LHRH Agonist Buserelin Research Articles

MAB using LHRH agonist Buserelin in combination with short‐term (two weeks) or long‐term (continuous) cyproterone acetate is not superior to standard androgen deprivation in the treatment of advanced prostate cancer

Correspondence to Mr Christopher R. Chapple, Urology Research Department, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel: +44 114 271 2791; fax: +44 114 279 8318 University of Vienna, Vienna, Austria

Maximum Androgen Blockade Using LHRH Agonist Buserelin in Combination with Short-Term (Two Weeks) or Long-Term (Continuous) Cyproterone Acetate Is Not Superior to Standard Androgen Deprivation in the Treatment of Advanced Prostate Cancer

This is the final analysis of EORTC GU Group Trial 30843 in which the treatment of advanced, metastatic prostate cancer with a combination of the LHRH agonist buserelin (nasal spray) and cyproterone acetate (Androcur), either continuously of only during the first 2 weeks, was compared with orchidectomy. There was no significant difference between the three arms as far as response rate, time to progression (subjective and objective) and duration of survival are concerned. Retrospective stratification according to the most important prognostic factors did not change the conclusions. Possible reasons for the difference with trial 30853, which used the same entry criteria but compared goserelin and flutamide with orchidectomy, are discussed. Reasons for using cyproterone acetate in combination treatment are the prevention of flare of the disease after LHRH agonists only and the prevention/reduction of toxicity in the form of hot flushes.

Lack of suppressive action of luteal factors from sheep corpus luteum on LH response to exogenous LHRH in ovariectomized, pregnant and post-partum ewes.

In vivo studies have provided evidence of a non-steroidal factor from ovine corpora lutea (CL) of pregnancy called LH-release inhibiting factor (LH-RIF), which specifically inhibits tonic LH release without affecting FSH secretion. To study the possible pituitary site of action of LH-RIF and other factors from sheep CL of pregnancy, the LH response to LHRH was investigated in ovariectomized (OVX) ewes pretreated with ovine luteal extract (oLE) from CL of mid-pregnancy, and in pregnant and post-partum ewes from which the CL were removed at mid-pregnancy. In view of the fact that human follicular fluid (hFF) contains a non-steroidal factor, called gonadotrophin surge-attenuating factor, which attenuates the LHRH-induced LH release, it was clearly important to examine the LHRH-induced LH release in OVX ewes pretreated with oLE or hFF In experiment 1, the LH and FSH responses (the maximum LH and FSH concentrations, the time to maximum LH and FSH concentrations and the area under the LH and FSH response curves) to a single i.v. injection of 5 microg of the LHRH agonist buserelin was not significantly different between ewes pretreated with oLE and ewes pretreated with BSA. Although the LHRH-induced LH and FSH release was slightly attenuated in OVX ewes pretreated with hFF as compared with OVX ewes pretreated with BSA, the maximum LH and FSH concentrations and the area under the LH and FSH response curves were not significantly different between the two groups of ewes. In experiment 2, the LH responses to a single i.v. injection of 0.5 microg LHRH on days 80 and 100 of pregnancy were not significantly different between intact ewes and ewes from which the CL were removed on day 70 of pregnancy. In both groups of ewes the maximum LH concentration and the area under the LH response curve were significantly lower (P <0.02) on day 100 than on day 80 of pregnancy. In experiment 3, the LH responses to a single i.v. injection of 50 microg LHRH on day 140 of pregnancy and on day 10 post-partum were not significantly different between intact ewes and ewes from which the CL were removed on day 70 of pregnancy. In both groups of ewes the maximum LH concentration and the area under the LH response curve were significantly lower (P <0.01) on day 140 of pregnancy than on day 10 post-partum. These experiments provide evidence for a lack of suppressive action of luteal secretory products from the ovine CL of pregnancy on the pituitary LH response to LHRH in OVX, pregnant and post-partum ewes.

