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PURPOSE To study the efficacy and safety of the dienogest and the gonadotropin-releasing hormone agonist (GnRH-a) in symptomatic females with uterine adenomyosis. METHODS A total of 127 patients with adenomyosis with a chief complaint of dysmenorrhea were recruited. The first group received 2 mg of dienogest (DNG) daily, whereas the second group received goserelin acetate (GS) (3.6 mg/4 weeks) for 12 weeks. Outpatient follow-up was undertaken after 12 weeks. RESULTS Among 127 women, 56/63 (88.9%) patients completed the treatment in the DNG group, whereas 62/64 (96.9%) patients completed the treatment in the GS group. A significant decrease in dysmenorrhea symptoms as measured by the visual analog scale (VAS) and Carcinoma antigen125 (CA125) after 12 weeks of treatment was observed in both groups (p

Introdução: Leiomiomas são tumores benignos que surgem no miométrio e são comuns em mulheres em idade fértil. Eles podem ser assintomáticos ou podem estar associados a sintomas pélvicos, como sangramento e dor. Objetivo: Neste presente estudo, foram analisadas situações clínicas de 64 mulheres portadoras de leiomiomatose uterina sintomática que foram submetidas ao tratamento com a injeção de análogo de GnRH (agonista do hormônio liberador de gonadotrofina), sendo acompanhadas no período de 2009- 2019. Material e Método: Os dados foram coletados de prontuários do ambulatório de Ginecologia do Hospital Santa Casa de Curitiba. Trata-se de um método observacional,retrospectivo com variáveis quantitativas e qualitativas. Os critérios de inclusão foram mulheres portadoras de leiomiomatose uterina comprovada por ultrassonografia e quese submeteram ao tratamento com o análogo de GnRH. A quantificação da redução do volume uterino após aplicação do GnRH; avaliação na melhora dos níveis hematimétricos;mensuração e discriminação de quantas pacientes foram submetidas a cirurgia e correlação com a história clínica; a aferição de qual cirurgia foi mais realizada e a identificação das queixas pré e pós aplicação da injeção correspondem aos objetivos encontrados no atual estudo. Resultados: O uso com análogo de GnRH pré-operatório contribuiu para melhora dos índices hematimétricos onde se foi observado um aumento médio de 20,1% de hemoglobina. Além disso, a pré-aplicação colaborou com uma redução de volumeuterino em 90,6% das pacientes. Mediante isso, obteve-se um cenário cirúrgico mais seguro para as 23 pacientes que necessitaram de cirurgia, seja via histerectomia abdominal, vaginal ou mesmo miomectomia. Concordante com o arsenal literário, neste estudo observou-se que as queixas principais pré aplicação do análogo foram sangramento uterino anormal e dismenorreia; assim como a queixa pós injeção foi principalmente o fogacho, que ocorre devido ao estado de hipoestrogenismo o qual o GnRH ocasiona. Conclusão: À luz dessas evidências, o análogo de GnRH traz inúmeros benefícios, como tratamento terapêutico e pré-operatório da leiomiomatose uterina, porém seus efeitos adversos e seu alto custo contribuem para a menor acessibilidade às pacientes. Palavras-chave: Leiomiomatose, Gosserrelina, Sangramento uterino, Infertilidade, Dor pélvica, Dismenorreia ABSTRACT Introduction: Leiomyomas are benign tumors that appear in the myometrium and are common in women of childbearing age. They may be asymptomatic or may be associatedwith pelvic symptoms, such as bleeding and pain. Objective: In the present study, we analyzed clinical situations of 64 women with symptomatic uterine leiomyomatosis whounderwent treatment with GnRH analogue (gonadotropin releasing hormone agonist) injection, these patients were followed up in 2009-2019. Data were collected from medicalrecords of the Gynecology outpatient clinic of the Santa Casa Hospital in Curitiba. Material and Method: It is an observational, retrospective study, with quantitative andqualitative variables. Inclusion criteria were women with ultrasound-proven uterine leiomyomatosis who underwent GnRH analogue treatment. Quantification of uterinevolume reduction after GnRH application; assessment of improvement in hematimetric levels; measurement and discrimination of how many patients underwent surgeryand correlation with clinical history; the assessment of which surgery was mostly performed and the identification of complaints before and after injection correspond to theobjectives found in the current study. Results: The use of preoperative GnRH analogue contributed to the improvement of hematimetric indices, in which an average increaseof hemoglobin of 20.1% was observed, and pre-application contributed to a reduction of uterine volume by 90.6% of the patients. Thus, a safer surgical scenario was obtainedfor the 23 patients who required surgery, whether abdominal or vaginal hysterectomy, or even myomectomy. In accordance with the literary arsenal, this study noted thatthe main complaints – pre-application of the analogue – were abnormal uterine bleeding and dysmenorrhea; just as the complaint after injection was mainly of hot flashes, that occurs due to the state of hypoestrogenism, caused by the GnRH. Conclusion: Considering this evidence, the GnRH analogue has numerous benefits as a therapeutic and preoperative treatment for uterine leiomyomatosis; its adverse effects and high cost, however, contribute to loweraccessibility to patients. Keywords: Leiomyomatosis, Goserelin, Uterine bleeding, Infertility, Pelvic pain, Dysmenorrhea Introduction: Leiomyomas are benign tumors that appear in the myometrium and are common in women of childbearing age. They may be asymptomatic or may be associated with pelvic symptoms, such as bleeding and pain. Objectives: In the present study, we analyzed clinical situations of 64 women with symptomatic uterine leiomyomatosis who underwent treatment with GnRH analogue (gonadotropin releasing hormone agonist) injection, these patients were followed up in 2009-2019. Data were collected from medical records of the Gynecology outpatient clinic of the Santa Casa Hospital in Curitiba. Method: It is an observational, retrospective study, with quantitative and qualitative variables. Inclusion criterias were women with ultrasound-proven uterine leiomyomatosis who underwent GnRH analogue treatment. Quantification of uterine volume reduction after GnRH application; assessment of improvement in hematimetric levels after analogue application; measurement and discrimination of how many patients underwent surgery and correlation with clinical history; the assessment of which surgery was most performed and the identification of complaints before and after injection correspond to the objectives found in the current study. Results: In fact, the use of preoperative GnRH analogue contributed to the improvement of hematimetric indices, in which an average increase of hemoglobin of 20.1% was observed, and pre-application contributed to a reduction of uterine volume by 90.6% of the patients. Thus, a safer surgical scenario was obtained for the 23 patients who required surgery, whether via abdominal, vaginal hysterectomy or even myomectomy. In line with the literary arsenal, this study noted that the main complaints – pre-application of the analogue – were abnormal uterine bleeding and dysmenorrhea; just as the complaint after injection was mainly the hot flush, that occurs due to the state of hypoestrogenism, caused by the GnRH. Conclusion: In light of this evidence, the GnRH analogue has numerous benefits as a therapeutic and preoperative treatment for uterine leiomyomatosis; its adverse effects and high cost, however, contribute to lower accessibility to patients.

Purpose: This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). Patients and Methods: This study enrolled premenopausal women with HR+, HER2− ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed. Results: The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group. Conclusions: The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2− ABC. See related commentary by Clark et al., p. 371

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.

