Effects of bovine follicular fluid on the secretion of LH and FSH in inhibin-immunized seasonally anoestrous ewes

ABSTRACT It has been shown previously that treatment of seasonally anoestrous ewes with steroid-free bovine follicular fluid (FF), a crude inhibin-containing preparation, leads to a decrease in plasma FSH level which is accompanied by a marked increase in pulsatile LH secretion. Since FF contains several factors (e.g. activin, follistatin, unidentified components) other than inhibin, which might act to modify gonadotrophin secretion, it was of interest to establish whether these concurrent effects of FF on FSH and LH secretion persisted in ewes which had been actively immunized against a synthetic peptide replica of the α subunit of bovine inhibin. In June 1989 (anoestrous period) groups of inhibin-immune and control ewes (n = 5 per group) received 6-hourly s.c. injections of either bovine serum (2 ml) or one of two doses of FF (0·5 ml or 2 ml) for 3 days. Blood was withdrawn at 6-h intervals for 6 days beginning 24 h before the first injection. On the final day of treatment, additional blood samples were withdrawn at 15-min intervals for 8 h to monitor pulsatile LH secretion. Ewes were then challenged with exogenous gonadotrophin-releasing hormone (GnRH; 2 μg i.v. bolus) to assess pituitary responsiveness. In control ewes, FF promoted a dose-dependent suppression of basal (maximum suppression 65%; P < 0·01) and post-GnRH (maximum suppression 72%; P < 0·01) levels of FSH in plasma. This was accompanied by an increase (P < 0·01) in LH pulse frequency from 1·40±0·24 (s.e.m.) to 3·20±0·37 pulses/8 h. In contrast, FF did not affect secretion of either FSH or LH in inhibin-immunized ewes. However, mean plasma LH levels in immunized ewes were significantly lower (43%; P < 0·02) than in control ewes, irrespective of treatment. These findings indicate that in the anoestrous ewe the ability of FF to suppress plasma FSH is due entirely to its content of inhibin, that FF-induced enhancement of pulsatile LH secretion is mediated by inhibin, rather than some additional component of FF, and that immunoneutralization of endogenous inhibin can reduce LH secretion. Journal of Endocrinology (1991) 128, 403–410

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Relationship between gonadotrophin subunit gene expression, gonadotrophin-releasing hormone receptor content and pituitary and plasma gonadotrophin concentrations during the rebound release of FSH after treatment of ewes with bovine follicular fluid during the luteal phase of the cycle

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0080109 ◽

1992 ◽

Vol 8 (2) ◽

pp. 109-118 ◽

Cited By ~ 15

Author(s):

J. Brooks ◽

W. J. Crow ◽

J. R. McNeilly ◽

A. S. McNeilly

Keyword(s):

