An implant of a gonadotropin releasing hormone agonist (buserelin) which suppresses ovarian function in the macaque for 3–5 months

Fraser, Hamish M.; Sandow, J.; Seidel, H.; Rechenberg, W. von

doi:10.1530/acta.0.1150521

Cited by 26 publications

(8 citation statements)

References 16 publications

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“…The remaining 24 animals were infused continuously for 6 weeks with the GnRH agonist D-Ser(Bul)6GnRH(l-9)-nonapeptide-ethylamide (buserelin; kindly supplied by Dr J. Sandow, Hoechst A. G, Frankfurt, F.R.G). The buserelin was incorporated into 0-8 012 cm rod implants made of a slowly biodegradable polylactide/ glycolide copolymer (molar ratio 75:25 polylactide to glycolide) previously described by Fraser, Sandow & Seidel (1987). Each implant contained 3-3 mg buser¬ elin.…”

Section: Methodsmentioning

confidence: 99%

Effect of basal and pulsatile LH release on FSH-stimulated follicle growth in ewes chronically treated with gonadotrophin-releasing hormone agonist

Picton

McNeilly²

1991

Journal of Endocrinology

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Ewes chronically treated with gonadotrophin-releasing hormone (GnRH) agonist were used to investigate the importance of the peripheral concentration of LH in FSH-stimulated follicular development. Twenty-four Welsh Mountain ewes were treated with two agonist implants containing 3.3 mg buserelin. During week 6 of treatment all the ewes were given a 72-h continuous infusion of ovine FSH alone (3 micrograms/h) or FSH with large (7.5 micrograms)- or small (2.5 micrograms) amplitude pulses of ovine LH delivered at 4-hourly intervals. The importance of baseline LH throughout the FSH infusion was evaluated in six animals which were treated with a specific antiserum against bovine LH (LH-AS) 15-20 h before the start of FSH treatment. In the absence of LH-AS, infusion of FSH alone or with large or small pulses of LH stimulated the development of a normal number of small follicles (less than or equal to 2.5 mm in diameter) and large follicles (greater than 2.5 mm in diameter). These follicles had normal diameter and steroid secretion compared with control ewes on day 8 of the luteal phase. In contrast, the animals pretreated with LH-AS developed no follicles greater than 2.0 mm in diameter but the number of small follicles per ewe was significantly (P less than 0.05) increased. These results support the hypothesis that FSH in the absence of pulsatile LH release stimulates preovulatory follicular development in ewes treated with GnRH agonist. The follicular response to LH pulses of different amplitude is dependent on both the stage of development of the follicle and the peripheral concentration of FSH.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Methodsmentioning

confidence: 99%

Effect of basal and pulsatile LH release on FSH-stimulated follicle growth in ewes chronically treated with gonadotrophin-releasing hormone agonist

Picton

McNeilly²

1991

Journal of Endocrinology

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“…The implants were made of slowly biodegradable polylactic/glycolide (molar ratio 75: 25) sterilized by gamma radiation. The LHRH agonist implant was administered during the early follicular phase of the cycle as described previously (Fraser et a!, 1987). The macaques were sedated using ketamine hydrochloride (Vetalar: Parke, Davis and Co., Pontypool, Gwent, UK) and the implant was injected s.c. in the lateral region of the abdominal wall using a sterile applicator.…”

Section: Methodsmentioning

confidence: 99%

“…Inter-and intra-assay coefficients of variance were 15 and 11 % respectively. To determine the day of the preovulatory LH surge, serum LH was measured by radioimmunoassay (Fraser et a!, 1987). Progesterone was determined as described previously (Fraser et al, 1986) using a rabbit antibody R31.…”

Section: Methodsmentioning

confidence: 99%

Inhibin secretion after treatment with an LHRH agonist and subsequent ovarian hyperstimulation induced by FSH in the macaque (Macaca arctoides)

Fraser

Smith²,

Reddi³

et al. 1990

Reproduction

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The effect of ovarian hyperstimulation with 'pure' FSH on serum concentrations of immunoreactive inhibin in macaques in which endogenous gonadotrophin secretion and ovarian activity had been suppressed by an LHRH agonist implant was studied. Four stump-tailed macaques were treated with an LHRH agonist implant in the early follicular phase of the cycle. After a transient stimulatory phase oestradiol secretion was markedly suppressed, and the rises in progesterone and inhibin observed after ovulation were absent. At 8 weeks after implant administration, when serum LH was only just detectable, FSH (Metrodin) was administered to the LHRH agonist-treated macaques once daily for 9 days (75 i.u. on Day 0, 35 i.u. Days 1-8). FSH treatment stimulated a marked increase in oestradiol and immunoreactive inhibin secretion in the absence of a rise in serum progesterone concentrations. Comparison of the FSH-induced pattern of inhibin secretion with the profile during the normal menstrual cycle showed that during the normal cycle inhibin is secreted into the peripheral blood almost exclusively during the luteal phase in the macaque, but stimulation of follicular development by exogenous FSH was associated with a rise in inhibin concentrations in the absence of ovulation. These results suggest that this non-physiological rise in inhibin may be one of the factors involved in the changes in endogenous gonadotrophin secretion which can occur during ovarian hyperstimulation.

