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PubMed1989

Effect of 3-week treatment with [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination on testicular, serum, adrenal and prostatic steroid levels in the dog.

Adult male mongrel dogs were treated with the LHRH agonist [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination for 21 days before measurement of steroid levels in the testes, prostate, adrenals and serum. Ketoconazole alone caused a marked stimulation of the intra-testicular concentration of pregnenolone, 17OH-pregnenolone, progesterone and 17OH-progesterone with no or little change of androstenedione, testosterone and dihydrotestosterone. Aminoglutethimide caused a 30-95% inhibition in the concentration of all steroids in the tests while treatment with the LHRH agonist caused a near complete inhibition of all testicular steroids. When administered concomitantly with the LHRH agonist, ketoconazole partly prevented the inhibitory effect of the LHRH agonist on testicular steroid levels. Serum levels of dehydroepiandrosterone, androst-5-ene-3 beta,17 beta-diol, androstenedione and androstane-3 alpha, 17 beta-diol were 75 to 95% inhibited by the LHRH agonist while serum testosterone and dihydrotestosterone concentrations were reduced below detection limits by the same treatment. Moreover, treatment with the LHRH agonist caused a 70-95% reduction in the intraprostatic concentration of testosterone and dihydrotestosterone in all the groups although maximal effect was observed when the LHRH agonist was combined with any of the three other agents. The present data show that while treatment with ketoconazole, aminoglutethimide or Flutamide alone has only partial inhibitory effects on androgen levels, combination with an LHRH agonist provides maximal inhibition. In addition to its direct blockade of the androgen receptor, some of the effect of Flutamide could be related to its blockade of testicular 3 beta-hydroxy-steroid dehydrogenase activity.

Adrenal Glands↗
PubMed1989

[Treatment of precocious puberty with an LH-RH agonist (D-TRP6-LH-RH)].

Chronic administration of luteinizing hormone-releasing hormone (LH-RH) is currently considered as the most appropriate therapy of precocious puberty. A delayed release preparation of D-Trp-6-LH-RH (Décapeptyl in microcapsules) designed to release the agonist for 28 days after intramuscular injection of 60 micrograms/kg body wt was given to 12 boys and 26 girls with precocious puberty. Plasma levels of gonadotropins and sex steroids were suppressed to prepubertal levels within 3 weeks, whilst pituitary responses to LH-RH test were almost abolished within 7 weeks. A significant improvement of secondary sex characteristics, as well as gonadal size, was observed within 6 months. Growth velocity (cm/yr, mean +/- SD) was reduced in boys and girls from 9.9 +/- 3.4 and 9.6 +/- 3.3 respectively before treatment to 5.2 +/- 1.0 and 5.3 +/- 1.3 respectively during the third year of treatment. The mean ratio height age/bone age was just before treatment 0.91 in boys and 0.88 in girls and increased to 1 after 3 yr of treatment. This study shows that Décapeptyl in microcapsules induced a prolonged suppression of gonadal function and a relative blockade of bone maturation. A significant improvement of adult height relative to the effect of conventional treatments should be expected.

Female↗
PubMed1989

[Simulation of ovulation using two types of LH-RH agonists].

Luteinizing hormone-releasing hormone (LH-RH) agonists are being increasingly used in ovulation stimulation protocols in IVF programs. The results of two methods of utilization of LH-RH agonists are compared. There was difference in the ovarian response on the day of human chorionic gonadotropin (hCG) higher in the short protocol (69% vs 56%, P less than 0.001). The ongoing pregnancy rate per treatment cycle was similar in both groups (18% in the long protocol and 16% in the short protocol).

Chorionic Gonadotropin↗
PubMed1992

Differential effects of LHRH and somatostatin analogs on human breast cancer.

We have been interested in the possible direct effects of luteinizing hormone releasing hormone (LHRH) and somatostatin (SS) analogs on the growth of human mammary tumor cells. Four recently synthesized peptide hormones including the LHRH agonists D-Trp6-LHRH and zoladex, LHRH antagonists SB30 and SB75, and the somatostatin analog RC 160 were analyzed for their effects on DNA synthesis of MCF-7 breast cancer cells in culture. At 48 hr, D-Trp6-LHRH and SB30 did not show significant effects (dose range, 10(-12)-10(-6) M). However, the combination of these two peptides at 10(-10) M produced significant inhibition of 3[H]thymidine incorporation (50% control). At 72 hr in the absence of estradiol-stimulated growth, D-Trp6-LHRH showed inhibition at 10(-12) and 10(-10) M (P less than 0.005 and 0.001). At higher concentrations, no significant inhibition was noted. In contrast to D-Trp6, SB30 (antagonist) showed no inhibition but significant stimulation of DNA synthesis at 10(-6) and 10(-4) M. In the presence of added estradiol (10(-9) M), complete reversal of D-Trp6-LHRH analog inhibition is noted. In contrast, there is persistent stimulation by SB30 (P less than 0.001). At 96 hr, D-Trp6-LHRH continued to show maximal inhibition of 70% in the absence of estradiol. SB30 stimulated DNA synthesis 100% at 10(-6) M. At 72 hr, the SS analog RC 160 demonstrated significant inhibition (53%) that was similar to D-Trp6 and SB75 peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1985

Effects of luteinizing hormone-releasing hormone agonist and calcium upon adenylyl cyclase activity of human corpus luteum membranes.

