Attenuation of preovulatory gonadotrophin surges by epostane: a new inhibitor of 3β-hydroxysteroid dehydrogenase

1988 ◽  
Vol 118 (1) ◽  
pp. 59-68 ◽  
Author(s):  
L. V. DePaolo
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Hydroxysteroid Dehydrogenase ◽  
Inhibitory Effects ◽  
Plasma Progesterone ◽  
Ru 486 ◽  
Progesterone Secretion ◽  
Progesterone Antagonist

ABSTRACT Epostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, was administered orally to pro-oestrous rats to evaluate further a possible role for preovulatory progesterone secretion in eliciting surges of LH and FSH. Whereas a dose of 10 mg epostane/kg had essentially no effects on preovulatory gonadotrophin surges and ovulation, 200 mg epostane/kg markedly attenuated LH and FSH surges and blocked ovulation. A dose of 50 mg epostane/kg exerted effects on LH and FSH surges and ovulation intermediate between those of doses of 10 and 200 mg/kg. Plasma concentrations of progesterone were significantly lower in all anovulatory epostane-treated rats at 18.00 and 22.00 h on pro-oestrus than those measured in vehicle-treated rats. Concurrent injection of 2 mg progesterone in rats given 200 mg epostane/kg restored gonadotrophin surges to normal, but consistently failed to reverse the inhibitory effects of epostane on ovulation. Peak plasma progesterone levels produced by the progesterone injections were eight- to tenfold higher than the highest levels measured in vehicle-treated rats during the afternoon of pro-oestrus. Insertion of progesterone capsules was less effective than injections of progesterone in restoring gonadotrophin surges to normal, even though peak plasma progesterone concentrations achieved after insertion of two 20 mm long progesterone capsules were double the peak progesterone concentrations measured in control rats. Nevertheless, taken together with recent reports showing attenuation of preovulatory gonadotrophin surges by the progesterone antagonist RU 486 (17β-hydroxy-11β-[4-dimethyl-aminophenyl]-17α-[prop-1-ynl]estra-4,9-diene-3-one), the present results provide support for a role of preovulatory progesterone secretion in enhancing oestrogen-dependent LH/FSH surges on pro-oestrus. J. Endocr. (1988) 118, 59–68

Inhibition of progesterone secretion by a 3β-hydroxysteroid dehydrogenase inhibitor in late pregnant sheep

1985 ◽  
Vol 63 (2) ◽  
pp. 136-142 ◽  
Author(s):  
Graham Jenkin ◽  
Geoffrey D. Thorburn
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Placental Lactogen ◽  
Plasma Progesterone ◽  
Progesterone Secretion ◽  
Pregnant Sheep ◽  
Plasma Estradiol ◽  
Prostaglandin F ◽  
Essential Prerequisite ◽  
Estradiol 17Β

The role of progesterone in the initiation of parturition in the sheep is unclear. Whether a decrease in plasma progesterone is the essential prerequisite for the initiation of parturition or whether other factors also maintain uterine quiescence until delivery is not known. The effect of withdrawal of progesterone on the initiation of parturition has been investigated by intravenous administration of trilostane, a 3β-hydroxysteroid dehydrogenase Δ5−4 isomerase inhibitor, to late pregnant sheep. Twenty-five or 100 mg trilostane caused a precipitous decrease in plasma progesterone to about 30% of preinjection levels. Progesterone remained depressed for up to 7 days after treatment. 13,14-Dihydro-15-keto-prostaglandin F2α (PGFM) became elevated between 7 and 36 h after trilostane injection but gradually returned to preinjection levels during the subsequent 36 h, at a time when plasma progesterone was still depressed. Four of 11 animals treated with 100 or 200 mg trilostane aborted prematurely at a time when plasma PGFM was maximal and plasma progesterone minimal. There were no consistent changes in plasma estradiol-17β or ovine placental lactogen concentrations after treatment with trilostane. It is suggested that a decrease in plasma progesterone will cause a transient increase in plasma PGFM concentrations which can lead to the premature initiation of parturition. In some instances the myometrium does not appear to respond to the elevated PGFM concentrations even when the estrogen:progesterone ratio is elevated by a decrease in plasma progesterone.