Context Most labs set the lower limit of normal for testosterone at the 2.5th percentile of values in young or age-matched men, an approach that does not consider the physiologic changes associated with various testosterone concentrations. Objective To characterize the dose-response relationships between gonadal steroid concentrations and measures regulated by gonadal steroids in older men. Design, Participants, and Intervention 177 men aged 60 to 80 were randomly assigned to receive goserelin acetate plus either 0 (placebo), 1.25, 2.5, 5, or 10 grams of a 1% testosterone gel daily for 16 weeks or placebos for both medications (controls). Primary Outcomes Changes in serum C-telopeptide (CTX), total body fat by dual energy X-ray absorptiometry, and self-reported sexual desire. Results Clear relationships between the testosterone dosage (or the resulting testosterone levels) and a variety of outcome measures were observed. Changes in serum CTX exceeded changes in the controls in men whose testosterone levels were 0 to 99, 100 to 199, 200 to 299, or 300 to 499 ng/dL, whereas increases in total body fat, subcutaneous fat, and thigh fat exceeded controls when testosterone levels were 0 to 99 or 100 to 199 ng/dL. Sexual desire and erectile function were indistinguishable from controls until testosterone levels were Conclusion Changes in measures of bone resorption, body fat, and sexual function begin at a variety of testosterone concentrations with many outcome measures remaining stable until testosterone levels are well below the stated normal ranges. In light of this variation, novel approaches for establishing the normal range for testosterone are needed.

Purpose Goserelin is a drug used for chemical castration. In a rat model, we investigated whether surgical and chemical castration affected memory ability through the protein kinase A (PKA)/cyclic adenosine monophosphate response elementbinding protein (CREB)/brain-derived neurotrophic factor (BDNF) and c-Raf/mitogen-activated protein kinases-extracellular signal-regulated kinases (MEK)/extracellular signal-regulated kinases (ERK) pathways in the hippocampus. Methods Orchiectomy was performed for surgical castration and goserelin acetate was subcutaneously transplanted into the anterior abdominal wall for chemical castration. Immunohistochemistry was done to quantify neurogenesis. To assess the involvement of the PKA/CREB/BDNF and c-Raf/MEK/ERK pathways in the memory process, western blots were used. Results The orchiectomy group and the goserelin group showed less neurogenesis and impaired short-term and spatial memory. Phosphorylation of PKA/CREB/BDNF and phosphorylation of c-Raf/MEK/ERK decreased in the orchiectomy and goserelin groups. Conclusion Short-term memory and spatial memory were affected by surgical and chemical castration via the PKA/CREB/BDNF and c-Raf/MEK/ERK signaling pathways.

Background: COVID-19 pandemic created major challenges in cancer care. Studies have shown increased risk for COVID-19 infectivity, severe disease and death in patients with cancer. Cancer centers worldwide adapted by modifying and often delaying treatment to minimize contact with patients. Methods: To provide safe and uninterrupted care for patients, a home care program was created for patients with prostate cancer at Acad. F. Todua Medical center. Men with locally advanced or metastatic prostate cancer (MPC) receiving androgen deprivation therapy (ADT) were enrolled. Patients and their caretakers were instructed on gonadotropin-releasing hormone (GnRH) subcutaneous injections (SQ) for home administration. Monthly at home laboratory testing and virtual consultations with medical oncologists every 1-3 months were arranged. Results: A total of 52 patients were enrolled during the period of March 2020 – March 2021. All men were White and had ECOG 0/1. The mean age was 71 [±6.3 y] years. Sixteen (31%) patients had stage IIIB PC and 36 (69%) patients had stage IV disease. Stage IIIB patients were receiving adjuvant ADT with SQ Goserelin Acetate 10,8mg every 8 weeks and bicalutamide 50mg daily for two weeks after definitive local treatment. Thirty-one (86%) patients had hormone sensitive metastatic PC and were receiving SQ Goserelin Acetate 10.8mg (28) every 8 weeks or SQ Leuprolide Acetate 22,5mg every 8 weeks (3) with 2 weeks of Bicalutamide 50mg daily. Five (14%) patients had castration resistant (CR) PC and were receiving SQ Goserelin Acetate 10,8mg every 8 weeks with Enzalutamide 160mg daily. Thirty-three (63%) patients had Gleason’s score of 8/9. All patients were compliant with home injections, laboratory tests and virtual physician visits. Thirty-nine (75%) patients administered injections by themselves. Forty-two (80%) patients had PSA reduction >50%. Ten (20%) patients had disease progression and required clinic visits for investigations. Median time to progression was 12 months. Only 1 (2%) patient acquired COVID-19 infection, was hospitalized and died of respiratory failure. Conclusions: At home ADT with appropriate patient/caregiver education and close follow up may be safe for patients with PC during the COVID-19 pandemic. Legal entity responsible for the study: Acad. F. Todua Medical Center Department of Oncology and Hematology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists is well established for the treatment of men with metastatic prostate cancer. As clear differences in efficacy, safety, or tolerability between the available LHRH agonists are lacking, the healthcare management team needs to look to practical differences between the formulations when selecting therapy for their patients. Moreover, as the economic burden of prostate cancer rises alongside earlier diagnosis and improved survival, the possibility for cost savings by using products with specific features is growing in importance. Methods: A review was conducted to summarize the information on the different LHRH agonist formulations currently available and offer insight into their relative benefits and disadvantages from the perspectives of physicians, a pharmacist, and a nurse. Results: The leuprorelin acetate and goserelin acetate solid implants have the advantage of being ready to use with no requirement for refrigeration, whereas powder and microsphere formulations have to be reconstituted and have specific storage or handling constraints. The single-step administration of solid implants, therefore, has potential to reduce labor time and associated costs. Dosing frequency is another key consideration, as administering the injection provides an opportunity for face-to-face interaction between the patient and healthcare professionals to ensure therapy is optimized and give reassurance to patients. Prostate cancer patients are reported to prefer 3- or 6-monthly dosing, which aligns with the monitoring frequency recommended in European Association of Urology guidelines and has been shown to result in reduced annual costs compared with 1-month formulations. Conclusions: A number of practical differences exist between the different LHRH agonist preparations available, which may impact on clinical practice. It is important for healthcare providers to be aware and carefully consider these differences when selecting treatments for their prostate cancer patients.

BACKGROUND: Aggressive angiomyxoma is a rare, locally infiltrative tumor, frequently occurring in female patients. Although wide local excision is considered standard therapy, radical surgery may be needed. CASE: A 49-year-old woman presented with an aggressive angiomyxoma involving the vulva and bladder. Given the hormone receptor status and size of the tumor, the patient was initially treated with fulvestrant and goserelin acetate in an attempt to reduce the size of the mass. She was followed up at 1- to 3-month intervals; after 6 months of treatment, owing to increasing size of the mass and worsening symptoms, the decision was made to proceed with radical surgery. CONCLUSION: Although a less radical surgical approach is preferred, radical surgery is possible for treatment of aggressive angiomyxoma when needed.

