Leuprolide Research Articles

ODP397 Small-volume, Subcutaneous, 6-month Leuprolide Acetate Effectively Reduces Growth Velocity to Prepubertal Levels in Children with Central Precocious Puberty

Abstract Introduction Clinical signs of puberty, growth rate, rate of bone maturation, luteinizing hormone concentrations and estimates of change in predicted adult height are the common variables for assessing efficacy of central precocious puberty (CPP) therapies. (1, 2) All clinical and laboratory parameters are essential when interpreting treatment response. (3) Preservation of adult height potential is an important goal of CPP treatment and accelerated growth velocity can contribute to reduced adult height. (4) We present secondary analyses of growth velocity data from the pivotal trial of the first small-volume, long-acting, subcutaneously administered GnRH agonist for central precocious puberty (CPP), approved in 2020. (5) Methods: 62 children (60 girls, 2 boys) with treatment-naïve CPP received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals. We measured standing height with a calibrated stadiometer at Baseline and Weeks 4, 12, 20, 24, 36, 44, and 48. Growth velocity (cm/year) was calculated as a change in height (cm) between visits/((number of weeks between visits)/52). Results Mean growth velocity decreased throughout treatment from 10.4 cm/year for the time period from screening to baseline to 6. 0 cm/year for Week 34 to 48. The proportion of children who achieved growth velocity 4-6 cm/year increased 2.5-fold from baseline (10%) to Week 48 (25%). Conclusions Subcutaneous leuprolide acetate effectively decreased growth velocity to prepubertal rates in children with CPP. Mean growth velocity from Week 24 to 48 was similar to what is seen in children of the same age without CPP (5.8-6.1 cm/year, depending on sex and race). (6) These data indicate that subcutaneous leuprolide acetate may increase adult height and improve the likelihood of achieving genetic target height range. References Cited 1. Klein KO, et al. Phase 3 trial of a small-volume subcutaneous 6-month duration leuprolide acetate treatment for central precocious puberty. JCEM. 2020. 2. Lee HS, et al. Increased final adult height by gonadotropin-releasing hormone agonist in girls with idiopathic central precocious puberty. PLoS One. 2018. 3. Klein KO, Lee PA. Gonadotropin-releasing hormone (GnRHa) therapy for central precocious puberty (CPP): Review of nuances in assessment of height, hormonal suppression, psychosocial issues, and weight gain, with patient examples. PER. 4. Chen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. Paediatr Drugs. 2015. 5. FENSOLVI® (leuprolide acetate) for injectable suspension, for subcutaneous use [prescribing information]. 2020. 6. Kelly A, et al. Age-based reference ranges for annual height velocity in US children. JCEM. 2014. Presentation: No date and time listed

RF21 | PSAT93 Improvement of Final Height in Congenital Adrenal Hyperplasia Patients Treated With Recombinant Growth Hormone

Abstract Final height (FH) in congenital adrenal hyperplasia (CAH) patients is frequently under -1.5 SDS in relation to the normal population, even in those with good compliance, chronic androgen exposure or supraphysiological glucocorticoid doses could corroborate to this finding. Recombinant human growth hormone (GH) has been used as adjuvant therapy to improve FH in many disorders, but there are scarce data in CAH patients. Objective to analyze the effect of GH therapy on final height of CAH patients with compromised height prediction. Patients and Methods data of 26 patients (7F/19M) were retrospectively evaluated: 10 salt wasting-SW, 11 simple virilizing-SV and 5 with nonclassical form-NC. The SW patients were diagnosed at the neonatal period, SV and NC patients at mean chronological age of 3.6±2 and 7.2±3.8 yrs, respectively. All patients received cortisone acetate, hydrocortisone equivalent dose of 12.6±6.6 mg/m2/day in classical and 8.24±4.7 mg/m2/day in NC form; SW patients also received fludrocortisone 36±9.6mcg/m2/day. Near final height (NFH) was considered as BA of 13yrs for girls and 15yrs for boys; height and target height (TH) were described as SDS. All patients presented hormonal/molecular CAH diagnosis. The t test was used in the statistical analysis. Results Mean chronological and bone age (BA) at the beginning of GH therapy was 9.0±2.4 and 12.3±2yrs, respectively, mean duration of GH therapy was 4.1±1.9yrs and daily dose was 0.15 UI/kg/day. All patients were submitted to pubertal blockage with leuprorelin acetate 11.25 mg each 3 months during 3.9±1.1yrs or cyproterone acetate, mean dose 70±19 mg/m2/d during 4.7±2.5yrs. At the last evaluation, 19 patients (14M/5F) achieved FH: at the beginning of GH therapy mean H/BA in males was -2.1±0.38 and after -0.65±1 SDS (p<0.001). Mean FH in males was 165.7±5.9 cm and mean TH 170.7±8 cm (p>0.05); the TH-FH was -0.6±1.2 SDS. Among females, mean H/BA at the beginning of GH therapy was -2.2±0.7 and after -0.84±0.9 SDS (p=0.01). Mean FH in females was 156±8 cm, mean TH was 160±5.8cm (p>0.05); the TH-FH was -0.6±0.7 SDS. Considering patients with FH and NFH, the FH-TH in males was 0.4±0.2 SDS and -0.15±0.9 SDS in females. An improvement of approximately 12.7cm in males and 12.4cm in females was observed. No patient presented hypertension and 7/26 patients presented insulin resistance, which normalized after GH withdrawal. Conclusion we observed that GH therapy associated with puberty blockers allowed the achievement of final height in the expected range of target height, without significant side effects. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m.