Concentrations of progesterone and oestradiol-17β after administration of a 3β-hydroxysteroid dehydrogenase inhibitor to sheep in late pregnancy

1987 ◽  
Vol 113 (1) ◽  
pp. 97-101 ◽  
Author(s):  
M. J. Taylor
Keyword(s):  
Plasma Concentrations ◽  
Late Pregnancy ◽  
Hydroxysteroid Dehydrogenase ◽  
Premature Delivery ◽  
Plasma Progesterone ◽  
Twofold Increase ◽  
Rapid Fall

ABSTRACT An inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) activity was administered to sheep in late pregnancy. A rapid fall in plasma progesterone concentrations followed, associated with premature delivery by all animals 44±3 h (s.e.m.) after administration of inhibitor. A significant (about twofold) increase in plasma concentrations of oestradiol-17β was detected immediately before delivery. These results demonstrate, in contrast to previous reports, that 3β-HSD inhibitors have the capacity consistently to induce premature delivery associated with increased oestrogen release in sheep. J. Endocr. (1987) 113, 97–101

scholarly journals Comparative changes in plasma concentrations of progesterone, oestradiol and LH during the ovulatory cycle in a multiple ovulating male line and a single ovulating traditional line of turkeys

Reproduction ◽  
2002 ◽  
pp. 127-133 ◽  
Author(s):  
S Buchanan ◽  
GW Robertson ◽  
PM Hocking
Keyword(s):  
Peak Plasma ◽  
Ovarian Tissue ◽  
Plasma Concentrations ◽  
High Growth ◽  
Correlated Response ◽  
Ovulatory Cycle ◽  
Plasma Progesterone ◽  
Multiple Ovulation ◽  
Male Line ◽  
The Mean

The aim of this study was to compare the profile of circulating concentrations of LH, progesterone and oestradiol in a multiple ovulating male line with that of a single ovulating line of traditional turkeys. Plasma samples from seven traditional and 12 male-line turkeys were obtained every 3 h for 36 h. Male-line and traditional turkeys had single peaks of LH and progesterone that were of similar duration in both lines. The mean height of the plasma peaks of LH and progesterone were similar in the two lines and there was no detectable peak plasma oestrogen concentration. Mean plasma concentrations of LH and oestrogen were higher in single compared with multiple ovulating turkeys, whereas there were no differences in mean plasma progesterone concentrations. The results indicate that the multiple ovulation state in genetically selected high-growth lines of turkey may be the result of a correlated response in the steroidogenic capacity of ovarian tissue associated with low plasma concentrations of oestrogen rather than of a disturbance in the hormone profile of the ovulatory cycle.

EFFECTS OF PINEALECTOMY ON THE SECRETION OF LUTEINIZING HORMONE, TESTOSTERONE AND PROLACTIN IN RAMS EXPOSED TO VARIOUS LIGHTING RÉGIMES

1979 ◽  
Vol 80 (3) ◽  
pp. 397-405 ◽  
Author(s):  
G. K. BARRELL ◽  
K. R. LAPWOOD
Keyword(s):  
Luteinizing Hormone ◽  
Pineal Gland ◽  
Plasma Levels ◽  
Seasonal Changes ◽  
Peak Plasma ◽  
Plasma Concentrations

Two experiments were carried out to study the effects of controlled lighting régimes on plasma levels of LH, testosterone and prolactin in Romney rams. In the second experiment the rams were either pinealectomized or sham-operated so that the role of the pineal gland in mediating seasonal changes in reproduction could be examined. Levels of testosterone and prolactin were considerably influenced by the lighting schedule. Peak plasma concentrations of testosterone were associated with periods during which the daily photoperiod decreased, whereas plasma levels of prolactin showed a pattern of changes approximately in phase with the lighting cycles. Mean plasma concentrations of LH were low in all groups of rams, which made the detection of significant effects of any treatment very unlikely. Pinealectomy reduced the effects of changes in the daily photoperiod on the patterns of secretion of testosterone and prolactin. These findings establish the pineal gland as an organ which influences the endocrine responses of rams to photoperiodic stimuli and it is concluded that the pineal gland is probably important as a mediator of seasonal reproductive changes in these animals.

scholarly journals Intracerebroventricular administration of the prolactin (PRL) receptor antagonist, S179D PRL, disrupts parturition in rats

