Leuprolide Research Articles

A Phase I Clinical Trial Evaluating the Safety and Dosing of Relugolix with Novel Hormonal Therapy for the Treatment of Advanced Prostate Cancer.

Androgen deprivation therapy (ADT), a cornerstone of prostate cancer treatment, is commonly co-prescribed as combination therapy. To better understand the safety and tolerability profile of relugolix, an oral non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, in combination with abiraterone acetate (abiraterone) and apalutamide, a phase I study was undertaken. This is an ongoing, 52-week, open-label, parallel cohort study of relugolix in combination with abiraterone in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) [Part 1] and apalutamide in men with mCSPC or non-metastatic castration-resistant prostate cancer (nmCRPC) [Part 2]. Eligible patients treated with leuprolide acetate or degarelix with abiraterone or apalutamide prior to baseline, at which time they were transitioned to relugolix. Assessments included reporting of adverse events, clinical laboratory tests, vital sign measurements, electrocardiogram (ECG) parameters, and testosterone serum concentrations. In this interim report, patients completing ≥12 weeks were included. Overall, 15 men were enrolled in Part 1 and 10 in Part 2. Adverse events were mostly mild-to-moderate in intensity and were consistent with the known safety profiles of the individual medications. No transition (from prior ADT treatment)- or time-related trends in clinical laboratory tests, vital sign measurements, or ECG parameters were observed. Mean testosterone concentrations remained below castration levels. Combination therapy of relugolix and abiraterone or apalutamide was associated with a favorable safety and tolerability profile consistent with the known profiles of the individual medications. Castration levels of testosterone were maintained after transitioning to relugolix from other ADTs. ClinicalTrials.gov identifier: NCT04666129.

Leuprolide Acetate, a GnRH Agonist, Holds Up Neurodegeneration in an Experimental Glaucoma Model

Glaucoma is the main cause of irreversible blindness worldwide. In short, it is a multifactorial progressive optic neuropathy that correlates with retinal ganglion cell death, optic nerve head disturbances, and visual field disorders. Leuprolide acetate have recently been reported to have neurotrophic properties, the aim of this work was to determine whether it´s systemic administration holds up the neurodegenerative process in an experimental glaucoma model. Wistar rats divided into three groups were included: 1) a control group, 2) a hyaluronic acid-induced glaucoma group, and 3) a hyaluronic acid-induced glaucoma group treated with intramuscular leuprolide acetate. The eye electrical responses to light were recorded by simultaneous full-field electroretinography, and the eyes were processed for histological study. The results showed an improvement in the electrical activity, a recovery of fibers from the optic nerve as well as a reduction of the reactive astrogliosis in the leuprolide acetate treated group. In short, leuprolide acetate is a new potential alternative treatment in glaucoma, as it holds up the neurodegenerative process.