Follicular Fluid ◽

Luteal Phase ◽

Gnrh Receptor ◽

Mrna Levels ◽

Α Subunit ◽

Luteal Regression ◽

Releasing Hormone ◽

Gonadotrophin Releasing Hormone ◽

Lh Secretion ◽

Cessation Of Treatment

ABSTRACT The modulation of FSH secretion at the beginning and middle of the follicular phase of the cycle represents the key event in the growth and selection of the preovulatory follicle. However, the mechanisms that operate within the pituitary gland to control the increased release of FSH and its subsequent inhibition in vivo remain unclear. Treatment of ewes with bovine follicular fluid (bFF) during the luteal phase has been previously shown to suppress the plasma concentrations of FSH and, following cessation of treatment on day 11, a rebound release of FSH occurs on days 12 and 13. When luteal regression is induced on day 12, this hypersecretion of FSH results in an increase in follicle growth and ovulation rate. To investigate the mechanisms involved in the control of FSH secretion, ewes were treated with twice daily s.c. injections of 5 ml bFF on days 3–11 of the oestrous cycle and luteal regression was induced on day 12 with prostaglandin (PG). The treated ewes and their controls were then killed on day 11 (luteal), or 16 or 32h after PG and their pituitaries removed and halved. One half was analysed for gonadotrophin and gonadotrophin-releasing hormone (GnRH) receptor content. Total pituitary RNA was extracted from the other half and subjected to Northern analysis using probes for FSH-β, LH-β and common α subunit. Frequent blood samples were taken and assayed for gonadotrophins. FSH secretion was significantly (P<0.01) reduced during bFF treatment throughout the luteal phase and then significantly (P<0.01) increased after cessation of treatment, with maximum secretion being reached 18– 22h after PG, and then declining towards control values by 32h after PG. A similar pattern of LH secretion was seen after bFF treatment. Pituitary FSH content was significantly (P<0.05) reduced by bFF treatment at all stages of the cycle. No difference in the pituitary LH content was seen. The increase in GnRH receptor content after PG in the controls was delayed in the treated animals. Analysis of pituitary mRNA levels revealed that bFF treatment significantly (P<0.01) reduced FSH-β mRNA levels in the luteal phase. Increased levels of FSH-β, LH-β and α subunit mRNA were seen 16h after PG in the bFF-treated animals, at the time when FSH and LH secretion from the pituitary was near maximum. These results suggest that the rebound release of FSH after treatment with bFF (as a source of inhibin) is related to a rapid increase in FSH-β mRNA, supporting the concept that the rate of FSH release is directly related to the rate of synthesis.

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An unexpected increase in pituitary sensitivity to gonadotropin releasing hormone after treatment with porcine follicular fluid (inhibin) in immature hemicastrate rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y80-037 ◽

1980 ◽

Vol 58 (2) ◽

pp. 220-222 ◽

Cited By ~ 2

Author(s):

M. Wilkinson ◽

W. H. Moger ◽

Liisa K. Selin

Keyword(s):

Follicular Fluid ◽

Anterior Pituitary ◽

Chronic Treatment ◽

Follicle Stimulating Hormone ◽

Gonadotropin Releasing Hormone ◽

Releasing Hormone ◽

Gonadotrophin Secretion ◽

Increased Sensitivity ◽

Gonadotrophin Releasing Hormone ◽

Lh Secretion

Porcine follicular fluid (PFF) contains a factor (inhibin or folliculostatin) which is reported to selectively inhibit the secretion of follicle-stimulating hormone (FSH) from the anterior pituitary gland. Chronic treatment of hemicastrate immature rats with PFF is able to partially inhibit the FSH-mediated hypertrophy of the remaining testis. However, the pituitaries from PFF-treated rats are paradoxically very sensitive to stimulation with gonadotrophin-releasing hormone (GnRH) and secrete significantly more FSH than control glands. Furthermore, this increased sensitivity results in a large increase in luteinizing hormone (LH) secretion. These observations suggest that under certain circumstances PFF is not selective for FSH and that it surprisingly stimulates rather than inhibits gonadotrophin secretion.

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Changes in FSH and the pulsatile secretion of LH during treatment of ewes with bovine follicular fluid throughout the luteal phase of the oestrous cycle

Journal of Endocrinology ◽

10.1677/joe.0.1110317 ◽

1986 ◽

Vol 111 (2) ◽

pp. 317-327 ◽

Cited By ~ 30

Author(s):

J. M. Wallace ◽

A. S. McNeilly

Keyword(s):

Follicular Fluid ◽

Luteal Phase ◽

Treatment Cycle ◽

Day Treatment ◽

Pulse Amplitude ◽

Pulse Frequency ◽

Feedback Effects ◽

Blood Samples ◽

Three Stages ◽

Lh Secretion

ABSTRACT Treatment of Damline ewes with twice-daily i.v. injections of bovine follicular fluid during the luteal phase for 10 or 2 days before prostaglandin-induced luteolysis resulted in a delay in the onset of oestrous behaviour and a marginal increase in ovulation rate. During the treatment cycle, blood samples were withdrawn at 15-min intervals for 25 h from 08.00 h on days 1, 6 and 10 (day 0 = oestrus). At all three stages of the luteal phase, plasma FSH concentrations were suppressed relative to controls 3 h after the 09.00 h injection of follicular fluid and remained low until 06.00 h on the following day. In the 10-day treatment group LH pulse amplitude was significantly greater than that of controls on days 6 and 10. Pulse frequency remained high throughout treatment and was significantly higher relative to controls on day 10 despite normal progesterone levels. The results suggest that the higher pulsatile LH secretion during the luteal phase is due to reduced negative feedback effects of oestradiol occurring as a result of the follicular fluid-induced reduction in FSH. J. Endocr. (1986) 111, 317–327

