Goserelin/PLGA solid dispersion used to prepare long-acting microspheres with reduced initial release and reduced fluctuation of drug serum concentration in vivo.

To prepare Goserelin (GOS) loaded long-acting microspheres with reduced initial release and prolonged drug release time of GOS, GOS/PLGA solid dispersion (by hot-melt extrusion, HME) was dissolved/dispersed in dichloromethane (DCM) to prepare microspheres by O/W method. From results of molecular dynamics simulation, PLGA and GOS molecules completely and uniformly dissolved and dispersed in DCM, respectively. In F5 microspheres (prepared by HME-O/W method), GOS existed as molecular or amorphous state, but not aggregation. Burst release of F5 microspheres (2.75%) was similar with Zoladex™ implant (0.39%) and less than F10 microspheres (prepared by S/O/W method, 25.92%). After lag phase, GOS released rapidly from F5 microspheres and the cumulative release on the 45th days was 95.14%. After injection of F5 microspheres, GOS serum concentration was relative steady at the range of 27.64-175.27 ng/mL for nearly 35 days. AUC(0-35 day) of F5 microspheres was almost 2 times that of F10 microspheres. Pharmacodynamics study also showed potential effect of F5 microspheres on inhibiting the secretion of testosterone in male rats. HME-O/W method is potential to establish long-acting PLGA microspheres (loading water-soluble drug), exhibiting stable drug serum concentration in vivo, and without large concentration fluctuation or serious pain/side effects.

Goserelin Acetate Loaded Poloxamer Hydrogel in PLGA Microspheres: Core-Shell Di-Depot Intramuscular Sustained Release Delivery System.

This study aimed to prepare and optimize goserelin acetate (GOS) loaded hydrogel poly(d,l-lactic acid-co-glycolic acid) (PLGA) microsphere that is suitable for long-acting clinical treatment, investigate its structure, and regulate the initial release manner. Here, the PLGA microsphere containing Poloxamer hydrogel loaded with ∼15% (w/w) GOS was prepared by double-emulsion-solvent evaporation method and evaluated in terms of microscopic structure, physicochemical properties, and release manner in vitro and in vivo. Raman volume imaging and scanning electron microscopy studies revealed a core-shell Di-Depot structure of the microsphere, in which multi-GOS-loaded hydrogel depots were distributed in the core region. Under the interaction of hydrogel and PLGA depots, high encapsulation efficiency (94.16%) and low burst release (less than 2%) were achieved, along with the accompanying prolonged administration interval (49 days); an enhanced relative bioavailability 9.36-fold higher than that of Zoladex implant was also observed. Also, by addition of 1-5% acetic acid, the lag time was shortened to 6 days. The strategy for regulating the initial release provides new insights for manipulating the release behavior of the PLGA microspheres. The desirable property of the Poloxamer hydrogel PLGA microsphere indicated its promising application in controlled release drug delivery system.

Transdermal Delivery of Luteinizing Hormone-releasing Hormone with Chitosan Microneedles: A Promising Tool for Androgen Deprivation Therapy.

Long-term administration of luteinizing hormone-releasing hormone analogs (LHRHa) is the main type of androgen-deprivation therapy (ADT) for lethal prostate cancer. A fully insertable microneedle system, composed of embeddable chitosan microneedles and a dissolvable polyvinyl alcohol/polyvinyl pyrrolidone supporting array, was developed for sustained delivery of LHRHa to the skin. A porcine cadaver skin test showed that chitosan microneedles can be fully embedded within the skin and microneedle-created micropores reseal within 7 days. The measured LHRHa loading amount was 73.3±2.8 µg per microneedle patch. After applying goserelin-containing microneedles to mice, serum LH levels increased initially and then declined below baseline at day 7. In contrast, serum testosterone levels increased to reach a peak at day 14 and then declined to a castration level at day 21. Additionally, such a castration level was maintained for 2 weeks. Therefore, transdermal delivery of goserelin with embeddable chitosan microneedles can produce a castrated state in mice. Such a system is a promising, feasible means of delivering ADT.

Phase 3, open-label, randomized study comparing 3-monthly with monthly goserelin in pre-menopausal women with estrogen receptor-positive advanced breast cancer.