LBA02-09 EMBARK: A PHASE 3 RANDOMIZED STUDY OF ENZALUTAMIDE OR PLACEBO PLUS LEUPROLIDE ACETATE AND ENZALUTAMIDE MONOTHERAPY IN HIGH-RISK BIOCHEMICALLY RECURRENT PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023LBA02-09 EMBARK: A PHASE 3 RANDOMIZED STUDY OF ENZALUTAMIDE OR PLACEBO PLUS LEUPROLIDE ACETATE AND ENZALUTAMIDE MONOTHERAPY IN HIGH-RISK BIOCHEMICALLY RECURRENT PROSTATE CANCER Neal D. Shore, Murilo de Almeida Luz, Ugo De Giorgi, Martin Gleave, Geoffrey T. Gotto, Gabriel P. Haas, Miguel Ramirez-Backhaus, Antti Rannikko, Jamal Tarazi, Swetha Sridharan, Jennifer Sugg, Yiyun Tang, Ronald F. Tutrone, Balaji Venugopal, Arnauld Villers, Henry H. Woo, Fabian Zohren, and Stephen J. Freedland Neal D. ShoreNeal D. Shore More articles by this author , Murilo de Almeida LuzMurilo de Almeida Luz More articles by this author , Ugo De GiorgiUgo De Giorgi More articles by this author , Martin GleaveMartin Gleave More articles by this author , Geoffrey T. GottoGeoffrey T. Gotto More articles by this author , Gabriel P. HaasGabriel P. Haas More articles by this author , Miguel Ramirez-BackhausMiguel Ramirez-Backhaus More articles by this author , Antti RannikkoAntti Rannikko More articles by this author , Jamal TaraziJamal Tarazi More articles by this author , Swetha SridharanSwetha Sridharan More articles by this author , Jennifer SuggJennifer Sugg More articles by this author , Yiyun TangYiyun Tang More articles by this author , Ronald F. TutroneRonald F. Tutrone More articles by this author , Balaji VenugopalBalaji Venugopal More articles by this author , Arnauld VillersArnauld Villers More articles by this author , Henry H. WooHenry H. Woo More articles by this author , Fabian ZohrenFabian Zohren More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003361.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Within 10 years of following definitive therapy for prostate cancer, ∼20–50% of patients experience biochemical recurrence (BCR) characterized by rising prostate-specific antigen (PSA) levels. Given that novel hormone therapy plus androgen deprivation therapy has shown improved survival in metastatic hormone-sensitive prostate cancer, the objective of EMBARK was to evaluate the efficacy and safety of enzalutamide plus leuprolide acetate (LA) and enzalutamide monotherapy, earlier in the disease course in patients with high-risk BCR. METHODS: EMBARK (NCT02319837) is a randomized, phase 3 study of patients with BCR after local therapy considered high-risk: PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP)±postoperative RT. Patients were randomized (1:1:1) to enzalutamide 160 mg/day plus LA (double-blind), placebo plus LA (double-blind), or enzalutamide monotherapy (open-label). LA 22.5 mg was administered every 12 weeks. If the PSA was <0.2 ng/mL at Week 36, therapy was stopped and restarted when PSA was ≥2 ng/mL for patients with primary RP, and ≥5 ng/mL for patients without RP. The primary endpoint, determined by blinded, independent central review, was metastasis-free survival (MFS) with enzalutamide plus LA vs placebo plus LA. Key secondary endpoints were MFS of enzalutamide monotherapy vs placebo plus LA, time to PSA progression, time to antineoplastic therapy, and overall survival of enzalutamide monotherapy or enzalutamide plus LA vs placebo plus LA. RESULTS: A total of 1068 patients were eligible and randomized in the study. The primary hypothesis was that treatment intensification with enzalutamide is associated with improved MFS vs placebo. Results will be analyzed to determine if enzalutamide in combination with LA and enzalutamide monotherapy significantly improved MFS vs placebo with LA and demonstrated an acceptable safety profile consistent with previous randomized controlled trials. Data analysis is ongoing and detailed outcomes will be provided in the late-breaking submission. CONCLUSIONS: The results will address the hypothesis that in patients with high-risk BCR, enzalutamide plus LA and enzalutamide monotherapy were associated with improved MFS vs placebo plus LA. Source of Funding: Pfizer Inc. and Astellas Pharma Inc © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1190 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Murilo de Almeida Luz More articles by this author Ugo De Giorgi More articles by this author Martin Gleave More articles by this author Geoffrey T. Gotto More articles by this author Gabriel P. Haas More articles by this author Miguel Ramirez-Backhaus More articles by this author Antti Rannikko More articles by this author Jamal Tarazi More articles by this author Swetha Sridharan More articles by this author Jennifer Sugg More articles by this author Yiyun Tang More articles by this author Ronald F. Tutrone More articles by this author Balaji Venugopal More articles by this author Arnauld Villers More articles by this author Henry H. Woo More articles by this author Fabian Zohren More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Successful in vitro fertilization following conservative surgery for synchronous endometrioid tumor of ovary and uterus