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Inhibin immunoneutralization by antibodies raised against synthetic peptide sequences of inhibin α subunit: effects on gonadotrophin concentrations and ovulation rate in sheep

Journal of Endocrinology ◽

10.1677/joe.0.1240167 ◽

1990 ◽

Vol 124 (1) ◽

pp. 167-176 ◽

Cited By ~ 47

Author(s):

J. H. M. Wrathall ◽

B. J. McLeod ◽

R. G. Glencross ◽

A. J. Beard ◽

P. G. Knight

Keyword(s):

Plasma Levels ◽

Synthetic Peptide ◽

Plasma Concentrations ◽

Ovulation Rate ◽

Control Groups ◽

Α Subunit ◽

Blood Samples ◽

Antigenic Properties ◽

N Terminus ◽

The Mean

ABSTRACT Two experiments were conducted to explore the effectiveness of synthetic peptide-based vaccines for active and passive autoimmunization of sheep against inhibin. In the first experiment, adult Romney ewes (n = 20) were actively immunized against a synthetically produced peptide that corresponded to the N-terminus of the α-subunit of bovine inhibin (bIα(1–29)-Tyr30). This peptide was conjugated to tuberculin purified protein derivative (PPD) to increase its antigenic properties. Control groups comprised non-immunized (n = 10) and PPD-immunized (n = 10) ewes. Primary immunization (400 μg conjugate/ewe) was followed by two booster immunizations (200 μg conjugate/ewe), given 5 and 8 weeks later. Following synchronization of oestrus using progestagen sponges, ovulation rates were assessed by laparoscopy. Weekly blood samples were taken throughout the experiment. All inhibin-immunized ewes produced antibodies which bound 125I-labelled bovine inhibin (Mr 32 000), and ovulation rate in inhibin-immunized ewes (2·15 ± 0·22; mean ± s.e.m.) was significantly (P<0·01) greater than in both non-immunized (0·90 ± 0·23) and PPD-immunized (1·20 ± 0·13) control groups. Immunization against the peptide, but not against PPD alone, resulted in a modest rise in plasma FSH, with mean levels after the second boost being significantly (P<0·025) higher (22%) than those before immunization. Moreover, when blood samples were taken (2-h intervals) from randomly selected groups of control (n = 7) and inhibin-immunized (n = 7) ewes for an 84-h period following withdrawal of progestagen sponges, the mean plasma concentration of FSH during the 48 h immediately before the preovulatory LH surge was 37% greater (P< 0·025) in immunized than in control animals. However, more frequent blood sampling (every 15 min for 12 h) during follicular and mid-luteal phases of the oestrous cycle revealed no significant differences between treatment groups in mean plasma concentrations of FSH. In addition, neither mean concentrations of LH nor the frequency and amplitude of LH episodes differed between immunized and control ewes. However, the mean response of LH to a 2 μg bolus of gonadotrophin-releasing hormone, given during the luteal phase, was significantly (P<0·05) less in immunized than in control ewes. These findings indicate that active immunization of Romney ewes against a synthetic fragment of inhibin can promote a controlled increase in ovulation rate, but this response cannot be unequivocally related to an increase in plasma levels of FSH. In the second experiment, passive immunization of seasonally anoestrous ewes (mule × Suffolk crossbred; n = 6 per group) against inhibin, using an antiserum raised in sheep against a synthetic peptide corresponding to the N-terminus of the α-subunit of human inhibin promoted a rapid (<3 h), dose-dependent rise in plasma levels of FSH which remained increased (2·5-fold; P<0·001) for up to 30 h. Plasma concentrations of LH, however, were unaffected by treatment with the antiserum. It is deduced from this observation that, even in the seasonally anoestrous ewe, the ovary secretes physiologically active levels of inhibin, which exert an inhibitory action on the synthesis and secretion of FSH. Journal of Endocrinology (1990) 124, 167–176

