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 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 Free Fatty Acids Inhibit Growth Hormone/Signal Transducer and Activator of Transcription-5 Signaling in Human Muscle: A Potential Feedback Mechanism

2009 ◽  
Vol 30 (3) ◽  
pp. 289-289
Author(s):  
Niels Møller ◽  
Lars C. Gormsen ◽  
Ole Schmitz ◽  
Sten Lund ◽  
Jens Otto L. Jørgensen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Negative Feedback ◽  
Feedback Inhibition ◽  
Research Unit ◽  
Feedback Mechanism ◽  
Signal Transducer ◽  
Blood Concentrations ◽  
Clinical Research Unit

ABSTRACT Context: Stimulation of lipolysis, leading to increased blood concentrations of free fatty acids (FFAs), is a primary effect of GH and phosphorylation of intracellular signal transducer and activator of transcription (STAT)-5 is a primary mediator of the effects of GH. Objective: Based on preliminary results, we intended to test whether FFAs exert a negative feedback inhibition of STAT5 phosphorylation in skeletal muscle. Design and Participants: Eight healthy young men were investigated for 8 h on four occasions at four different FFA levels in a single blind, randomized manner. Acipimox was used to suppress FFA levels and Intralipid was infused to obtain appropriate FFA concentrations. Somatostatin was infused to control GH levels and GH, insulin, and glucagon were replaced. Muscle biopsies were taken after 8 h and compared with a fifth biopsy taken under normal basal conditions. Setting: The study was conducted at a university clinical research unit. Results: GH concentrations remained steady and comparable in all studies and FFA concentrations varied between 0.01 and 1.71 mmol/liter on the four occasions (P < 0.05). We observed a dose-dependent 40% decrease of STAT5 phosphorylation in skeletal muscle with increasing concentrations of FFAs. Conclusions: Our results strongly suggest the existence of a negative feedback loop, whereby effects of GH may be dampened by FFA inhibition of GH-dependent STAT5 phosphorylation. The mechanisms behind and biological consequences of this finding awaits additional studies.

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

scholarly journals Pubertal Acceleration of Pulsatile Gonadotropin-Releasing Hormone Release in Male Rats as Revealed by Microdialysis

Endocrinology ◽  
2003 ◽  
Vol 144 (1) ◽  
pp. 163-171 ◽  
Author(s):  
Glenn C. Harris ◽  
Jon E. Levine
Keyword(s):  
Vas Deferens ◽  
Pulse Generator ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Male Rats ◽  
Male Rat ◽  
Pubertal Maturation ◽  
Repeated Sampling ◽  
Generator Activity ◽  
Mature Spermatozoa

Abstract A microdialysis technique was used in male rats to directly assess the postulate that pubertal maturation is associated with accelerated GnRH pulsatility. Juvenile male rats, postnatal d 43 or 45 (n = 4) were stereotaxically fitted with guide cannulas directed toward the lateral median eminence, and repeated microdialysis experiments were conducted over 4–6 d. In each session, samples were collected continuously over 12 h (0900–2100 h) at 5-min intervals Results from individual peripubertal animals were pooled into two time bins for postnatal d 45–47 and 48–50, respectively, and GnRH characteristics were compared between the two epochs. The GnRH pulse frequency and mean GnRH concentration were significantly elevated at 48–50 d compared with 45–47 d. The GnRH pulsatility characteristics for 45–47 d vs. 48–50 d were as follows: pulse frequency, 0.74 ± 0.16 vs. 1.79 ± 0.19 pulses/h (P < 0.05); pulse amplitude, 254.1 ± 22.3 vs. 347.2 ± 15.8 Δpg/ml (difference in value from trough to peak); and mean release, 0.55 ± 0.03 vs. 2.04 ± 0.04 pg/5 min (P < 0.05). An additional two rats were dialyzed only once on postnatal d 50 to assess the effects of repeated sampling; the GnRH pulse characteristics in these animals were similar to those in rats sampled for a third or fourth time on postnatal d 48–50. To further assess the possible effects of repeated sampling on GnRH release profiles, a group of adult male rats (postnatal d 95–105; n = 3) was also dialyzed on four consecutive days. In these rats no significant alteration in GnRH pulse generator activity was observed over the four sessions. Moreover, the increase in GnRH pulse frequency observed in the peripubertal rats was found to be sustained in adult animals. To better understand the temporal relationship of GnRH pulse generator activity to reproductive maturation, groups of male rats were killed from postnatal d 45–56 along with an adult group at 95–105 d (n = 5/group) and examined for physiological signs of reproductive development. Gradual increases in serum levels of LH and testosterone and decreases in FSH and inhibin B were seen from postnatal d 45–56 to adulthood. Mature spermatozoa were found in the vas deferens by postnatal d 53. Our results demonstrate that in the late juvenile stage of male rat development, GnRH pulse generator activity is gradually accelerated over the course of consecutive days. This acceleration occurs over a period during which serum LH and testosterone are rising to adult levels, and it precedes the presence of mature spermatozoa in the vas deferens by 3 d. Our observations provide direct support for the hypothesis that an acceleration of GnRH pulsatility is the critical neural stimulus for the initiation of pubertal maturation in males. The peripheral and central cues that prompt the pubertal activation of the GnRH pulse generator remain to be characterized.