This study was conducted to determine the efficacy of switching therapy with a second-line luteinizing hormone–releasing hormone (LHRH) analogue after prostate-specific antigen (PSA) progression for advanced prostate cancer. We enrolled 200 patients, from December 2005 to September 2013, with nodal positive, metastatic prostate cancer or disease progression after definite treatment receiving continuous LHRH analogue therapy with monthly depot leuprorelin(sc) acetate 3.75 mg/vial (LA) or goserelin acetate(sc) 3.6 mg/vial (GA). If the patients had castration-resistant prostate cancer, the treatment choice of switching therapy (from LA to GA or from GA to LA) prior to starting chemotherapy was given. The LH, testosterone level, and PSA change were recorded. The records showed that there were 127 patients receiving LA as initial ADT therapy, whereas the other 73 patients were in GA therapy. A total of 92 patients received LHRH analogue switching therapy (54 patients switched from LA to GA and 38 switched from GA to LA). The effect of LH and testosterone reduction prior to and after switching therapy was comparable between the two groups, and increased PSA level after 3 months of treatment was seen in both groups (median PSA: 15.7–67.7 ng/mL in the LA to GA group; 15.2–71.4 ng/mL in the GA to LA group). This study concluded that switching therapy for patients with PSA progression after ADT has no efficacy of further PSA response.

BACKGROUND. Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. METHODS. One hundred ninety-eight healthy men, ages 20–50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS. As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS. Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION. ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00114114","term_id":"NCT00114114"}}NCT00114114. FUNDING. AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Background: Growing evidence suggests that concomitant inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway could enhance and extend the clinical benefit of endocrine therapies in hormone receptor-positive (HR+) metastatic breast cancer (mBC). In this Phase Ib study (NCT02058381), alpelisib (a p110α-selective inhibitor) or buparlisib (a pan-PI3K inhibitor) was combined with tamoxifen and goserelin acetate in premenopausal women with mBC, a more prevalent patient population in Asian vs Western countries. Methods: Premenopausal women with HR+/human epidermal growth factor receptor 2-negative (HER2–) locally advanced or mBC and no prior endocrine therapy for metastatic disease were recruited in Taiwan, Republic of Korea, and Thailand. Patients (pts) received tamoxifen (20 mg once daily [QD]) and goserelin (3.6 mg Q28D) with either alpelisib (350 mg QD; Group 1) or buparlisib (100 mg QD; Group 2) on a continuous dosing schedule in 28-day cycles. The primary objective was to define the recommended Phase II dose (RP2D) for each combination, based on dose-limiting toxicities (DLTs) observed during Cycle 1, using a dose de-escalation design. Secondary objectives included pharmacokinetics, safety and tolerability (per Common Terminology Criteria for Adverse Events v4.03), efficacy (per Response Evaluation Criteria In Solid Tumors v1.1), and impact on quality of life. Results: As of February 2, 2015, 12 pts, all Asian, have been treated in the first cohort. In Group 1, 6 pts with a median age of 43 were treated with alpelisib (350 mg starting dose), and no DLTs were observed in Cycle 1. In Group 2, 6 pts with a median age of 47 were treated with buparlisib (100 mg starting dose), and 1 DLT of Grade (G) 3 alanine aminotransferase/aspartate aminotransferase elevation was observed. In Group 1, significant toxicities included hypokalemia (G3: 1 pt), rash (G3: 1 pt; G1/2: 2 pts), anemia (G3: 1 pt), leukopenia (G3: 1 pt), and infections (G3: 1 pt; G1/2: 1 pt); no G4 toxicities were reported. In Group 2, significant toxicities included liver toxicity (G4: 1 pt; G3: 1 pt; G1/2: 2 pts), psychiatric disorders (G4: 1 pt; G3: 1 pt; G1/2: 1 pt), rash (G3: 1 pt; G1/2: 2 pts), hypertension (G3: 1 pt; G1/2: 1 pt), and hyperglycemia (G3: 1 pt). No pts in Group 1, and 5/6 pts in Group 2, have discontinued treatment due to adverse events (AEs). Median treatment duration was 110 days in Group 1 and 71 days in Group 2. Conclusions: The combination of alpelisib (350 mg) with tamoxifen and goserelin resulted in a manageable toxicity profile. Meanwhile, the same combination with full-dose buparlisib (100 mg) was less well tolerated; despite the appearance of only one DLT during Cycle 1, the majority of pts subsequently stopped treatment due to AEs. An expansion phase is ongoing, and results will be integrated with safety, tolerability, and efficacy results for the first 15 pts enrolled in each group. PIK3CA status at baseline will also be assessed. Citation Format: Lu Y-S, Ro J, Tseng L-M, Chao T-Y, Chitapanarux I, Valenti R, Canatar A, Salomon H, Park YH. A phase Ib dose de-escalation study of combined tamoxifen and goserelin acetate with alpelisib (BYL719) or buparlisib (BKM120) in premenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-27.

Andreas Lammerich, Peter Bias, Beate Gertz Merckle GmbH, Ulm, Germany Background: XM17 is a recombinant human follicle-stimulating hormone (follitropin alfa) for stimulation of multifollicular development in women undergoing controlled ovarian hyperstimulation during assisted reproductive therapy and for treatment of anovulation. Manufactured using Chinese hamster ovary cells transfected with the human follicle-stimulating hormone gene, XM17 has an identical amino acid sequence to that of the human protein as well as to those of the other approved recombinant human follicle-stimulating hormone products. Glycosylation patterns may differ slightly between products. The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics, and dose-proportionality of single ascending subcutaneous doses of XM17 in healthy young female volunteers.Methods: Endogenous follicle-stimulating hormone was downregulated by implanting a 1-month depot of goserelin acetate 3.6 mg on day 0 in eligible subjects. On day 14 of the experimental period, subjects received one of four ascending doses of XM17. Blood sampling to obtain the pharmacokinetic profile of XM17 was done at frequent intervals until 168 hours post-dose.Results: Following downregulation of endogenous follicle-stimulating hormone to

Highlights • Peripubertal GnRHa impaired long-term spatial memory. • This impairment was not reversed after discontinuing GnRHa-treatment. • Spatial orientation and learning performance remained unaffected following GnRHa withdrawal. • Speed of progression through these spatial tasks was altered after discontinuing GnRHa. • GnRH irreversibly alters these cognitive functions during critical window of development., Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P

We compared the efficacy and safety of 1- and 3-month depots of the luteinizing hormone-releasing hormone (LH-RH) agonist goserelin acetate in prostate cancer patients. Patients were randomly assigned to the Direct Group that received the goserelin 3-month depot or the Switch Group that began with the 1-month depot for the first 3 months and then switched to the 3-month depot. All patients were co-administered the antiandrogen agent bicalutamide. Serum testosterone and prostate-specific antigen (PSA) levels and adverse events were recorded at weeks 4, 8, 12, and 24. Baseline testosterone levels in the Direct and Switch Groups were 4.98 and 5.07 ng/mL, respectively (P = 0.798). At each week, the levels in both groups were a parts per thousand currency sign0.50 ng/mL (castration level) with no significant differences between them. All of the patients in the Switch Group and 98.1 % in the Direct Group had achieved castration levels at week 12, and 100 % had achieved such levels at week 24. Baseline PSA levels in the Direct and Switch Groups were 52.37 and 46.72 ng/mL, respectively (P = 0.793). Levels in both groups dropped continuously, to about 1.0 ng/mL at week 24, with no significant differences between the groups at any time. Three patients in the Direct Group experienced adverse events that were attributed to the co-administered bicalutamide. There was no difference in the efficacy or safety between the 1- and 3-month depots of goserelin when given as initial prostate cancer treatment in combination with bicalutamide. Patients must be monitored for adverse events associated with bicalutamide., Article, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY. 18(3):524-530 (2013)