PMON69 Effective Suppression of Gonadotropins and Gonadal Steroids Following Oral Administration of Leuprolide

Abstract A platform designed to enable systemic delivery of peptides via the oral-GI route was employed to deliver low doses of leuprolide --- 4 mg qd (Treatment A, n=9), 4 mg bid (Treatment B, n=9), and 10 mg bid (Treatment D, n=12) --- daily for 28 days to regularly-menstruating, healthy female volunteers. Pharmacodynamic (PD) effects on LH, FSH, estradiol, and progesterone, along with leuprolide drug levels, were assessed weekly and compared to those following a single intramuscular injection of leuprolide acetate 3.75 mg (Treatment C, n=5) in a parallel-group design. The primary PD endpoint was the subject incidence of E2 suppression to ≤40 pg/mL on Treatment Day 29; additional endpoints --- E2 suppression rates on Treatment Days 8, 15 and 22, incidence of 'ovulation' defined as progesterone level ≥3 ng/mL, and suppression of LH and FSH levels --- were assessed on Treatment Days 8, 15, 22, and 29. Safety and tolerability of the test drugs was also assessed. Dose-dependent suppression of E2 was seen, with 66.7%, 87.5%, 100% and 100% of subjects in Treatments A, B, C and D, respectively, achieving E2 ≤40 pg/mL. Median E2 levels on days 15, 22, and 29 were <40 pg/mL after 4 mg bid po, and <20 pg/mL after both 10 mg bid po and the 3.75 mg injection. 'Ovulation rates’ on days 22 and 29 were 0% after both 10 mg bid po and 3.75 mg im. Because of the initial burst following injection of the monthly depot, leuprolide Cmax was greater in Treatment C (17.5 ±2.7 ng/mL) on Dosing Day 1 than for oral leuprolide (3.7 ±3.2 ng/mL for 4 mg qd, 4.1 ±5.1 ng/mL for 4 mg bid), though by Day 29, Css in Treatment C (1.7 ±1.2 ng/mL) was lower than that day's Cmax for oral leuprolide (2.7 ±3.6 ng/mL for 4 mg qd, 4.8 ±6.2 ng/mL for 4 mg bid). Cmax and AUC0-24h were dose-dependent but not strictly dose-proportional. Leuprolide "trough" levels prior to oral dosing were frequently below LLQ (25 pg/mL) in subjects treated with 4 mg qd; this occurred in only 6% of samples on 10 mg bid, and 0% on 4 mg bid, thus confirming reliability of oral delivery of leuprolide. There were no Serious or severe Adverse Events, nor changes in laboratory values of concern. One subject discontinued the study due to a transient episode of nausea, vomiting, and headache during her initial dose of 4 mg po. A total of 80 AEs were treatment-emergent, generally mild in intensity, and spread relatively evenly across all 4 treatment groups. This investigation confirms effective suppression of gonadal steroids via oral administration of leuprolide, comparable to that of injectable leuprolide, and to some marketed doses of GnRH antagonists (historical data). Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