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

scholarly journals Disposition of MDMA and Metabolites in Human Sweat Following Controlled MDMA Administration

2009 ◽  
Vol 55 (3) ◽  
pp. 454-462 ◽  
Author(s):  
Allan J Barnes ◽  
Bruno S De Martinis ◽  
David A Gorelick ◽  
Robert S Goodwin ◽  
Erin A Kolbrich ◽  
...  
Keyword(s):  
Solid Phase ◽  
Random Order ◽  
Research Unit ◽  
Sweat Test ◽  
Test Results ◽  
Double Blind ◽  
Scientific Database ◽  
Sweat Testing ◽  
Clinical Research Unit ◽  
Sweat Tests

Abstract Background: Understanding the excretion of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites in sweat is vital for interpretation of sweat tests in drug treatment, criminal justice, and workplace programs. Methods: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were given double-blind in random order to healthy volunteers (n = 15) with histories of MDMA use. Participants resided on the closed clinical research unit for up to 7 days after each dose. Volunteers wore PharmChek® sweat patches (n = 640) before, during, and after controlled dosing. Patches were analyzed by solid phase extraction and GC-MS for MDMA, methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification (LOQ) were 2.5 ng/patch for MDMA and 5 ng/patch for HMA, HMMA, and MDA. Results: MDMA was the primary analyte detected in 382 patches (59.7%), with concentrations up to 3007 ng/patch. MDA was detected in 188 patches (29.4%) at <172 ng/patch, whereas no HMMA or HMA was detected; 224 patches (35.0%) and 60 patches (9.4%) were positive for MDMA and MDA, respectively, at the 25-ng/patch threshold proposed by the Substance Abuse and Mental Health Services Administration. Conclusions: Sweat testing was shown to be an effective and reliable method for monitoring MDMA use in this controlled MDMA administration study. However, variability in sweat excretion suggests that results should be interpreted qualitatively rather than quantitatively. These data provide a scientific database for interpretation of MDMA sweat test results.

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.

scholarly journals New clusters of type 2 diabetes mellitus and their outcomes: relation between pharmacological treatment and previous cardiovascular events

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Claudio Santos ◽  
Sonia Brito-Costa ◽  
Luis Margalho ◽  
Pedro Monteiro
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pharmacological Treatment ◽  
Cardiovascular Events ◽  
Glycated Haemoglobin ◽  
Research Unit ◽  
Clinical Research Unit ◽  
History Of

