scholarly journals Modeling the Male Reproductive Endocrine Axis: Potential Role for a Delay Mechanism in the Inhibitory Action of Gonadal Steroids on GnRH Pulse Frequency

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 2080-2092 ◽  
Author(s):  
Teuku R. Ferasyi ◽  
P. Hugh R. Barrett ◽  
Dominique Blache ◽  
Graeme B. Martin
Keyword(s):  
Negative Feedback ◽  
Time Delays ◽  
Model Development ◽  
Computer Software ◽  
Critical Factor ◽  
Pulse Frequency ◽  
Primary Control ◽  
Reproductive Endocrine ◽  
Endocrine Axis ◽  
Male Sheep

Abstract We developed a compartmental model so we could test mechanistic concepts in the control of the male reproductive endocrine axis. Using SAAM II computer software and a bank of experimental data from male sheep, we began by modeling GnRH-LH feed-forward and LH-T feedback. A key assumption was that the primary control signal comes from a hypothetical neural network (the PULSAR) that emits a digital (pulsatile) signal of variable frequency that drives GnRH secretion in square wave-like pulses. This model produced endocrine profiles that matched experimental observations for the testis-intact animal and for changes in GnRH pulse frequency after castration and T replacement. In the second stage of the model development, we introduced a delay in the negative feedback caused by the aromatization of T to estradiol at the brain level, a concept supported by empirical observations. The simulations showed how changes in the process of aromatization could affect the response of the pulsatile signal to inhibition by steroid feedback. The sensitivity of the PULSAR to estradiol was a critical factor, but the most striking observation was the effect of time delays. With longer delays, there was a reduction in the rate of aromatization and therefore a decrease in local estradiol concentrations, and the outcome was multiple-pulse events in the secretion of GnRH/LH, reflecting experimental observations. In conclusion, our model successfully emulates the GnRH-LH-T-GnRH loop, accommodates a pivotal role for central aromatization in negative feedback, and suggests that time delays in negative feedback are an important aspect of the control of GnRH pulse frequency.

scholarly journals MOSAIK and FMI-Based Co-Simulation Applied to Transient Stability Analysis of Grid-Forming Converter Modulated Wind Power Plants

2021 ◽  
Vol 11 (5) ◽  
pp. 2410
Author(s):  
Nakisa Farrokhseresht ◽  
Arjen A. van der Meer ◽  
José Rueda Torres ◽  
Mart A. M. M. van der Meijden
Keyword(s):  
Power System ◽  
Time Domain ◽  
Power Plants ◽  
Transient Stability ◽  
Renewable Energy Sources ◽  
Critical Factor ◽  
Primary Control ◽  
Simulation Approach ◽  
Wide Range ◽  
Grid Side

The grid integration of renewable energy sources interfaced through power electronic converters is undergoing a significant acceleration to meet environmental and political targets. The rapid deployment of converters brings new challenges in ensuring robustness, transient stability, among others. In order to enhance transient stability, transmission system operators established network grid code requirements for converter-based generators to support the primary control task during faults. A critical factor in terms of implementing grid codes is the control strategy of the grid-side converters. Grid-forming converters are a promising solution which could perform properly in a weak-grid condition as well as in an islanded operation. In order to ensure grid code compliance, a wide range of transient stability studies is required. Time-domain simulations are common practice for that purpose. However, performing traditional monolithic time domain simulations (single solver, single domain) on a converter-dominated power system is a very complex and computationally intensive task. In this paper, a co-simulation approach using the mosaik framework is applied on a power system with grid-forming converters. A validation workflow is proposed to verify the co-simulation framework. The results of comprehensive simulation studies show a proof of concept for the applicability of this co-simulation approach to evaluate the transient stability of a dominant grid-forming converter-based power system.

