Biomedical subjects

J Rivier

Publications and source records attributed to J Rivier.

At least 91 records · Page 5Linked to original sources

PubMed1993

New technique for quantitation of pituitary adenoma size: use in evaluating treatment of gonadotroph adenomas with a gonadotropin-releasing hormone antagonist.

Because administration for 1 week of the GnRH antagonist Nal-Glu GnRH had been shown to decrease FSH secretion from supranormal to normal in men with gonadotroph adenomas, we investigated the effect of prolonged administration of Nal-Glu on the size of gonadotroph adenomas. To quantitate the effect of Nal-Glu GnRH on gonadotroph adenoma size, we first developed a technique for calculating adenoma volume. The technique involved collecting magnetic resonance (MR) imaging data from each adenoma at 1-mm slice intervals in the coronal, axial, and sagittal views and using the Softvu computer program to calculate adenoma volume from the MR data. The precision of this technique, as judged by the coefficients of variation of the calculations of the same view of the same study three times, was 1.7%, 1.0%, and 1.0% for each of three studies. When Nal-Glu GnRH (5 mg, sc, every 12 h) was self-administered for 3-12 months to five men with gonadotroph adenomas and supra-normal serum FSH concentrations, the serum FSH concentrations decreased to normal or below normal for the entire treatment period. Adenoma size, however, did not change during treatment in any of the five men. We conclude that calculating pituitary adenoma volume from MR data using the Softvu computer program is a highly reproducible technique, but that Nal-Glu GnRH is not an effective treatment for reducing gonadotroph adenoma size. The failure of Nal-Glu to reduce adenoma size despite its success in reducing FSH secretion suggests that FSH secretion from gonadotroph adenomas is dependent on endogenous GnRH, but growth of gonadotroph adenomas is not.

Adenoma↗

PubMed1992

Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine, -lysine, or -p-aminophenylalanine residues at positions 5 and 6.

In order to be used as fertility regulators in humans, gonadotropin releasing hormone (GnRH) antagonists must be extremely potent and long acting and exhibit negligible side effects such as stimulating histamine release. To this aim, we have recently synthesized a series of analogues with the standard Ac-DNal1-DCpa2-DPal3 substitutions, where the N omega-amino function of ornithine, lysine, or p-aminophenylalanine (Aph) was converted to the aminotriazolyl (atz) derivatives at positions 5 and 6 with further modifications at positions 7 and 10. The analogues were tested for their ability to bind to pituitary cell membranes, to release histamine in a mast cell assay, to inhibit luteinizing hormone (LH) secretion by castrated male rats or cultured pituitary cells, and to interfere with the ovulation in intact female rats. While the subcutaneous (sc) injection of 50 micrograms of Azaline A (7, [Ac-DNal1,DCpa2,DPal3,Lys5(atz),DLys6++ +(atz),ILys8,DAla10]GnRH) dissolved in 0.2 mL of an aqueous media significantly inhibited LH release in the castrated male rat for 24 h, the same dose of Azaline B (11), [Ac-DNal1,DCpa2,DPal3,Aph5(atz),DAph6++ +(atz),ILys8,DAla10]GnRH, inhibited LH release for 72 h. A similar long duration of action was observed for Antide ([Ac-DNal1,DCpa2,DPal3,Lys5(Nic),DLys6(Nic ),ILys8,DAla10]GnRH) but not for Nal-Glu ([Ac-DNal1,DCpa2,DPal3,Arg5,4-(pmethoxybenzoy l)-D-2-Abu6,DAla10]GnRH). In the same paradigm, a 5-fold dilution of the peptide (50 micrograms in 1 mL) and the use of three injection sites rather than one resulted in significantly shorter duration of action for most of the peptides tested. This suggested that long duration of action might be the result of slow release from the injection site(s). In order to investigate this possibility, Nal-Glu and Azaline B were injected intravenously (i.v.) at three doses (10, 50, 250 micrograms) to castrated male rats. At all doses, both peptides significantly lowered LH levels for 8 h. By 24 h, Nal-Glu (250 micrograms) and Azaline B (50 and 250 micrograms) still measurably inhibited LH secretion. Finally, only Azaline B (250 micrograms) was still active at 48 h. These findings demonstrate that subtle structural modifications will yield peptides with different half-lives after iv administration. These findings led us to investigate the effects of other structural modifications on duration of action. We observed that systematic substitutions at positions 7 (NMeLeu) and 10 (Pro9-NHEt, and Gly-NH2) were found to be deleterious. Of interest was the observation that only the DAla10-NH2 substitution led to long duration of action and enzymatic stability under the conditions tested.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Alanine series of ovine corticotropin releasing factor (oCRF): a structure-activity relationship study.