Abstract Background Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes in adults, with 90% to 95% of cases. This study aims to establish clusters and have knowledge about the relationship between previous cardiovascular events and pharmacological treatment for T2DM. Methods 191 participants (EG) with T2DM with the average of 70.3 years (SD = 8.3) and 36 with pre-diabetes (CG) with an average of 62 years (SD = 10.3) who participated in clinical trials at Clinical Research Unit in Cardiology of Coimbra Hospital and Universitary Centre without cognitive difficulties, were divided in 5 different clusters. These were established based on six different variables: body mass index (BMI), age of each individual, age at diagnosis of DMT2, glycated haemoglobin value (HbA1c), homeostatic model that estimates the function of β cells (HOMA2-B) and insulin resistance (HOMA2-IR). Results Cluster 1 presented pre-diabetic individuals (15.9%), while diabetic individuals were divided into clusters 2 (1.8%), 3 (17.6%), 4 (21.1%) and 5 (43.6%). Regarding the study of the prevalence of previous cardiovascular events, the majority of individuals present in the different clusters had history of acute myocardial infarction (AMI). As for the prevalence of pharmacological treatment for DMT2, it was found that metformin was the most used drug. It was observed a relationship between previous AMI and metformin administration in clusters 3 (P = 0.0027; P &lt; 0.05) and 5 (P = 0.0059; P &lt; 0.05). Conclusions It was possible to create different clusters in a sample of the Portuguese population and to observe the existence of dependency relationships between different previous cardiovascular events and pharmacological treatment.

scholarly journals Correlation of serum androgen and gonadotropin with anti-mullerian hormone in polycystic ovarian syndrome in Eastern Indian population

2019 ◽  
Vol 8 (1) ◽  
pp. 256
Author(s):  
Somnath Singh Raghuvanshi ◽  
Anirban Sinha ◽  
Animesh Maiti ◽  
Partha Pratim Chakraborty ◽  
Asish Kumar Basu ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovarian Syndrome ◽  
Pulse Generator ◽  
Polycystic Ovary ◽  
Serum Testosterone ◽  
Pulse Frequency ◽  
Strong Positive Correlation ◽  
Ovary Syndrome ◽  
Cross Sectional ◽  
Ovarian Syndrome

Background: Ovarian steroidogenesis requires gonadotropin stimulation, Luteinizing Hormone (LH) is a key factor in the hyperandrogenaemia of the polycystic ovary syndrome. Progesterone is the primary regulator of Gonadotropin-Releasing Hormone (GnRH) pulse frequency; however, in the polycystic ovary syndrome, the GnRH pulse generator is relatively resistant to the negative feedback effects of progesterone.  Study aims to evaluate the association of Anti-mullerian hormone with serum androgen and gonadotropin level in adolescents and young women of Polycystic Ovary Syndrome (PCOS).Methods: This was a single centre observational Cross-sectional study carried out in the department of Endocrinology and metabolism, Medical College, Kolkata from March 2017 to January 2019. Total number of study subjects were 207 out of which 138 were cases.Results: The AMH had strong positive correlation with serum testosterone in both case and control groups (r 0.542, p<0.001 and r 0.57, p<0.001) respectively .After the adjustment of age and BMI , the AMH moderately positive  but extremely significant correlation with serum testosterone as compare to control.Conclusions: Hyperandrogenaemia and higher ratio of LH and FSH associated with higher serum AMH level is associated with the higher serum AMH in polycystic ovarian syndrome.

scholarly journals New technologies to improve healthcare in low- and middle-income countries: Global Grand Challenges satellite event, Oxford University Clinical Research Unit, Ho Chi Minh City, 17th-18th September 2019

2020 ◽  
Vol 5 ◽  
pp. 142
Author(s):  
Minh Ngoc Dinh ◽  
Joseph Nygate ◽  
Van Hoang Minh Tu ◽  
C. Louise Thwaites ◽  
Keyword(s):  
New Technologies ◽  
Research Unit ◽  
Ho Chi Minh City ◽  
Middle Income ◽  
Grand Challenges ◽  
Middle Income Countries ◽  
Oxford University ◽  
Key Stakeholders ◽  
Clinical Research Unit ◽  
Low And Middle Income

We report the outputs of a satellite event in Ho Chi Minh City, Vietnam, organized as part of the “2nd Global Grand Challenges of Engineering Summit”. The event considered challenges and potential solutions for improving low- and middle-income country (LMIC) healthcare systems, with particular reference to critical care.  Participants from key regional and local stakeholders in healthcare and engineering discussed how new advances in technology, especially in the field of Artificial Intelligence, could be of potential benefit. This article summarizes the perspectives and conclusions of a group of key stakeholders from LMICs across South and South East Asia.

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