Background Normal brain maturation is the result of molecular changes that can be modulated by endocrine variables associated with brain plasticity and results in sex- and age specific changes in cognitive performance. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors results in increased sex-differences in cognitive executive function and emotional control. In this study we explore effects of this treatment regime on hippocampal gene expression and spatial orientation. Methods The study was conducted with 30 same-sex twin lambs, half of which were treated with the GnRH analog (GnRHa) goserelin acetate every 4th week, beginning before puberty, until 50 weeks of age. Animals were tested in their spatial orientation ability at 48 weeks of age. Quantitative real time PCR analysis was conducted to examine effects of treatment on the expression of genes associated with synaptic plasticity and endocrine signaling. Results GnRHa treatment was associated with significant sex- and hemisphere specific changes in mRNA expression for some of the genes studied. The treatment had no significant effect on spatial orientation. However, there was a tendency that females performed better than males in spatial orientation. Conclusion Our results indicate that GnRH directly and/or indirectly, is involved in the regulation of sex- and side-specific expression patterns of genes. Hence, these results should be considered when long-term peri-pubertal GnRHa treatment is used in children.

Objective: The aim of our study was to assess the long-term efficacy of conservative surgery combined with gonadotropin-releasing hormone agonist therapy for uterine adenomyoma. Materials and Methods: We carried out an uncontrolled descriptive study of 285 women who had symptomatic uterine adenomyoma. A total of 186 women with pathologically proven adenomyoma underwent ultramini-laparoscopic adenomyomectomy and a 6-month course of goserelin acetate treatment, and were evaluated semi-annually during a follow-up period of at least 3 years. Results: Patient scores for dysmenorrhea using a self-reported six-point verbal numeric rating scale significantly declined compared with the baseline assessment, from 3.84 ± 0.65 to 0.33 ± 0.57, 0.52 ± 0.86, and 0.88 ± 1.29 at the end of the 1-, 2-, and 3-year follow-up visits, respectively (p

We report on a 62-year-old man with metastatic prostate cancer (cT3b N1) diagnosed in 2011, treated with total androgen blockage with flutamide and goserelin acetate (Zoladex). He presented with left suprascapular swelling and low-back pain after being asymptomatic for 5 years. His prostate-specific antigen was 0.049 ng/mL. F-NaF PET-CT and Ga-PSMA scan were negative, whereas Ga-DOTA NOC scan done after 10 days showed multiple somatostatin-avid hepatic and lymph node metastasis.

The hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood.To determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men.Two randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately.A single-site academic medical center.Healthy men ages 20-50, with normal serum testosterone levels.Cohort 1 (n = 198, 81% completion) received goserelin acetate every 4 weeks to suppress gonadal steroids and were randomized to placebo or 1.25, 2.5, 5, or 10 g of testosterone gel daily for 16 weeks. Cohort 2 (n = 202, 78% completion) received the same regimen as cohort 1 plus anastrozole to block aromatization of testosterone. Controls (n = 37, 89% completion) received placebos for goserelin acetate and testosterone.Incidence of visits with VMS. This was a preplanned secondary analysis.VMS were reported at 26% of visits in cohort 1, and 35% of visits in cohort 2 (P = .02), demonstrating an effect of estradiol deficiency. When adjacent estradiol level groups in cohort 1 were compared, the largest difference in VMS incidence was observed between the 5-9.9 and 10-14.9 pg/mL groups (38% vs 16%, P.001). In cohort 2, the 10-g testosterone group differed significantly from placebo (16% vs 43%, P = .048) after adjustment for small differences in estradiol levels, indicating that high testosterone levels may suppress VMS.Estradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect.

Men with castrate resistant prostate cancer have limited treatment options. Although luteinizing hormone-releasing hormone agonists are in the same class, they are slightly different in their pharmacology. We determined whether rechallenging patients with prostate cancer, who were receiving a luteinizing hormone-releasing hormone analogue but had progression, with a different luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate) would result in a prostate specific antigen response. Secondary objectives were to calculate the PSA response and determine whether sequence order impacted the response.We performed a retrospective, ethics approved review of the records of patients with prostate cancer at multiple institutions who received a luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate), experienced progression, as measured by 2 consecutive prostate specific antigen increases, and were rechallenged with the other analogue (goserelin or leuprolide acetate). Prostate specific antigen and relevant clinical data were obtained and statistical analysis was done.Of 39 available men 27 (69%) had decreased prostate specific antigen after 3 months of switching regimens. The median change in prostate specific antigen was -1.5 (IQR -10.0, 0.8), indicating a statistically significant decrease (p=0.01). The median percent prostate specific antigen change for leuprolide acetate to goserelin was -69.3% (IQR -81.5, 26.2) and for goserelin to leuprolide acetate it was -6.4% (IQR -61.7, 21.8, p=0.05). Median time to a subsequent prostate specific antigen increase was 5.2 months (95% CI 3.5-17.4).Prostate specific antigen decreased after switching luteinizing hormone-releasing hormone therapies. This decrease appeared most significant in the group that switched from leuprolide acetate to goserelin. The duration of response after switching was approximately 5 months. The study is limited by its retrospective nature but should encourage prospective evaluation of this observation.

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.

Background We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. Methods For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1-2 prostatic adenocarcinoma with WHO histological grade 3 or T3-4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0-2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3.6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. Findings Between May 22,1987, and Oct 31,1995,415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9.1 years (IQR 5.1-12.6). 10-year clinical disease-free survival was 22.7% (95% CI 16.3-29.7) in the radiotherapy-alone group and 47.7% (39.0-56.0) in the combined treatment group (hazard ratio [HR] 0.42,95% CI 0.33-0.55, p

Goserelin acetate, which is injected through a 16-gauge needle, makes some patients feel substantial, although tolerable, pain. We tried to clarify whether injection pain was reduced by icing the skin at the injection site. Pain associated with the injection of goserelin acetate was prospectively evaluated in 48 patients who had received an 10.8-mg goserelin injection at least once previously. In this study, the first injection was administered by usual methods, and 3 months later a second injection was administered after icing the skin at the injection site. Pain intensity was evaluated by visual analogue scale (VAS) pain score. VAS pain scores for the usual injection method were 32.4 ± 21.7 mm [mean ± 2 standard deviation (SD)] and was significantly lower (16.4 ± 17.9) for the icing method (p = 0.001, paired t test). Thirty-three (68.8%), eight (16.7%), and seven (14.6%) of the 48 patients reported a decrease, no change, and increase, respectively, in VAS pain score by the icing method. Icing at the injection site of goserelin acetate is a safe and effective method to reduce injection pain. This method can be easily performed in daily practice if a patient complains of pain at the injection site.

Background Hormone receptor-positive, pre-menopausal breast cancer patients can be treated by chemotherapy and/or ovarian suppression therapy. We reported our experience of gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa + T) or adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC → T) in pre-menopausal women with hormone-response, node-negative breast cancer. Methods We retrospectively reviewed the records of 587 pre-menopausal women with hormone-responsive, node-negative breast cancer. Of these, 269 were treated with adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC → T), and 318 were treated with gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa + T). Among them, 151 patients were treated by goserelin acetate 3.6 mg/kg and 125 patients were treated by leuprorelin acetate 3.75 mg/kg every 28 days subcutaneously. Findings At a median follow-up time of 30 months, eight patients had relapsed and three had died. DFS did not differ between the AC → T and GnRHa + T groups. Of the three deaths, two were not related to breast cancer. The third patient, in the AC → T group, died because of brain metastasis. GnRHa + T treatment had no effect on blood profile and did not cause the development of detrimental symptoms but decreased bone mineral density. The efficacy of leuprorelin was similar to that of goserelin. Interpretation GnRHa + T treatment can be an alternative treatment option in pre-menopausal women with endocrine-responsive, node-negative, breast cancer patients. The efficacy and tolerability of leuprorelin were similar to that of goserelin.

