scholarly journals Progesterone Positive Feedback on Pulsatile LH Secretion and FSH Release May Be Blunted in Estradiol-Pretreated Women With PCOS

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A744-A744
Author(s):  
Christopher Rolland McCartney ◽  
Su Hee Kim ◽  
Jessica A Lundgren ◽  
Christine Michele Burt Solorzano ◽  
James T Patrie
Keyword(s):  
Positive Feedback ◽  
A Priori ◽  
Pulse Frequency ◽  
Research Unit ◽  
Analysis Of Covariance ◽  
Clinical Research Unit ◽  
Exogenous Progesterone ◽  
Secondary Hypothesis ◽  
Induced Changes ◽  
Lh Secretion

Abstract In women pretreated with estradiol (E2), exogenous progesterone (P4) acutely augments LH and FSH release (P4 positive feedback). Women with PCOS exhibit impaired P4 negative feedback on LH pulse frequency, but it remains unclear whether such women exhibit impaired P4 positive feedback on LH/FSH release. We sought to explore the latter notion as an a priori secondary hypothesis in a study primarily designed to assess whether P4 acutely suppresses LH pulse frequency. We studied 12 women with PCOS and 12 normally-cycling, non-hyperandrogenic controls. After 3 days of transdermal E2 pretreatment (0.2 mg/day), subjects were admitted to the Clinical Research Unit (CRU) for a 24-hour frequent blood sampling protocol starting at 2000 h. (CRU admissions occurred no earlier than cycle day 7 in PCOS and between days 7 and 11 inclusive in controls.) At 0600 h, subjects received either 100 mg oral micronized P4 or placebo (PBO). In a subsequent menstrual cycle, subjects underwent an identical CRU protocol except that P4 was exchanged for PBO or vice versa. LH secretion was analyzed using Autodecon, a deconvolution program that provides estimates of LH pulse frequency, pulsatile LH secretion (amount of LH secreted as pulses), and basal (non-pulsatile) LH secretion. Results were analyzed using 2-period crossover design analysis of covariance. In both groups, neither LH pulse frequency nor basal LH secretion changed significantly with P4 (compared to changes with PBO). Mean LH increased with P4 in both groups—3.1-fold (95% CI, 2.4–4.0) in controls and 2.7-fold (95% CI, 2.1–3.5) in PCOS; in both groups, P4-related changes were significantly greater than PBO-related changes (Bonferroni-corrected p=0.012 and 0.010, respectively). In controls, pulsatile LH secretion increased 3.5-fold (95% CI, 2.3–5.2) with P4—significantly more than with PBO (p=0.029); while in PCOS, a 2.6-fold (95% CI, 1.8–3.9) increase with P4 was not significantly different from changes with PBO (p=0.911). In controls, mean FSH increased 2.0-fold (95% CI, 1.7–2.3) with P4—significantly more than with PBO (p=0.004); but in PCOS, a 1.5-fold (95% CI, 1.3–1.8) increase was not significantly different from changes with PBO (p=0.072). Despite the above, between-group (PCOS vs. controls) differences in P4-induced changes in pulsatile LH secretion and mean FSH were not formally (statistically) demonstrable. Between-group differences representing potential confounders included age (median 25.5 vs. 19.0 y; p=0.029), body mass index (29.9 vs. 21.8 kg/m2; p=0.006), and cycle day of CRU admissions (day 45.0 vs. 10.4 for P4 admissions; 30.0 vs. 10.0 for PBO admissions). In summary, these data suggest that P4-induced increases in pulsatile LH secretion and mean FSH may be blunted in PCOS compared to controls, which could contribute to ovulatory dysfunction in PCOS. However, our results do not confirm this possibility, and further study is needed.

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.

Photoperiodic modulation of the dopaminergic control of pulsatile LH secretion in sheep

1994 ◽  
Vol 143 (1) ◽  
pp. 25-32 ◽  
Author(s):  
D J Tortonese ◽  
G A Lincoln
Keyword(s):  
Dopaminergic System ◽  
Pulse Frequency ◽  
Inhibitory System ◽  
Pulsatile Gnrh ◽  
Photoperiodic Regulation ◽  
Series Of Experiments ◽  
Induced Changes ◽  
Lh Secretion ◽  
Short Days ◽  
Sustained Increase