8569 Approach to a Giant Pedunculated Fibroid

<h3>Study Objective</h3> This video reviews the surgical approach to a large pedunculated fibroid including preoperative assessment and intraoperative considerations for performing a laparoscopic myomectomy with contained tissue extraction. <h3>Design</h3> Surgical technique demonstration. <h3>Setting</h3> The patient was seen in an academic medical center. In the outpatient setting, she was consulted by a minimally invasive gynecologic surgeon with expertise in fibroid management. The surgery was performed in the outpatient surgery center. <h3>Patients or Participants</h3> A 37-year-old nulliparous female with a fibroid uterus. Based on preoperative imaging, the predominant fibroid was a posterior, pedunculated fibroid with an estimated weight of 1300 grams. The patient agreed to the use of photos and videos for educational purposes via an informed consent process. <h3>Interventions</h3> Preoperatively, the patient received leuprolide acetate injection in effort to decrease the size and vascularity of the large, broad-stalked, pedunculated fibroid. Eight weeks later she underwent laparoscopic myomectomy with a minilaparotomy for contained tissue extraction. Prior to the start of the surgery, she received misoprostol and tranexamic acid to aid in hemostasis. The video demonstrates the intraoperative use of vasopressin in addition to the surgical approach to the primary myomectomy. Use of the minilaparotomy for surgical assistance, open myomectomy of an additional fibroid, and contained morcellation is portrayed in the video. <h3>Measurements and Main Results</h3> N/A. <h3>Conclusion</h3> This video reviews the surgical approach to a large, pedunculated fibroid via laparoscopic myomectomy with minilaparotomy. The surgery was without complication and the patient was discharged on the same day. Key learning points that lead to a successful case included: preoperative optimization when you expect to encounter high risk of blood loss, retention of a rim of serosa overlying a broad pedicle when performing myomectomy of an exophytic fibroid, and use of minilaparotomy to aid progression of case, not only for tissue extraction.

PMON70 Systemic Delivery of Leuprolide via Oral Administration

Abstract We have developed a technology platform employing enteric coating and permeation enhancement to enable systemic delivery of peptides via the oral route. To determine whether this platform can deliver therapeutic doses of the GnRH agonist leuprolide, we conducted a randomized, four-period, four-treatment, crossover pharmacokinetic and food effect study in 14 healthy female volunteers, which compared PK profiles following single administrations of 1 and 4 mg of leuprolide --- the latter under both fasting and fed conditions --- to that of a single subcutaneous injection of 1 mg of leuprolide acetate. Study objectives were to assess the relative bioavailability, dose proportionality, safety and tolerability of orally administered leuprolide, as well as the effect of food on drug absorption. Frequent blood sampling for 24 hours followed each dose, and each treatment was separated by 7 days. Of the 14 subjects enrolled and dosed, 12 completed the study. Mean Tmax occurred at 2.24 ±0.38, 2.77 ±0.46, and 3.49 ±0.23 hrs, for 1 mg po, 4 mg po (fasting), and 1 mg sc leuprolide, respectively. Mean Cmax was 1.9 ±1.3, 10.2 ±9.6, and 59.4 ±9.1 ng/mL, for the aforementioned treatments. Mean AUC0-24h was 3.5 ±2.1, 19.3 ±16.8, and 163.0 ±18.8 ng*h/mL, respectively. Relative to 1 mg sc leuprolide, oral doses of 1 mg and 4 mg (fasted) achieved 2.2 ±1.3% and 3.0 ±2.5% bioavailability. While differences in the dose-normalized parameters were not statistically significant, formal criterion of dose-proportionality (i.e. 90% CI within 80-125%) was not met. 'Fasting' conditions included an overnight (10-hr) fast prior to dosing, and no food consumption for 4 hours following dosing. The 'fed' condition involved consumption of a high-fat, high-calorie meal 30 minutes prior to drug administration. Significant negative impact of food on both rapidity and extent of drug absorption was observed in nearly all subjects, with measurable leuprolide levels sufficiently sparse as to prevent robust PK assessments in this group. The subject incidence of treatment-emergent adverse events (TEAEs) was comparable across all four treatment groups, including sc leuprolide, and was not dose-dependent. The most commonly observed TEAEs across all treatment groups combined were nausea (43%), headache (43%), and increased libido (21%). All other TEAEs were reported by only one or two subjects. The study drugs were well tolerated; most AEs were mild in severity (none were severe or serious), and 30 of 53 (57%) deemed unrelated to study drug. No notable changes were observed in laboratory values or vital signs. This study thus confirmed the successful oral delivery of leuprolide, a 1209-dalton nonapeptide, via the oral route. Investigations now in progress are assessing the feasibility of delivering substantially greater amounts of the drug orally, in order to provide an alternative to parenteral administration of this widely used therapeutic. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Spawning induction and larval rearing in the thinlip gray mullet (Chelon ramada): The use of the slow release gonadotropin releasing hormone analog (GnRHa) preparation, leuprorelin acetate