Effect of administration and subsequent cessation of buserelin on cancellous bone of female rats

Although hormone replacement therapy is effective in preventing postmenopausal bone loss, it fails to cause a return of bone mass to normal in patients with established osteoporosis. Similarly, in the ovariectomized rat, estrogen administration protects the skeleton from bone loss but fails to reverse this once it has occurred. However, physiologically produced sex steroids may, in contrast to conventional methods of sex steroid administration, be capable of restoring bone mass in osteopenic states. To investigate this question, we analyzed the effect of treatment with the LHRH agonist buserelin for varying durations, and subsequent cessation thereof, on histomorphometric indices of rat cancellous bone. Female rats 13 weeks old were given daily SC injections of vehicle or buserelin as follows: vehicle days 1-90; vehicle days 1-150; vehicle days 1-60, buserelin days 61-90; vehicle days 1-60, buserelin days 61-90, vehicle days 91-150; vehicle days 1-30, buserelin days 31-90; vehicle days 1-30, buserelin days 31-90, vehicle days 91-150; buserelin days 1-90; buserelin days 1-90, vehicle days 91-150. At the end of the treatment period, animals were killed, tibiae removed, and histomorphometric indices assessed at the secondary spongiosa of the proximal metaphysis. Analysis of vaginal smears confirmed that buserelin rapidly suppressed ovulation, which quickly returned once treatment was stopped. We found that administration of buserelin for 30, 60, or 90 days reduced cancellous bone volume because of a reduction in both the number and thickness of trabeculae.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled release of the LHRH agonist buserelin acetate from injectable suspensions containing triacetylated cyclodextrins in an oil vehicle

Abstract Heptakis (2,3,6-tri- O -acetyl)-β-cyclodextrin) ( TA  β  CyD ) and octakis (2,3,6-tri- O -acetyl- γ - cyclodextrin) (TAβCyD) were prepared for use as hydrophobic carriers of buserelin acetate (BLA), an agonist of luteinizing hormone-releasing hormone. The results from this study suggest that the in vitro release of BLA from the peanut oil suspension into the aqueous phase was retarded by complexation with TACyDs. A single subcutaneous injection of the oily suspension of BLA containing TAβCyD and TAγCyD in rats led to retardation of plasma levels of BLA containing in 25- and 39-fold longer mean residence times, respectively, than that of BLA alone. Simultaneously with the suppression of plasma testosterone to castrate level, the pharmacological effectiveness of BLA continued for 1–2 weeks and significant weight reduction of genital organs was observed due to the antigonadal effect. Since TAβCyD and TAγCyD were degraded enzymatically in rat skin homogenates, both TACyDs can be useful as bioabsorbable sustained-release carriers for hydrophilic peptides following the subcutaneous injection of an oily suspension.

Orchidectomy versus buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843

This prospective randomized phase III trial compares orchidectomy as standard androgen-deprivative therapy of advanced (metastatic) prostatic cancer with treatment using the LHRH agonist Buserelin ® administered as nasal spray 3 daily doses of 400 μg, and combined with cyproterone acetate (CPA) 3 daily doses of 50 mg orally for 2 weeks initially to prevent flare-up of the disease, or continuously as complete androgen blockade. The trial was closed to entry in September 1989 when 367 patients were recruited. Patients were stratified for performance status (WHO) and metastatic status prior to randomization. According to patient and disease characteristics spreading of patients over the 3 arms was without statistical significant differences. Ineligibility was 5 and 4% of the patients were only partly evaluable. In March 1990 a first, preliminary analysis was performed. At that time 207 patients were off-study for progression or death and median follow-up was 1 yr. As to time-to-progression and survival there were no significant differences between the 3 arms. The meaning of this in regard to results of other trials with complete androgen blockade is discussed.