Abstract This study was conducted to investigate whether the photoperiodic regulation of the seasonal changes in pulsatile LH secretion in the ram involves changes in the activity of inhibitory hypothalamic dopaminergic (DA) pathways. To test this hypothesis, a series of experiments was carried out in Soay rams in which the effects of a DA-D2 receptor antagonist (sulpiride) or a DA-D2 receptor agonist (bromocriptine) on the pulsatile secretion of LH were determined under both long and short days. In each experiment blood samples were collected every 10 min for 8 h starting at the time of vehicle, sulpiride or bromocriptine injections to assess concentrations of LH. Sulpiride (0·59 mg/kg, s.c.) administered to rams under long days induced an immediate and sustained increase in the secretion of LH that lasted for approximately 4 h (P<0·05; ANOVA); this LH response reflected both a rise in mean concentrations (0·247 ± 0·03 vs.0·452 ± 0·1 μg/1) and an increase in the frequency of LH pulses (0·5±0·5 vs. 2·33±0·42 pulses/8 h; P<0·01). In contrast, under short days sulpiride had no effect. Bromocriptine (0·06 mg/kg, s.c.) administered to rams under long days, when LH concentrations were low, was without effect, but when given to rams under short days significantly (P<0·05) suppressed mean LH concentrations (0·627 ±0·08 vs. 0·320 ± 0·02 μg/l) and LH pulse frequency (4·86 ±0·46 vs. 2·43 ±0·37 pulses/8 h). In an additional experiment, pimozide (total dose: 0·16 mg/kg, i.m.), a DA antagonist less specific for DA-D2 receptors than sulpiride, was ineffective in modifying LH secretion in sexually inactive rams exposed to long days. These results are consistent with the hypothesis that an inhibitory dopaminergic system is involved in the regulation of pulsatile LH secretion in the ram. The induced changes in LH pulse frequency under long days (increased by sulpiride) and under short days (decreased by bromocriptine) indicate that, under both photoperiods, DA acts within the hypothalamus, via a specific DA-D2 receptor, to influence pulsatile GnRH secretion. A photoperiodic-induced activation of this inhibitory system may therefore represent the mechanism whereby long days suppress LH secretion and lead to the sexually inactive state characteristic of the non-breeding season. Journal of Endocrinology (1994) 143, 25–32

scholarly journals Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status

2017 ◽  
Vol 103 (3) ◽  
pp. 1112-1121 ◽  
Author(s):  
Su Hee Kim ◽  
Jessica A Lundgren ◽  
Ruchi Bhabhra ◽  
Jessicah S Collins ◽  
James T Patrie ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Pulse Generator ◽  
Pulse Frequency ◽  
Research Unit ◽  
Differential Sensitivity ◽  
Early Puberty ◽  
Clinical Research Unit ◽  
Frequency Changes ◽  
Function Of Sleep ◽  
Double Blinded

Abstract Context During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role. Objective To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls. Design Randomized, placebo-controlled, double-blinded crossover study. Setting Academic clinical research unit. Participants Eleven normal, postmenarcheal girls, ages 12 to 15 years. Intervention Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover). Main Outcome Measures LH pulse frequency during waking and sleeping hours. Results Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007). Conclusions In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.

scholarly journals Influence of steroids and GnRH on biosynthesis and secretion of secretogranin II and chromogranin A in relation to LH release in LbetaT2 gonadotroph cells

2002 ◽  
Vol 174 (3) ◽  
pp. 473-483 ◽  
Author(s):  
L Nicol ◽  
M Stridsberg ◽  
JL Crawford ◽  
AS McNeilly ◽  
Keyword(s):  
Chromogranin A ◽  
Secretory Granules ◽  
Close Correlation ◽  
Pulse Frequency ◽  
Mrna Levels ◽  
Secretogranin Ii ◽  
Mouse Pituitary ◽  
Induced Changes ◽  
Lh Secretion ◽  
Dose Dependent