Previous structure-activity relationship studies of CRF have shown that residues 1-4 were not necessary for receptor binding or transduction, that residues 4-8 were important for activation, and that residues 12-41 were mostly responsible for binding. Finally it was proposed that CRF assumed an alpha-helical structure when interacting with its receptor. By systematic substitution of each residue (except residues 1-4) in ovine CRF (oCRF) by Ala, we have investigated the role played by individual side chains in receptor recognition and activation. Out of 33 analogues (synthesized using SPPS on an MBHA resin, purified by RPHPLC and characterized by amino acid and mass spectral analyses), a significant loss of biological potency (less than 1% potency of native) was observed for 6 analogues ([Ala6], [Ala8], [Ala10], [Ala12], [Ala14], and [Ala38]); 12 analogues had biological potencies ranging from 1% to 60% and ranked as follows: [Ala35] less than [Ala16] less than [Ala9] less than [Ala19] less than [Ala15] less than [Ala13] less than [Ala7] less than [Ala23] less than [Ala11] less than or equal to [Ala21] less than [Ala27] less than or equal to [Ala18]; 8 analogues were found to be equipotent (greater than 60% and less than 150%) ([Ala5], [Ala17], [Ala26], [Ala29], [Ala30], [Ala34], [Ala36], and [Ala37]; and 7 analogues were found to be approximately 2-5 times more potent than native oCRF ([Ala25] = [Ala40] less than or equal to [Ala39] less than or equal to [Ala33] less than [Ala20] less than [Ala22] less than [Ala32], in an in vitro pituitary cell culture assay. In summary, the Ala substitutions which showed the greatest loss of potency (less than 1% of native oCRF) were those replacing hydrophobic residues while those showing the greatest increase in potency were replacing hydrophilic residues. Of the 22 Ala-containing analogues in the C-terminal half of the molecule, 17 analogues have equal or greater potencies than native oCRF. Substitution of Ala in the N-terminal region (residues 5-19) on the other hand is generally detrimental to biological activity. These results suggest that the side chains of residues 5-19 are very important for receptor binding and activation while, in the C-terminal region, the amino acid side chains may be more responsible for structural conservation than for functional expression.

Adrenocorticotropic Hormone↗

PubMed1992

Immunoreactivities for antisera to three putative neuropeptides of the rat melanin-concentrating hormone precursor are coexpressed in neurons of the rat lateral dorsal hypothalamus.

Antisera (AS) raised against rat melanin-concentrating hormone (rMCH) and against two additional peptides sequences derived from the rat MCH precursor (neuropeptide glutamic acid-isoleucineamide (NEI), and neuropeptide glycine-glutamic acid (NGE)) exclusively stained the hypothalamic neurons previously described using AS to salmon MCH, human somatocrinin 1-37 (GRF37) and alpha-MSH. Liquid phase and dot-blot controls for specificity indicated that rMCH-, NEI- and NGE-AS bound epitopes recognized by sMCH-, alpha-MSH- and GRF-37-AS, respectively. The distinct intracellular patterns of immunoreactivity obtained in control animals with rMCH-, NGE- and NEI-AS, as well as the changes observed after intracerebroventricular injection of colchicine matched previous findings using sMCH-, GRF37- and alpha-MSH-AS.

Animals↗

PubMed1992

Total chemical synthesis, characterization, and immunological properties of an MHC class I model using the TASP concept for protein de novo design.

The design, total chemical synthesis, and immunological properties of a four-alpha-helix bundle template-assembled synthetic protein (TASP) mimicking some of the structural features of the major histocompatibility complex (MHC) class I is described. In a first approach, the native sequence 58-74 of the alpha 1 heavy chain domain of HLA-A2 was modeled in order to increase helix stability and amphiphilicity of the 17-mer peptide, preserving the residues for potential T-cell receptor (TcR) binding properties. According to the TASP concept, these helical segments were covalently attached to a cyclic template molecule designed for the induction of a four-helix-bundle topology of the assembled peptide blocks. After extensive HPLC purification, stepwise solid-phase synthesis resulted in a TASP molecule of high chemical purity as demonstrated by analytical HPLC, mass spectrometry, and amino acid analysis. CD spectroscopic investigations are consistent with the onset of a partial alpha-helical conformation in aqueous buffer as well as in TFE. Antibodies raised directly against this four-alpha-helix bundle TASP molecule (without prior conjugation to a carrier molecule) were detected by ELISA. Flow cytometry studies showed that these antibodies recognize the native MHC class I molecule on the surface of HLA-A2-positive cells. The results indicate that the TASP approach represents a versatile tool for mimicking conformational epitopes.