The somatostatin analog Sandostatin (SMS201-995) in treatment of DMBA-induced rat mammary tumors

The effects of treatment with a somatostatin analog (Sandostatin, SMS201-995) were investigated in female rats with dimethylbenzanthracene (DMBA)-induced rat mammary tumors. A 3-week treatment was performed using sandostatin, the LHRH-agonist buserelin alone, or buserelin in combination with sandostatin. Twice daily sandostatin treatment was performed with dosages of 0.05 microgram, 0.2 microgram, 1 microgram, 5 micrograms, and 20 micrograms. Buserelin was used in a 2 x 5 micrograms/day dosage. The combined results from six different experiments show that the various dosages of sandostatin caused no tumor growth inhibition. Somatostatin receptors could not be demonstrated in these mammary tumors. Sandostatin treatment by daily injections did not suppress levels of growth hormone, prolactin, or epidermal growth factor-like activities. Estrogen (ER) and progesterone (PgR) receptor contents of the mammary tumors were not changed. In contrast, buserelin treatment caused highly significant tumor remission. The combined treatment with sandostatin and buserelin did not alter the treatment results obtained after treatment with buserelin alone. In conclusion, sandostatin treatment in this tumor model had no direct growth inhibitory effect and did not cause an endocrine inhibition of mammary tumor growth. However, these results do not exclude antitumor effects in human breast cancer in view of the presence of somatostatin receptors in approximately 20-45% of human tumors, besides possible different endocrine effects.

Inhibin, gonadotrophins and sex steroids in dogs with Sertoli cell tumours

Inhibin bioactivity and mRNA for inhibin subunits were measured in four dog Sertoli cell tumours and in the testes of five normal control dogs. The tumours contained increased levels of inhibin (P less than 0.05) and mRNA for the alpha and beta B subunits when compared with controls, whereas the mRNA for the beta A subunit was not detected in tumours or control testes. The inhibin bioactivity was associated with a 32 kDa molecule in both Sertoli cell tumours and normal dog testes; no higher molecular weight forms were found after sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Peripheral levels of immunoassayable inhibin in dogs with Sertoli cell tumours were higher than those in the controls (P = 0.01), indicating that it might be possible to use this parameter as a marker for Sertoli cell tumours. Other testicular tumours, however, might also secrete immunoactive inhibin. The increased inhibin concentrations are likely to be the cause of the suppressed peripheral levels of FSH (P less than 0.02). However, peripheral levels of LH (P less than 0.02) and testosterone (P less than 0.01) were also suppressed in the dogs with Sertoli cell tumours, whereas the concentrations of oestradiol in the peripheral plasma of both groups did not differ. Finally, i.v. injection of the LHRH agonist buserelin caused a significant increase in LH and testosterone in the control dogs, but not in the dogs with Sertoli cell tumours. It was concluded that secretory products from the Sertoli cell tumours suppressed pituitary gonadotrophin secretion. It is unlikely that testosterone or oestradiol play a role in this respect. FSH may be suppressed by the high levels of inhibin in tumour-bearing dogs, but it remains unclear whether inhibin or another Sertoli cell product is responsible for the unresponsiveness of the pituitary gland to LHRH and the suppression of LH.

Pituitary-testicular function is suppressed by an LHRH antagonist but not by an LHRH agonist in the marmoset monkey

The use of pituitary desensitization by an LHRH agonist (buserelin) to examine pituitary-testicular function was investigated in a New World primate. Six adult male marmoset monkeys were injected s.c. with an LHRH agonist implant (1.5 mg in a rod 0.5 cm long). Pharmacokinetics, determined by radioimmunoassay of urinary buserelin, revealed a rapid initial release of the agonist followed by a steady decline during a 200-day period. The LHRH agonist treatment resulted in a rapid initial rise in plasma LH followed by a return to mean values similar to those seen in the control samples by 7 days after implantation. Using the present protocol, no evidence of subsequent pituitary desensitization or suppression of testicular function was observed, plasma concentrations of LH and testosterone remaining within the normal range during the 200-day study period. In contrast, pituitary-testicular function was suppressed in the male marmoset after blockade of pituitary LHRH receptors by an LHRH antagonist. Five adults were treated with a single s.c. injection of the antagonist [Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-Ser(Rha)6,AzGlyNH2(10)]-LHRH at a dose of 300 micrograms/kg. The LHRH antagonist induced a marked suppression of plasma LH and testosterone by 6-8 h, the low levels being maintained for 24-48 h. These results show that, whereas treatment with an LHRH antagonist can inhibit pituitary-testicular function in the male marmoset, it may be that desensitization cannot be induced by the LHRH agonist used.