The granin proteins secretogranin II (SgII) and chromogranin A (CgA) are commonly found associated with LH and/or FSH within specialised secretory granules in gonadotroph cells, and it is possible that they play an important role in the differential secretion of the gonadotrophins. In this study we have examined the regulation of the biosynthesis and secretion of SgII and CgA, in relation to LH secretion, in the LbetaT2 mouse pituitary gonadotroph cell line. Three experiments were carried out to investigate the effects of oestradiol (E2) and dexamethasone (Dex) in the presence and absence of GnRH (experiment 1), differing GnRH concentrations (experiment 2) and alterations in GnRH pulse frequency (experiment 3). In experiment 1, exposure to E2, Dex or E2+Dex, either with or without GnRH treatment, resulted in increased LH secretion. Steroids alone had no effect on LHbeta mRNA levels, but in the presence of GnRH LHbeta mRNA levels were increased in Dex- and E2+Dex-treated cells. GnRH receptor (GnRH-R) mRNA levels were up-regulated by Dex and E2+Dex, but were unaffected by GnRH. There were no steroid-induced changes in SgII or CgA mRNA, but increased levels of CgA mRNA were observed after GnRH treatment in cells cultured in the presence of Dex. In experiment 2, increasing concentrations of GnRH resulted in increases in LH secretion that were inversely dose-dependent. No changes in LHbeta, GnRH-R or SgII mRNA levels were observed, but there were dose-dependent increases in CgA mRNA levels. In experiment 3, GnRH was given as either 1 pulse/day or 4 pulses/day for 3 days. Both pulse regimes resulted in increased LH, SgII and CgA secretion compared with controls during the first 15 min pulse on day 3. Exposure to GnRH at 4 pulses/day increased LH and SgII secretion compared with controls during all 4 pulses, but secretion of both proteins was reduced during pulses 2-4 compared with pulse 1. CgA secretion also increased due to GnRH in pulse 1, but was decreased by GnRH treatment during pulse 2, and unchanged by GnRH during pulses 3 and 4. Total daily secretion of LH and SgII from cells given 1 pulse/day of GnRH increased compared with controls on all three treatment days, while total CgA secretion increased in response to GnRH on days 2 and 3 only. Intracellular levels of SgII, but not LH, decreased after GnRH treatment. In contrast, intracellular CgA was increased, but only after 4 pulses/day of GnRH. Levels of LHbeta, but not SgII, mRNA were increased by both pulse regimes, while CgA mRNA levels increased after 1 pulse/day of GnRH. These results indicate that there is a close correlation between the GnRH-stimulated release of LH and SgII from LbetaT2 cells, suggesting that SgII may have an influential role in the regulated secretion of LH, possibly by inducing LH aggregation to facilitate trafficking into secretory granules. CgA secretion does not appear to be closely associated with that of LH, but CgA expression does appear to be regulated by GnRH, which may indicate involvement in the control of LH secretion, possibly by influencing the proportion of LH in the different types of secretory granules.

Comparison of actigraphy and polysomnography to assess effects of zolpidem in a clinical research unit

2012 ◽  
Vol 13 (4) ◽  
pp. 419-424 ◽  
Author(s):  
Barry T. Peterson ◽  
Ping Chiao ◽  
Eve Pickering ◽  
Jon Freeman ◽  
Gary K. Zammit ◽  
...  
Keyword(s):  
Clinical Research ◽  
Research Unit ◽  
Clinical Research Unit

Feedback-Induced Variations of Distribution in a Representative Gene Model

2015 ◽  
Vol 25 (07) ◽  
pp. 1540008
Author(s):  
Peijiang Liu ◽  
Zhanjiang Yuan ◽  
Lifang Huang ◽  
Tianshou Zhou
Keyword(s):  
Gene Expression ◽  
Power Law ◽  
Positive Feedback ◽  
Bimodal Distribution ◽  
Stochastic Bifurcation ◽  
Protein Distribution ◽  
Identical Cell ◽  
Induced Changes ◽  
Gene Switching ◽  
Cell To Cell Variability

Gene expression is inherently noisy, implying that the number of mRNAs or proteins is not invariant rather than follows a distribution. This distribution can not only provide the exact information on the dynamics of gene expression but also describe cell-to-cell variability in a genetically identical cell population. Here, we systematically investigate a two-state model of gene expression, a model paradigm used to study expression dynamics, focusing on the effect of feedback on the type of mRNA or protein distribution. If there is no feedback, then the distribution may be bimodal, power-law tailed, or Poisson-like, depending on gene switching rates. However, we find that feedback can tune or change the type of the distribution in each case and tends to unimodalize the distribution as its strength increases. Specifically, positive feedback can change not only a power-law tailed distribution into a bimodal or Poisson-like distribution but also a bimodal distribution into a Poisson-like distribution (implying that stochastic bifurcation can take place). In addition, it can make a Poisson-like distribution become more peaked but does not change the type of this distribution. In contrast to positive feedback, negative feedback has less influence on the shape of the distributions except for the bimodal case. In all cases, the noise-feedback curve used extensively in previous studies cannot well reflect the feedback-induced changes in the shape of distributions. Feedback-induced variations in distribution would be important for cell survival in fluctuating environments.