BackgroundSuccessful pregnancy outcome in women with synchronous ovarian and endometrial cancers is very rare. We report successful pregnancy outcome in a young woman managed conservatively for synchronous endometrial and ovarian cancer.Case presentationThirty years old nulliparous lady presented following exploratory laparotomy, left salpingo-oophorectomy and hysteroscopic polypectomy for left adnexal mass. Histology revealed endometrioid carcinoma of left ovary and moderately differentiated adenocarcinoma in the resected polyp. She underwent staging laparotomy along with hysteroscopy which confirmed above findings without any evidence of further tumor spread. She was treated conservatively with high dose oral progestin (megestrol acetate, 160 mg) and leuprolide acetate 3.75 mg monthly injections for three months along with four cycles of carboplatin and paclitaxel based chemotherapy followed by monthly injection of leuprolide for further three months. After failure of spontaneous conception, she underwent ovulation induction for six cycles along with intrauterine insemination which failed. She underwent in vitro fertilization with donor egg followed by elective cesarean section at 37 weeks of gestation. She delivered a healthy baby of weight 2.7 kg. Intraoperatively 5 × 6 cm right ovarian cyst was found which drained chocolate coloured fluid on puncture and cystectomy was carried out. Histological examination revealed endometrioid cyst of right ovary. Uterus was spared as she wanted to preserve her fertility. She is being followed periodically and is normal nine months following delivery. She is on injection Depot medroxy progesterone acetate once every three months.

Investigation of Lyophilized Microspheres Loaded with Leuprolide Acetate

Abstract: Leuprolide acetate (LA) - a nonapeptide, used for the treatment of some hormone-depending diseases, is unstable and very susceptible to degradation in the aqueous media. Poly (lactic-co-glycolic) acid (PLGA) is a copolymer of lactide and glycolide, that has generated tremendous interest in pharmaceutics because of their excellent biocompatibility, biodegradability, and mechanical strength. PLGA is used for the preparation of biocompatible biodegradable extended-release microspheres. However, the PLGA undergoes hydrolytic degradation in an aqueous environment through cleavage of its backbone ester linkages. As a consequence, PLGA-based microspheres loaded with LA are usually lyophilized to ensure the stability of LA and PGLA and reduce agglomeration, sedimentation, and size change of microspheres during storage. The aim of this present study is to evaluate the influence of lyoprotectants namely mannitol, trehalose, lactose, and saccharose on the stability of LA and characteristics of PLGA-based microspheres loaded with LA upon lyophilization. DSC and FTIR were used to evaluate the biocompatibility of LA and lyoprotectants. The results showed that there was no incompatibility between the LA and lyoprotectants. Mannitol solution 1.25% was used in freeze-drying PLGA-based microspheres loaded with LA. The obtained lyophilized microspheres had a good appearance and low moisture. Lyophilized microspheres after reconstitution had no significant change in drug content, size, and size distribution in comparison to that before freeze-drying.&#x0D; Keywords: Leuprolide acetate, PGLA, lyophilized, stability, biodegradable microspheres.&#x0D; &#x0D;

Clinical outcomes of leuprolide acetate in the treatment of recurrent ovarian granulosa cell tumors

The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach. This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors. This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy. Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of 2 (interquartile range, 1-3) systemic therapy regimens before their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common before first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (interquartile range, 4.8-16.5). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only 1 patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% confidence interval, 54-82). Median progression-free survival was not statistically different compared with that which followed chemotherapy (10.3 months [95% confidence interval, 8.0-16.0] vs 8.0 months [95% confidence interval, 5.0-15.3]; P=.3). In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond.

Abstract OT3-04-01: A Phase 3 study evaluating ovarian suppression following three-month leuprolide acetate in combination with endocrine therapy in premenopausal subjects with HR+, HER2-negative breast cancer (OVELIA)