A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P0.05). GA treatment had no effect on cortical bone architecture in neither sex (P0.05). Cancellous bone degeneration, however, was observed in M and F SED+GA (P0.05). No significant differences were observed in M WR+GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED+CON (P0.05). In F WR+GA, trabecular thickness did not differ from that of F SED+CON (P0.05), and trabecular spacing was found to be significantly lower than F SED+GA (P0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.

OBJECTIVE To compare the effects of leuprolide acetate and goserelin acetate for suppressing serum testosterone levels in Japanese patients with prostate cancer, as several recent studies suggested that serum testosterone is not always suppressed below the upper limit of the castration range in patients using luteinizing hormone-releasing hormone (LH-RH) agonists, especially leuprolide acetate. PATIENTS AND METHODS In all, 232 patients with prostate cancer, whose serum testosterone levels were measured before and during treatment using a 1- or 3-monthly formulation of leuprolide or goserelin, were enrolled in a retrospective study. The mean age of the patients was 69.8 years and the mean testosterone level before the LHRH treatment was 4.54 ng/mL. The patients had their testosterone levels assessed a mean (range) of 5.4 (1–35) times during the LHRH treatment. A castrate serum testosterone level was defined as ≤0.5 ng/mL. RESULTS The mean maximum testosterone level during 1-monthly leuprolide (40 patients), 3-monthly leuprolide (68), 1-monthly goserelin (50), or 3-monthly goserelin (74) treatment was 0.22, 0.20, 0.19 and 0.20 ng/mL, respectively (not significant). Four patients, including two treated with 1-monthly leuprolide, one with 3-monthly leuprolide and one with 3-monthly goserelin, had serum testosterone above the castrate level, with a maximum of 0.5–0.65 ng/mL. Three of these patients had elevated testosterone only once or twice during the follow-up, and the remaining patient had serum testosterone fluctuating at 0.4–0.6 ng/mL throughout the follow-up. CONCLUSIONS One- and 3-monthly formulations of leuprolide and goserelin have equivalent and sufficient effects to suppress serum testosterone levels in men with prostate cancer. There were testosterone levels just outside the castrate range in a few patients during treatment.

PURPOSE There were few studies which reported the longitudinal quality of life (QOL) for Japanese men who received endocrine therapy for advanced or metastatic prostate cancer. A pilot randomized trial was conducted to assess QOL and the incidence of hot flash following endocrine therapy using luteinizing hormone-releasing hormone (LH-RH) agonist goserelin acetate 1-month or 3-month depot alone in patients with advanced or metastatic prostate cancer. MATERIAL AND METHODS A total of 28 patients with advanced or metastatic prostate cancer who received LH-RH analogue goserelin acetate depot alone for 12 months were randomized (1:1) to two different formulations. Fifteen patients received the 1-month depot and thirteen patients received 3-month depot, namely Zoladex 3.6 mg depot and Zoladex LA 10.8 mg depot, respectively. We measured health related QOL using European Organization for Research and Treatment of Cancer (EORTC) and EuroQol (EQ-5D) questionnaire and evaluated the incidence of hot flashes between the two groups for one year after diagnosis. Moreover, we evaluated the incidence of hot flashes between the 1M and 3M depot. A baseline interview was conducted before treatment. Follow-up interviews were conducted in person at scheduled study visits of 3, 6, 9 and 12 months after treatment. RESULTS Five (18%) patients dropped out of the study. Thus, we analyzed 23 eligible patients (11 in the 1M arms and 12 in the 3M arms). No significant differences between the two treatment arms were detected in categories of age, average pre- PSA values, Gleason scores and clinical T stage. According to EORTC, each treatment group showed similar QOL scores in all domains before and after treatment. With regard to EQ-5D, the 1M-treatnent arm reported better utility scores than 3M treatment arm, which was no significant statistically. The overall incidence of hot flash was 61% (58% in 1M group and 64% in 3M group). CONCLUSION There were no differences with regard to general and disease specific HRQOL between the both formulations of goserelin acetate. Hot flashes are the major adverse effects of endocrine therapy for Japanese patients with prostate cancer.

Objective To evaluate the impact of a luteinising hormone-releasing hormone (LHRH) agonist, goserelin acetate (GA), on surgical blood loss during transurethral resection of the prostate (TURP), as well as its histopathological effect on prostatic microvessel density (MVD). Patients and methods Patients who underwent TURP due to benign prostatic enlargement (60–100 mL) were randomly subdivided into two equal groups according to whether they received preoperative GA administration (3.6 mg; group A) or not (group B). Evaluation parameters were operative time, weight of resected prostatic tissue, perioperative haematocrit (HCT) changes, estimation of intraoperative blood loss, and suburethral and stromal prostatic MVD. Effects of GA on prostate weight and any possible side-effects were also monitored. Results In all, 35 and 33 patients were included in groups A and B, respectively. Operative time and HCT values’ changes were significantly less in group A (P

Goserelin acetate (Gos) is a synthetic analogue of luteinizing hormone-releasing hormone (LHRH) used in treatment of prostate cancer. The objective of this study is to investigate the in vitro cytotoxic effect of Goserelin loaded nanoparticles on both androgen dependent and androgen independent cell lines. Goserelin causes cell death of prostate cancer cell lines by inducing apoptosis. Treatment of Goserelin loaded nanoparticles inhibited the proliferation of LNCaP and DU145 in the dose-dependent manner, however did not affect the cell proliferation in PC-3 cell lines. Blank nanoparticles exhibited negligible cytotoxicity on cell lines. In addition, immunocytochemical studies indicated that Gos induced apoptosis in prostate cancer cells. The presence and characteristics of LHRH receptors and their messenger ribonucleic acid (mRNA) expression in human prostate cancer cell line LNCaP were investigated by polymerase chain reaction. Changes in nuclear morphology and DNA fragmentation associated with Gos induced apoptosis were clearly seen in both LNCaP and DU145 cell lines by DNA studies. The PCR product of the expected size of 319 bp for human LHRH receptors was obtained in cell line sample. Goserelin loaded nanoparticles are the potential tool for site specific delivery for prostate cancer treatment.

An 8-year-old girl with idiopathic central precocious puberty experienced multiple episodes of anaphylaxis after receiving a goserelin acetate implant. She was hospitalized and treated with epinephrine, antihistamine, and corticosteroids. The goserelin implant was surgically excised; however, anaphylactic symptoms continued for 4 days after excision. Less severe systemic symptoms recurred 6 weeks after removal; these were possibly due to leakage of the depot drug into subcutaneous tissues. It was noted that 3 years earlier, the patient had developed a similar, milder systemic allergic reaction to leuprolide acetate that required treatment with oral prednisone and antihistamines. Intradermal testing yielded positive results for leuprolide. Gonadotropin-releasing hormone (GnRH) analogs, including leuprolide acetate and goserelin acetate, are commonly prescribed for patients with prostatic carcinoma, endometriosis, and precocious puberty. A literature review identified a single case report of a systemic hypersensitivity reaction involving goserelin acetate and several reports of systemic hypersensitivity reactions associated with leuprolide acetate. We found no reports of systemic reactions to GnRH analogs in pediatric patients. Clinicians should be aware of the potential association of GnRH analogs with systemic reactions. They should also recognize that recurrent anaphylaxis may occur due to the long half-life of these therapeutic agents in tissue.