Amino Acid Sequence↗

PubMed1992

Ovulation and embryo recovery rates following immunization of mares against an inhibin alpha-subunit fragment.

Six normally cycling mares were immunized 5 times at 3-week intervals with a synthetic porcine inhibin alpha-subunit fragment which had been conjugated to bovine serum albumin and emulsified in Freund's incomplete adjuvant. Immunized mares ovulated a significantly larger (P < 0.01) number of follicles per estrous cycle (2.8 +/- 1.1; range 1 to 8 ovulations) than 14 nonimmunized control mares (1.1 +/- 0.1; range 1 to 2 ovulations). Day-7 embryo recovery rates tended to be higher (P < 0.1) in immunized mares (1.6 +/- 0.5 embryos per flush) than in control mares (0.7 +/- 0.2 embryos per flush). No differences in interovulatory intervals were found between the 2 groups. These results indicate that immunization against inhibin may be useful in inducing development and ovulation of multiple follicles for embryo transfer in the mare.

Journal Article↗

PubMed1992

Abdominal surgery-induced delayed gastric emptying in rats: role of CRF and sensory neurons.

The role of peripheral corticotropin-releasing factor (CRF) and afferent pathways in mediating abdominal surgery-induced delayed gastric emptying was investigated using an intravenous injection of the competitive CRF antagonist alpha-helical CRF9-41 and capsaicin pretreatment in adult fasted rats. Gastric emptying of a non-caloric solution was measured by the phenol red method. Intravenous CRF (0.13 nmol) inhibited by 65% gastric emptying. CRF effect was completely reversed by simultaneous intravenous injection of alpha-helical CRF9-41 (13 nmol). Abdominal surgery under enflurane anesthesia inhibited gastric emptying by 60% measured 3 h postoperatively. Enflurane anesthesia alone had no effect on gastric emptying 3 h after exposure. Abdominal surgery-induced delay of gastric emptying was reversed by 46, 60, and 100% by capsaicin pretreatment (125 mg/kg, -3 wk), intravenous injection of alpha-helical CRF9-41 (13 nmol), and combined pretreatments with capsaicin and CRF antagonist, respectively. Capsaicin and alpha-helical CRF9-41 given alone or in combination did not influence gastric emptying. These results indicate that peripheral CRF receptors along with capsaicin-sensitive afferent neurons contribute to somatovisceral stress (abdominal surgery)-induced delayed gastric emptying.

Abdomen↗

PubMed1992

Isolation and characterization of hypothalamic growth-hormone releasing factor from common carp, Cyprinus carpio.

A growth hormone-releasing factor (GRF)-like peptide was isolated from the hypothalamus of common carp, Cyprinus carpio, by acid extraction, gel filtration chromatography, immunoaffinity chromatography using antiserum directed against rat GRF, and multiple steps of HPLC using octadecyl columns. Based on Edman degradation and peptide mapping, this teleost GRF was established to be a 45-residue peptide with the following primary structure: His-Ala-Asp-Gly-Met-Phe-Asn-Lys-Ala-Tyr-Arg-Lys-Ala-Leu-Gly-Gln-Leu-Ser- Ala-Arg - Lys-Tyr-Leu-His-Thr-Leu-Met-Ala-Lys-Arg-Val-Gly-Gly-Gly-Ser-Met-Ile-Glu- Asp-Asp-Asn-Glu-Pro-Leu-Ser. Carp GRF is closely related structurally to peptides of the glucagon-secretin superfamily, and more particularly to mammalian vasoactive intestinal peptide (VIP) precursors and the N-terminal portion of mammalian GRFs. A synthetic replicate of this peptide is highly potent [50% effective dose (ED50) approximately 0.08 nM] in stimulating GH release from cultured goldfish pituitary glands and in elevating serum GH levels 30 min after injection (0.1 micrograms/g) in goldfish.

Amino Acid Sequence↗

PubMed1992

Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood-brain barrier.