We have investigated the ability of the agonist analog of luteinizing hormone-releasing hormone (LH-RH), D-Trp6-LH-RH (LH-RHa), and of CaCl2 to inhibit directly gonadotropin stimulation of adenylyl cyclase in a cell-free system prepared from human corpus luteum. In the presence of a submaximally effective concentration of hCG, addition of 10(-5)M final concentration of LH-RHa did not alter the gonadotropin-stimulated enzyme activity, nor did LH-RHa alone show any effect upon basal levels of the enzyme. The failure to inhibit adenylyl cyclase would indicate that the LH-RHa does not affect gonadotropin receptor binding or cAMP synthesis and/or degradation in this membrane system, suggesting that the luteolytic effects of LH-RH are unlikely to involve a direct antigonadotropic activity at the level of the human corpus luteum. In great contrast to LH-RHa, addition of CaCl2 resulted in a dose-dependent inhibition of hCG-stimulable adenylyl cyclase. Thus, in the presence of either a maximally or submaximally effective concentration of hCG, inhibition was significant at 0.5 mM CaCl2 added in excess of ATP (2 mM) and EDTA (1 mM), being about 90% upon addition of 2.5 mM CaCl2. We also found that calcium reduced enzyme stimulation by forskolin and the GTP analog, guanyl 5'-yl imidodiphosphate [GMP-P(NH)P] in a dose-related manner and that activation by NaF was less sensitive to inhibition by calcium. Accordingly, at 2.5 mM CaCl2, guanyl nucleotide and forskolin stimulations were inhibited 96% and 86%, respectively, while NaF stimulation was reduced by 40%. Because previous studies have shown that calcium does not impair gonadotropin binding activity, the calcium-dependent inhibition of gonadotropin responsiveness reported here would imply an alteration in the functional coupling of the components of the luteal adenylyl cyclase system. These data suggest that calcium may play a role in the regulation of gonadotropin action in the human corpus luteum.

Adenylyl Cyclases↗
PubMed1987

Sensitivity differences in reproductive/endocrine organs to chronically administered LHRH agonists in female rats.

The acute and chronic effects of two LHRH agonists on reproductive endocrine target organs were examined in female rats. Animals were injected twice daily with [(ImBzl)-D-His6,Pro9-NEt]LHRH (histrelin) or [D-Trp6,Pro9-NEt]LHRH for 1, 3, 5, 7, 11 or 28 days at 1, 10, 100 or 1000 micrograms/kg/day beginning in the luteal phase. The responses observed with the two agonists were similar. An initial stimulatory phase was observed on the first day of treatment with substantial increases in serum LH and progesterone levels. A significant diminution of hormone response was seen by day 3. Only 1000 micrograms/kg abolished the pituitary LH response at later treatment periods. Estrous cyclicity, ovarian and uterine weight, and progesterone and estradiol levels were inhibited in a time and dose dependent manner. The results demonstrate target organ sensitivity differences. In contrast to the relatively high doses needed to inhibit the pituitary response and decrease ovarian weight, doses as low as 1 microgram/kg were sufficient to decrease uterine weight. If these findings extrapolate to humans, it may be that conditions in which the desired therapeutic action is suppression of uterine tissue, may be treated with lower doses of LHRH agonists than conditions requiring complete gonadal suppression.

Adrenal Glands↗
PubMed1990

Partial reversal of behavioral action of the agonist D-Trp-6-LH-RH by naloxone in mice.

The effects of the superactive agonist analog D-Trp-6-LH-RH were investigated in several neuropharmacological tests: inhibition of picrotoxin-induced seizures, open-field behavior, hot-plate and tail-flick tests, assessment of catalepsy and apomorphine-induced cage-climbing. In most tests, D-Trp-6-LH-RH was administered subcutaneously (sc.) at the dose of 100 micrograms/kg. The opiate involvement in the peptide action was checked by using naloxone HCl (NX) in a dose of 1 mg/kg intraperitoneally (ip.), with the exception of the analgesic tests where the dose was 0.5 mg/kg. The analog significantly suppressed the open-field parameters of ambulation, rearing and grooming; except for grooming, these actions were fully antagonized by NX. Similarly, NX pretreatment restored to the control levels the latencies of seizure parameters increased by D-Trp-6-LH-RH. The hot-plate latencies did not change after pretreatment with NX but the opiate antagonist was fully able to antagonize the analgesic effect of the peptide in the tail-flick test. The cataleptogenic effect and the inhibition of apomorphine-induced cage-climbing demonstrated after D-Trp-LH-RH were not antagonized by NX.