Reproductive hormone secretion and spermatogenic function in thyroidectomized rams receiving graded doses of exogenous thyroxine

1986 ◽  
Vol 111 (2) ◽  
pp. 245-253 ◽  
Author(s):  
Y. Chandrasekhar ◽  
M. J. D'Occhio ◽  
B. P. Setchell
Keyword(s):  
Hormone Secretion ◽  
Reproductive Function ◽  
Pulse Frequency ◽  
Endocrine Function ◽  
Sex Hormone Binding Globulin ◽  
Testosterone Levels ◽  
Reproductive Endocrine ◽  
Lh Release ◽  
Lh Releasing Hormone ◽  
The Relationship

ABSTRACT This study aimed to obtain a better understanding of the relationship between circulating thyroxine (T4) concentrations and reproductive endocrine function in the ram. Mature Merino rams were thyroidectomized and supplemented with 0, 30, 100 and 300% of normal T4 for 10 weeks. Thyroidectomy had no apparent effect on spermatogenic function but interfered with sperm maturation, the latter being returned to normal by 30% T4 replacement. Circulating testosterone levels were reduced by thyroidectomy and restored to control levels by 30% T4; when T4 levels were supranormal (300%), circulating testosterone levels were again reduced. The lowered circulating testosterone levels in thyroidectomized rams occurred as a result of suppressed testosterone secretion from the testis, observed under basal conditions and also following LH-releasing hormone (LHRH) and human chorionic gonadotrophin injection. In thyroidectomized rams, sex hormone binding globulin (SHBG) levels were depressed without changes in testosterone clearance rate (TCR), while in rams with supranormal T4 levels, TCR was increased without changes in SHBG levels. Subnormal levels of T4 also restored to normal the reduced LH pulse frequency in thyroidectomized rams. Reduced LH pulse frequency, together with diminished LH release following LHRH injection in thyroidectomized rams, suggested effects of T4 at the hypothalamo-pituitary axis. The present study demonstrates that complete lack of thyroid hormones suppresses normal reproductive endocrine function in the ram, but that this can be restored to normal by 30% T4 replacement. The results support the theory that T4 plays a permissive rather than a regulatory role in reproductive function in males. J. Endocr. (1986) 111, 245–253

scholarly journals Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men

2010 ◽  
Vol 299 (4) ◽  
pp. E675-E682 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Paul Y. Takahashi ◽  
Daniel M. Keenan ◽  
Peter Y. Liu ◽  
Kristi L. Mielke ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Negative Feedback ◽  
Pulse Frequency ◽  
Analysis Of Covariance ◽  
Double Blind ◽  
Healthy Men ◽  
Age Related ◽  
Lh Release ◽  
Lh Secretion ◽  
Double Blind Crossover Study

Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20–73 yr, BMI 21–32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion ( P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts ( P = 0.025), 3) suppressed incremental GnRH-induced LH release ( P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release ( P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH ( P = 0.002) and T ( P = 0.017) concentrations, 2) accelerating LH pulse frequency ( P = 0.013), 3) amplifying total (basal plus pulsatile) LH ( P = 0.002) and T ( P < 0.001) secretion, 4) shortening LH secretory bursts ( P = 0.032), and 5) reducing LH secretory regularity ( P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion ( P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.

Effect of chronic food restriction on pulsatile luteinizing hormone secretion and hypothalamic neuropeptide Y gene expression in castrate male sheep

1997 ◽  
Vol 152 (2) ◽  
pp. 329-337 ◽  
Author(s):  
C L Adam ◽  
P A Findlay ◽  
C E Kyle ◽  
P Young ◽  
J G Mercer
Keyword(s):  
Gene Expression ◽  
Neuropeptide Y ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
High Energy ◽  
Low Energy ◽  
High Protein ◽  
Castrate Male ◽  
Low Protein ◽  
Male Sheep