Reversibility of the Effect of LHRH Agonists and Other Antiandrogenic Hormones on the Testis: A Histomorphometric Study

Changes in testicular morphology are quantified in patients with metastatic prostatic cancer, treated with LHRH agonist Buserelin and compared with testes of young transsexuals and patients with metastatic prostatic cancer treated with orchidectomy only. No significant changes within 18 months were seen, suggesting reversibility of LHRH agonist effects on testicular morphology in this time period. Histomorphometrics of the testis are useful to quantify these changes.

Luteinizing Hormone Releasing Hormone Agonist for Contraception in Breast Feeding Women*

During the period of lactation there is a need for a reliable method of contraception since the suppressive effects of lactation on ovulation decline as the duration of breastfeeding is decreased. The aim of this study was to establish that chronic treatment with a LHRH agonist would prevent ovulation throughout the period of lactation and to evaluate the effects of the treatment on estrogen production, bleeding patterns, and nursing practice. Starting 6 weeks postpartum, nine mothers took 300 micrograms LHRH agonist (buserelin), intranasally once daily for the remainder of the duration of breastfeeding [216 +/- 18 days (mean +/- SEM)]. Urinary excretion of LH, estrone, and pregnanediol was compared to that of nine control breastfeeding mothers. In the control subjects follicular development, as assessed by rises in estrone, was minimal during the first 90 days of the study. Thereafter, phases of estrogen secretion were observed. Ovulation occurred in seven of the nine mothers on one to six occasions; time to first ovulation varied from 90-296 days. In the women taking buserelin, LH and estrone were initially stimulated for 1 and 2 weeks, respectively, then declined to basal levels. No ovulations occurred in the treated group. In six treated mothers only minor fluctuations in estrone were observed during the remainder of agonist treatment. In three subjects more frequent and sustained episodes of estrogen secretion were observed, but in contrast to the controls the rises in estrone were not followed by a typical LH surge or a rise in pregnanediol. Bleeding occurred in eight of the nine of the control mothers on one to seven occasions during the study period. The first bleed in five of the mothers was anovular, while other menstrual bleeds occurred in response to falling levels of pregnanediol. Of the mothers taking buserelin, one was amenorrhoeic, and five had only one light bleeding associated with the initial stimulation of estrone. Of the three women with continued fluctuations of estrone, one had three light bleeds, one experienced frequent spotting, while one had regular bleeding. No other side-effects, such as hot flashes or changes in nursing practices, were reported. Our results indicate that LHRH agonist treatment has the potential to be developed as an acceptable method of contraception during the postpartum period. The duration of treatment may be long enough to have a significant effect on maternal-infant well-being without encountering significant problems associated with low estrogen output.

A new way to induce oestrogen-deficiency osteopaenia in the rat: comparison of the effects of surgical ovariectomy and administration of the LHRH agonist buserelin on bone resorption and composition

Prolonged administration of LHRH agonist suppresses pituitary gonadotrophin secretion, thereby lowering blood oestrogen. This study was undertaken to compare the osteopaenic effects of bilateral ovariectomy and chronic administration of the LHRH agonist, buserelin, in the rat. Four groups of animals which had their skeletons labelled with 45Ca were studied for 4 weeks. Group 1 underwent a sham-ovariectomy, group 2 were surgically ovariectomized, group 3 were given buserelin by daily s.c. injection and group 4 were given a continuous infusion of buserelin by osmotic minipump. Plasma concentrations of oestradiol were measured weekly. Bone resorption was assessed by measuring the urinary excretion of 45Ca and hydroxyproline and determining bone 45Ca content. Ovariectomy and buserelin treatments lowered blood oestradiol, increased biochemical indices of bone resorption and decreased femur and total body calcium and 45Ca values. The degree of oesteopaenia elicited by ovariectomy and buserelin treatment was similar. Bone responses to s.c. buserelin and to continuous buserelin infusion were alike. We attribute evidence of increases in bone resorption and induction of osteopaenia with buserelin treatment to hypo-oestrogenism. We have shown for the first time by bone analysis that buserelin induces osteopaenia as effectively as bilateral ovariectomy. This appears to be the first demonstration in the rat that long-term administration of LHRH agonist influences bone. Administration of buserelin provides a new way of inducing oestrogen-deficiency osteopaenia in the rat without removing the ovaries.

