Zoladex Depot Research Articles

Gonadotropin-releasing hormone agonist suppression of ovarian tumorigenesis in mice of the Wx/Wv genotype.

Although many investigations have shown a correlation between elevated gonadotropin levels and ovarian tumors (the gonadotropin theory), the ovarian response to a specific suppression of the gonadotropins has not been elucidated. The ovaries of (C57BL/6J x C3H/HeJ)F1-Wx/Wv mice, which contain 1% of the normal oocyte count at birth, rapidly lose the follicular apparatus and develop a 100% incidence of bilateral complex tubular adenomas from the surface germinal epithelium, which is also the origin of 90% of human ovarian carcinomas. Plasma levels of LH and FSH are known to rise fourfold during the period of tumorigenesis. We compared tumor development in Wx/Wv mice after either injecting a GnRH agonist (3.6 mg slow-release goserelin depot, Zoladex Depot) or administering a sham injection every 28 days from the age of 7 days up to 245 days. All 15 Wx/Wv mice that received sham injections developed bilateral ovarian tubular adenomas from the surface germinal epithelium. In none of the 11 mice receiving the GnRH agonist was any tumor found (p < 0.00005), and a significant suppression of the gonadotropins was demonstrated (p < 0.00005).

A Randomised Trial Comparing the Safety and Efficacy of the Zoladex 10.8-mg Depot, Administered Every 12 Weeks, to That of the Zoladex 3.6-mg Depot, Administered Every 4 Weeks, in Patients with Advanced Prostate Cancer

A new longer-acting depot formulation containing 10.8 mg Zoladex administered every 12 weeks was compared to the 3.6-mg Zoladex depot administered every 28 days, in a randomised trial in patients with advanced prostatic carcinoma in which pharmacodynamic efficacy and safety were assessed. Effective induction of mean serum testosterone suppression into the surgically castrate range by 21 days and maintenance of suppression for the duration of therapy was achieved with both the 3.6-mg and the 10.8-mg depot formulations. The Zoladex 10.8-mg depot was well tolerated both locally and systemically. This new formulation which is equivalent to three successive 3.6-mg depots will provide a more convenient dosing regime for both patient and doctor in this indication.

Endocrinology: Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study

One-hundred women undergoing ovarian stimulation with gonadotrophin-releasing hormone agonist (GnRH-a) and a human menopausal gonadotrophin (HMG) for in-vitro fertilization (IVF) participated in this randomized comparative study. The effectiveness of long-acting s.c. goserelin (Zoladex depot; 49 patients) and intranasally (i.n.) administered buserelin acetate (Suprefact; 51 patients) for pituitary down-regulation was compared. Treatment with s.c. goserelin (3.6 mg) or i.n. buserelin acetate (200 micrograms; 6 times/day) was started on day 21-23 of the cycle. Stimulation with 150 IU of HMG/day was started after at least 11 days of GnRH-a treatment. There were no differences in the time required for follicular development nor in the clinical outcome between groups treated with either goserelin or buserelin. The number of oocytes recovered in the goserelin group was 6.7 +/- 5.0 versus 6.3 +/- 4.9 in the buserelin group. There were 11 pregnancies after the use of goserelin (22.4%) and 12 pregnancies in those given buserelin (24.0%). The number of HMG ampoules needed for follicular maturation was higher in the goserelin group (27.9 +/- 7.8) than in the buserelin group (24.6 +/- 7.8, P < 0.05). The patients given buserelin suffered significantly more from tiredness, depression, headache and abdominal pain than those receiving goserelin, whereas there were no differences between the groups in experiencing mental irritability, nausea and swelling. Subcutaneous goserelin depot injection offers a useful alternative for pituitary down-regulation in IVF stimulation.

Goserelin (Zoladex ) depot in the treatment of endometriosis

To evaluate the safety and efficacy of Goserelin (Zoladex depot; ICI Pharmaceuticals, Macclesfield, Cheshire, United Kingdom) in the treatment of endometriosis. Open study. Eleven centers in Germany and 1 center in Austria. One hundred forty-six patients with pelvic endometriosis. Goserelin (Zoladex depot) therapy, one depot (3.6 mg) subcutaneously every 4 weeks for 6 months. Total subjective score and total pelvic symptom score showed a reduction by 86% and 93%, respectively, at the end of the treatment and did not exceed one fifth of the pretreatment value throughout the follow-up period of 48 weeks. One hundred seven women underwent a second laparoscopy at the end of the therapy for determination of objective efficacy: 54% of the patients showed a reduction of implants and adhesions by at least 50% or more, and 31.5% had a complete resolution of visible deposits. The mean reduction of implants and adhesions was 50%, and the mean reduction of implants 72%. Twenty of 64 (31.3%) previously infertile patients successfully conceived within 12 months after discontinuation of the therapy. Goserelin led to a down regulation of the pituitary ovarian axis and as a pharmacological effect of this hypoestrogenism most patients had hot flushes and vaginal dryness. Zoladex depot therapy proved to be safe and effective in the medical treatment of endometriosis.