Objective To determine if goserelin immediately after uterine artery embolization (UAE) affected myoma reduction. Design Randomized pilot study (level 1). Setting Teaching hospital. Patient(s) Twenty-six women. Intervention(s) All patients underwent UAE, and then 12 patients received 10.8 mg of goserelin 24 hours later. The treatment group was 5 years older: 43 versus 37.7 years. Uterine and myoma volumes were measured by ultrasound 2 weeks before UAE and at 3, 6, and 12 months. Main Outcome Measure(s) Uterine and fibroid volumes. Result(s) Pretreatment uterine volume was 477 versus 556 cm 3 , and dominant fibroid volume was 257 versus 225 cm 3 in the control versus goserelin groups. Analysis of variance measurements indicated that the change over time did not significantly differ between the two groups. By 12 months, the control group had a mean uterine volume reduction of 58%, while the goserelin group had a reduction of 45%. Dominant fibroid changes over time did not differ between the two groups. At 12 months, the mean fibroid volume had decreased by 86% and 58% in the control and goserelin groups, respectively. Conclusion(s) The addition of goserelin therapy to UAE did not alter the reduction rate or volume of uterine myomas.

We studied hormonal changes resulting from long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate in 40 healthy middle-aged male-to-female transsexuals over a period of two years. All of the participants received injections of 3.8 mg goserelin acetate every four weeks in combination with 6 mg oral 17beta estradiol valerate per day for cross-sex hormone treatment for male-to-female transsexuals. There was a significant reduction in the levels of serum luteinizing hormone and follicle-stimulating hormone to the hypogonadal stage. Mean testosterone levels decreased by 97% to 0.52 and 0.59 nmol/l after 12 months and 24 months, respectively. There was a significant reduction in dehydroepiandrosterone sulfate by 37% after 12 months and 43% after 24 months, and androstendione by 29% after 12 months and 27% after 24 months, respectively. Cortisol levels were reduced by 43% and 50%, respectively. Estrogen levels were significantly increased from 77.51 to 677 after 12 months and 661 pmol/l after 24 months. Sex hormone-binding globulin and corticoid-binding globulin levels were significantly increased after 12 and 24 months. There was a significant decrease in all measured androgen fractions and cortisol during long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate. Apart from suppression of testicular hormone production, one possible interpretation is that treatment with long-term gonadotropin-releasing hormone agonist and 17beta estradiol valerate influences adrenal hormone levels in healthy middle-aged male-to-female transsexuals. Cortisol serum levels may be decreased due to estrogen-induced increase in corticoid-binding globulin.

To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women.In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score).Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups.Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.

Objective In a cross-sectional, retrospective, non-randomised study to investigate the possibility that some patients treated with luteinizing hormone releasing hormone analogues (LHRH analogues) fail to reach castration levels of serum testosterone. Methods 40 patients treated with a 3-monthly formulation of leuprolide acetate and continuous use of an oral antiandrogen ("Leu group") and 25 patients treated with a 3-monthly formulation of goserelin acetate and an oral antiandrogen for one month ("Gos group") were identified from our hospital's registry. Serum testosterone was measured during treatment with the respective LHRH-analogue and compared between the two groups. In the Leu group, serum testosterone was measured during week 11 or 12 of treatment. In the Gos group, serum testosterone was assessed during week 23 or 24. Results Four patients (10%) treated with leuprolide acetate failed to reach the castration level of serum testosterone after treatment with one injection of a three-monthly formulation of leuprolide acetate. All patients treated with goserelin acetate achieved the castration level. Conclusion Although the overwhelming majority of prostate cancer patients during treatment of LHRH analogue achieve serum testosterone values within the castration range, individual patients may fail to reach this therapeutic goal, probably more often during treatment with leuprolide acetate than with goserelin acetate.

The aim of this study was to compare the speed of administration (preparation and delivery) and nurses' perceived ease of use and relative safety of two injection systems used to administer luteinising hormone-releasing hormone agonists: a depot system used to administer goserelin acetate ('Zoladex', AstraZeneca) and a vial system used to administer leuprorelin acetate ('Prostap', Wyeth). This was a randomised, crossover study with 82 volunteer nurses (50 pre-registration and 32 post-registration). All nurses were timed in the administration of both systems and all were required to assess the two systems by completing a questionnaire. Results indicate that both pre- and post-registration nurses administered the depot system in less time than the vial system. Overall mean times for administration of the depot system and the vial system were 1.70 and 3.34min, respectively. In questionnaire responses, significantly more nurses thought that the depot system had 'good safety precautions' compared with the vial system (85% versus 40%; P

To explore the effects of a gonadotropin-releasing hormone (GnRH) agonist depot (goserelin acetate) in women with Hodgkin's disease receiving chemotherapy while taking a continuous combined estrogen-progestin preparation as add-back on the prevention of premature ovarian failure (POF).In a prospective pilot study, five premenopausal women with Hodgkin's disease received a GnRH agonist depot plus add-back until polychemotherapy was completed. Every 4 weeks during treatment and thereafter, a hormonal profile (follicle-stimulating hormone (FSH), luteinizing hormone, 17beta-estradiol, progesterone and inhibin B) was measured until resumption of menstruation or the development of a hypergonadotropic state (2 x FSH30 U/l).All patients reached prepubertal status during treatment. After discontinuation of goserelin acetate, one patient developed a hypergonadotropic state and four patients resumed menstruation. One of those patients became pregnant and delivered a healthy son.The effectiveness of GnRH agonist plus add-back on the prevention of POF during polychemotherapy in women with Hodgkin's disease needs further elucidation in randomized controlled trials. The results of our pilot study are promising.

Objective: To evaluate the efficacy of bicalutamide vs cyproterone acetate in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing hormone-releasing hormone (LHRH) analogue therapy for prostate cancer. Patients and Methods: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to goserelin acetate and continued for 21 days thereafter. PSA, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone pain were secondary end points. Results: Both groups were equally matched apart from serum creatinine and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period. Conclusion: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study.