Results of a Dutch Trial With the LHRH Agonist Buserelin in Patients With Metastatic Prostatic Cancer and Results of RORTC Studies in Prostatic Cancer

Results of a Dutch Trial With the LHRH Agonist Buserelin in Patients With Metastatic Prostatic Cancer and Results of RORTC Studies in Prostatic Cancer

LH-RH agonist (Buserelin): treatment of endometriosis

To investigate the effects of the LH-RH agonist Buserelin [D-Ser (But)6 des-Gly10-LHRH ethylamide] on endometriosis, 64 patients were treated with 900 micrograms/d Buserelin intranasally over 6 months after histological verification of the disease. As shown by the follow-up operation at the end of treatment, 73% of cases showed regression of implants, whereas adhesions seemed to be unaffected. The uncorrected pregnancy rate of the 45 patients with a history of infertility was 40%, while the overall recurrence rate--confirmed by histological examination--was 9.4%. The endocrine parameters demonstrated a highly significant suppression of estradiol (E2) and a sharp decline of progesterone (Prog), indicating anovulatory cycles. Follicle-stimulating hormone (FSH) was unchanged, while luteinizing hormone (LH) and prolactin (Prl) decreased significantly. The androgenic parameters testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), and sex-hormone-binding globulin (SHBG) revealed no relevant changes. Influence on bone metabolism could not be detected by measuring calcitonin and parathyroid hormone fragments (PTH-C and PTH-MM). Negative metabolic effects were absent in terms of hematology, clotting system, liver enzymes, renal parameters and lipid metabolism. Remarkable was a significant increase of high-density-lipoprotein cholesterol (HDL). Subjective complaints were mostly attributed to the therapy-induced hypoestrogenism. We consider Buserelin to be an effective drug in the treatment of endometriosis, with a low incidence of relevant side effects.

The antiandrogen anandron potentiates the castrating effect of the LH-RH agonist buserelin in the rat.

When buserelin (0.04-25 micrograms/kg/day), a potent LH-RH agonist, was administered s.c. daily for 15 days to male rats, prostate weight decreased after a transient increase in the first days of treatment but never as much as after orchidectomy, since testosterone secretion was never totally suppressed. The combination of the pure nonsteroid antiandrogen Anandron (20 mg/kg/day) with even low doses of buserelin led to an immediate decrease in prostate weight that was complete at 15 days. This could be explained (a) by an additivity of effects: inhibition by Anandron of the action of residual testosterone unsuppressed by buserelin on the prostate and prevention by buserelin of the rebound testosterone increase induced by Anandron: (b) by a potentiation by Anadron of the direct castrating effect of buserelin on the testis since testis weight and testosterone secretion were lowered to a greater extent by the combination than by buserelin alone. Anandron might increase the sensitivity of LH-RH receptors to LH-RH agonist in the testes, as has been shown in the pituitary. In contrast, the combination of the antiandrogenic steroid progestin, cyproterone acetate, with buserelin never potentiated the castrating effect of buserelin on testis weight and testosterone and only partially potentiated prostate atrophy. If such actions also exist in the human, the addition of Anandron to LH-RH agonist treatment would not only counter flare-up and adrenal androgen effects on the prostate but would also lower the doses of peptide or the time required for chemical castration.