Animals↗
PubMed1996

Metabolism of [Des-Gly10,D-Trp6]LHRH ethylamide in rabbit nasal tissue.

The objective of this study was to determine whether [Des-Gly10, D-Trp6] LHRH ethylamide, a nonapeptide LHRH agonist known as deslorelin, is degraded by the rabbit nasal tissue. Deslorelin was incubated with nasal tissue either alone or in the presence of 0.1 mM ouabain, 0.1% 2,4-dinitrophenol, 0.1 mM phosphoramidon, 0.1 mM N-tosyl-L-phenylalanine chloromethylketone (TPCK) or 2% EDTA at 37 degrees C. Furthermore, deslorelin alone was incubated with nasal tissue at 4 degrees C. All incubation solutions were adjusted to isotonicity and pH 5.0. At the end of 90 min, the supernatants were analyzed using a reversed-phase HPLC. Metabolite peaks could be detected in all the above experiments except the low temperature study, suggesting inhibition of metabolism at low temperature. Intact drug remaining in the supernatant was elevated by about 32% by ouabain and dinitrophenol, suggesting that energy-dependent cellular uptake is likely for deslorelin. Phosphoramidon and TPCK failed to alter deslorelin levels, suggesting that phosphoramidon and TPCK sensitive endopeptidases did not contribute to the observed deslorelin metabolism. However, EDTA significantly elevated the intact deslorelin levels in a dose-dependent manner, with an elevation of 113% with 2% EDTA. With 2% EDTA, the metabolite peaks almost completely disappeared, indicating a possible role for either metal-activated peptidases or metallo-endopeptidases in the nasal metabolism of deslorelin.

Amino Acid Sequence↗
PubMed1989

IVF-ET in women with refractory polycystic ovarian disease.

Polycystic ovarian disease may be a cause of hormonal infertility. This condition is often refractory to therapy. Three groups of randomly chosen women with refractory polycystic ovarian disease (PCOD) were treated by induction of ovulation with pFSH/hCG, pFSH/hMG/hCG or after down-regulation of the ovaries with a GnRH analogue (Decapeptyl). Out of 18 patients six conceived in the first in vitro fertilization-embryo transfer (IVF-ET) cycle, and two further women conceived in a later cycle. It is suggested that patients with refractory PCOD should be referred for IVF-ET therapy, possibly after treatment with a GnRH analogue.

Adult↗
PubMed1989

Some observations on the effect of a GnRH analog in ovarian cancer.

Observations in healthy women led us to suppose that the increase of the tumor marker CA 125 observed during progression of ovarian cancer could be dependent on pituitary gonadotropins. Therefore we administered the GnRH-analog, DTrp 6-LH-RH, to 19 patients with progressive ovarian cancer and increasing CA 125 serum levels. When compared to 11 untreated patients, CA 125 levels increased at a considerably slower rate in 9 of 11 patients who were treated with the substance for more than 3 months. This was associated with stable disease, ranging from 4 to 20 months so far. The further analysis of 2 patients who developed an increase in CA 125 serum levels and a progression of disease during treatment demonstrated that FSH and LH levels had escaped suppression. The results support our assumption, that gonadotropins may be involved in the mechanisms leading to increasing CA 125 concentrations in ovarian cancer. The reduced increase of CA 125 and the observed stabilisation of disease during pituitary blockade offers a rationale for GnRH analogues in the therapeutic approach to this disease.

Adult↗
PubMedDate not supplied

The value of GnRH agonists in the treatment of failed cycles in an IVF-ET program: a comparative study.

Occasionally, menotropins fail to induce ovulation for IVF-ET, due to early luteinization resulting in high cancellation rates of 15-40% of cycles. The efficacy of GnRH agonists in reducing these problems was prospectively studied in 91 women undergoing repeated IVF-ET, after desensitization with GnRH agonists. In all patients, the cycles that had been induced by menotropins alone failed due to early luteinization. By comparing these patients to a control group with significantly lower cancellation rates as well as significantly higher fertilization, the cleavage and pregnancy rates were achieved for the former group (p less than 0.001 in all parameters). Pituitary down-regulation by means of GnRH agonists prior to the induction of ovulation seems to be an effective and rewarding method for minimizing cancellation rates, and for achieving improved results in IVF-ET therapy.