Melanin-concentrating hormone (MCH) is a peptide reported to inhibit ACTH and cortisol secretion in teleost fish. Its ability to modify the activity of rat corticotrophs, however, remains controversial. We report here that while the peripheral injection of rat (r) MCH failed to alter plasma ACTH levels of conscious rats with an intact blood-brain barrier (BBB), it significantly activated the hypothalamic-pituitary-adrenocortical axis of rats with increased BBB permeability induced by protamine sulfate administration into the internal carotid artery. Similarly, the intracerebroventricular injection of this peptide into rats with intact BBB measurably released ACTH. The ACTH response to rMCH was markedly, but not totally, inhibited by passive immunoneutralization of CRF. These results indicate that rMCH acts within the central nervous system to stimulate the hypothalamic-pituitary-adrenocortical axis of rats, and that the site of action of the peptide is located in brain structures protected by the BBB. Activation of CRF-secreting neurons represents an important final pathway, although other regulatory factors also seem to be involved.

Adrenocorticotropic Hormone↗

PubMed1992

Effects of porcine follicular fluid, inhibin-A, and activin-A on goldfish gonadotropin release in vitro.

Inhibin and activin are important reproductive regulators in mammalian species and have been demonstrated to be highly conserved in structure. The present study examines the effects of porcine follicular fluid (pFF; a crude inhibin and activin preparation) and purified porcine inhibin-A and activin-A on goldfish gonadotropin-II (GTH-II) release. In studies using primary cultures of dispersed goldfish pituitary cells in static incubation, treatments with pFF, inhibin-A, and activin-A for 10 h caused dose-dependent increase in GTH-II release. In perifusion studies using goldfish pituitary fragments, basal GTH-II release was significantly elevated after 12-h exposure to 500 micrograms/ml pFF. Furthermore, GnRH-induced GTH-II secretion was potentiated by pretreatment with pFF. When pFF was applied in the form of 5-min pulses, a rapid dose-related stimulation of GTH-II was observed. Similarly, challenges with 2-min pulses of 15, 150, and 1500 pM inhibin-A and activin-A stimulated GTH-II release by goldfish pituitary fragments in a rapid and dose-dependent manner. This acute stimulatory action of inhibin on goldfish GTH-II release was completely abolished after pretreatment with specific inhibin antibodies. The acute actions of inhibin and activin on GTH-II release are probably not due to the release of endogenous GnRH from nerve terminals in the pituitary fragments or binding to the GnRH receptors. First, a specific GnRH antagonist did not block the actions of inhibin and activin. Second, dopamine, a potent inhibitor of GnRH-stimulated GTH-II secretion in goldfish, was only partially effective in decreasing inhibin- and activin-induced GTH-II release. Third, the stimulatory effects of inhibin and GnRH on GTH-II release were additive. These lines of evidence also indicate that the mechanisms mediating inhibin and activin stimulation of goldfish GTH-II release may be somewhat different from those of GnRH. These results demonstrate that in contrast with the usual inhibitory effects of inhibin on GTH release in mammals, both inhibin and activin exert long term and acute stimulatory actions on GTH-II release in the goldfish.

Activins↗

PubMed1992

Induction of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing hormone antagonist and testosterone enanthate.

The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropins and spermatogenesis were examined to assess its potential as a male contraceptive regimen. The potent Nal-Glu GnRH antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5, D4-p-methoxybenzoyl-2-amino butyric acid6,D-Ala10]GnRH) was administered daily (7.5 mg, sc) to eight normal men for 16 weeks. T enanthate was given im starting at week 2 and every 2 weeks thereafter through week 14 of the treatment phase. Serum LH, FSH, T, and estradiol concentrations were measured frequently during the 5-week control period, the 16-week treatment phase, and the 14-week recovery phase. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. Seven of eight subjects became azoospermic by 6-10 weeks of treatment; the eighth subject, who failed to achieve azoospermia, suppressed his sperm count to 7 million/mL by week 14 (from a mean baseline of 42 million/mL) before treatment was prematurely terminated because of localized swelling at each of his injection sites. Sperm counts returned to baseline 10-14 weeks after the end of Nal-Glu administration. Seven of the eight subjects showed suppression of LH to the limit of assay detection (less than 0.2 U/L), whereas the eighth subject showed incomplete suppression. Serum bioactive and immunoreactive LH concentrations showed concordant responses. Mean serum FSH concentrations were also markedly suppressed. Serum T and estradiol concentrations declined dramatically during the first 2 weeks of Nal-Glu GnRH treatment, but returned to the normal physiological range after T enanthate replacement was initiated. Libido and sexual potency were maintained. No systemic side-effects, other than erythema and induration at injection sites, were observed. These data demonstrate that combined GnRH antagonist plus T treatment can predictably and reversibly induce azoospermia in most men and has potential as a male contraceptive regimen.