The thinlip gray mullet (Chelon ramada) belongs to the Mugilidae family, it is a low-trophic, euryhaline species adapted to a wide range of environmental conditions. As such, it represent a candidate to diversify aquaculture production toward more sustainable species. Nonetheless, several bottlenecks have to be overcome before production is undertaken at commercial scale. Indeed, C. ramada mature females do not spawn without hormonal treatments in captivity. This report describes the use of the gonadotropin releasing hormone analog (GnRHa), leuprorelin acetate as an effective single-dose inducer of spawning in this species. Wild mature females (n = 10; 29 ± 1 cm total length, TL and 199 ± 20 g body weight, BW) exhibiting protruded papilla and bulging abdomen, presenting vitellogenic oocytes (diameters higher than 657 µm) and fluent males (n = 21; 28 ± 1 cm TL and 181 ± 80 g BW) were treated with a single injection of leuprorelin acetate. Breeders spawned more than 500,000 eggs with a mean fertilization and hatching rate of 92 ± 3 and 91.4 ± 0.4 %, respectively. Larvae grew according to the equation y = 2.6841e0.044x, mean survival rate at 19 dph was 13.8 ± 1.5 %. Mean SGR% day−1 slightly decreased concomitantly with tail flexion, probably for a greater investment on ontogenic development rather than growth. Present results suggest that mature C. ramada presents easily recognizable reproductive traits, adapts without difficulty to captive conditions, and can be easily induced to spawn administrating a single dose of leuprorelin acetate. The protocol used in our study resulted in high fertilization and hatching rates, as well as promising larval survival minimizing broodstock stress.

Calsium Supplementation with Rasbora sp. to Prevent Loss of Bone Mineral Density during Gonadotropin-releasing hormone Agonis Long-term Treatment

Background. Gonadotropin-releasing hormone (GnRH) agonist widely used to induce hypoestrogenic climate overcoming any benign gynecologic abnormalities such as endometriosis, adenomyosis, or various cause of abnormal uterine bleeding. Hypoestrogenic cause some of adverse effect mainly loss of bone mineral density (BMD). Suplementation of calcium improve loss in BMD, hence prevent development of osteoporosis. Certain area of Indonesia shows specific biodiversity, for example South Borneo has its wetland biodiversity in swamp and river. Processed food from fishery like Rasbora sp. (locally called Seluang fish) is local favourite due to access and economical reason.&#x0D; Method. Studies included 24 reproductive age (15-49 years old) female on agonist GnRH leuprolide acetate 11,25 mcg regimen given subcutaneously. Measurement of bone mineral density was done twice within 3 months apart, before and after first agonist GnRH treatment. During observation, subject was divided to one of three daily supplementation belows, placebo containing saccharum lactis, grinded powder of 500 mg of calcium, or grinded powder of dried Rasbora sp containing 500 mg of calcium. Measurement pre- and post- supplementation was count using bone quality index with Osteosys of Sonost 3000.&#x0D; Result. Placebo supplementation group in GnRH agonist has bone mineral density loss of -22,7201 greater than 500 mg grinded powder of lactate calcium dan grinded powder of rasbora sp, respectively -4,4570 and -3,3634 after 3 months of trial. Homogeneity test shown p=0.031 level of significancy and ANOVA resulted a significant difference from three classes. Post Hoc resulted calcium lactate supplementation 18,26 + 3,20 greater (p = 0.001) and grinded powder of Seluang 19,36 + 3,20 greater (p = 0.000). Both form of calcium lactate and fish powder supplementation have no significant differences.&#x0D; Conclusion. Calcium supplementation in both of calcium lactate powder and natural resources help maintaining bone mineral density during GnRH agonist treatment. Seluang fish (Rasbora sp.), abundantly found along Indonesia people especially in South Borneo, has similar potency with pharmaceutical calcium lactate product in same weight. Fishery product, has beneficial trace element for bodies, 84 mg of calcium (Ca), 6,81 % of magnesium (Mg), 13,4 mg of iron (Fe), dan 3.97 % of zinc (Zn).&#x0D; Keyword: Bone mineral density, Calcium supplementation, Agonist GnRH, Rasbora Sp.

Case - Leuprolide acetate-induced necrotic skin ulceration.

Androgen deprivation therapy (ADT) has become a well-established modality in the management of locally advanced and metastatic prostate cancer.1 Leuprolide acetate, a synthetically derived gonadotropin-releasing hormone receptor (GnRHR) agonist, is commonly used for ADT in men.2 Despite proven effectiveness, the administration of GnRHR agonists is associated with common adverse reactions, such as impotence, hot flashes, and fatigue. Injection site reactions have also been documented, however, are infrequent, with the most common being localized pain.3,4 Here, we report a case of necrotic skin ulceration following multiple administrations of intramuscular leuprolide acetate.