Reproduction ◽  
2007 ◽  
Vol 134 (1) ◽  
pp. 155-160 ◽  
Author(s):  
B C Nephew ◽  
J Amico ◽  
H M Cai ◽  
A M Walker ◽  
R S Bridges
Keyword(s):  
Receptor Antagonist ◽  
Plasma Concentrations ◽  
Female Rats ◽  
Plasma Progesterone ◽  
Blood Samples ◽  
Period Effects ◽  
Preliminary Study ◽  
Nulliparous Female ◽  
Plasma Prl

The prolactin (PRL) receptor antagonist S179D PRL delays the onset of maternal behavior in steroid-primed nulliparous female rats. The present study investigated the role of the neural PRL system in the process of parturition. A preliminary study indicated that S179D PRL treatments administered by ALZET minipump to the lateral ventricle severely disrupted parturition. To examine the likely causes of this disruption, a group of timed-pregnant catheterized rats was continuously infused with S-179D PRL (0.001 and 0.1 ng/h) or vehicle control to the lateral ventricles for 3 days (gestation days 21–23), and serial blood samples were taken throughout this period. Effects of the treatments on parturition were recorded, and blood samples were assayed for PRL, progesterone, and oxytocin. Significantly fewer S179D PRL-treated rats successfully delivered by 1500 h on day 23 of gestation when compared with controls. The higher dose of S179D PRL also significantly suppressed the prepartum rise in PRL throughout the prepartum period, while the lower dose only affected plasma PRL during the first 24 h of treatment. No significant effects of the antagonist on plasma progesterone or oxytocin were detected. We conclude that disruption of parturition by S179D PRL is not caused by significant alterations in the plasma concentrations of progesterone or oxytocin. S179D PRL may indirectly act on parturition through the modulation of prepartum PRL. These findings suggest a previously unrecognized role for PRL in the regulation of parturition.

Role of p38 MAPK and Tie2 in the Pathogenesis of MDS and Their Inhibition by Dual Inhibitor ARRY-614.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2825-2825
Author(s):  
Shannon L Winski ◽  
LouAnn Cable ◽  
Grant Hogeland ◽  
Suzy Brown ◽  
Dan Weaver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Study ◽  
P38 Mapk ◽  
Peak Plasma ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Second Phase ◽  
Cd34 Cells ◽  
Myeloid Progenitors

Abstract Abstract 2825 Myelodysplastic syndromes (MDS) are a heterogeneous collection of disorders characterized by dysfunctional bone marrow progenitors leading to peripheral cytopenias. The molecular mechanisms underlying MDS pathophysiology are unclear, but emerging data support a role for both p38 MAPK (p38) and TEK (Tie2). Over-activation of the p38 pathway and increased apoptosis have been reported in the bone marrow of MDS patients, and dysregulation of Tie2 signaling, a potential regulator of hematopoiesis via maintenance of normal hematopoietic stems cell (HSC) quiescence, is associated with worse outcome. To better understand the role of Tie2 in hematopoiesis, CD34+ cells from human cord blood were separated by multi-parameter flow cytometry and cell sorted into HSCs (i.e., CD34+, CD38−) or the more differentiated common myeloid progenitors (CMPs; i.e., CD38+, IL-3Rαlo, CD45RA−), myeloid erythroid progenitors (MEPs; i.e., CD38+, IL-3Rα−, CD45RA−), and granulocyte myeloid progenitors (GMPs; i.e., CD38+, IL-3Rαlo, CD45RA+). Expression of Tie2, Tie1, Ang-1 (Tie2 agonist) and Ang-2 (Tie2 antagonist) was determined by qPCR. The data showed that Tie2, Tie1, and Ang-1 were expressed in CD34+ cells and appeared to be regulated during differentiation, with reduced Tie2 expression observed in the GMP population. To further understand the roles of p38 and Tie2 in MDS, bone marrow and plasma samples were analyzed from a Phase 1 clinical study conducted with ARRY-614, a p38/Tie2 inhibitor, in patients with IPSS Low/Int-1 Risk MDS. At baseline, 65% (13/20) of the MDS patients showed aberrant p38 activation (≥5% phospho-p38 positive cells). Following treatment with ARRY-614, the median percent of cells positive for phospho-p38 was decreased by 85% through up to 4 cycles of treatment (∼112 days). Apoptosis in patient bone marrow samples was reduced as well (monitored by cleaved caspase-3). In cell-based assays, ARRY-614 inhibits both p38-mediated HSP27 phosphorylation (IC50 = 1 nM) and Tie2-dependent AKT phosphorylation (IC50 = 13 nM). Cellular IC50 values, corrected for plasma protein binding, and preliminary pharmacokinetic parameters were used to predict inhibition of these targets in patients. Analysis of the highest administered dose (1200 mg QD) of ARRY-614 as a powder-in-capsule (PiC) formulation in the Phase 1 clinical study predicted robust suppression of phospho-p38 (≥ 50% for 24 hours), consistent with bone marrow and plasma biomarker findings. However, partial inhibition of Tie2 (≥ 50% for 17.1 hours) was predicted. In a second Phase 1 clinical study, an optimized ARRY-614 formulation has demonstrated decreased intra- and inter-patient variability and increased peak plasma concentrations. With this new formulation, peak plasma concentrations of the 400 mg QD cohort were ∼50% higher than those of the 1200 mg QD PiC formulation cohort, possibly affording more extensive Tie2 inhibition. In summary, these observations suggest that inhibition of both p38 and Tie2 may be important for the effects of ARRY-614 in MDS patients. The ongoing Phase 1 dose escalation trial of the optimized ARRY-614 formulation may further our understanding of the contributions of these targets to the pathogenesis of MDS. Disclosures: Winski: Array Biopharma Inc.: Employment. Cable:Array Biopharma Inc.: Employment. Hogeland:Array Biopharma Inc.: Employment. Brown:Array Biopharma Inc.: Employment. Weaver:Array Biopharma Inc.: Employment. Garrus:Array Biopharma Inc.: Employment. Rhodes:Array Biopharma Inc.: Employment. Maloney:Array Biopharma Inc.: Employment. Ptaszynski:Array BioPharma: Consultancy. Chantry:Array Biopharma Inc.: Employment.