Adult↗

PubMed1992

Pituitary response to growth hormone-releasing hormone in IDDM. Abnormal responses to insulin and hyperglycemia.

In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone-releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 micrograms/kg i.v. GRF 1-40 was administered to nine poorly controlled IDDM subjects (HbA1 greater than 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (approximately 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 +/- 90 pM) and hyperglycemia (16.5 +/- 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 +/- 11 vs. 20 +/- 4 micrograms/L without insulin infusion, P less than 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 +/- 7 micrograms/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 +/- 84 pM) and hyperglycemia (16.41 +/- 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.

Adult↗

PubMed1991

Conotoxins.

Explore the source record for details and available documents.

Amino Acid Sequence↗

PubMed1991

Gonadotropin releasing hormone antagonists: novel structures incorporating N omega-cyano modified guanidine moieties.

A series of GnRH antagonists with substitutions at positions 1, 2, 3, 5 and 6 that included the recently reported homoArg-N omega-cyano-N omega'-alkyl- or Lysine-N epsilon-5'-(3-amino-1H-1,2,4-triazole) [Lys(atz)] amino acid derivatives was synthesized, characterized and tested for antiovulatory and anaphylactoid activities and binding affinity. Overall, these analogs were found to be considerably more soluble at neutral pH than their homologs Nal-Glu or Antide. The decapeptides with these substitutions in positions 5 and/or 6 retained high in vivo potency while those with similar substitutions at positions 1, 2 and 3 were significantly less potent than Nal-Glu or Antide. Of the 16 new analogs reported here, Azaline (Ac-DNal1, DCpa2, DPal3, Lys5(atz),DLys6(atz), ILys8,DA1a10]-GnRH) showed the most promising physico-chemical and biological properties [Lys(atz) = N epsilon-5'-(3-amino-1H-1,2,4-triazole) lysine]. Azaline is readily soluble in dilute buffers at pH 7.0, completely inhibits ovulation at 2.0 to 3.0 micrograms per rat, is equipotent to GnRH in releasing histamine in the rat and has a weaker anaphylactoid response in the rat than other analogs such as Nal-Glu or even Antide.

Amino Acid Sequence↗

PubMed1991

CRF antagonist reverses the "anxiogenic" response to ethanol withdrawal in the rat.

The role of the neuropeptide corticotropin-releasing factor (CRF) in mediating the behavioral effects of ethanol withdrawal in the rat was examined using the elevated plus-maze test. In Experiment 1, CRF (0.5 microgram ICV) reduced the percentage of time spent on the open arms of the elevated plus-maze, consistent with an "anxiogenic-like" effect. CRF also reduced the total number of arm entries, indicating a reduction in general activity. Low doses (5 and 25 micrograms ICV) of the CRF antagonist, alpha-helical CRF produced no behavioral effects in the elevated plus-maze, while a higher dose (50 micrograms ICV) elicited CRF-like activity. In experiment 2, rats were maintained for 2-3 weeks on a liquid diet containing ethanol (8.5-11.5% v/v) or sucrose. Eight hours after withdrawal from the ethanol diet rats displayed "anxiogenic-like" responses as well as a reduction in general activity in the elevated plus-maze compared with rats withdrawn from control diet. Alpha-helical CRF significantly antagonized the "anxiogenic-like" effects of ethanol withdrawal in the plus-maze. General activity and physical signs of ethanol withdrawal such as tail stiffness, body tremor and ventromedial distal flexion were unaffected by alpha-helical CRF. Blood Alcohol Levels (BALs) determined immediately after removal of the ethanol diet showed no group differences in ethanol consumption. These results suggest that increased activity of central CRF systems may mediate the anxiogenic effects of ethanol withdrawal.

Animals↗

PubMed1991

Comparison of intermittent and continuous use of a gonadotropin-releasing hormone antagonist (Nal-Glu) in in vitro fertilization cycles: a preliminary report.