Continuous administration of leuprolide acetate improves urinary function in male rats with severe thoracic spinal cord injury

AimsTo determine if a continuous administration of leuprolide acetate (LA), a synthetic agonist for the gonadotrophin-releasing hormone receptor, facilitates the recovery of urinary function in spinal cord injured male rats. Main methodsMale Wistar rats were randomized into spinal cord injury (SCI; n = 7), SCI with continuous administration of LA for two weeks via implantation of a subcutaneous osmotic pump (SCI + LA; n = 7), Sham SCI (SH-SCI; n = 6) or no surgery (Intact; n = 6) groups. Micturition, hind-limb nociception and locomotor behaviors were analyzed before and after surgical procedures on days 7, 14, 21 and 28. After behavioral studies, electromyography of the external urethral sphincter (EUS-EMG) and cystometric (CMG) studies were performed in all groups. Key findingsSCI significantly decreased frequency of voids and CMG parameters (p < 0.001), abolished the bursting activity of the EUS during CMG, significantly increased hind limb sensory threshold and decreased locomotor performance in comparison to the other groups (p < 0.001). Continuous LA treatment significantly increased the frequency of voids and improved CMG parameters (p < 0.001), exhibiting bursting EUS activity during CMGs, and enhanced locomotor performance in comparison to SCI rats (p < 0.001). SignificanceSCI severely affected behavioral and functional micturition processes, including sensory and locomotor functions. Systemic and uninterrupted treatment with LA improves the recovery of micturition behavior and the synergistic function of the EUS. Furthermore, sensory and locomotor responses were also improved in SCI rats. This procedure may have a therapeutic potential to facilitate urinary function recovery in patients with SCI.

Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States.

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.

Hormonal Therapy in Pretreated Patients With Recurrent Ovary Granulosa Cell Tumor

Objective: To evaluate the effectiveness of hormonal therapy (HT) in patients with recurrent adult ovary granulosa cell tumors. Methods: The clinical and treatments features of the patients who received HT were studied retrospectively. The efficacy and safety of HT were evaluated. The Kaplan-Meier technique was used to conduct survival analysis. Results: The research involved a total of thirteen patients. The median age of the participants was 49 years (range: 34-61). Since diagnosis, the median number of surgeries has been three (range: 2-8). At least one chemotherapy regimen has been administered to 12 (92.3%) patients. Ten of the patients (76.9%) had at least two metastatic areas. Lung metastases were found in two (15.4%) of the patients. Inhibin B levels were elevated in 81.2% of patients before hormone treatment. The patients received different HTs (Leuprolide acetate + anastrozole-three patients, leuprolide acetate + tamoxifen-six patients, only anastrozole-three patients, only tamoxifen-one patients). The median progression-free survival was found 17.7 months (95 % CI: 14.7-20.6). In four (33.4%) patients, an overall response (complete or partial) was identified. A stable response was observed in eight (66.7%) patients. Conclusions: HT is effective in pretreated individuals with recurrent ovarian granulosa cell tumors, according to this research. Despite the limited number of patients and treatment variability, disease control was achieved in all patients. Also, we found that Inhibin B levels were associated with treatment response.

MED12 mutations in uterine leiomyomas: prediction of volume reduction by gonadotropin-releasing hormone agonists

Gonadotropin-releasing hormone agonists are used to treat premenopausal uterine leiomyomas; however, leiomyoma volume reduction is not always achieved. The reduction rate after this treatment varies for each leiomyoma, even in the same patient. Therefore, an effective method for predicting uterine leiomyoma volume reduction is required to reduce the adverse hypoestrogenic effects and drug-related economic burden related to gonadotropin-releasing hormone agonists. This study aimed to determine the predictive use of MED12 mutations for evaluating the effect of gonadotropin-releasing hormone agonist treatment concerning reducing uterine leiomyoma volume and to predict the MED12 mutation status based on the findings of magnetic resonance imaging performed before treatment. MED12 exon 2 mutation and erythropoietin expression in uterine leiomyomas were evaluated concerning volume reduction, as measured using magnetic resonance imaging. We developed a system for classifying leiomyomas according to T2-weighted magnetic resonance imaging signals to noninvasively predict the presence or absence of MED12 mutations in leiomyomas. Leiomyoma samples (>5 cm) were obtained from 168 patients during surgery (hysterectomy or myomectomy) between 2005 and 2021 at Yokohama City University Hospital. To analyze the rate of leiomyoma volume reduction, 41 patients had been preoperatively administered the gonadotropin-releasing hormone agonist (leuprorelin acetate 3.75 mg, monthly subcutaneous injection) for 3 months; magnetic resonance imaging was performed before and after treatment without contrast material. Patients with MED12 exon 2 mutations had smaller volume reduction after treatment with the gonadotropin-releasing hormone agonist (P<.001, Mann-Whitney U test) and displayed lower signal intensity on T2-weighted images than those with leiomyomas expressing wild-type MED12 exon 2. The newly proposed magnetic resonance imaging-based classification system showed that MED12 exon 2 mutations were more frequent in the low-signal group than in the high-signal group, with nearly equal proportions of mutated and wild-type MED12 exon 2 leiomyomas noted in the intermediate group. The low-signal group had significantly lower erythropoietin expression levels than the high-signal group (P<.001, Kruskal-Wallis test with the Dunn posthoc analysis). MED12 mutation status can be a candidate marker for predicting the effect of gonadotropin-releasing hormone agonists on uterine leiomyoma reduction. Magnetic resonance imaging findings can be used to determine MED12 mutation status as a noninvasive strategy to select patients who will most likely benefit from gonadotropin-releasing hormone agonist treatment.