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Suppression of the GnRH Pulse Generator by Neurokinin B Involves a κ-Opioid Receptor-Dependent Mechanism

Endocrinology ◽

10.1210/en.2012-1574 ◽

2012 ◽

Vol 153 (10) ◽

pp. 4894-4904 ◽

Cited By ~ 53

Author(s):

P. Grachev ◽

X. F. Li ◽

J. S. Kinsey-Jones ◽

A. L. di Domenico ◽

R. P. Millar ◽

...

Keyword(s):

Opioid Receptor ◽

Pulse Generator ◽

Pulse Frequency ◽

Mrna Levels ◽

Dependent Manner ◽

Neurokinin B ◽

Kndy Neurons ◽

Lh Secretion ◽

Dose Dependent

Abstract Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First, we investigated the effect of intra-ARC administration of the selective NK3R agonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17β-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion in response to senktide in rats pretreated with nor-binaltorphimine, a selective KOR antagonist. We show that nor-binaltorphimine blocks the senktide-induced suppression of pulsatile LH secretion but does not affect LH pulse frequency per se. In order to address the effects of acute activation of ARC NK3R, we quantified (using quantitative RT-PCR) changes in mRNA levels of KNDy-associated genes in hypothalamic micropunches following intra-ARC administration of senktide. Senktide down-regulated expression of genes encoding GnRH and GPR54 (GNRH1 and Kiss1r, respectively), but did not affect the expression of Kiss1 (which encodes kisspeptin). We conclude that NKB suppresses the GnRH pulse generator in a KOR-dependent fashion and regulates gene expression in GnRH neurons.

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Gonadotrophin-releasing hormone (GnRH) overcomes GnRH antagonist-induced suppression of LH secretion in primates

Journal of Endocrinology ◽

10.1677/joe.0.1100145 ◽

1986 ◽

Vol 110 (1) ◽

pp. 145-150 ◽

Cited By ~ 16

Author(s):

G. R. Marshall ◽

F. Bint Akhtar ◽

G. F. Weinbauer ◽

E. Nieschlag

Keyword(s):

Gnrh Antagonist ◽

Receptor Occupancy ◽

Gnrh Receptor ◽

Dependent Manner ◽

Response Curves ◽

Gnrh Antagonists ◽

Releasing Hormone ◽

Gonadotrophin Secretion ◽

Gonadotrophin Releasing Hormone ◽

Lh Secretion

ABSTRACT If the suppressive effects of gonadotrophin-releasing hormone (GnRH) antagonists on gonadotrophin secretion are mediated through GnRH-receptor occupancy alone, it should be possible to restore serum gonadotrophin levels by displacing the antagonist with exogenous GnRH. To test this hypothesis, eight adult crab-eating macaques (Macaca fascicularis), weight 4·7–7·6 kg, were subjected to the following treatment regimens. A GnRH-stimulation test was performed before and 4, 12 and 24 h after a single s.c. injection of the GnRH antagonist (N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10)-GnRH (ORG 30276). The stimulation tests were performed with 0·5, 5·0 or 50 μg GnRH given as a single i.v. bolus. Blood was taken before and 15, 30 and 60 min after each bolus for analysis of bioactive LH and testosterone. The GnRH-challenging doses were given as follows: 0·5 μg GnRH was injected at 0 and 4 h, followed by 5·0 μg after 12 h and 50 μg after 24 h. One week later, 5·0 μg GnRH were given at 0 and 4 h, followed by 50 μg after 12 h and 0·5 μg after 24 h. Finally, after another week, the GnRH challenges began with 50 μg at 0 and 4 h, followed by 0·5 μg at 12 h and 5·0 μg at 24 h. This design permitted comparison of the LH and testosterone responses with respect to the dose of GnRH and the time after administration of GnRH antagonist. The areas under the response curves were measured and statistical evaluation was carried out by means of non-parametric two-way analysis of variance followed by the multiple comparisons of Wilcoxon and Wilcox. Four hours after the antagonist was injected, the LH and testosterone responses to all three doses of GnRH were suppressed. At the lowest dose of GnRH (0·5 μg) the responses remained reduced even after 24 h, whereas the higher doses of GnRH elicited an LH and testosterone response at 12 and 24 h which was not significantly different from that at 0 h. These data demonstrate that the suppression of LH secretion by a GnRH antagonist in vivo can be overcome by exogenously administered GnRH in a dose- and time-dependent manner, thus strongly supporting the contention that GnRH antagonists prevent gonadotrophin secretion by GnRH-receptor occupancy. J. Endocr. (1986) 110, 145–150