Abstract Castrate male sheep (wethers, average liveweight 38 ± 0·6 kg) were given one of the following diets for 10 weeks followed by euthanasia (n=8/group): high-energy high-protein providing 1·5 times the energy required to maintain liveweight (maintenance) (group 1·5M), low-energy low-protein at 0·5 maintenance (0·5M), or low-energy high-protein at 0·5 maintenance (0·5M+P). 1·5M wethers gained 22% liveweight whereas 0·5M and 0·5M+P wethers lost 18 and 13% liveweight respectively. Relative to the 1·5M group, the 0·5M and 0·5M+P groups had similar plasma concentrations of glucose and cortisol throughout, but elevated non-esterified fatty acids (P<0·001) and reduced IGF-I and insulin (P<0·05, 0·01 or 0·001) from 1 week onwards. Each week blood samples were taken every 12 min for 4 h and plasma assayed for LH. Mean concentration over 4 h, LH pulse frequency and LH pulse amplitude showed no progressive change in 1·5M sheep. However, in both 0·5M and 0·5M+P groups mean LH increased (P<0·001 and P<0·01 respectively), pulse frequency decreased (P<0·01 and P<0·01) and pulse amplitude increased (P<0·001 and P<0·01) over the 10-week period. Anterior pituitary LH content was greater in 0·5M (P<0·01) and 0·5M+P (P<0·05) than in 1·5M sheep. Coronal sections (20 μm) of hypothalamic brain tissue were subjected to in situ hybridisation to determine gene expression for neuropeptide Y (NPY). NPY mRNA was concentrated in the arcuate nucleus and median eminence, with total amounts greater in both 0·5M (310%, P<0·001) and 0·5M+P (333%, P<0·01) groups than in 1·5M sheep (100%). These data reveal that chronic low dietary energy intake by long-term castrates, with high or low protein intake, reduces LH pulse frequency but increases the circulating levels of LH by virtue of an increase in pulse amplitude, and concomitantly increases hypothalamic NPY gene expression. Journal of Endocrinology (1997) 152, 329–337

scholarly journals INFLUENCE OF SEASON AND SOCIAL ENVIRONMENT ON THE REPRODUCTIVE-ENDOCRINE STATUS OF THE ADULT LANDRACE BOAR

1990 ◽  
Vol 70 (1) ◽  
pp. 121-128 ◽  
Author(s):  
V. L. TRUDEAU ◽  
L. M. SANFORD
Keyword(s):  
Social Environment ◽  
Late Summer ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Social Environments ◽  
Blood Samples ◽  
Testosterone Secretion ◽  
Endocrine Status ◽  
Reproductive Endocrine ◽  
Basal Concentration

Seasonal variations in LH, FSH, and testosterone secretion were investigated for adult Landrace boars housed in different social environments for 1 yr. Socially nonrestricted boars (n = 4) were penned adjacent to ovariectomized gilts that were hormonally brought into estrus every 2 wk, while socially restricted boars (n = 4) were kept in pens with solid walls. Mean hormone concentrations were determined from the assay of single AM and PM blood samples collected from the jugular vein by venipuncture once a month. In November, February, May and August, blood samples were collected serially over 12 h from jugular catheters for assessment of pulsatile LH and testosterone secretion, and the LH response to a GnRH injection (1 μg kg−1 body weight). Mean LH and testosterone concentrations were relatively high in all boars during the late summer and fall, and often were greater for the socially nonrestricted versus the restricted boars (group × month), P < 0.05) in the winter (December and January). Mean FSH concentration also varied with month (P < 0.05). Pulse analysis indicated that higher mean testosterone concentrations in November and August were the result of increases (month, P < 0.05) in testosterone-pulse frequency and basal concentration. Maximal mean LH concentration in August was associated with maximal (month, P < 0.05) LH-pulse amplitude and basal concentration. The amplitude of the LH peak following GnRH injection increased (P < 0.05) between November and May, and remained high in August. Key words: Gonadotropins, testosterone, blood, season, social environment, boar

I Play, I Pay?