Abstract Background: In US clinical practice, GnRH agonists are widely used to suppress ovarian function in pre/perimenopausal patients with breast cancer that is moderate-to high-risk for recurrence. Despite extensive use of leuprolide acetate (LA) for ovarian suppression, regulatory approval for this indication has not been established in the US. Additionally, existing three month formulations may not reliably provide ovarian suppression, as demonstrated by escapes in estradiol (E2). An extended-release LA product with a 3-month dosing period specifically developed for ovarian suppression in patients with breast cancer could fill this unmet need. TOL2506 is a 3-month, extended-release formulation of 30 mg of LA. This combination of active drug and in situ polymeric extended release technology is expected to deliver higher exposure to drug than the currently available 3-month (22.5 mg) formulations of LA marketed for advanced prostate cancer and potentially reduce escapes in E2 over the dosing period. Methods: TOL2506A (OVELIA) is a phase 3, single arm, open-label study evaluating the effectiveness of TOL2506 to suppress ovarian function in premenopausal women with HR+, HER2-negative breast cancer. Approximately 250 subjects will be enrolled targeting 220 evaluable subjects, with 30% aged 40 years or younger. Subjects must be premenopausal women, age 18-49 (inclusive), with a diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER&amp;gt;1% and/or, PR&amp;gt;1%, HER2-negative per ASCO CAP guidelines), who are candidates for ovarian suppression with endocrine therapy. For subjects receiving chemotherapy, premenopausal status will be determined prior to initiating chemotherapy. Male subjects with HR+, HER2-negative breast cancer may also be eligible, but will be evaluated for safety analyses only. Eligible subjects will enter the 48 week Treatment Period in 2 groups: those receiving tamoxifen concurrently with TOL2506 or those who initiate therapy with an aromatase inhibitor (AI; letrozole, anastrozole, or exemestane) beginning 6 weeks after the first administration of TOL2506, if E2 &amp;lt; 20 pg/mL has been achieved. After Week 12, subjects will be allowed to switch from receiving an AI to receiving tamoxifen or from tamoxifen to AI at the Investigator’s discretion. Subjects will receive 4 doses of TOL2506 every 12 weeks over the 48 week study duration. The primary endpoint to be evaluated is ovarian suppression, defined as ≥ 90% of subjects with LH levels &amp;lt; 4 IU/L at Week 6. Secondary endpoints include suppression of LH, E2 (&amp;lt; 20 pg/mL for tamoxifen cohort and &amp;lt; 2.72 pg/mL for AI cohort) and absence of menses at weeks 6, 12, 24, 36, and 48. NCT04906395 Citation Format: Ryan Turncliff, Erika Hamilton, Kerlin Lynch, Stuart N. Atkinson. A Phase 3 study evaluating ovarian suppression following three-month leuprolide acetate in combination with endocrine therapy in premenopausal subjects with HR+, HER2-negative breast cancer (OVELIA) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-04-01.

Spontaneous dichorionic diamniotic twin pregnancy following a leuprolide acetate trigger and freeze all cycle for OHSS risk: A case report

Introduction: Gonadotropin-releasing hormone (GnRH) agonist triggers are increasingly used in antagonist in vitro fertilization (IVF) cycles to prevent ovarian hyperstimulation syndrome (OHSS) following a robust ovarian response. The luteolytic effects of GnRH agonists inhibit implantation or spontaneous pregnancy, warranting freezing available blastocysts for future transfer after the risk of OHSS subsides. Case Report: A 33-year-old G1P1 with secondary infertility due to polycystic ovarian syndrome underwent IVF with a GnRH antagonist cycle. A leuprolide acetate trigger for final oocyte maturation was prescribed given her risk of OHSS. A spontaneous dichorionic/diamniotic twin pregnancy ensued. Conclusion: This case reinforces the importance of advising abstinence during the stimulation phase of an IVF cycle and that, although rare, the endometrium may allow for spontaneous conception following a leuprolide acetate trigger, which may further potentiate the risk of late OHSS.

De novo prostate cancer in renal transplant recipients: A single-center study.

326 Background: Renal transplant recipients (RTRs) are at an increased risk of developing solid organ malignancies. Given improved allograft survival and life expectancy, the incidence of prostate cancer (PC) in RTRs appears to be increasing. Previous studies have reported the incidence of PC among RTRs to be between 0.3% and 3.24%. Limited data is available on the clinical characteristics, treatment, predictive markers, and outcomes of PC in RTRs. Methods: We performed a single-center retrospective study of male RTRs who developed PC. We collected the following data on RTRs who underwent transplantation between January 1, 1999, and December 31, 2019: baseline demographics, cause of end-stage renal disease (ESRD), duration of dialysis prior to RT, type of RT (cadaveric vs. living donor), immunosuppressive regimen, interval from RT to diagnosis of PC, stage of PC, type of treatment received, allograft survival, and overall survival (OS) were collected. Results: Among 1093 male RTRs, 15 (1.37%) developed PC. The median age at diagnosis of PC was 60 (range, 49-75) years. Subject races were African American (n=7), Hispanic (n=3), White (n=3), and other (n=2). The median duration from transplant to diagnosis of PC was 72 (range, 12-156) months. PC was diagnosed at stage I in 13 patients, stage II in 1 patient, and stage IV in 1 patient. The management of these patients consisted of local radiation (LR) alone in 6 patients, LR with leuprolide therapy in 6 patients, and radical prostatectomy alone in 1 patient. The patient with stage IV PC was treated with leuprolide and abiraterone acetate and remains progression free at follow-up of 41 months. The 5-year OS for this cohort of patients was 73.3%. Allograft function was preserved in 13 patients 12 months after diagnosis of PC. No PC-related mortality was noted. Conclusions: The incidence of PC in our analysis appears to be consistent with prior published studies. Most of our RTRs with PC had early-stage disease with excellent 5-year survival. The current standard-of-care treatment modalities for PC appear to be effective in the management of these patients. Allograft function was preserved in the majority of RTRs with PC in this study. Further research is required to evaluate the predictive factors for developing PC in RTR.