In living organism, excessive free radicals oroxidative damage which occur as a result of deficient antioxidant defensive mechanisms by the effect of endogenous and exogenous factors, influences especially developmental steps of chemically induced cancers [1, 2]. In our study, plasma malondialdehyde level (MDA) as an indicator of lipid peroxidation, erythrocyte glutathione (GSH) level as an indicator of antioxidant state, glutathione reductase (GSH-Red), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST) as an antioxidant enzymes and plasma vitamin E level were detected in patients with prostate cancer (21 males; age, 69.4 ± 4.8 years) before and after three months of antiandrogenic therapy with goserelin acetate as luteinizing hormone releasing hormone (LHRH) analogue. Healthy people evaluated as a control group (20 males; age, 63.7 ± 3.9). Erythrocyte GSH levels, the activities of GSH-Red and GSH-Px and plasma vitamin E levels were found significantly low in patients with prostate cancer when compared with the healthy subjects (p < 0.01, p < 0.05, p ≤ 0.001 and p ≤ 0.001 respectively). Plasma MDA level and erythrocyte GST activity of patient group were significantly higher than the levels of control group (p ≤ 0.001 and p ≤ 0.001 respectively). After antiandrogenic therapy erythrocyte GSH level, GSH-Red, GSH-Px activity and plasma vitamin E level were found unchanged. Significant decrease in plasma MDA level and significant increase in erythrocyte GST activity were detected in patient group (p < 0.05 and p ≤ 0.01 respectively). The study has revealed the shift in the oxidant-antioxidant balance towards oxidative state in patients with metastatic prostate cancer. Our results showed that antiandrogenic therapy increased in GST activity, decreased in lipid peroxidation.

Objectives: The aim of this study was to assess the efficacy of topically applied trichloroacetic acid (TCA) for endometrial ablation in patients with dysfunctional uterine bleeding (DUB). This trial has also compared the advantages of prethinning the endometrium with danazol and goserelin acetate before ablation with TCA. Methods: This prospective trial was conducted on 90 volunteer cases. Patients were allocated into three treatment groups comprised of 30 patients. In group I cases underwent dilatation and curettage before endometrial ablation. In group II cases were administered danazol before ablation. Cases in group III received goserelin acetate on the same day and 28 days after ablation. Endometrium was evaluated by biopsy transvaginal ultrasonography and hysteroscopy. Endometrial ablation was performed with 95% TCA. All of the patients were evaluated 3 and 6 months after TCA application. Results: After 6 months of treatment the success rate was recorded as 83% in the first group 92.3% in the second group and 96.6% in the third group. The mean length of uterine cavity was reduced in all groups being only significant in Goserelin group (P-0.5). Endometrial thickness was decreased significantly in all treatment groups (P-0.001). Conclusions: This study concluded that endometrial ablation by TCA may readily be performed as an alternative treatment method in the management of DUB. Moreover suppression of endometrium with danazol or especially with goserelin acetate before ablation resulted in significant success rate. (authors)

Androgen deprivation as a treatment for prostate cancer has evolved since the pioneering studies of Huggins and Hodges 60 years ago using surgical castration or estrogen treatments. The most common hormonal treatments today use injections of luteinizing hormone-releasing hormone (LHRH) agonists. The US Food and Drug Administration (FDA) has approved 5 LHRH agonist formulations for treatment of prostate cancer in the United States. Of these approved products, 3 involve different delivery systems for the LHRH superagonist leuprolide acetate. Sustained-release formulations of 2 distinct LHRH agonists, goserelin acetate and triptorelin pamoate, are also commercially available. This review focuses on new data on a novel formulation of leuprolide acetate (Eligard; Atrix Laboratories Inc., Fort Collins, CO) that incorporates a unique mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection. The FDA has approved 1-month and 3-month formulations of Eligard, and 4-month and 6-month products are in development. In clinical trials, Eligard achieves reliable and sustained suppression of serum testosterone to castration levels (or =50 ng/dL). Of the patients treated with the 1-month and 3-month formulations, 98% (115 of 117) and 94% (104 of 111), respectively, reached testosterone levels ofor =20 ng/dL. Breakthroughs, defined as testosterone levels50 ng/dL after achievement of castration levels, occurred rarely at 0% (0 of 117) for the 1-month and at 0.9% (1 of 111) for the 3-month formulations in patients receiving Eligard. The degree of disease control and the adverse-events profile are commensurate with the effectiveness of the testosterone suppression; the incidence of severe hot flashes is actually lower than anticipated. Additional studies with these novel formulations are warranted.

Objectives: To determine the endocrine effects, efficacy and tolerability of the 3-month formulation of goserelin acetate (‘Zoladex’ 10.8-mg depot; ‘Zoladex’ is a trade mark of the AstraZeneca group of companies) in the treatment of patients with advanced prostate cancer. Methods: Between February 1996 and October 1997, this open, multicentre study enrolled 120 patients with locally advanced (T3/4) or metastatic (N+ or M1) disease, or an increase in prostate-specific antigen (PSA) level after radical prostatectomy. Patients received goserelin acetate 10.8-mg depot every 12 weeks until clinical progression or interruption for adverse events or other reasons. Results: The mean testosterone concentrations were suppressed to the castration range (≤2 nmol/l) after 4 weeks of treatment and remained suppressed throughout the study. In total, 99/115 (86%) patients had a serum PSA response, and the mean PSA value decreased significantly during treatment (p = 0.006). The mean PSA level at baseline was significantly lower in patients without disease progression compared to those who experienced disease progression (p = 0.0002). Goserelin acetate 10.8-mg depot was well tolerated and there were no injection site reactions. Conclusions: The goserelin acetate 10.8-mg depot is well tolerated with no injection site reactions. It produces PSA responses and provides reliable suppression of serum testosterone.

The physiologic role of androgens and estrogens in the maintenance of normal bone turnover in men is a fundamental issue in bone biology. To address this question, we randomized 70 men between the ages of 20 and 44 yr to receive one of three treatment regimens. Group 1 (n = 25) received a GnRH analog (goserelin acetate 3.6 mg by sc injection every 4 wk) alone for 12 wk to suppress endogenous gonadal steroids to prepubertal levels. Group 2 (n = 22) received goserelin plus transdermal testosterone (Androderm 5 mg topically daily) to normalize circulating testosterone and estradiol levels. Group 3 (n = 23) received goserelin plus testosterone plus an aromatase inhibitor (anastrozole 1 mg orally daily) to induce selective estrogen deficiency. The selective effects of androgens and estrogens on skeletal homeostasis were then assessed by measuring changes in biochemical markers of bone turnover and analyzing the between-group differences. Bone resorption markers increased in both the hypogonadal group (group 1) and in the group with selective estrogen deficiency (group 3). Urinary deoxypyridinoline excretion increased more in group 1 than in group 3 (P = 0.023), suggesting a significant effect of androgens on bone resorption, whereas serum N-telopeptide levels increased more in group 3 than in group 2 (P = 0.037), suggesting a significant effect of estrogen on bone resorption. Bone formation markers initially declined in all groups and then increased in groups 1 and 3. The between-group comparisons were consistent for all formation markers. Bone formation markers increased more in group 1 than in group 2 (P = 0.001, 0.037, 0.005 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Bone formation markers also increased more in group 1 than in group 3 but these differences were not statistically significant (P = 0.065 0.073, 0.099 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Taken together, these data suggest that both androgens and estrogens play independent and fundamental roles in regulating bone resorption in men. These data also suggest that androgens may play an important role in the regulation of bone formation in men.

We report a case of acute icteric hepatitis attributed to goserelin acetate, occurred during prostate cancer treatment. Gosereline acetate could induce acute hepatitis, which characteristics are close to autoimmune hepatitis type I and may require hepatic monitoring.