Adult↗
PubMed1991

GnRH agonist increases pregnancy potential of retrieved oocytes given adequate preincubation before insemination: a comparative study.

Preincubation of oocytes aspirated from follicles in IVF-ET programs is a controversial approach. While some investigators recommend this technique others doubt its necessity. We have studied the embryo quality in 100 women, undergoing IVF-ET, in whom ovulation was induced by the combination of GnRH agonists (GnRHa) and menotropins and compared to a control group in whom ovulation was induced with menotropins alone. No statistically significant difference was noted with regard to the fertilization and cleavage rates as well as to the preincubation period. Significantly higher pregnancy rates (P less than 0.001) were encountered in the first group in comparison with the control group.

Female↗
PubMed1991

The impact of the refractory period to gonadotropin therapy in IVF-ET cycles post longacting gonadotropin-releasing hormone (GNRH) analogue.

Sixty-nine women were treated with a long-acting gonadotropin-releasing hormone analogue (GnRHa), D-Trp-6-LH-RH (DTRP6) 3.2 mg (Decapeptyl, Ferring, Kiel, F.R.G.) prior to induction of ovulation for in vitro fertilization (IVF) with human menopausal gonadotropin (hMG; Pergonal; Serono Laboratories, Inc., Randolph MA). Three types of response were noted: Group I (18 patients) responded between days 1-3 of the treatment; Group II (30 patients) responded between days 4-6 of the therapy, and Group III (21 patients) responded after 7 days of treatment. Although a higher number of oocytes were encountered in Group I than in the latter two groups fertilization and clinical pregnancy rates were lower than in Group II (P less than 0.05), respectively, but higher than in Group III (P less than 0.07 and P less than 0.01), respectively. The best results were achieved by Group II patients, while Group III seemed to represent low responders as the number of embryos and pregnancy rate were significantly lower than in the other two groups. It seems that the level of ovarian suppression achieved by GnRH analogue results in a period of refraction of the ovary, and its duration has most probably an effect upon the results of the IVF cycles.

Adult↗
PubMed1992

Paradoxical ovarian stimulations in the use of LHRH analogs.

In the case of in vitro fertilization, LHRH analogs are used to induce an hypophysary blockage, before the phase of stimulation, via administration of exogenous gonadotropin. During in vitro fertilization attempts using LHRH analogs, the blockage is controlled after 14 days of treatment through measurement of the plasmatic estradiol and pelvic ultra-sonography. In this retrospective study, which concerned 1075 in vitro fertilization cycles, a paradoxical ovarian stimulation with LHRH analogs was observed in 93 cases (8.7%), with high estradiol levels and follicular growth (detected by ultra-sonography), in spite of low FSH and LH levels. In 4 cases, a follicular puncture was performed, which allowed to collect oocytes from which embryos were obtained, thus confirming the observed follicular growth and maturation. The most probable hypothesis explaining this phenomenon seems to be a direct ovarian stimulation, effectuated in vivo by LHRH analogs. This stimulation is only observed in certain patients, and apparently more frequently, with certain LHRH analogs, probably through a variation in the expression of ovarian LHRH receptors.

Estradiol↗
PubMed1993

Predictive parameters for ovarian response to hyperstimulation with exogenous gonadotropins after suppression of gonadotropin secretion of the pituitary using a long-acting GnRH agonist.

Individually adapted gonadotropin dosage is more successful than standardized schemes for ovarian stimulation prior to in vitro fertilization and embryo transfer. Unfortunately, differences in ovarian response can not be predicted reliably. In order to develop predictive parameters for ovarian response the data from 99 cycles in 69 patients were analysed retrospectively. Before initiating ovarian stimulation for in vitro fertilization, an untreated menstrual cycle was examined using a commonly used endocrinological screening protocol. The ovaries were then stimulated with exogenous gonadotropins after previous suppression of endogenous gonadotropin secretion using a long-acting GnRH-analogue. The predictive value of this endocrinological screening protocol for ovarian response was evaluated. Ovarian response was defined as the logarithmically transformed ratio of the serum estradiol concentration at ovulation induction, divided by the number of ampoules of exogenous gonadotropins administered. Comparison of the various hormone characteristics with ovarian response led to identification of two distinct groups of patients showing reduced ovarian response: those with elevated serum levels of FSH on the third cycle day (> 9 units/l, P < 0.0001), and those with elevated serum levels of estradiol on the third cycle day (> 190 pmol/l, P < 0.02). Patients with high serum levels of TSH in the TRH test responded poorly to ovarian stimulation (P < 0.05), but also showed significantly higher serum concentrations of FSH (P < 0.01). No parameter correlated positively with ovarian response.

Adult↗