A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.

TPS398 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients &gt; 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .

Discovery of microglia gonadotropin‑releasing hormone receptor and its potential role in polycystic ovarian syndrome.

Hypothalamic inflammation is a pathophysiological basis of polycystic ovarian syndrome (PCOS), while overactivated and/or excess M1 polarized microglia are considered to be the main reason for the occurrence of hypothalamic inflammation. Therefore, invitro and invivo experiments were performed to assess the relationships between microglia‑mediated inflammatory reactions and endocrine functions in the PCOS hypothalamus. The expression of gonadotropin‑releasing hormone (GnRH) receptor (GnRHR) was demonstrated in hypothalamic microglia, and it was found that low concentration, GnRH agonist, leuprolide acetate accelerated the expression of M2 polarization marker CD206, while high concentration leuprolide acetate increased the expression of M1 polarization marker CD86 invitro. Furthermore, aerobic exercise not only reduced the levels of serum testosterone, luteinizing hormone and GnRH and the amount of overactivated microglia, but also increased the number of M2 microglia in the hypothalamus of letrozole‑induced PCOS rats. In combination, these results not only demonstrated the expression of GnRHR in hypothalamic microglia, but also demonstrated that GnRH can induce microglial polarization, while aerobic exercise may improve the microglia‑mediated inflammatory reaction by reducing the expression of GnRHR in the hypothalamic microglia of PCOS rats.

Vitiligo-like lesions associated with ribociclib in a woman with metastatic breast cancer.

Cyclin-dependent kinase 4/6 inhibitors are new generation drugs that have recently been used in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negativenegative metastatic breast cancer. Recent studies have shown that the use of cyclin-dependent kinase 4/6 inhibitors significantly improves the outcomes of these patients. The most common side effects of cyclin-dependent kinase 4/6 inhibitors are hematological toxicity, gastrointestinal side effects, and fatigue. We aimed to present a case of metastatic breast cancer who was treated with ribociclib and developed vitiligo-like lesions after treatment. A 56-year-old female patient was diagnosed with locally advanced hormone receptor (+)/human epidermal growth factor receptor 2 (-) breast cancer in May 2000. She was followed up with hormonal therapy after adjuvant chemotherapy and radiotherapy. The patient progressed with lung metastases in 2012. Ribociclib, anastrozole, and leuprolide acetate were started in November 2021 after multiple-line chemotherapy. After six cycles of ribociclib, vitiligo-like lesions that developed in the last 1 month were detected on the upper extremities, both hands, neck, chest, and upper back. The patient was referred to dermatology. Topical immunosuppressive therapy and oral corticosteroids were recommended. At the first and third-month follow-up examinations, vitiligo-like lesions were observed to persist. Vitiligo-like lesions are not a life-threatening side effect. However, it significantly affects the quality of life and disrupts the patient's compliance with treatment. Cyclin-dependent kinase 4/6 inhibitors can inhibit cell division or cause premature cell death by acting on the melanocyte cell cycle.