"Electromyographic and Clinical Improvement in a Chronic Spinal Cord Injury Patient Treated with Leuprolide Acetate, a Case Report"

"Electromyographic and Clinical Improvement in a Chronic Spinal Cord Injury Patient Treated with Leuprolide Acetate, a Case Report"

A single-dose, randomized, open-labeled, parallel-group study comparing the pharmacokinetics, pharmacodynamics and safety of leuprolide acetate microspheres 3.75mg and Enantone® 3.75mg in healthy male subjects.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43–118.53%, 109.13–141.88%, 109.53–139.54%, and 105.17–145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80–93.57%, 88.17–110.55, 95.72%–118.50%, and 79.77–105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20200641.

Long-acting injectable PLGA/PLA depots for leuprolide acetate: successful translation from bench to clinic.

The excellent properties of polyesters combined with their ease of synthesis and modification enabled their wide use in the pharmaceutical industry. This has been translated into the approval of several injectable depots for clinical use. Long-acting depots for leuprolide acetate were among the first and most successful examples including Lupron Depot® and ELIGARD®. Studying these products is of great interest for researchers in both industry and academia. This will undoubtedly pave the road for the development of new as well as generic long-acting depots for a variety of drugs.

Fertility-sparing surgery for diffuse adenomyosis: a narrated, stepwise approach to the Osada procedure

To equip reproductive surgeons with an approach to the Osada procedure and critical prophylactic hemostatic measures that optimize perioperative outcomes. Stepwise demonstration of the Osada procedure with narrated video footage. Definitive management of symptomatic adenomyosis requires hysterectomy. However, adenomyomectomy can improve symptoms and restore anatomy while maintaining fertility potential. Limited but comparable perioperative outcomes exist for minimally invasive methods of adenomyomectomy, and most involve resection of focal, not diffuse, adenomyosis. Among the literature involving resection of diffuse adenomyosis using minimally invasive methods, relatively small volumes of resected tissue are reported and none include obstetric outcomes. Most published reports for excision of diffuse adenomyosis involve laparotomic resection, likely because of specific intraoperative challenges curtailed by this approach. In response, a laparoscopic-assisted laparotomic approach was developed in 2011 by Dr. Hisao Osada, a reproductive surgeon in Japan. This procedure involves aggressive excision of adenomyotic tissue with prophylactic hemostatic techniques and subsequent uterine wall reconstruction using a triple-flap method. Compared with other excisional methods for diffuse adenomyomectomy, the Osada procedure has the best reported obstetric outcomes. A 37-year-old nulliparous female presented with pelvic pain, bulk symptoms, abnormal uterine bleeding, and infertility. Physical examination demonstrated a 20-week, bulky uterus with limited bimanual mobility. Her endometrial cavity was inaccessible because of marked anatomic distortion. Magnetic resonance imaging revealed marked abnormality of her endometrial contour because of a 15 cm adenomyoma with diffuse adenomyomatous tissue in the posterior uterine compartment. Prior interventions included a trial of combined hormonal contraceptive, leuprolide acetate, and tranexamic acid. She was interested in fertility-sparing adenomyomectomy to address symptoms and fertility potential and chose to proceed with the Osada procedure. She was optimized medically with oral and parenteral iron therapy to bring her hemoglobin from 55-111 g/L preoperatively. Institutional review board approval and informed consent from the patient were obtained. The Osada procedure was performed using the following 8 surgical steps: Systemic administration of tranexamic acid was also administered intraoperatively. Perioperative blood loss, anatomic normalization, symptom remediation, and maintenance of fertility potential. Perioperative blood loss was minimal, 469 g of adenomyotic tissue was extracted, and discharge was on postoperative day 2 without any complications. Three months later, cyclic pain and bleeding had improved markedly, ultrasound confirmed Doppler flow throughout the uterus, hysterosalpingogram demonstrated a nonobliterated endometrial cavity and tubal patency, and magnetic resonance imaging confirmed normalized uterine dimensions measuring 11 × 7 cm from 19 × 10 cm. Most literature supports waiting at least 6-12 months and until demonstration of normalized uterine blood flow in the operated area before attempting conception. Fertility-sparing excision of diffuse adenomyosis can be achieved safely using the Osada procedure, following the 8 discrete steps demonstrated in this video. Reproductive surgeons can reference this video to teach and maintain this important procedure.