2012 ◽  
Vol 4 (1) ◽  
pp. 19-31 ◽  
Author(s):  
Bo Han
Keyword(s):  
Willingness To Pay ◽  
Success Factors ◽  
Business Models ◽  
Economic Value ◽  
Model Development ◽  
Critical Factor ◽  
Influential Factors ◽  
Perceived Playfulness ◽  
New Business ◽  
Marketing Activities

The user’s willingness to pay has become one of the most important success factors of hedonic social network site new business models and social media marketing activities. In the current study, the author investigates the influential factors of the user’s willingness to pay from the hedonic system use theories and the social capital based view. The author finds that the user’s perceived playfulness, which is considered a critical factor by practitioners, has no significant positive effect on the user’s willingness to pay. Along with other findings, the author has a further discussion on the fun-based business model development. This study provides a theoretical foundation for the future HSNS economic value research and offers several implications to practitioners.

scholarly journals The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS)

2019 ◽  
Vol 7 (8) ◽  
pp. 84 ◽  
Author(s):  
Coutinho ◽  
Kauffman
Keyword(s):  
Animal Models ◽  
Polycystic Ovary Syndrome ◽  
Neural Circuit ◽  
Polycystic Ovary ◽  
Pulse Frequency ◽  
Reproductive Age ◽  
Neuron Activity ◽  
Ovary Syndrome ◽  
Gnrh Neurons ◽  
Reproductive Endocrine

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women.

scholarly journals OR11-01 Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yee-Ming Chan ◽  
Margaret Flynn Lippincott ◽  
Priscila Sales Barroso ◽  
Cielo Alleyn ◽  
Jill Brodsky ◽  
...  
Keyword(s):  
Inhibin B ◽  
Stimulation Test ◽  
Delayed Puberty ◽  
Laboratory Studies ◽  
Pubertal Delay ◽  
Gnrh Release ◽  
Reproductive Endocrine ◽  
Physical Examinations ◽  
Outcomes For Children ◽  
Endocrine Axis

Abstract Background: The management of youth presenting with delayed puberty is challenging because it can be difficult to predict which children will eventually progress through puberty and which children will not. We have previously shown that exogenous administration of the neuropeptide kisspeptin, which stimulates GnRH release, can be used to probe the integrity of the reproductive endocrine axis. We hypothesized that responses to kisspeptin could predict outcomes for individuals with pubertal delay. Methods: We conducted a longitudinal study of 16 children (3 girls and 13 boys) with delayed or stalled puberty who had undergone stimulation testing with kisspeptin and GnRH. Participants were followed with serial physical examinations and laboratory studies every six months for evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results: “Kisspeptin responders” who had responded to kisspeptin with a rise in LH of 0.8 mIU/mL or greater all subsequently progressed through puberty (n = 8). In contrast, “kisspeptin nonresponders” who had exhibited LH responses to kisspeptin ≤0.4 mIU/mL all reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (p = 0.0002), with sensitivity and specificity of 100% (95% CI 74-100%). Moreover, the kisspeptin-stimulation test outperformed overnight LH measurements, GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion: The kisspeptin-stimulation test can be used to reveal future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty. Trial registration: ClinicalTrials.gov NCT01438034

scholarly journals Evidence that Orphanin FQ Mediates Progesterone Negative Feedback in the Ewe

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4249-4258 ◽  
Author(s):  
Casey C Nestor ◽  
Lique M. Coolen ◽  
Gail L. Nesselrod ◽  
Miro Valent ◽  
John M. Connors ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Negative Feedback ◽  
Luteal Phase ◽  
Arcuate Nucleus ◽  
Pulse Amplitude ◽  
Estrogen Receptor Α ◽  
Pulse Frequency ◽  
Orphanin Fq ◽  
High Degree ◽  
Lh Secretion

Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor α and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin-NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid-treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 ± 0.5 pulses/6 h) compared with saline infusion (2.6 ± 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep.

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