Seasonal and steroid-dependent effects on the modulation of LH secretion in the ewe by intracerebroventricularly administered β-endorphin or naloxone

1989 ◽  
Vol 122 (2) ◽  
pp. 509-517 ◽  
Author(s):  
R. J. E. Horton ◽  
H. Francis ◽  
I. J. Clarke
Keyword(s):  
Breeding Season ◽  
Luteal Phase ◽  
Pulse Frequency ◽  
Opioid Peptide ◽  
Follicular Phase ◽  
Oestrous Cycle ◽  
Opioid Antagonist ◽  
Endogenous Opioid ◽  
Endogenous Opioid Peptide ◽  
Lh Secretion

ABSTRACT The natural opioid ligand, β-endorphin, and the opioid antagonist, naloxone, were administered intracerebroventricularly (i.c.v.) to evaluate effects on LH secretion in ovariectomized ewes and in ovariectomized ewes treated with oestradiol-17β plus progesterone either during the breeding season or the anoestrous season. Ovary-intact ewes were also studied during the follicular phase of the oestrous cycle. Jugular blood samples were taken at 10-min intervals for 8 h and either saline (20–50 μl), 100 μg naloxone or 10 μg β-endorphin were injected i.c.v. after 4 h. In addition, luteal phase ewes were injected i.c.v. with 25 μg β-endorphin(1–27), a purported endogenous opioid antagonist. In ovariectomized ewes, irrespective of season, saline and naloxone did not affect LH secretion, but β-endorphin decreased the plasma LH concentrations, by reducing LH pulse frequency. The effect of β-endorphin was blocked by administering naloxone 30 min beforehand. Treating ovariectomized ewes with oestradiol-17β plus progesterone during the breeding season reduced plasma LH concentrations from 6–8 μg/l to less than 1 μg/l. In these ewes, saline did not alter LH secretion, but naloxone increased LH pulse frequency and the plasma concentrations of LH within 15–20 min. During anoestrus, the combination of oestradiol-17β plus progesterone to ovariectomized ewes reduced the plasma LH concentrations from 3–5 μg/l to undetectable levels, and neither saline nor naloxone affected LH secretion. During the follicular phase of the oestrous cycle, naloxone enhanced LH pulse frequency, which resulted in increased plasma LH concentrations; saline had no effect. In these sheep, β-endorphin decreased LH pulse frequency and the mean concentrations of LH, and this effect was prevented by the previous administration of naloxone. The i.c.v. administration of β-endorphin(1–27) to luteal phase ewes did not affect LH secretion. These data demonstrate the ability of a naturally occurring opioid peptide to inhibit LH secretion in ewes during the breeding and non-breeding seasons, irrespective of the gonadal steroid background. In contrast, whilst the gonadal steroids suppress LH secretion in ovariectomized ewes during both seasons, they only appear to activate endogenous opioid peptide (EOP)-mediated inhibition of LH secretion during the breeding season. Furthermore, these data support the notion that LH secretion in ovariectomized ewes is not normally under the control of EOP, so that naloxone has no effect. Journal of Endocrinology (1989) 122, 509–517

Pulsatile LH secretion in streptozotocin-induced diabetes in the rat

1991 ◽  
Vol 131 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Q. Dong ◽  
R. M. Lazarus ◽  
L. S. Wong ◽  
M. Vellios ◽  
D. J. Handelsman
Keyword(s):  
Weight Loss ◽  
Insulin Treatment ◽  
Pulse Generator ◽  
Latin Square ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Metabolic Effect ◽  
Male Rat ◽  
Free Access ◽  
Lh Secretion

ABSTRACT This study aimed to determine the effect of streptozotocin (STZ)-induced diabetes on pulsatile LH secretion in the mature male rat. LH pulse frequency was reduced by 56% and pulse amplitude by 54%, with a consequential decrease of 72% in mean LH levels 8 days after i.v. administration of STZ (55 mg/kg) to castrated Wistar rats compared with castrated non-diabetic controls. Twice daily insulin treatment completely reversed all parameters of pulsatile LH secretion to control values. Food-restricted non-diabetic controls, studied to distinguish the metabolic effect of diabetes from that of concurrent weight loss, demonstrated a 34% reduction in LH pulse frequency but no significant changes in LH pulse amplitude or mean LH levels compared with non-diabetic controls given free access to food. To distinguish whether the decreased LH pulse amplitude in diabetes was due to a reduction in either the quantity of hypothalamic gonadotrophin-releasing hormone (GnRH) released per secretory episode or to decreased pituitary responsiveness to GnRH, the responsiveness of the pituitary to exogenous GnRH (1–1000 ng/kg body weight) was tested in diabetic rats after castration, using a full Latin square experimental design. The net LH response (total area under response curve over 40 min following GnRH) was decreased by 33% (P=0·001) in diabetic compared with control rats. The decreased LH pulse frequency in STZ-induced diabetes therefore suggests that the metabolic effect of diabetes is to decelerate directly the firing rate of the hypothalamic GnRH pulse generator independent of testicular feed-back. These effects were fully reversed by insulin treatment and were only partly due to the associated weight loss. The impaired pituitary responsiveness to GnRH is at least partly involved in the reduction of LH pulse amplitude. Journal of Endocrinology (1991) 131, 49–55

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