A case series of androgen receptor (AR) inhibition by bicalutamide in combination with leuprolide acetate and exemestane in recurrent AR positive adult-type ovarian granulosa cell tumor (AGCT) (158)

Objectives: There remains a need to develop targeted therapies for recurrent AGCT that produce measurable tumor responses. The FOXL2C134W mutation is identified in nearly all AGCT. In a genetically engineered mouse model utilized by Cluzet et al., tumorigenesis was associated with the inactivation of p53 and Rb pathways, increased circulating androgens, estradiol, and antimullerian hormone along with decreased FOXL2 abundance [1]. By examining the pathways involved in granulosa cell development, including limitations on GnRH-induced apoptosis, aromatase induction, and increased androgen expression, a novel treatment regimen is proposed for recurrent AGCT: bicalutamide (androgen receptor antagonist), exemestane (aromatase inhibitor), and leuprolide acetate (gonadotropin-releasing hormone receptor agonist) to block excess steroidogenesis seen in AGCT. Methods: Six patients identified at our institution with recurrent AGCT and tumor AR positive (by Leica IHC-AR27 antibody) were treated with bicalutamide 50mg PO once daily, Exemestane 25mg PO once daily, and Leuprolide acetate 3.75mg IM every four weeks. All patients were heavily pre-treated, with two to seven prior lines of therapy and had undergone two to seven surgeries. Prior treatment lines consisted of prior chemotherapy, hormonal therapy, and targeted therapies, including bevacizumab and everolimus. Patients were monitored for toxicities and for response to treatment via surveillance exams, inhibin B levels and CT scans. Results: Based on RECIST v1.1 criteria, of the six patients receiving bicalutamide, exemestane, and leuprolide acetate, two patients had a partial response, four patients had stable disease and one patient had progressive disease. Strong AR expression in 95% of cells was identified in the tumors of patients who had a partial response. This drug combination has been well-tolerated. There has been one hospitalization for disease-related complications; no other grade 3 or higher toxicities reported thus far. Conclusions: Based on the response of our institutional cohort and the rationale behind the antiandrogen/aromatase inhibitor/GnRH agonist combination in recurrent AGCT, this regimen of bicalutamide/exemestane/leuprolide acetate is a promising treatment. An NRG concept has been submitted to proceed with a single-arm, multicenter phase II study of this regimen in patients who meet the criteria of recurrent AGCT, AR expression, measurable disease, and one prior line of therapy. Objectives: There remains a need to develop targeted therapies for recurrent AGCT that produce measurable tumor responses. The FOXL2C134W mutation is identified in nearly all AGCT. In a genetically engineered mouse model utilized by Cluzet et al., tumorigenesis was associated with the inactivation of p53 and Rb pathways, increased circulating androgens, estradiol, and antimullerian hormone along with decreased FOXL2 abundance [1]. By examining the pathways involved in granulosa cell development, including limitations on GnRH-induced apoptosis, aromatase induction, and increased androgen expression, a novel treatment regimen is proposed for recurrent AGCT: bicalutamide (androgen receptor antagonist), exemestane (aromatase inhibitor), and leuprolide acetate (gonadotropin-releasing hormone receptor agonist) to block excess steroidogenesis seen in AGCT. Methods: Six patients identified at our institution with recurrent AGCT and tumor AR positive (by Leica IHC-AR27 antibody) were treated with bicalutamide 50mg PO once daily, Exemestane 25mg PO once daily, and Leuprolide acetate 3.75mg IM every four weeks. All patients were heavily pre-treated, with two to seven prior lines of therapy and had undergone two to seven surgeries. Prior treatment lines consisted of prior chemotherapy, hormonal therapy, and targeted therapies, including bevacizumab and everolimus. Patients were monitored for toxicities and for response to treatment via surveillance exams, inhibin B levels and CT scans. Results: Based on RECIST v1.1 criteria, of the six patients receiving bicalutamide, exemestane, and leuprolide acetate, two patients had a partial response, four patients had stable disease and one patient had progressive disease. Strong AR expression in 95% of cells was identified in the tumors of patients who had a partial response. This drug combination has been well-tolerated. There has been one hospitalization for disease-related complications; no other grade 3 or higher toxicities reported thus far. Conclusions: Based on the response of our institutional cohort and the rationale behind the antiandrogen/aromatase inhibitor/GnRH agonist combination in recurrent AGCT, this regimen of bicalutamide/exemestane/leuprolide acetate is a promising treatment. An NRG concept has been submitted to proceed with a single-arm, multicenter phase II study of this regimen in patients who meet the criteria of recurrent AGCT, AR expression, measurable disease, and one prior line of therapy.