Cannabidiol as a potential novel treatment for endometriosis by its anti-inflammatory, antioxidative and antiangiogenic effects in an experimental rat model

Research questionCan cannabidiol (CBD) be used in the treatment of endometriosis for its anti-inflammatory, antioxidative and antiangiogenic effects? DesignEndometrial implants were surgically induced in 36 female Wistar albino rats. After confirmation of endometriotic foci, the rats were randomized into four groups. In the leuprolide acetate group, rats were given a single 1 mg/kg s.c. leuprolide acetate injection. The other groups were 5 mg/kg CBD (CBD5), saline solution and 20 mg/kg CBD (CBD20); daily i.p. injections were administered for 7 days. After 21 days, the rats were euthanised, and total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) measurements in blood and peritoneal fluid samples, and immunohistochemical staining for TNF-α, IL-6 and vascular endothelial growth factor (VEGF) of endometriotic tissues were evaluated. ResultsSignificant reductions in the endometriotic implant surface area (P = 0.0213), serum TOS (P = 0.0491), OSI (P = 0.0056), IL-6 (P = 0.0236), TNF-α (P = 0.0083) and peritoneal fluid OSI (P = 0.0401), IL-6 (P = 0.0205) and TNF-α (P = 0.0045) concentrations were observed in the CBD5 group when compared with the saline solution group. Compared with the saline solution group, increased TAS concentrations in serum (P = 0.0012) and peritoneal fluid (P = 0.0145) were found in the CBD5 group. The CBD5 and leuprolide acetate groups were similar regarding inflammatory and oxidative stress parameters of serum and peritoneal fluid samples. The CBD5 group showed significantly lower mean intensity in both surface epithelium and stromal cells for VEGF (both P = 0.002) and only in surface epithelium cells for IL-6 (P = 0.0108), when compared with the leuprolide acetate group. ConclusionDue to its anti-inflammatory, antioxidative and antiangiogenic effects, CBD might be a therapeutic agent candidate for endometriosis.

Chronic periadolescent leuprolide exposure affects the development of reproductive physiology and behavior of female and male rats differently, but both mature after treatment termination

BackgroundGnRH agonists have been used to halt the development of puberty in children with precocious puberty since the 1980s. Recently, drugs like Lupron Depot® (leuprolide acetate), have been used to suppress pubertal progression in adolescents who are questioning their gender identity. However, few preclinical studies have been conducted to investigate potential effects of using GnRH agonists in this context.MethodsThe present study tested the effects of daily leuprolide treatment (50 µg/kg, postnatal day (PD) 25–50) on pubertal onset in female (i.e., vaginal opening) and male (i.e., preputial separation) Long-Evans rats. The first estrous cycle immediately after vaginal opening was also measured. Sexual behavior and sexual motivation were tested using the partner-preference paradigm. Female rats were tested during the first behavioral estrus after treatment ended (between PD 51–64). Male rats were tested weekly for four consecutive weeks starting three days after treatment ended (PD 53).ResultsConsistent with previous findings, leuprolide significantly delayed pubertal onset in both female and male rats. In addition, the first estrous cycle during the treatment period was disrupted by leuprolide, as indicated by a failure to cycle into estrus after vaginal opening until treatment ended. However, leuprolide affected neither sexual motivation nor fertility when female rats were tested within 14 days of leuprolide treatment ending. In contrast, the development of copulatory behavior and sexual motivation was significantly delayed by leuprolide in male rats; however, mature reproductive behavior was observed by the fourth week post-treatment.ConclusionsTaken together with previous findings, the present results indicate that male rats may be more sensitive to periadolescent leuprolide administration, taking longer to overcome the effects of leuprolide than female rats. Nevertheless, not long after leuprolide treatment is discontinued, sex-typical reproductive physiology and behavior emerge fully in female and male rats, indicating that the drug’s effects are not permanent. If translatable to humans, leuprolide may be a reversible option to give adolescents more time to consider their gender identity with minimal long-term effects on sexual development.

Efficacy of Leuprorelin 3-Month Depot (11.25 mg) Compared to 1-Month Depot (3.75 mg) for Central Precocious Puberty in Chinese Girls: A Prospective Cohort Study.