BACKGROUND: Monthly goserelin 3.6 mg dosing suppresses estradiol (E2) production and has proven efficacy in pre-menopausal women with estrogen receptor (ER)-positive breast cancer. This non-inferiority study evaluated the efficacy and safety of 3-monthly goserelin 10.8 mg compared with monthly goserelin 3.6 mg. METHODS: This was a Phase 3, open-label, multicenter trial. Pre-menopausal women with ER-positive advanced breast cancer were randomized to 3-monthly goserelin 10.8 mg or monthly goserelin 3.6 mg; all patients received concomitant tamoxifen (20 mg daily). The primary endpoint was progression-free survival (PFS) rate at 24 weeks; non-inferiority was to be confirmed if the entire 95 % confidence interval (CI) for the treatment difference was above -17.5 %. Secondary endpoints included objective response rate (ORR), serum E2 levels, safety, and tolerability. RESULTS: In total, 222 patients were randomized (goserelin 10.8 mg, n = 109; goserelin 3.6 mg, n = 113). PFS rate at week 24 was 61.5 % (goserelin 10.8 mg) and 60.2 % (goserelin 3.6 mg); treatment difference (95 % CI) was 1.3 % (-11.4, 13.9), confirming non-inferiority of goserelin 10.8 mg compared with goserelin 3.6 mg. ORR was 23.9 % (goserelin 10.8 mg) and 26.9 % (goserelin 3.6 mg); treatment difference (95 % CI) was -3.0 % (-15.5, 9.7). At week 24, mean serum E2 concentrations were similar in the goserelin 10.8 mg and goserelin 3.6 mg groups (20.3 pg/mL and 24.8 pg/mL, respectively). CONCLUSION: A regimen of 3-monthly goserelin 10.8 mg demonstrated non-inferiority compared with monthly goserelin 3.6 mg for PFS rate at 24 weeks, with similar pharmacodynamic and safety profiles, in pre-menopausal women with ER-positive breast cancer.

Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo.

We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell the possibility of eventual clinical translation of this approach. FROM THE CLINICAL EDITOR: The ability of gold nanoparticles (AuNPs) to enhance the effect of physical radiation dose on tumor cells is known. This radiosensitization effect is thought to result from an increased number of photoelectric absorption events and the increased number of electrons present in gold. The authors here sought to further increase the amount and specificity of gold accumulation in prostatic cancer cells by conjugating gold nanorods to goserelin, a synthetic luteinizing hormone releasing hormone (LHRH) analogue that would bind to the LHRH receptor overexpressed in prostate cancers. It was shown that tumour cells were more sensitive to megavoltage radiation therapy. It is hoped that there would be eventual clinical translation of this approach.

An LC-MS/MS method for the simultaneous determination of goserelin and testosterone in rat plasma for pharmacokinetic and pharmacodynamic studies.

A liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed, using testosterone-d3 as a surrogate analyte, for the simultaneous quantification of goserelin and testosterone in rat plasma. According to this method, the pharmacokinetic and pharmacodynamic data were obtained from a single plasma sample aliquot. The method involved the addition of alarelin as an internal standard (IS) for goserelin and testosterone-(13)C3 for testosterone or testosterone-d3. The conditions for the separation of these two compounds were achieved on a ZORBAX Eclipse Plus C18 column (Agilent, 2.1 × 50 mm, 1.8 µm, Stockport, UK) in a single chromatographic run at a flow rate of 400 µL/min. In order to minimize interferences of complex matrix, the extraction of plasma consisted of a protein precipitation step using methanol, followed by purification using an Oasis(®) HLB solid-phase extraction column. The method was validated in the concentration range of 0.01-30.0 ng/mL for goserelin and 0.05-30.0 ng/mL for testosterone-d3, respectively. The within- and between-run precisions were 1.7-9.2% and 2.1-6.9%, respectively. The within- and between-run accuracies were -1.8 to 5.3% and -4.9 to 4.0%, respectively. This accurate and highly specific assay provides a useful method to evaluate the pharmacokinetics and pharmacodynamics of goserelin in rats.