Reciprocal inhibition of the long-acting luteinizing hormone releasing hormone agonist buserelin and human chorionic gonadotropin in stimulating leydig cell steroidogenesis

The interference between human chorionic gonadotropin (hCG, Pregnyl, Organen 1500IU i.m.) and the long acting LHRH agonist Buserelin® (500 μg s.c.) in stimulating Leydig cell steroidogenesis was studied in 6 eugonadal men. Simultaneous administration of a single injection of the agonist (LHRH α) and hCG blunted the plasma testosterone response observed 24 h after LHRH. alone, enhanced the secretion of oestradiol without affecting 17-hydroxy-progesterone and aggravated the late steroidogenic block at the 17,20-lyase locus. As compared to hCG alone, combined LHRH α and hCG administration also decreased the maximum and 48 h testosterone increments and the testosterone production reflected by the area under the curve, enhanced the production of oestradiol and again aggravated the 17, 20-lyase lesion. The data show that the long acting agonist LHRH α and hCG reciprocally inhibit their stimulatory effect on Leydig cell testosterone secretion probably by a suppressive effect of oestrogens on the conversion of C 21- to C 19-steroids. The mechanism underlying this reciprocal inhibition remains to be elucidated.

Utilization of luteinizing hormone-releasing hormone agonist in pulmonary leiomyomatosis

A patient presenting a recurrent episode of pulmonary leiomyomatosis has been treated with the LH-RH agonist buserelin at a dosage of 200 micrograms tid SC for 7 days, then 500 micrograms SC daily for a total period of 6 months. Basal serum E2 was suppressed during treatment and varied between 62 and 180 pmol/ml (mean, 129.4 +/- 14.5). Pulmonary symptoms completely disappeared during treatment, but no objective regression of the pulmonary lesions was observed. Because of the uncertainty of response of benign metastasizing leiomyomas to castration and because of the reversibility of the medical treatment, LH-RH agonist may be preferred to surgical castration in this pathology.

Long-term stimulatory effects of a continuous infusion of LHRH agonist on testicular function in male red deer (Cervus elaphus).

Red deer stags were infused continuously with the LHRH agonist buserelin at 180-270 micrograms/day (1.2-1.8 micrograms/kg/day) for 72 days starting in late winter with the aim of suppressing reproductive function and inducing premature casting of the antlers. Contrary to expectation, the treatment resulted in a long-term stimulation of testicular activity lasting at least 2 months; the increases in plasma concentrations of testosterone were associated with an increase in aggressive behaviour and the development of rutting odour in the urine. The stags cast their antlers at the normal time in spring after the end of the treatments. The results indicate that the pituitary gonadotroph cells in the stag can continue to secrete LH in response to chronic exposure to an LHRH agonist and do not become rapidly desensitized. The effect of the agonist is therefore to cause significant stimulation of testicular activity which is a conspicuous response in the non-breeding season when the stags are already in a hypogonadal state.

Metabolic effects and general side effects in the treatment of endometriosis with an LHRH agonist

Between 1983 and 1986 40 patients were treated for external genital endometriosis with the LHRH agonist buserelin. Ovarian suppression was achieved for a period of six months with a dose of 900 to 1,800 mcg per day. In addition to gynecological findings, liver and kidney function and lipid metabolism were checked prior to treatment and at regular intervals during treatment. No deviations from normal ranges were found. The general side effects observed during treatment were as a rule attributable to the buserelin-induced relative estrogen deficiency. The efficacy of the medication in the treatment of endometriosis was demonstrated by control pelviscopy. Since no undesirable metabolic side effects have so far been observed with buserelin, it may be considered an effective new alternative treatment for endometriosis.

Hormone levels during treatment with the LHRH agonist buserelin

In this paper we develop the Wiener functional for an N-level uniformly distributed discrete random process for use in non-linear system identification. We show that the kernels of the functional may be estimated using cross correlation in a manner equivalent to that developed by Lee and Schetzen for Gaussian processes. The uniformly distributed process provides more power to the systen being studied than does a Gaussian process with the same amplitude ranne and is easy to generate on a dioital computer.