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“…To date, these slow release formulations have been based upon incorporation of GnRH agonist in a matrix of polylactide/glycolide copolymers (PLG) and administered as a small rod or as microcapsules (6,(11)(12)(13)(14)(15). The matrix material must sat¬ isfy a number of criteria; be non-irritant, non-toxic and non-carcinogenic and allow release of the pep¬ tide at a controlled optimal rate.…”

mentioning

confidence: 99%

“…While the release profile can be followed in serum, we have found that urinary levels can be detected over a longer period. The effects of the implants on endocrine changes during the men¬ strual cycle and the reversibility from implant sup¬ pression were assessed in the stumptailed ma¬ caque, a species we have used extensively for investigations into the effects of GnRH analogues (5)(6)(7)(8)(9)(10)(11)16,17).…”

mentioning

confidence: 99%

Controlled release of a GnRH agonist from a polyhydroxybutyric acid implant: reversible suppression of the menstrual cycle in the macaque

Fraser

Sandow²,

Seidel³

et al. 1989

Acta Endocrinologica

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The use of polyhydroxybutyric acid as a matrix for delivery of the GnRH agonist buserelin was studied in adult stumptailed macaques with regular menstrual cycles. This material contained 5.0 mg buserelin in a disk of 0.6 cm diameter and 0.15 cm thickness. The effects on pituitary-ovarian function were examined and buserelin release profiles from 30 000 and 150 000 molecular weight polyhydroxybutyric acid matrices were compared. In an attempt to reduce the high initial release rate of buserelin from these disks, and to prolong the effective period of release, implants of 30 000 molecular weight were coated with cyanoacrylate. The implants were removed after 28, 35 or 42 days for the 30 000, the 150 000 and the coated implants, respectively. The urinary excretion profile for the agonist revealed a high initial release of buserelin from these implants followed by a rapid decline. The coated disks released significantly less (p < 0.05) buserelin over the first 3 days than did either of the uncoated implants, but maintained release of the agonist over a longer period. Inhibition of ovulation and suppression of estradiol secretion lasted for the duration of treatment in 3 of 5 macaques receiving the 30 000 implant, and in 5 of 5 receiving the 150 000 or the coated implant. In 3 macaques in whom the coated implant was left in situ, ovulation was suppressed for 104 \ m=+-\ 3.7 days. These results demonstrate that a polyhydroxybutyric acid matrix can be used as a depot formulation for a GnRH agonist and that improved control of release of the agonist can be achieved by coating such implants with cyanoacrylate. This approach may be useful in experimental and clinical situations and may be applicable for delivery of other peptide hormones.The ability of agonist analogues of gonadotropinreleasing hormone to suppress pituitary-ovarian function by inducing desensitization of the pitui¬ tary gonadotrope has been studied extensively for evaluation as a potential contraceptive and in treatment of sex hormone-dependent disorders (reviewed in 1). These therapeutic advances have been made despite the fact that GnRH analogues cannot be administered by mouth as they are inac¬ tivated when taken orally. Studies using daily in¬ jections were followed by the development of nasal sprays for clinical application (2,3). Although nasal administration has the advantage of long-term self-medication, it has a low efficiency of absorp¬ tion and there are variations in the dose require¬ ments for ovarian suppression between individ¬ uals. Furthermore, multiple daily injections or nasal spray administration are generally unsuit¬ able for application to animal studies. Administra¬ tion of GnRH and its agonists by long-term infu¬ sion shows that continued exposure is most effec¬ tive in suppressing pituitary-gonadal function; pi¬ tuitary receptors and gonadotropin content in ex¬ perimental animals are more suppressed than after daily injections (4)(5)(6)(7)(8).Initially, such experiments involved infusion of peptide via osmotic minipumps or portable...

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An implant of a gonadotropin releasing hormone agonist (buserelin) which suppresses ovarian function in the macaque for 3–5 months

Cited by 26 publications

References 16 publications

Effect of basal and pulsatile LH release on FSH-stimulated follicle growth in ewes chronically treated with gonadotrophin-releasing hormone agonist

Effect of basal and pulsatile LH release on FSH-stimulated follicle growth in ewes chronically treated with gonadotrophin-releasing hormone agonist

Inhibin secretion after treatment with an LHRH agonist and subsequent ovarian hyperstimulation induced by FSH in the macaque (Macaca arctoides)

Controlled release of a GnRH agonist from a polyhydroxybutyric acid implant: reversible suppression of the menstrual cycle in the macaque

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