A 3-month depot of leuprorelin acetate (LA) was introduced in China in July 2020. However, the clinical experience is limited. The purpose of this study was to compare the efficacy of a LA 11.25 mg 3-month depot with that of a 3.75 mg 1-month depot in suppressing pubertal development for the treatment of central precocious puberty (CPP). Subjects and Methods. A prospective study, including 78 girls with CPP treated with LA, was conducted. 31 patients were treated with a LA 3-month depot, and 47 were treated with a LA 1-month depot. Participants were interviewed at baseline and 6 months. Anthropometric, metabolic, and reproductive data were assessed at each interview. Bone age, serum endocrine hormones, maximum diameter of uterus and volume of ovary of each patient were evaluated. A pharmacoeconomic evaluation was also conducted. Treatment with a 3-month depot was similar to treatment with a 1-month depot in terms of baseline characteristics. After 6 months of treatment, a suppressed level of luteinizing hormone (LH) (LH < 2.5 IU/L) was found in 100% and 95% of the 11.25 mg and 3.75 mg groups, respectively. LH decreased from 2.11 ± 1.83 and 2.82 ± 2.31 at baseline (P=0.172) to 0.37 ± 0.39 and 0.44 ± 0.76 (P=0.758) in the 3-month and 1-month groups, respectively. Follicle stimulating hormone and estradiol levels, bone age/chronological age (BA/CA), height velocity, maximum diameter of uterus and volume of ovary did not show any distinction between the two groups after 6 months of treatment, but both were significantly ameliorated compared with the baseline. The loss of working time of parents and study time of patients and the numbers of visits, injections and laboratory examinations obviously decreased in the 3-month depots. An LA 3-month depot was equally effective and safe as a 1-month depot for hormonal suppression and bone maturation inhibition, providing clinical experience in China. The 11.25 mg depot of LA is a safe, efficient, and economical treatment method for the advanced activation of the hypothalamic-pituitary-gonadal (HPG) axis.

Using change in predicted adult height during GnRH agonist treatment for individualized treatment decisions in girls with central precocious puberty.

It is important to understand what variables influence change in predicted adult height (PAH) throughout GnRHa treatment for central precocious puberty (CPP) to individualize treatment decisions and optimize care. Changes in PAH, chronological age (CA), bone age (BA), BA/CA, and height velocity (HV) were evaluated in girls with CPP throughout treatment with leuprolide acetate (n=77). A second analysis focused on changes in the 3years preceding the first observed BA of≥12years. Relationships were characterized using plot inspection andlinear mixed-effects analyses. Association between treatment duration and last assessed PAH was examined using multiple linear regression models. BA/CA and HV showed a nonlinear change during treatment, with the largest changes and improvement in PAH observed in the first 6-18months. Rate of BA advancement tended to decrease more slowly in girls initiating treatment at a younger BA. On-treatment change in PAH was predicted by concurrent BA/CA change, HV, and BA, as well as CA at treatment initiation. Last assessed PAH was positively associated with longer treatment durations (primary/exploratory models cut-offs of≥33/≥55months). These findings support individualized monitoring during GnRHa treatment. Initial response should be interpreted with caution until 6-18months after treatment initiation and failure should not be assumed based on continued bone maturation in girls starting therapy at a younger age. Treatment cessation should not be automatically based on a diminishing change in PAH or HV, as ongoing treatment may result in continued increase or maintenance of PAH.

Influence of encapsulation variables on formation of leuprolide-loaded PLGA microspheres

Emulsion-based solvent evaporation microencapsulation methods for producing PLGA microspheres are complex often leading to empirical optimization. This study aimed to develop a more detailed understanding of the effects of process variables on the complex emulsification processes during encapsulation of leuprolide in PLGA microspheres using a high-shear rotor–stator mixer. Following extensive analysis of previously developed formulation conditions that yield microspheres of equivalent composition to the commercial 1-month Lupron Depot, multiple variables during the formation of primary and secondary emulsion were investigated with the aid of dimensional analysis, including: rotor speed (ω) and time (t), dispersed phase fraction (Φ) and continuous phase viscosity (µc). The dimensionless Sauter mean diameter (d3,2) of primary emulsion was observed to be proportional to the product of several key dimensionless groups (Φ1,We,Re,ω1t1) raised to the appropriate power indices. A new dimensionless group (Θ ) (surface energy/energy input) was used to rationalize insertion of a proportionate time dependence in the scaling of the d3,2. The dimensionless d3,2 of secondary emulsion was found proportional to the product of three dimensionless groups (Φ2,μ1′μc2,ω2t2) raised to the appropriate power indices. The increased viscosity of the primary emulsion, decreased secondary water phase volume and reduced second homogenization time each elevated encapsulation efficiency of peptide by reducing drug leakage to the outer water phase. These results could be useful for dimensional analysis and improving manufacturing of PLGA microspheres by the solvent evaporation method.

Evaluation of safety and effectiveness of gestrinone in the treatment of endometriosis: a systematic review and meta-analysis.