Monthly versus 3-monthly goserelin acetate treatment in pre-menopausal patients with estrogen receptor-positive early breast cancer.

This study compared the efficacy and safety of a 3-monthly 10.8-mg depot goserelin (Zoladex(TM)) injection with the current 3.6 mg monthly dose in pre-menopausal Japanese women with estrogen receptor-positive (ER+) early breast cancer. This was a multicenter, open-label, randomized study. Primary endpoint was a non-inferiority analysis (10.8/3.6 mg) of the area under the concentration-time curve (AUC) of estradiol (E(2)) over the first 24 weeks. Secondary endpoints included E(2) and follicle-stimulating hormone (FSH) concentrations, menstruation, and safety and tolerability. In total, 170 patients were randomized to receive goserelin 10.8 mg every 3 months (n = 86) or 3.6 mg every month (n = 84). Mean AUCs for E(2) were similar between treatment groups (18.32 and 18.95 pg/ml·week for goserelin 10.8 and 3.6 mg, respectively). AUC ratio was 0.974 (95% confidence interval, 0.80, 1.19), indicating non-inferiority for goserelin 10.8 mg. Serum E(2) and FSH remained suppressed throughout the study and no patient experienced menses after week 16. No clinically important differences in safety and tolerability were observed between the two groups. In terms of E(2) suppression, 3-monthly goserelin 10.8 mg was non-inferior to monthly goserelin 3.6 mg in pre-menopausal women with ER+ breast cancer.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of goserelin in rabbit plasma.

A rapid and sensitive liquid chromatography-electrospray ionization tandem mass spectrometry method (LC-ESI-MS/MS) was developed and validated for the determination of goserelin in rabbit plasma. Various parameters affecting plasma sample preparation, LC separation, and MS/MS detection were investigated, and optimized conditions were identified. Acidified plasma samples were applied to Oasis((R)) HLB solid-phase extraction (SPE) cartridges. Extracted samples were evaporated under a stream of nitrogen and then reconstituted with 100microL mobile phase A. The separation was achieved on a Capcell-Pak C18 (2.0mmx150mm, 5microm, AQ type) column with a gradient elution of solvent A (0.05% acetic acid in deionized water/acetonitrile=85/15; v/v) and solvent B (acetonitrile) at a flow rate of 250microL/min. The LC-MS/MS system was equipped with an electrospray ion source operating in positive ion mode. Multiple-reaction monitoring (MRM) of the precursor-product ion transitions consisted of m/z 635.7-->m/z 607.5 for goserelin and m/z 424.0-->m/z 292.1 for cephapirin (internal standard). The proposed method was validated by assessing specificity, linearity, limit of quantification (LOQ), intra- and inter-day precision and accuracy, recovery, and stability. Linear calibration curves were obtained in the concentration range of 0.1-20ng/mL (the correlation coefficients were above 0.99). The LOQ of the method was 0.1ng/mL. Results obtained from the validation study of goserelin showed good accuracy and precision at concentrations of 0.1, 1, 5, 10, and 20ng/mL. The validated method was successfully applied to a pharmacokinetic study of goserelin after a single subcutaneous injection of 3.6mg of goserelin in healthy white rabbits.

Effect of medical castration on CYP3A4 enzyme activity using the erythromycin breath test.

PURPOSE: Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported. METHODS: Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone. RESULTS: All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (<50 ng/dl). There was no statistically significant change in CYP3A4 activity using the EBT method (p = 0.88). The extent and direction of changes in CYP3A4 activity was highly variable, with three subjects experiencing an increase in activity, and five demonstrating a decrease in activity. CONCLUSION: There is no clinically significant change in CYP3A4 activity after medical castration. No changes in the clearance of docetaxel or other CYP3A4 substrates are likely during and after medical castration. Although similar findings are expected after orchiectomy, we were not able to test this presumption because of patient preference for medical castration.

Goserelin acetate in combination with radiotherapy for prostate cancer.