Intrauterine pregnancy with uterine myoma after downregulation with GnRH analogs

GnRH analogues are widely used for the reduction of uterine fibroids. This case report describes the therapy of a 27-year-old woman, whose uterus had a diameter of about 13 cm. After 7 injections of Zoladex Depot (ICI Pharma, Heidelberg, Germany), the uterus was reduced to normal size carrying dorsally a myoma of the same size. After only 7 weeks of medroxyprogesterone acetate (5 mg twice daily, Clinofem, Upjohn, Heppenheim, Germany) the uterus had grown again, so that therapy was changed to Zoladex Depot for another 3 months. On the 27th day of the first spontaneous cycle, the patient ovulated and conceived. Up to the 29th week of gestation (Aug '91), the foetal growth and development was normal, the uterus was normal in size, a childhead sized myoma being situated unproblematically behind the foetus.

Influence of luteinizing hormone-releasing hormone agonists on human mammary carcinoma cell lines and their xenografts

The specific binding of luteinizing hormone-releasing hormone (LH-RH) agonist in estradiol-dependent MCF-7 and estradiol-independent MDA-MB-231 human breast cancer cells has been studied using [ 3H]Ovurelin [ d- 3H-Phe 6),des-Gly 10-LH-RH-ethylamide]. The results of Scatchard analyses suggest the presence of a single class of receptor sites, both in cell suspensions and membrane fractions. Evaluation of these peptide receptors appears to reflect additional characteristics of biological behaviour of these human breast cancer cells. The synthetic LH-RH agonist Ovurelin [( d-Phe 6),des-Gly 10-LH-RH-ethylamide] can directly interfere (25–30%) with the proliferation of MDA-MB-231 human breast cancer cells in culture. The inhibitory effect of Ovurelin in vitro was negligible in the MCF-7 cell line. In the in vivo experiments the treated immunosuppressed mice bearing either MCF-7 or MDA-MB-231 xenografts responded to the high-dose LH-RH analogue Zoladex depot and Decapeptyl depot therapy. Since the MDA-MB-231 tumour was found to be ER-negative it seems possible that the regression of this xenograft results from the direct antitumour action of the LH-RH agonist.

Zoladex and Flutamide Versus Bilateral Orchiectomy

A total of 327 patients with metastatic prostatic cancer were randomized to either bilateral orchiectomy or treatment with zoladex depot supplemented by flutamide 250 mg 3 qid. Statistically significant increases in time to subjective and objective progression were recorded in favor of the combination treatment. No differences in time to death by cancer or overall death were recorded. The clinical significance of these differences will be reassessed once additional follow‐up is available and further analysis of the overall clinical material has been carried out. Cancer 66:1045–1057, 1990.

Zoladex vs. Zoladex Plus Cyproterone Acetate in the Treatment of Advanced Prostatic Cancer: A Multicenter Italian Study

A collaborative multicenter trial was conducted by 17 Italian groups to verify whether the so-called total androgen blockade obtained with luteinizing hormone releasing hormone (LHRH) analogs combined with antiandrogens is more effective than conventional monotherapy in the treatment of advanced prostatic cancer. A total of 328 previously untreated patients were evaluated: 163 patients received Zoladex depot alone, 3.6 mg subcutaneously every 28 days, and 165 patients received Zoladex depot plus cyproterone acetate (CPA), 200 mg/day orally. The follow-up period ranged from 41-251 weeks. Treatment was well tolerated, and side-effects in both groups mainly comprised loss of libido and erections, hot flashes and breast swelling and tenderness. There was no significant difference in objective response after 6, 12 and 24 months of treatment between the 2 groups. Median time to disease progression was comparable in both groups: 55 weeks in the Zoladex group and 54 weeks in the Zoladex plus CPA group. The time to disease progression and the survival distribution was comparable in both groups. Although there were no significant differences in the overall subjective response to both treatments, a faster improvement, with respect to pain and performance status was noted in the Zoladex plus CPA group (8 weeks) compared to Zoladex alone (12 weeks). The addition of antiandrogen, by inhibiting the initial elevation of plasma testosterone, may prevent the disease flare-up which occurs in a small number of patients during the first few days of treatment with LHRH analogs alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Goserelin, a depot gonadotrophin-releasing hormone agonist in the treatment of premenopausal patients with metastatic breast cancer. German Zoladex Trial Group.