Endometriosis is a common chronic gynecological disease defined as the presence of endometrial glands and stroma tissue outside the uterus. Gestrinone is an effective antiestrogen that induces endometrial atrophy and/or amenorrhea. The purpose of this systematic review is to provide an evaluation of safety and effectiveness of gestrinone for the treatment of endometriosis. We performed a search in six electronic databases: PubMed, MEDLINE (ovid), Embase, Cochrane CENTRAL (clinical trials), Web of Science and Scopus. Our selected primary outcomes were the changes in dysmenorrhea, pain relief including pelvic pain and dyspareunia. The secondary outcomes embrace hormones parameters, pregnancy rate and adverse events. Of 3269 references screened, 16 studies were included involving 1286 women. All studies compared gestrinone with other drugs treatments (placebo, Danazol, Mifepristone tablets, Leuprolide acetate, Quyu Jiedu Recipe) during 6months. When compared with other drugs treatments, gestrinone relieved dysmenorrhea, pelvic pain, and morphologic response in the ovary. There was an increase on the pregnancy rate. Regarding the side effects observed, gestrinone showed the same adverse events and increased the risk of acne and seborrhea when compared to other treatments. Even if there was any difference in efficacy between gestrinone, danazol, leuprolide acetate, or Quyu Jiedu Recipe Chinese Medicine, it remains unclear due to insufficient data. Based limited evidence available suggests that gestrinone appeared to be safe and may have some efficacy advantages over danazol, as well as other therapeutic interventions for treating endometriosis. However, this conclusion should be interpreted with caution, due the quality of the evidence provided is generally very low or unclear. CRD42021284148.

Clinical development of the GnRH agonist leuprolide acetate depot

Leuprolide acetate is the first GnRH agonist that entered clinical development after the discovery of the native GnRH. Several long-acting depot formulations of leuprolide acetate (ranging from 1-month to 6-month intramuscular injections) have been successively developed for various suppressive treatments in men, women, and children, which are available in the United States and globally. This mini review aims to summarize the key clinical studies that led to regulatory approval of leuprolide acetate depot suspension for injection.

Does Leuprolide Acetate Predict Successful Pain Relief after Hysterectomy and BSO in Endometriosis Patients?

<h3>Study Objective</h3> Evaluate whether patients with endometriosis-associated pelvic pain who achieve pain relief with leuprolide acetate are more likely to achieve pain relief after hysterectomy and oophorectomy (BSO). <h3>Design</h3> Retrospective chart review. <h3>Setting</h3> Academic teaching hospital. <h3>Patients or Participants</h3> Patients who underwent trial of leuprolide acetate prior to hysterectomy and BSO for endometriosis. <h3>Interventions</h3> We performed a retrospective chart review of patients from 2015-2021 who had a diagnosis of endometriosis and underwent a trial of leuprolide acetate prior to hysterectomy with BSO for pelvic pain (n=31). We reviewed pre-operative records, operative notes, and postoperative records to assess whether patients achieved pain relief following ovarian suppression with leuprolide acetate or definitive surgical management with hysterectomy and oophorectomy. Patients who achieved complete pain relief with leuprolide acetate or hysterectomy with oophorectomy were considered having achieved "complete pain relief". <h3>Measurements and Main Results</h3> 31 patients underwent a trial of leuprolide acetate prior to hysterectomy and BSO for endometriosis. Fifteen patients reported "complete pain relief" with leuprolide acetate therapy and 16 did not. The groups were similar in age, ethnicity, race, BMI, parity, number of past treatments for pelvic pain, mode of hysterectomy, blood loss during surgery, presence of adhesions, and surgical complications. There was a significant difference between the two groups as to whether they achieved complete pain relief after hysterectomy with BSO. Among patients with complete pain relief after leuprolide acetate therapy, 73.7% reported complete pain relief after surgery. In patients who did not experience complete pain relief with leuprolide acetate therapy, only 37.5% reported complete pain relief after surgery (p=.045). <h3>Conclusion</h3> Patients who had complete preoperative pain relief using leuprolide acetate were more likely to achieve pain relief with hysterectomy and BSO. A trial of leuprolide acetate prior to surgery may be helpful to predict which patients will benefit from hysterectomy and BSO for endometriosis-related pelvic pain.