scholarly journals Studies on the role of zinc in parturition in the rat

1983 ◽  
Vol 210 (3) ◽  
pp. 761-767 ◽  
Author(s):  
G E Bunce ◽  
G R Wilson ◽  
C F Mills ◽  
A Klopper
Keyword(s):  
Dehydrogenase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Zn Deficiency ◽  
Progesterone Concentration ◽  
Pregnant Rats ◽  
Plasma Progesterone ◽  
Prostaglandin F2 Alpha

1. Pregnant rats were fed either low (less than 1 p.p.m.) Zn or control (40 p.p.m. Zn) diets from day 10 of gestation. They were killed at intervals during the last 96 h preceding the normal time for onset of parturition, and differences in plasma progesterone, oestradiol-17 beta and ovarian 20 alpha-hydroxysteroid dehydrogenase were assessed. 2. Gestation was prolonged in Zn-deficient rats. 3. Although the preparturient decline in plasma progesterone began at the same time in all groups, at term, plasma progesterone concentration in Zn-deficient rats remained significantly higher than in normal females. 4. Induction of ovarian 20 alpha-hydroxysteroid dehydrogenase activity was delayed by about 8 h by Zn deficiency. This delay was not observed if prostaglandin F2 alpha was injected previously. 5. The results suggest a Zn-dependent step(s) in uterine synthesis and/or release of prostanoids.

THE INTERRELATIONSHIP BETWEEN PROGESTERONE AND LUTEINIZING HORMONE DURING THE OVULATION CYCLE OF THE HEN (GALLUS DOMESTICUS)

1976 ◽  
Vol 71 (1) ◽  
pp. 51-58 ◽  
Author(s):  
R. J. ETCHES ◽  
F. J. CUNNINGHAM
Keyword(s):  
Luteinizing Hormone ◽  
Plasma Concentrations ◽  
Physiological Role ◽  
Follicular Development ◽  
Gallus Domesticus ◽  
Luteinizing Hormone Releasing Hormone ◽  
Progesterone Secretion ◽  
Lh Rh ◽  
Premature Ovulation