The agonistic effect of the gonadotropin-releasing hormone agonist often necessitates an extended period of treatment, resulting in a longer treatment cycle and increased cost. We have evaluated the intermittent use of a gonadotropin-releasing hormone antagonist, Nal-Glu, and have designed a new, simplified protocol for its use in in vitro fertilization. Seven women who had previously undergone treatment with leuprolide acetate and human menopausal gonadotropins were treated with Nal-Glu. Leuprolide acetate, 1 mg/day subcutaneously, was administered in the midluteal phase until down regulation was achieved (estradiol less than 30 pg/ml). Human menopausal gonadotropins, three to four ampules per day intramuscularly, was administered in conjunction with 500 micrograms subcutaneous leuprolide acetate. In the treatment cycles Nal-Glu (50 micrograms/kg/day) was administered intramuscularly on cycle day 1 or 2 for 3 days to achieve down regulation. Human menopausal gonadotropins, three to four ampules intramuscularly, was then administered daily without the antagonist. Nal-Glu was resumed when the follicles reached 14 to 16 mm and was continued until the day of human chorionic gonadotropin administration. Compared with leuprolide acetate-human menopausal gonadotropins cycles, the days required for down-regulation with Nal-Glu were significantly shortened (20.6 +/- 4.1 vs 1.6 +/- 0.3 days, p less than 0.001), as was total cycle length (31.3 +/- 5.8 vs 11.0 +/- 1.0 days, p less than 0.01). The mean number of days of treatment with human menopausal gonadotropins, the mean number of ampules of human menopausal gonadotropins, peak estradiol levels, the number of oocytes, and the percent of oocytes fertilized were not statistically different. No luteinizing hormone surges were detected with Nal-Glu in serum or urine. Nal-Glu was well tolerated, and five pregnancies have resulted. We conclude that intermittent administration of Nal-Glu is highly effective in achieving down-regulation and blocking spontaneous luteinizing hormone surges. Compared with leuprolide acetate-human menopausal gonadotropins cycles, an equally high oocyte and embryo yield may be anticipated. This new protocol substantially decreases cycle length and increases patient convenience.

Adult↗

PubMed1991

The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women.

The gonadotropin-releasing hormone antagonist offers several advantages over the use of the agonist and allows several physiologic questions to be addressed. In this study, we evaluated the ability of Nal-Glu to acutely inhibit the luteinizing hormone surge and prevent ovulation. We also assessed whether recovery of the follicle would be possible after several days of gonadotropin deprivation and estradiol decrement. Eight normal ovulatory women were randomized to control or Nal-Glu-treated cycles (50 micrograms/kg intramuscularly) for 3 to 4 days. Monitoring was carried out with daily vaginal ultrasonographic scans and serum estradiol levels and twice-daily serum luteinizing and follicle-stimulating hormone levels. Nal-Glu acutely inhibited the luteinizing hormone surge and ovulation, even when administered as late as the onset of the luteinizing hormone surge. Evidence was provided that spontaneous follicular rescue recurred in eight of 10 cycles after 3 to 4 days of Nal-Glu administration. Although an estradiol to follicular size dissociation occurred with Nal-Glu, subsequent ovulation occurred in 5.1 +/- 0.6 days after the last Nal-Glu dose. The decrement in estradiol after Nal-Glu administration correlated negatively with the days required for subsequent ovulation to occur (r = 0.77, p less than 0.05). The subsequent luteal phase also was normal in terms of length and progesterone levels. These data confirm the potency and efficacy of Nal-Glu in acutely inhibiting gonadotropins and extends our knowledge on the physiologic characteristics of the dominant follicle.

Adult↗

PubMed1991

Somatostatin 28 interacts with CCK receptor in brain and pancreas.

The ability of somatostatin analogs to interact with the binding of cholecystokinin has been studied in pancreatic and brain cortical membranes. Only the 28 amino-acid forms of somatostatin (S28), [Nle8]S28 and [Des Lys14,DTrp22]S28 were found to inhibit the binding of cholecystokinin to rat pancreatic plasma membranes and to increase the amylase release from pancreatic acini. This effect was independent of somatostatin receptor and resulted from an interaction between S28 and CCK receptor. This interaction was not observed with [Leu8, DTrp22, Tyr25]S28, indicating that this analog does not possess the biological activity of the native peptide and that the iodinated peptide could not label specific S28 receptors. S28 interacted also with CCK receptors in cortical brain membranes. Our results support the concept that S28, but not S14, may function as a regulatory molecule at CCK receptors and emphasize that S28 and S14 may be distinct neuromodulators.

Amylases↗