One hundred thirty-four pre- and perimenopausal patients presenting with metastatic breast cancer (median age, 42 years; range, 25 to 55) were treated with goserelin (Zoladex [ICI 118 630]; ICI Pharma, Plankstadt, Germany) a long-acting gonadotrophin-releasing hormone (GnRH)-analogue depot formulation, injected subcutaneously every 4 weeks, as a first-line therapy. One hundred eighteen patients were evaluable for response. Serum concentrations of estradiol, luteinizing hormones (LH), and follicle-stimulating hormones were significantly suppressed by Zoladex. Mean serum estradiol values fell into the range of castrated or postmenopausal women within 2 to 3 weeks of therapy. This suppression was maintained for the duration of therapy. Overall objective response was: 12 (10.2%) complete remission; 41 (34.7%) partial remission; 33 (28.0%) no change; and 32 (27.1%) progression. In responders, the median time to response was 4 months (range, 2 to 11 months), median duration of response was 8 + months (range 2 to 24 months), and median time to progression was 11 + months (range, 5 to 30 months). Objective responses were seen for different sites of metastases: loco-regional (62.5%), bone (46.7%), visceral (45.0%), and multiple (35.1%). Tumor remission was more common in patients in which the primary tumor was estrogen receptor (ER)-positive (49.3%) or ER-unknown (44.0%), but appreciable response rates were also observed in ER-poor patients (33.3%). Zoladex depot was well tolerated both locally and systemically. It produced effective castration and the objective response rates and duration of remission are at least comparable to those seen following oophorectomy; however, the side effects are less. The use of depot Zoladex avoids the psychological trauma and operative morbidity of the irreversible operative castration.

A Multi-Centre Randomised Study to Compare the Effects of Ovarian Ablation with Zoladex Depot in Pre- and Perimenopausal Patients with Advanced Breast Cancer

The aim of a trial that will determine and compare the efficacy and safety of ovarian ablation (either surgical oophorectomy or irradiation) with depot Zoladex in the treatment of pre- and perimenopausal patients with advanced breast cancer is discussed.

Zoladex in the Treatment of Premenopausal Metastatic Breast Cancer Patients

In an open phase II, multicentre study with 118 pre- or perimenopausal women with histologically proven advanced breast cancer, Zoladex depot (3.6 mg) has been shown to produce an effective castration and response rates, which are comparable to those from oophorectomy.

Modification of symptoms of the premenstrual syndrome during ovarian suppression with goserelin (Zoladex) depot – potential for research and clinical investigation

Eleven women with premenstrual problems were treated in an open study for up to 6 months with goserelin (Zoladex) 3.6mg by monthly subcutaneous depot. Twice weekly assay of urinary estronc glucuronide and pregnanediol demonstrated absence of ovulation and suppression of estrogen excretion to within or below the early follicular phase range. Physical and psychological symptoms, measured by daily self assessment, were significantly improved during therapy. However, some subjects continued to record intermittent episodes of swelling and adverse mood in the absence of changes in ovarian activity. Three women reported marked but transient worsening of anxiety and/or depression soon after the onset of ovarian suppression, one later withdrawing from the study. Return of ovulatory menstruation was preceded by recurrence of symptoms at pretreatment levels, although breast discomfort which was consistently improved during therapy showed a more sustained improvement. Although conclusions are limited by the lack of a...

Simultaneous administration of a luteinizing hormone releasing hormone agonist and diethylstilbestrol in the initial treatment of prostatic cancer.

It is well known that the first administration of luteinizing hormone releasing hormone (LH-RH) analogues induces an initial increase of luteinizing hormone (LH) release and a subsequent rise in testosterone (T). This rise is maximal after 3-4 days and is followed by a steady fall of LH and T. Several investigators have reported flare-up symptoms in patients with advanced prostatic cancer, associated with the rise of T, when treated by LH-RH analogue alone. In order to prevent these flare-up symptoms, we treated 20 patients with advanced prostatic cancer with an association of a LH-RH analogue (Zoladex Depot) and diethylstilbestrol (DES) 1 mg/day. DES was given for 14 days, starting 7 days before the first Zoladex Depot injection. T fell to near castrate levels within a few days, but rose again 3-4 days after the administration of the LH-RH analogue to pretreatment values before returning to castrate levels. No clinical flare-up manifestations were recorded. We conclude that combination treatment with DES can prevent the flare-up symptoms induced by LH-RH analogue in patients with prostatic cancer.