OBJECTIVE: To report a case of successful treatment of refractory hot flashes with gabapentin in a patient with prostate cancer who was receiving combination antiandrogen and gonadotropin hormone—releasing hormone (GnRH) analog therapy. CASE SUMMARY: A 70-year-old white man with a history of advancing prostate cancer experienced disabling hot flashes from combination therapy with the antiandrogen bicalutamide and the GnRH analog goserelin acetate. He failed to respond to clonidine 0.1 mg twice daily, megestrol acetate 40 mg/d, diethylstilbestrol 1 mg/d, and venlafaxine 25 mg twice daily. The patient was then treated with gabapentin 600 mg once daily, at which time he experienced near-complete resolution of his symptoms. DISCUSSION: This case supports a previous report of the marked improvement in severity and duration of hot flashes associated with antiandrogen or GnRH analog therapy in prostate cancer. The mechanism by which gabapentin reduces hot flashes is unknown. CONCLUSIONS: Hot flashes resulting from antiandrogen or GnRH analog therapy are often difficult to treat and leave many patients disabled. Gabapentin has been shown to markedly reduce the severity, frequency, and duration of these hot flashes. Controlled trials are necessary to evaluate gabapentin against other therapeutic modalities.

Objective. The aim of the study was to compare intermittent (IAD) and continuous (CAD) androgen deprivation therapy (ADT) between locally advanced (M0) and metastatic (M1) prostate cancer, and the effect of ADT on the quality of life. Material and methods. In total, 852 men with advanced prostate cancer were enrolled to receive goserelin acetate for 24 weeks. Of these, 554 patients whose prostate-specific antigen (PSA) decreased to less than 10 ng/ml or by at least 50% (Results. Median follow-up time was 65 months. Median times from randomization to progression, death, prostate cancer death and treatment failure in M0 and M1 patients were 46.8 and 21.4, 57.6 and 40.3, 59.5 and 40.7, and 41.9 and 20.0 months, respectively (p < 0.001). No significant differences emerged between IAD and CAD. ADT showed a beneficial effect on pain, activity limitation and social functioning in M1 patients, and a deleterious effect on physical capacity in M0 patients and on sexual functioning in both groups. IAD offered extra benefit for activity limitation, social functioning and recovery of sexual functioning. Conclusions. IAD is as efficient as CAD in treatment of locally advanced and metastatic prostate cancer. ADT improves quality of life in M1 patients, with IAD offering extra benefit.

Objective To determine the endocrine effects, efficacy and tolerability of a 10.8-mg depot formulation of Zoladex™(goserelin acetate, Zeneca Pharmaceuticals, Wilmington, Delaware, USA), a luteinizing hormone-releasing hormone agonist analogue, when administration was extended from every 12 weeks to every 13 weeks in patients with advanced prostate cancer. Patients and methods Between July 1995 and May 1996, 59 patients with either locally advanced (T3 or T4)or metastatic prostate cancer were enrolled in an open-label, multicentre trial. Primary efficacy endpoints were testosterone measurements, and assessments of prostate specific antigen (PSA) response, subjective and objective response. Quality of life (QoL) was a secondary efficacy endpoint. Results Mean testosterone concentrations decreased to < 0.3 μg/L by week 4 and remained so for the duration of treatment. There were no statistically significant differences in mean testosterone levels between weeks 12 and 13, or weeks 25 and 26. Serum testosterone suppression was adequate in all 58 evaluable patients at week 13, and 51 of 52 (98%) patients at week 26. Of the 58 evaluable patients, 52 (90%) had a PSA response. A subjective response was recorded for six of 11 evaluable patients. Of 58 patients evaluable for objective response, 46 (79%) had a partial response, three (5%) had stable disease and nine (16%) had objective progression. Except for a significant (P=0.014) decrease in overall sexual interest, QoL was unchanged during therapy. The most common side-effects, regardless of causality, were hot flushes (67%), pain (31%) and pelvic pain (22%). Mild injection-site complaints occurred with only three of 221 (1.4%) depot injections. Conclusions Zoladex™ 10.8-mg depot, administered every 13 weeks to patients with advanced prostatic cancer, is well tolerated, provides adequate suppression of serum testosterone and produces PSA, subjective and objective responses.

The objective of this study was to investigate whether baboon females respond to an ovar- ian stimulation protocol incorporating pituitary suppression with a GnRH agonist (GnRHa) and highly purified human FSH (hphFSH) with follicular development and oocyte maturation. An ovu- lation induction protocol was applied to 5 adult female baboons with a history of regular menstrual cycles (33-34 days). A long-acting GnRHa implant containing goserelin acetate was placed s.c. on days 22-24 of their menstrual cycle. Daily hphFSH (75 IU im) treatments were started ~10 days following menses. When the majority of the follicles were ≥ 5 mm in diameter and the E2 levels had reached a maximum, hCG (2000 IU i.m.) was administered to induce final maturation of the oocytes and ovulation. 30 to 34 h after hCG administration, transabdominal follicular aspiration was per- formed using a variable frequency transvaginal transducer with ultrasound. A total of 71 oocytes were collected (average: 17). 91% of the oocytes were morphologically normal indicating that they were appropriate for in vitro insemination. ovarian stimulation / highly purified human FSH / GnRH agonist / ultrasound-guided oocyte retrieval / baboon

The objective of this study was to investigate whether baboon females respond to an ovarian stimulation protocol incorporating pituitary suppression with a GnRH agonist (GnRHa) and either highly purified human FSH (hphFSH) or recombinant human FSH (rhFSH) with follicular development and oocyte maturation. A modified human ovulation induction protocol was applied to 5 adult female baboons with a history of regular menstrual cycles (33–34 days). A long-acting GnRHa implant containing goserelin acetate was placed subcutaneously (s.c.) on Days 22–24 of their menstrual cycle. Concentrations of serum oestradiol (E2), progesterone (P4) and human FSH were obtained by ELISA. Menses occurred ∼ 10 days after GnRHa implantation. Daily hphFSH or rhFSH (75 IU i.m.) treatments were started ∼ 10 days following menses. When the majority of follicles were ≥ 5 mm in diameter and the E2 levels had reached a maximum, hCG (2000 IU i.m.) was administered to induce final maturation of oocytes and ovulation. Thirty to 34 h after hCG administration, transabdominal follicular aspiration was performed using a variable frequency transvaginal transducer with ultrasound. A total of 71 oocytes were collected from 4 animals (average: 17). The meiotic maturity of oocytes was evaluated 3 h after retrieval. Ninety-one percent of oocytes were in metaphase 2 and of grades I and II which are appropriate for in vitro insemination.

Following identification of the proportion of pelvic congestion among symptomatic patients complaining of chronic pelvic pain, and in a totally asymptomatic group of patients requesting tubal ligation, the efficiency of goserelin acetate versus medroxyprogesterone acetate was compared objectively using pelvic venogram scores, and subjectively by symptom resolution, improvement of psychological status and sexual functioning in a prospective randomized trial in 47 patients with pure pelvic congestion syndrome. Patients received either goserelin acetate (3.6 mg/month for 6 months) or medroxyprogesterone acetate (MPA; 30 mg/day for 6 months). Among patients with chronic pelvic pain, those with pure pelvic congestion were mostly parous, had the most severe pelvic signs and symptom scores, lowest rates of sexual functioning, and higher states of anxiety and depression as compared with others. At 1 year after treatment, goserelin remained superior to MPA in terms of pelvic venographic improvement as an objective measure. In alleviation of signs and symptomatology, improvement of sexual functioning and reduction of anxiety and depressive states as subjective measures, goserelin acetate achieved a statistically significant advantage (P = 0.0001) compared with MPA.