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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.

The number, shape and position of NMR spectral lines depend on dynamic processes, and this creates certain difficulties in identification of pharmaceutical substances by NMR spectroscopy. The aim of the paper was to study instances of manifestation of intramolecular dynamic processes that affect identification of organic compounds by NMR, and to illustrate the potential of the methods used for their reduction, as well as associated problems.Materials and methods: 1H and 13C spectra of the following pharmaceutical substances: «buserelin acetate», «valsartan», «goserelin acetate», «iopromide», «clopidogrel hydrogensulfate», «omeprazole», «proroxan», «risperidone», «triptorelin acetate», and «enalapril maleate» were used to demonstrate negative effects of dynamic processes. The spatial structures of conformers were established by 1H-1H ROESY experiments. The quantum-chemical calculation of geometric and thermodynamic characteristics of different conformers was carried out by the PM3 method, and electronic characteristics—by the AM1 method with the help of the HyperChem software.Results: the authors analysed intramolecular dynamic processes which are most commonly encountered in expert work: pyramidal inversion of nitrogen in a heterocyclic compound (risperidone, proroxan, clopidogrel), rotation of molecular fragments around the amide bond (valsartan, iopromide, enalapril), prototropic rearrangements (buserelin, goserelin, omeprazole, triptorelin). The change in exchange rates was explained from the perspective of the change in the system of intra- and intermolecular nonvalent interactions.Conclusions: the use of traditional methods for increasing the rate of dynamic processes (increasing the temperature and changing the solvent) does not always eliminate the negative effects of intramolecular transformations. Methods of smoothing the spectral manifestations of dynamic processes have limited application due to strong intramolecular nonvalent interactions which prevent the conversion of the dynamic process rate into fast exchange. Experts and manufacturers should take into account the manifestation of dynamic processes during identification of pharmaceutical substances by NMR spectroscopy.

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.

Introduction:The design of advanced drug delivery systems based on synthetic and supramolecular chemistry has been very successful. Liposomal doxorubicin (Caelyx®), and liposomal daunorubicin (DaunoXome®), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (Oncaspar®) or goserelin acetate (Zoladex®) represent considerable achievements.Discussion:As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities.Conclusion:The first is using recombinant proteins as drugs i.e. denileukin diftitox (Ontak®) or agalsidase beta (Fabrazyme®). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein, the use of synthetic proteins for drug delivery has been reviewed.

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.

This review focuses on studying the pharmacological effect of cyclic peptides as anti-cancer drugs. There are many examples which are already used to treat cancer, either directly or in the treatment of episodes associated with cancer tumors. Goserelin acetate; is an anti-cancer drug, trade name Zoladex, is an injectable gonadotropin releasing hormone superagonist. Leuprolide acetate; is a gonadotropin-releasing hormone or luteinizing-hormone-releasing hormone analog used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer. Somatostatin, (SST), is a peptide hormone; the peptide hormone somatostatin regulates the endocrine system, affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibits the release of numerous secondary hormones. Octreotide: is a somatostatin mimic, trade name sandostatin, Octreotide is also a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. On the other hand there are many natural bioactive peptides: derived from different foods represent another source of health-enhancing or cancer fighting compounds. Different studies indicate that it is possible that many of these peptides may be released during digestion in the human stomach or during food processing from various plant and animal proteins, especially milk, soy, and fish proteins, for examples Depsipeptides and Argyrins.

The aim of this study was to resolve the lag time problem for peptides loaded PLGA-Hydrogel Microspheres (PLGA-gel-Ms) by blending low molecular PLGA (Mw. 1 kDa) into PLGA (Mw. 10 kDa) as an intrinsic porogen, and then assess the in vitro-in vivo relationship (IVIVR). Here, Goserelin acetate (GOS) was chosen as the model peptides. When compared to additional types of porogen, the intrinsic porogen avoided impurities remaining and protected the bioactivities of the peptides. By adding 10% PLGA (Mw. 1 kDa), the lag time was eliminated both in vitro and in vivo with a desirable EE (97.04% ± 0.51%). The release mechanisms were found to be: a) initial GOS release mainly controlled by pores diffusion and b) autocatalysis of PLGA (Mw. 1 kDa) which increased the quantity of aqueous pores, as revealed by SEM images. To solve the challenges caused by multiphasic release profiles, for the first time the Segmented phases IVIVR were proposed and developed, and showed improved linear fitting effects and supported the proposed release mechanisms. The application of PLGA blends could provide a new insight into PLGA microsphere initial release rate regulation.

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 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.

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.

Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths in men worldwide. This review article contains a summary of analyzes performed by chromatographic methods used for the determination of abiraterone acetate, bicalutamide, cabazitaxel, docetaxel, enzalutamide, flutamide, goserelin acetate, leuprolide acetate, and mitoxantrone hydrochloride drugs used in prostate cancer applications in biological and pharmacological samples. In this review, sample preparation procedures, chromatographic procedures, and detectors used for analytical determinations of these drugs are discussed.

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

Goserelin acetate (Gos) as a synthetic analog of the mammalian gonadotropin-releasing hormone (GnRH) is widely used in the treatment of sex hormone-related conditions. In this paper we present the chemical and biological aspects of its interaction with Cu(II) ions. The mode of Cu(II) binding and the thermodynamic stability of the obtained complexes were characterized by potentiometry, UV-Vis and CD spectroscopic methods. The DFT calculations were applied in order to investigate and confirm the molecular structure of the studied systems. The experimental and theoretical results clearly indicated the involvement of three nitrogens from the peptide and two oxygens from the acetate moieties in the Cu(II) coordination under physiological conditions. The investigated metallopeptide caused single- and/or double cleavage of the sugar-phosphate backbone of the plasmid DNA in the reaction accompanied by endogenous substances such as hydrogen peroxide or ascorbic acid. The degradation of the DNA molecule occurred via the free radical mechanism. Calculations based on measured spectra allowed determining the kinetic parameters of OH formation. The cytotoxic effects of Gos and its metallo-derivative were tested in vitro towards two cancer cell lines (A549 - human lung adenocarcinoma, CT26 - mouse colon carcinoma).

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.