SUMMARY The existence of a circadian rhythm in the sensitivity of the hypothalamus of the laying hen to stimulation by progesterone was investigated by injecting 0·5 mg progesterone subcutaneously during the proposed period of maximum insensitivity. Following this treatment increases in plasma concentrations of both LH and progesterone were observed which were comparable to the spontaneous preovulatory rises in the plasma levels of the hormones. The ability of either progesterone or luteinizing hormone releasing hormone (LH-RH) to induce premature ovulation varied according to the stage of follicular development. Neither hormone was more than 28% effective when injected within 6·5 h of the previous ovulation, whereas both hormones were 100% effective approximately 27 h after the terminal ovulation of a clutch sequence. Failure to ovulate in response to LH-RH given 6·5 h after ovulation was associated with a lack of progesterone secretion. Both LH and progesterone were secreted when ovulation was induced by injections of either LH-RH or progesterone, and LH was secreted in response to progesterone given 6·5 h after ovulation. These results demonstrate that progesterone stimulates the secretion of LH and LH stimulates the secretion of progesterone. The precise physiological role of these two hormones, however, was not established.

Relationship between plasma leptin concentration and reproductive function in dairy cows

2002 ◽  
Vol 2002 ◽  
pp. 2-2 ◽  
Author(s):  
GE Mann ◽  
D Blache
Keyword(s):  
Dairy Cows ◽  
Post Partum ◽  
Plasma Concentrations ◽  
Reproductive Function ◽  
Progesterone Concentration ◽  
Metabolic Demand ◽  
Plasma Progesterone ◽  
Progesterone Secretion ◽  
High Incidence ◽  
Plasma Leptin

In modern dairy cows, poor fertility is an ever-increasing problem. Milk progesterone analysis has revealed that this poor fertility is associated with a high incidence of reproductive cycle problems during the post partum period and with reduced progesterone secretion following mating. One of the likely causes of these problems is the increasing metabolic demand placed on these cows by increasing milk yield. In recent years, the search for an endocrine link between nutritional status and reproductive function has focussed on leptin. The aim of the present study was to determine whether plasma concentrations of leptin differ between cows with and without post partum reproductive problems and to determine if any relationship exists between plasma leptin and post mating plasma progesterone concentration.

CHANGES IN CONCENTRATIONS OF FOLLICLE-STIMULATING HORMONE, LUTEINIZING HORMONE, PROLACTIN AND PROGESTERONE IN THE PLASMA OF EWES DURING THE TRANSITION FROM ANOESTRUS TO BREEDING ACTIVITY

1977 ◽  
Vol 75 (1) ◽  
pp. 127-136 ◽  
Author(s):  
J. S. WALTON ◽  
JUDITH R. McNEILLY ◽  
A. S. McNEILLY ◽  
F. J. CUNNINGHAM
Keyword(s):  
Follicle Stimulating Hormone ◽  
Plasma Concentrations ◽  
Cyclic Activity ◽  
Plasma Progesterone ◽  
Progesterone Secretion ◽  
Group A ◽  
High Concentrations ◽  
Group B ◽  
Short Days

The plasma concentrations of FSH, LH, prolactin and progesterone were measured throughout anoestrus and during the resumption of cyclic activity in two groups of ewes. Group A was maintained under conditions of natural daylength throughout the experiment, whereas Group B was exposed to 6 h of light and 18 h of darkness, the change being made abruptly on the longest day. In those ewes kept on short days, oestrus and ovulation occurred 18·3 days (P < 0·05) and 23·4 days (P < 0·001) earlier than in the ewes under conditions of natural daylength. Ovulation preceded oestrus by 18·6 days and 23·1 days in Groups A and B respectively. The occurrence of ovulation was detected by the determination of plasma progesterone concentrations. In all ewes, progesterone levels were basal until the first ovulation when the pattern of secretion was typical of that seen during the oestrous cycle. In the 4 days before ovulation, the plasma progesterone concentration increased slowly to reach a maximum of 0·66 ± 0·12 (s.e.m.) ng/ml on day − 1. The first ovulation was associated with a substantial surge of LH. Similar release of LH, thought to be related to the increased progesterone secretion, was also observed on day −5. Sporadic release of LH was also found before this time in some animals. Plasma concentrations of FSH fluctuated randomly throughout anoestrus and during the transition to established oestrous cycles. These changes were not apparently related to ovulation. Throughout anoestrus, prolactin concentrations were raised but always declined before the time of ovulation. The fall in prolactin concentrations occurred sooner in the ewes on short days, pointing to a relationship with the decreased daylength. These data suggest that the return to oestrous cycles may be brought about by the removal of an antigonadotrophic effect exerted by high concentrations of prolactin in the blood during anoestrus.

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