known. This field study aimed to disclose influencing factors and evaluate if the differences at weaning were established during lactation. Ovaries were scanned using transrectal ultrasound. The first experiment was conducted over a year with 191 randomly chosen sows that were hierarchically grouped (p < 0.001) according to ovarian follicle diameter reached at weaning: Small (0.20–0.30 cm; n = 37), medium (0.31–0.39 cm; n = 75), and large (0.40-1.00 cm; n = 69). Sows with small follicles showed a higher incidence of post-weaning anestrus (p < 0.01), longer wean-to-estrus/ovulation intervals (p < 0.01) and farrowing smaller litters (p < 0.05). Ovaries with small follicles were more common among sows weaned in summer–autumn than in winter–spring (p < 0.01) and among sows of lower parity (1–3) (p < 0.05). In the second experiment, with 40 sows randomly chosen at farrowing, the ovaries were scanned at 7, 14, and 21 d post-partum. Sows showed great variability in ovarian follicular size during lactation with a consistent relationship between the three measurement times (r = 0.84, p < 0.01). Follicle size was smaller in sows nursing in summer–autumn than in winter–spring (p < 0.05). In conclusion, early lactation dictates the great variability in ovarian follicular diameter at weaning shown by sows. Sows with smaller follicles at weaning had longer intervals for estrus and ovulation and smaller litters at farrowing and they were in greater numbers among sows weaned during the summer and fall and among those with fewer previous farrowing.

scholarly journals Kisspeptin Signaling Is Indispensable for Neurokinin B, but not Glutamate, Stimulation of Gonadotropin Secretion in Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 316-328 ◽  
Author(s):  
David García-Galiano ◽  
Dorette van Ingen Schenau ◽  
Silvia Leon ◽  
Magda A. M. Krajnc-Franken ◽  
Maria Manfredi-Lozano ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Hypogonadotropic Hypogonadism ◽  
Neurokinin B ◽  
Gonadotropin Secretion ◽  
Gnrh Secretion ◽  
Metabotropic Glutamate ◽  
Gonadotropic Axis ◽  
Transgenic Lines ◽  
Lh Secretion

Kisspeptins (Kp), products of the Kiss1 gene that act via Gpr54 to potently stimulate GnRH secretion, operate as mediators of other regulatory signals of the gonadotropic axis. Mouse models of Gpr54 and/or Kiss1 inactivation have been used to address the contribution of Kp in the central control of gonadotropin secretion; yet, phenotypic and hormonal differences have been detected among the transgenic lines available. We report here a series of neuroendocrine analyses in male mice of a novel Gpr54 knockout (KO) model, generated by heterozygous crossing of a loxP-Gpr54/Protamine-Cre double mutant line. Gpr54-null males showed severe hypogonadotropic hypogonadism but retained robust responsiveness to GnRH. Gonadotropic responses to the agonist of ionotropic glutamate receptors, N-methyl-d-aspartate, were attenuated, but persisted, in Gpr54-null mice. In contrast, LH secretion after activation of metabotropic glutamate receptors was totally preserved in the absence of Gpr54 signaling. Detectable, albeit reduced, LH responses were also observed in Gpr54 KO mice after intracerebroventricular administration of galanin-like peptide or RF9, putative antagonist of neuropeptide FF receptors for the mammalian ortholog of gonadotropin-inhibiting hormone. In contrast, the stimulatory effect of senktide, agonist of neurokinin B (NKB; cotransmitter of Kiss1 neurons), was totally abrogated in Gpr54 KO males. Lack of Kp signaling also eliminated feedback LH responses to testosterone withdrawal. However, residual but sustained increases of FSH were detected in gonadectomized Gpr54 KO males, in which testosterone replacement failed to fully suppress circulating FSH levels. In sum, our study provides novel evidence for the relative importance of Kp-dependent vs. -independent actions of several key regulators of GnRH secretion, such as glutamate, galanin-like peptide, and testosterone. In addition, our data document for the first time the indispensable role of Kp signaling in mediating the stimulatory effects of NKB on LH secretion, thus supporting the hypothesis that NKB actions on GnRH neurons are indirectly mediated via its ability to regulate Kiss1 neuronal output.

scholarly journals KNDy (Kisspeptin/Neurokinin B/Dynorphin) Neurons Are Activated during Both Pulsatile and Surge Secretion of LH in the Ewe

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5406-5414 ◽  
Author(s):  
Christina M. Merkley ◽  
Katrina L. Porter ◽  
Lique M. Coolen ◽  
Stanley M. Hileman ◽  
Heather J. Billings ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Neurokinin B ◽  
Lh Surge ◽  
Short And Long Term ◽  
Positive And Negative Feedback ◽  
Kndy Neurons ◽  
Lh Secretion

Abstract KNDy (kisspeptin/neurokinin B/dynorphin) neurons of the arcuate nucleus (ARC) appear to mediate the negative feedback actions of estradiol and are thought to be key regulators of pulsatile LH secretion. In the ewe, KNDy neurons may also be involved with the positive feedback actions of estradiol (E2) to induce the LH surge, but the role of kisspeptin neurons in the preoptic area (POA) remains unclear. The goal of this study was to identify which population(s) of kisspeptin neurons is (are) activated during the LH surge and in response to the removal of E2-negative feedback, using Fos as an index of neuronal activation. Dual-label immunocytochemistry for kisspeptin and Fos was performed on sections containing the ARC and POA from ewes during the luteal phase of the estrous cycle, or before or after the onset of the LH surge (experiment 1), and from ovary-intact, short-term (24 h) and long-term (&gt;30 d) ovariectomized (OVX) ewes in anestrus (experiment 2). The percentage of kisspeptin neurons expressing Fos in both the ARC and POA was significantly higher during the LH surge. In contrast, the percentage of kisspeptin/Fos colocalization was significantly increased in the ARC, but not POA, after both short- and long-term E2 withdrawal. Thus, POA kisspeptin neurons in the sheep are activated during, and appear to contribute to, E2-positive feedback, whereas ARC kisspeptin (KNDy) neurons are activated during both surge and pulsatile modes of secretion and likely play a role in mediating both positive and negative feedback actions of E2 on GnRH secretion in the ewe.

scholarly journals Interactions Between Neurokinin B and Kisspeptin in Mediating Estrogen Feedback in Healthy Women

2016 ◽  
Vol 101 (12) ◽  
pp. 4628-4636 ◽  
Author(s):  
Karolina Skorupskaite ◽  
Jyothis T. George ◽  
Johannes D. Veldhuis ◽  
Robert P. Millar ◽  
Richard A. Anderson
Keyword(s):  
Pulse Frequency ◽  
Estradiol Treatment ◽  
Neurokinin B ◽  
Gonadotropin Secretion ◽  
Regular Menses ◽  
Clinical Research Facility ◽  
Transdermal Estradiol ◽  
Neurokinin 3 Receptor ◽  
Normal Women ◽  
Lh Secretion

Context: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. Objective: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. Design: Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study. Setting: Clinical research facility. Patients or other participants: Healthy females with regular menses. Intervention(s): NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4–6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. Main outcome measure(s): Plasma gonadotropin and estradiol secretion. Results: After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P &lt; .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P &lt; .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P &lt; .05). Conclusions: These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.

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