Improvements in longer-term survival rates have been demonstrated for locally advanced prostate cancer patients treated with adjuvant androgen deprivation therapy (ADT), and in subsets of men with clinically localized disease treated with ADT combined with external-beam radiotherapy (RT). In these studies, ADT was administered in the form of surgery (orchiectomy) or with a class of drugs called luteinizing hormone-releasing hormone agonists. Goserelin acetate is a member of this class, and 10 of 11 major Phase III trials demonstrating better outcomes with ADT and RT used goserelin acetate. The reduction in deaths from prostate cancer noted in the mid-1990s may largely be due to the early use of these agents in men with intermediate-to-high-risk disease.

Efecto de tibolona en el mioma uterino en pacientes tratadas con análogos de la hormona liberadora de gonadotropinas / Effect of tibolone on uterine fibroids in patients treated with gonadotropin-releasing hormone analogues

Objetivos: Evaluar la eficacia de tibolona, una molécula sintética con acción hormonal como terapia hormonal complementaria en la miomatosis uterina. Tibolona se ha mostrado eficaz en el tratamiento hormonal sustitutivo en la menopausia. Su débil acción estrogénica no debe modificar los efectos conseguidos en el útero miomatoso tras la administración de agonistas de la hormona liberadora de gonadotropinas, manteniendo la reducción del volumen uterino inducido por ellos. Material y métodos: Un total de 125 pacientes en edad fértil o premenopáusicas, con ciclos menstruales regulares, diagnosticadas de miomatosis uterina y candidatas a tratamiento quirúrgico, fueron incluidas en un estudio prospectivo y aleatorizado, en el que se ensayaron 5 protocolos terapéuticos previos a la cirugía: grupo 1 o grupo control, 3 viales de acetato de goserelina depot, 3,6 mg; grupo 2, 3 dosis de acetato de goserelina depot, asociada a tibolona (2,5 mg diarios) desde el primer vial de goserelina hasta la intervención quirúrgica; grupo 3, 3 dosis de acetato de goserelina depot, asociada a tibolona desde el segundo vial de goserelina hasta la intervención quirúrgica; grupo 4, 2 dosis de acetato de goserelina depot asociada a tibolona desde el segundo vial de goserelina hasta la intervención quirúrgica, y grupo 5, 3 dosis de acetato de goserelina depot asociada a estrógenos conjugados equinos, 0,625 mg, desde el segundo vial de goserelina hasta la intervención quirúrgica. Se evaluó ecográficamente la modificación del tamaño uterino y de los valores séricos de gonadotropinas y estradiol con los diferentes protocolos de tratamiento. Las diferencias se consideraron estadísticamente significativas para un valor de p < 0,05. Resultados: Las reducciones medias del volumen uterino (%) fueron mayores en los 3 primeros grupos de tratamiento (­30,1 ± 16,7; ­26,4 ± 21,2; ­25,1 ± 22,5; ­15,6 ± 23 y ­5,5 ± 15,1, respectivamente), con diferencias estadísticamente significativas respecto a este parámetro al comparar cada grupo con el grupo control (grupo 1). Las concentraciones medias de estradiol sérico (pg/ml) fueron, asimismo, inferiores en los 3 primeros grupos (26,2 ± 11,2; 45,7 ± 49,1; 35,9 ± 20,3; 97,9 ± 110,3; 111,4 ± 63,2, respectivamente) y estas diferencias fueron significativas. Conclusiones: La terapia hormonal complementaria con tibolona influye mínimamente en la disminución del tamaño del útero miomatoso promovido por 3 dosis de goserelina depot