Polymer source affects in vitro-in vivo correlation of leuprolide acetate PLGA microspheres

Poly(lactic-co-glycolic acid) PLGA (release controlling excipient) plays a dominant role on the performance of PLGA based long-acting parenterals. These types of drug products typically exhibit complex multi-phasic in vitro/in vivo release/absorption characteristics. In particular, owing to their large size, charged state, and hydrophilicity, peptide loaded microspheres can exhibit more complex release mechanisms. Accordingly, it is challenging to develop Level A in vitro-in vivo correlations (IVIVCs) for such complex long-acting parenterals. With the objective of gaining a better understanding of how to achieve IVIVCs for peptide loaded PLGA microspheres, formulations with similar as well as different release characteristics were prepared with PLGAs from different sources. Leuprolide acetate was selected as the model drug. Owning to the different physicochemical properties of the PLGAs (such as inherent viscosity, molecular weight and blockiness), the formulations exhibited significant differences in their critical quality attributes (such as particle size, porosity and pore size) and consequently had different in vitro and in vivo performance. Affirmative conventional IVIVCs were developed that were able to predict the in vivo performance using the corresponding in vitro release profiles. In addition, the developed conventional IVIVCs were able to discriminate between formulations with comparable in vitro/in vivo performance and those that had dissimilar in vitro/in vivo performance. The present work provides a comprehensive understanding of the influence of PLGA source variations on IVIVC development and predictability for peptide loaded PLGA microspheres.

Leuprolide Acetate Treatment for Ovarian Cysts in Breast Cancer Patients Under Tamoxifen Therapy

OBJECTIVE: The aim of this study is to evaluate the outcomes of gonadotropin-releasing hormone agonist treatment for ovarian cysts, which are developed during tamoxifen use due to breast cancer. STUDY DESIGN: This was a retrospective cohort study including the patients who were under tamoxifen treatment due to stage I-III breast cancer and who were administered leuprolide acetate for ovarian cysts with low malignancy risk between 2012-2020. RESULTS: Leuprolide acetate was administered to a total of 16 patients with ovarian cysts. The median age was 39.5 (33-52), the median size of the ovarian cyst was 42.5 (39-79) mm, and the median duration of tamoxifen use was 22 (7-36) months. Leuprolide acetate was administered at doses of 3.75 mg for 1 month at 10 (62.5%) patients, 7.5 mg in two months at 3 (18.75%) patients, and 11.25 mg in three months at 3 (18.75%) patients. Ovarian cysts were regressed after treatment at 13 patients, while 3 patients underwent surgery. CONCLUSION: Leuprolide acetate can be used as an option in the treatment of ovarian cysts that develop in breast cancer patients under tamoxifen therapy. Keywords: Breast neoplasms, Gonadotropin-releasing hormone, Ovary, Ovarian cyst, Tamoxifen

Advanced delivery of leuprorelin acetate for the treatment of prostatic cancer

ABSTRACT Introduction Androgen-deprivation therapy (ADT) is the main therapy for patients with advanced and metastatic prostate cancer (PCa) and, in combination with radiotherapy, for patients with localized high-risk PCa. Due to its favorable tolerability among different treatments available for ADT, leuprorelin acetate is well established as the leading luteinizing hormone-releasing hormone (LHRH) analog. The development of second-generation leuprorelin acetate (LA) depot formulation (Eligard®, Recordati S.p.A) allowed a consistent and controlled release of leuprorelin between injections and a more efficient reduction of testosterone levels with respect to conventional LHRH agonists. Areas covered This work provides a summary of the biological and clinical rationale for using LA to manage PCa and presents the current evidence about the therapeutic activity of the LA gel depot formulation, used as an advanced leuprorelin acetate delivery method. Expert opinion Results of the registration studies and post-marketing clinical trials demonstrate that the LA gel depot provides long-term efficacy in the clinical practice and a good degree of tolerability. Overall, collected data suggest that the LA gel depot can represent the ADT reference therapy in advanced PCa.