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Anti-Müllerian hormone receptor type 2 is expressed in gonadotrophs of postpubertal heifers to control gonadotrophin secretion

Reproduction Fertility and Development ◽

10.1071/rd17377 ◽

2018 ◽

Vol 30 (9) ◽

pp. 1192 ◽

Cited By ~ 14

Author(s):

Onalenna Kereilwe ◽

Kiran Pandey ◽

Vitaliano Borromeo ◽

Hiroya Kadokawa

Keyword(s):

Immunofluorescence Microscopy ◽

Receptor Type ◽

Chain Reaction ◽

Extracellular Region ◽

Gonadotrophin Secretion ◽

Secretion Expression ◽

Gonadotrophin Releasing Hormone ◽

Polymerase Chain ◽

Lh Secretion

Preantral and small antral follicles may secret anti-Müllerian hormone (AMH) to control gonadotrophin secretion from ruminant gonadotrophs. The present study investigated whether the main receptor for AMH, AMH receptor type 2 (AMHR2), is expressed in gonadotrophs of postpubertal heifers to control gonadotrophin secretion. Expression of AMHR2 mRNA was detected in anterior pituitaries (APs) of postpubertal heifers using reverse transcription–polymerase chain reaction. An anti-AMHR2 chicken antibody was developed against the extracellular region near the N-terminus of bovine AMHR2. Western blotting using this antibody detected the expression of AMHR2 protein in APs. Immunofluorescence microscopy using the same antibody visualised colocalisation of AMHR2 with gonadotrophin-releasing hormone (GnRH) receptor on the plasma membrane of gonadotrophs. AP cells were cultured for 3.5 days and then treated with increasing concentrations (0, 1, 10, 100, or 1000 pg mL−1) of AMH. AMH (10–1000 pg mL−1) stimulated (P < 0.05) basal FSH secretion. In addition, AMH (100–1000 pg mL−1) weakly stimulated (P < 0.05) basal LH secretion. AMH (100–1000 pg mL−1) inhibited GnRH-induced FSH secretion, but not GnRH-induced LH secretion, in AP cells. In conclusion, AMHR2 is expressed in gonadotrophs of postpubertal heifers to control gonadotrophin secretion.

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Long-term effects of a gonadotrophin-releasing hormone agonist ([d-Ser(But)6]GnRH(1–9)nonapeptide-ethylamide) on gonadotrophin secretion from human pituitary gonadotroph cell adenomas in vitro

Journal of Endocrinology ◽

10.1677/joe.0.1180491 ◽

1988 ◽

Vol 118 (3) ◽

pp. 491-496 ◽

Cited By ~ 3

Author(s):

M. Daniels ◽

P. Newland ◽

J. Dunn ◽

P. Kendall-Taylor ◽

M. C. White

Keyword(s):