Endocrinologic and clinical evaluation following a single administration of a gonadotrophin-releasing hormone agonist (Zoladex ), in a depot formulation, to premenopausal women

A single 3.6-mg Zoladex subcutaneous depot injection was effective in suppressing the pituitary-ovarian function for about 5 weeks in nine regularly menstruating, premenopausal volunteers. Menses returned approximately 9 weeks after the injection. Zoladex depot is a novel approach in the administration of GnRH agonists and offers great therapeutic potential.

Phase II study of Zoladex depot in advanced prostatic cancer with special reference to criteria of response and survival.

Zoladex is a potent decapeptide analogue of luteinising hormone releasing hormone (LHRH). The drug is formulated as a 3.6 mg depot dispersed in a matrix of d,l-lactide-glycolide copolymer, which is totally biodegradable. This formula releases drug continuously for at least 28 days and reliably suppresses serum testosterone into the castrate range. The effect of the depot was studied in 29 patients with locally advanced or metastatic carcinoma of the prostate. Average age at entry was 71 years (range 52-87) and follow-up was from 13.5 to 34.5 months (median 23). Endocrine studies showed that medical castration was maintained in all cases. Three patients experienced bone pain in the first month of treatment and two others had temporary nephrostomies for worsening ureteric obstruction. Subjective improvement was seen in 23/28 cases (82%). There were no complete responses, but partial response was seen in 24/28 (85.7%) using our own criteria, 24/28 (85.7%) using the criteria recommended by the British Prostate Group (BPG) and 15/28 (53.6%) using NPCP criteria. Stable disease was seen in 3/28 patients (10.7%) by our own or BPG criteria, and in 12/28 patients (42.9%) according to NPCP criteria. Progression of disease was measurable in 21 patients (72.4%) whatever criteria were applied; 11/29 (37.9%) have died, giving a median survival of 10 months (range 2.4-26). Following these encouraging results, a multicentre randomised comparative study with stilboestrol 3 mg daily is being undertaken.

LH-RH agonist, zoladex (goserelin) depot formulation in the treatment of prostatic cancer. Randomized dise-finding trial in Japan

LH-RH agonist, zoladex (goserelin) depot formulation in the treatment of prostatic cancer. Randomized dise-finding trial in Japan

Shrinkage of uterine fibroids during therapy with goserelin (Zoladex ): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot

Thirteen premenopausal women with uterine fibroids were treated for a maximum of 6 months with a long-acting agonist of luteinizing hormone-releasing hormone (LH-RH), goserelin (Zoladex depot, ICI Pharmaceuticals, Macclesfield, UK) 3.6 mg, administered subcutaneously every 28 days. A 55% reduction (range, 38% to 84%) in uterine volume assessed by ultrasound was obtained. The greatest reduction (30%) was apparent within the first treatment cycle regardless of whether treatment was started in the early follicular or the luteal phase. Fibroid regression was inversely correlated with urinary estrogen concentration. Treatment was well tolerated and only one subject withdrew from the study before its scheduled completion. Following cessation of therapy, ovulatory menstruation returned within 3 months in the majority of the subjects, but this was accompanied by a rapid regrowth of the fibroids. This medical approach to the management of fibroids merits further investigation but as yet cannot be regarded as an alternative to surgery.

Suppression of ovarian activity by Zoladex depot (ICI 118630), a long-acting luteinizing hormone releasing hormone agonist analogue.

A long-acting LHRH agonist, Zoladex depot 3.6 mg, was administered as a monthly s.c. injection to seven premenopausal volunteers for a maximum of 6 months, starting in the luteal phase of the cycle. Transient stimulation of gonadotrophin release was observed 24 h after the initial depot, followed by sustained suppression of plasma LH, while FSH levels returned to the normal range. Plasma oestradiol concentrations fell to early follicular phase values within 14 d. Twice-weekly monitoring of urinary oestrone-3-glucuronide and pregnanediol demonstrated inhibition of ovulation and almost complete suppression of ovarian follicular activity throughout therapy. All the subjects became amenorrhoeic. Mean plasma testosterone concentrations were also significantly reduced while androstenedione remained within the pretreatment range. SHBG concentrations were not significantly reduced. After cessation of therapy, postovulatory menstruation occurred within 80 d of administration of the last depot.

LHRH agonist ICI 118.630 (Zoladex depot) (Z) versus Z plus Cyproterone Acetate (CPA) in advanced prostatic cancer. Preliminary report

LHRH agonist ICI 118.630 (Zoladex depot) (Z) versus Z plus Cyproterone Acetate (CPA) in advanced prostatic cancer. Preliminary report

Treatment of hormone-responsive rat mammary and prostate tumours with zoladex depot

Treatment of hormone-responsive rat mammary and prostate tumours with zoladex depot