Objectives: To evaluate de effectiveness of tibolone, a synthetic steroid, as add-back therapy in patients diagnosed with leiomyoma. Tibolone has been demonstrated to be effective in inhibiting menopausal symptoms and in preventing post-menopausal bone loss. Its low estrogenic profile should not compromise the efficacy of gonadotropin-releasing hormone analogue (goserelin) in reducing the volume of uterine fibroids. Material and methods: A group of 125 pre-menopausal women (with regular menstrual cycle) diagnosed with uterine leiomyomata suitable for surgical treatment were recruited in a randomized, prospective study that evaluated 5 treatment regimens: group 1 (control group), three doses of goserelin acetate depot (3.6 mg); group 2, 3 doses of goserelin acetate depot associated with tibolone (2.5 mg daily) from the first dose of goserelin until surgery; group 3, 3 doses of goserelin acetate depot associated with tibolone from the second dose of goserelin until surgery; group 4, 2 doses of goserelin acetate depot associated with tibolone from the second dose of goserelin until surgery, and group 5, 3 doses of goserelin acetate depot associated with conjugated equine estrogens (0.625 mg daily) from the second dose of goserelin until surgery. Modification of uterine size was evaluated with ultrasound examination and serum levels of gonadotrophins and estradiol were evaluated with the different treatment protocols. Differences were considered significant when p < 0.05. Results: The mean reductions in uterine volume (%) were greater in the first 3 treatment groups (­30.1 ± 16.7; ­26.4 ± 21.2; ­25.1 ± 22.5; ­15.6 ± 23 y ­5.5 ± 15.1, respectively) and the differences were statistically significant when each group was compared with the control group (group 1). The mean concentrations of serum estradiol (pg/ml) were also significantly lower in the first 3 groups (26.2 ± 11.2; 45.7 ± 49.1; 35.9 ± 20.3; 97.9 ± 110.3; 111.4 ± 63.2, respectively). Conclusions: Add-back tibolone therapy does not significantly compromise the effect of goserelin acetate in patients with uterine fibroids

Use of goserelin in the treatment of breast cancer.

Gonadotropin-releasing hormone analogs are, alongside tamoxifen, one of the most commonly used drugs in the treatment of pre-/perimenopausal endocrine-responsive breast cancer. Goserelin, as a principal agent of this class of drugs, is mainly investigated in clinical trials. The indirect comparison of goserelin with tamoxifen as a single drug in the adjuvant setting showed similar efficacy. Furthermore, goserelin is as effective as cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, and total endocrine blockade as a combination of gonadotropin-releasing hormone analog and tamoxifen showed a comparable benefit with anthracycline-containing adjuvant chemotherapy. Goserelin administered after cessation of chemotherapy leads to a further improvement and may be equieffective as tamoxifen or a combination of both. Data concerning taxane-based and dose-dense chemotherapy as well as combination of gonadotropin-releasing hormone analogs with third-generation aromatase inhibitors are still lacking (ongoing suppression of ovarian function, tamoxifen and exemestane, and premenopausal endocrine-responsive chemotherapy trials). Moreover, duration of therapy with gonadotropin-releasing hormone analogs (2-3 years or longer) is still a matter of debate. Palliative endocrine treatment is standard in the first-line therapy of patients without life-threatening disease and endocrine-responsive breast cancer. Treatment decisions depend upon adjuvant endocrine pretreatment. Clinical data regarding ovarian protection by synchronous use of gonadotropin-releasing hormone in young breast cancer patients receiving chemotherapy are incoherent.

Goserelin: a review of its use in the treatment of early breast cancer in premenopausal and perimenopausal women.

Goserelin (Zoladex), a gonadotropin-releasing hormone analogue, reduces plasma/serum estrogen levels in pre- or perimenopausal women (to postmenopausal levels), and is indicated in hormone receptor-positive early breast cancer in this population group. Adjuvant goserelin monotherapy has similar efficacy to adjuvant chemotherapy in pre- or perimenopausal women with early, hormone receptor-positive breast cancer. Furthermore, the addition of goserelin to adjuvant chemotherapy appeared to offer an advantage over chemotherapy alone in younger patients. Fewer patients remained amenorrheic after goserelin therapy than after chemotherapy. Complete endocrine blockade provided by the addition of tamoxifen to therapy including goserelin appears to improve outcomes. Thus, goserelin offers a valuable addition to the currently available options for treating pre- or perimenopausal women with hormone therapy-responsive early breast cancer, particularly for women wishing to regain ovarian function after treatment.

[Clinical effects of a 3-month formulation LH-RH agonist (Zoladex LA 10.8 mg depot) in patients with prostate cancer].