Gnrh Agonist ◽

In Vitro Release ◽

Long Term Effects ◽

Human Pituitary ◽

Α Subunit ◽

Releasing Hormone ◽

Gonadotrophin Secretion ◽

Gonadotrophin Releasing Hormone

ABSTRACT We have studied the effects of TRH and native gonadotrophin-releasing hormone (GnRH), and of a GnRH agonist (Buserelin; [d-Ser(But)6]GnRH(1–9) nonapeptide-ethylamide), on LH, FSH, α subunit and LH-β subunit secretion from three human gonadotrophin-secreting pituitary adenomas in dispersed cell culture. During a 24 h study, treatment with 276 nmol TRH/1 resulted in a significant (P < 0·05) stimulated release of FSH and α subunit from all three adenomas, and LH from the two adenomas secreting detectable concentrations of this glycoprotein; treatment with 85 nmol GnRH/l significantly (P < 0·05) stimulated the release of α subunit from all three, but FSH from only two and LH from only one adenoma. During a long-term 28-day study, basal FSH and α subunit concentrations were maintained, but secretion of LH, and LH-β (detectable from one tumour only), declined with time from two of the three adenomas. Addition of Buserelin to the cultures resulted in the continuous (P < 0·05) stimulation of α subunit secretion from all three adenomas, and of LH and FSH from two, whilst a transient stimulatory effect on LH and FSH secretion was seen from a third adenoma, with subsequent secretion rates declining towards control values. These data show that human gonadotrophin-secreting adenomas demonstrate variable stimulatory responses to hypothalamic TRH and GnRH, and that during chronic treatment with a GnRH agonist the anticipated desensitizing effect of the drug was not observed in two out of three adenomas studied. The mechanism for this is not clear, but such drugs are unlikely to be of therapeutic value in the management of gonadotrophin-secreting tumours. The data also suggest that GnRH and GnRH agonists have a differential effect on the in-vitro release of intact gonadotrophins and the common α subunit. J. Endocr. (1988) 118, 491–496

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Determinants of the annual pattern of reproduction in mature male Merino and Suffolk sheep: responses to a nutritional stimulus in the breeding and non-breeding seasons

Reproduction Fertility and Development ◽

10.1071/rd02024 ◽

2003 ◽

Vol 15 (1) ◽

pp. 1 ◽

Cited By ~ 20

Author(s):

Maria J. Hötzel ◽

Stephen W. Walkden-Brown ◽

James S. Fisher ◽

Graeme B. Martin

Keyword(s):

Luteinizing Hormone ◽

Breeding Season ◽

Follicle Stimulating Hormone ◽

Hormone Secretion ◽

Pulse Frequency ◽

Mature Male ◽

Scrotal Circumference ◽

Gonadotrophin Secretion ◽

Gonadotrophin Releasing Hormone ◽

Breeding Seasons

This study was designed to test whether an acute improvement in diet would increase gonadotrophin secretion and testicular growth in strongly photoperiod-responsive Suffolk rams and weakly photoperiod-responsive Merino rams in both the breeding (February–March) and the non-breeding (July–August) seasons. Mature rams (n = 5 or 6) of these breeds were fed a maintenance diet (0.9 kg chaff + 100 g lupin grain) or the same diet supplemented with 1.5 kg lupin grain for 42 days in each season. Lupin grain is a rich source of both energy and protein. Testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured in plasma from blood sampled every 20 min for 24 h on Days −1, 12 and 35 relative to the change in feeding. In rams supplemented with lupins, body mass increased in both breeds in both seasons (P < 0.001). Scrotal circumference and LH pulse frequency increased with lupin supplementation in both seasons (P < 0.003) in Merinos, but only during the breeding season (P < 0.003) in Suffolks. Plasma FSH concentrations were affected by diet only during the breeding season, being elevated on Day 12 in lupin-supplemented rams of both breeds (P < 0.05). It was concluded that Merino rams exhibit reproductive responses to improved nutrition irrespective of time of the year, whereas Suffolk rams respond to nutrition only when the hypothalamic reproductive centres are not inhibited by photoperiod. Thus, Suffolks do respond to nutrition, just as Merinos do, but only when photoperiod allows. This difference between breeds appears to be a result of differences in the neuroendocrine pathways that control pulsatile gonadotrophin-releasing hormone secretion.

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