Pharmacodynamics (PD), anti-tumor effects, safety and pharmacokinetics of a 3-month formulation of goserelin (Zoladex LA 10.8 mg depot: "10.8 mg depot") were investigated in a collaborative multicenter study. Study participants were 40 Japanese patients with prostate cancer comprising 20 untreated patients and 20 switch patients who had been receiving Zoladex 3.6 mg depot for 3 months or longer. Serum testosterone levels, serum LH levels, prostate-specific antigen (PSA) levels and drug concentrations were measured until 12 weeks after a single subcutaneous dose of 10.8 mg depot. Anti-tumor effects were evaluated by means of changes in the tumor lesions and the PSA levels at 12 weeks. After administration to the untreated patients, 10.8 mg depot reduced serum testosterone to the castrate range within 4 weeks and the reduction was maintained for up to 12 weeks. In the switch patients, serum testosterone suppression that had been produced by previous treatment with Zoladex 3.6 mg depot was maintained for up to 12 weeks following 10.8 mg depot administration. The anti-tumor effect at 12 weeks was 90.0% including partial response cases. The ratio of PSA normalization at 12 weeks was 75.0%. Fifty-seven adverse reactions were observed in 27 of the 40 patients (67.5%), but none were clinically significant. Although a disease flare presented as urinary retention in 1 of the untreated patients, all patients completed the study. Serum goserelin was detected up to 12 weeks after the administration of 10.8 mg depot. In conclusion a single dose of 10.8 mg depot showed a satisfactory PD-effect and brought about clinical efficacy persisting for at least 12 weeks and was well tolerated in patients with prostate cancer.

Clinical pharmacokinetics of goserelin.

Goserelin is a synthetic decapeptide analogue of luteinising hormone-releasing hormone (LHRH). For experimental purposes it has been administered subcutaneously as an aqueous solution, but for therapeutic use it is formulated as subcutaneous depots releasing goserelin over periods of 1 (3.6 mg) or 3 (10.8 mg) months. Pharmacokinetic data have been generated using a specific radioimmunoassay. When administered as a solution, goserelin is rapidly absorbed and eliminated from serum with a mean elimination half-life (t1/2beta) of 4.2 hours in males and 2.3 hours in females. The shapes of the observed serum goserelin profiles following administration of the depots are primarily determined by the rate of goserelin release from the biodegradable lactide-glycolide copolymer matrix over periods of 1 or 3 months. There is no clinically relevant accumulation of goserelin during multiple administration of these depots. Goserelin is extensively metabolised prior to excretion. Its pharmacokinetics are unaffected by hepatic impairment, but the mean t1/2beta increases to 12.1 hours in patients with severe renal impairment. This suggests that the total renal clearance (renal metabolism and unchanged drug) is decreased in patients with renal dysfunction. It is unnecessary to adjust the dose or administration interval when the depot formulations are administered to elderly patients or to those with impaired renal or hepatic function. Administration of a goserelin 3.6 mg or 10.8 mg depot results in an initial increase of luteinising hormone (LH) levels and in increases of serum testosterone or oestradiol levels in males and females, respectively. This is followed by a decrease in serum LH levels and suppression of testosterone or oestradiol to within the castrate or menopausal range, respectively. Subsequently, throughout treatment with goserelin depots, serum testosterone or oestradiol levels remain suppressed. Clinical outcomes following treatment of patients with prostate cancer, breast cancer and benign gynaecological conditions with goserelin are described briefly.

Goserelin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in benign gynaecological disorders.

Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which, during continuous administration, down-regulates the pituitary-ovarian gonadal axis and reduces levels of the gonadotrophins, luteinising hormone and follicle-stimulating hormone. In women, this results in suppression of ovarian steroidogenesis and a decline in estrogen to levels similar to those observed after menopause or following surgical oophorectomy. Thus, goserelin has a useful role in the management of some benign estrogen-dependent gynaecological disorders. Goserelin is available as a biodegradable sustained release depot 3.6mg injection which is administered every 28 days. In women with endometriosis, monthly injections of depot goserelin were effective in achieving resolution of endometriotic implants and in improving pelvic symptoms, including pain and dyspareunia. Randomised clinical comparisons of depot goserelin with danazol indicate that goserelin is at least as effective as danazol and is better tolerated in the treatment of endometriosis. In the management of uterine leiomyomata (fibroids), goserelin depot injections reduce uterine size and the size of uterine leiomyomata, with maximum clinical benefit achieved approximately 3 to 4 months after initiation of treatment. When used as an adjunctive pretreatment for women undergoing surgical removal of uterine leiomyomata, goserelin was associated with technically easier surgical procedures, reduced intraoperative blood loss and reduced transfusion requirements around the time of surgery. As an alternative to surgery, therapeutic use of goserelin is limited by the rapid regrowth of leiomyomata following cessation of treatment. However, goserelin may be a useful treatment for women approaching menopause, in whom uterine leiomyomata shrink naturally as endogenous estrogen levels decline. In women with dysfunctional uterine bleeding, treatment with depot goserelin before surgery facilitates resection and ablative procedures by suppressing endometrial growth and thinning the endometrial mucosa. Goserelin is also an effective alternative to surgery in this patient group. As adjuvant therapy for women undergoing assisted reproduction procedures, goserelin is associated with reduced cycle cancellation rates and with an increase in the rate of oocyte retrieval. The tolerability profile of goserelin is characterised by adverse effects typical of hypoestrogenism, including hot flushes, loss of libido and loss of bone mineral density. However, concomitant 'add-back' hormone replacement therapy appears to effectively reduce these hypoestrogenic symptoms. In summary, the availability of depot goserelin has broadened the spectrum of effective treatments for benign estrogen-dependent gynaecological disorders. As goserelin is effective as a sustained release depot formulation suitable for administration on a monthly basis, it is also a convenient and practical treatment choice.

Goserelin. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in prostate cancer.

Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which during long term administration reduces circulating levels of gonadotrophins (luteinising hormone and follicle stimulating hormone) and sex hormones. Goserelin is administered subcutaneously as a biodegradable depot formulation incorporating 3.6mg of the drug, which is released continuously over 4 weeks. In men with untreated advanced prostate cancer, monthly goserelin 3.6mg has been confirmed as similar in efficacy to surgical castration and diethylstilbestrol (stilboestrol) 3mg daily taken orally. Goserelin is better tolerated than diethylstilbestrol and appears to have a more favourable effect on quality of life than surgical castration. Treatment of prostate cancer with a combination of goserelin and an antiandrogen remains controversial as a result of inconsistent findings, despite extended data from a large trial which indicated an advantage for the combined regimen over surgical castration with respect to duration of time to progression and survival. Combination therapy also minimises the initial increase in signs and symptoms (disease flare) that occurs in up to 4% of patients at the beginning of treatment with a GnRH analogue. Surgical castration remains the treatment of choice in patients at risk of metastatic compression of the spinal cord or ureteric obstruction. However, goserelin is an effective alternative to surgery, or estrogen therapy, in men with previously untreated advanced prostate cancer. Goserelin seems to be preferred to surgery by the majority of patients given a choice of treatment, and importantly in a palliative care situation where there are no survival advantages for treatment alternatives, it appears to have a more beneficial effect on the quality of life than surgery.

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. The Dutch South East Cooperative Urological Group.

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.

[The estimation of LHRH receptors in the tissue of human leiomyoma, myometrium and endometrium]. / Valutazione dei recettori per LHRH nel tessuto di leiomioma, miometrio ed endometrio umano.

Uterine leiomyoma is the most common female benign pelvic tumor, affecting 20-25% of women during their reproductive years. There is strong clinical evidence that these tumors are estrogen-dependent for their growth, as also supported by their clear regression after the menopause. Although large clinical trials have not yet been reported, according to the estrogen dependency of uterine fibroids, LHRH agonists have been shown to be effective in the treatment of these conditions because they produce a condition of temporary hypoestrogenism secondary to the specific hypogonadotrophinism. This study was designed to evaluate if specific binding sites for LHRH are present in human uterine leiomyomata, myometrium and endometrial tissue. These tissues were taken from the fresh operative specimens of 14 patients who had undergone total hysterectomy for uterine leiomyomata. The results of this study demonstrate the presence of a LHRH specific binding site in uterine leiomyomata in 26% of cases; this specific binding site is also present both in myometrium and in endometrial tissue in 71% of cases. Moreover our study shows, for the first time, the high specificity of binding between LHRH agonist (goserelin) and natural LHRH receptor. In accordance with our results, a direct effect of LHRH agonists on fibroid tissue can be stressed.