Injection Of Leuprolide Acetate Research Articles

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer

Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Testosterone Recovery for Relugolix Versus Leuprolide in Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study

BackgroundIn the HERO study, relugolix demonstrated sustained testosterone suppression superior to that of leuprolide acetate (97% vs 89%; difference 7.9% [95% confidence interval, 4.1–12%; p < 0.001]). ObjectiveTo analyze testosterone recovery in a prespecified subset of men from the HERO study not indicated to continue androgen deprivation therapy. Design, setting, and participantsMen (N = 934) were randomized (2:1) to receive relugolix 120 mg orally daily or leuprolide acetate injections every 12 wk for 48 wk. Outcome measurements and statistical analysisTestosterone recovery was assessed in 184 men who completed 48 wk of treatment. During the 90-d recovery period, assessments included time to testosterone recovery (>280 ng/dl; ≥80% of baseline testosterone), serum levels of prostate-specific antigen and pituitary hormones, and adverse events. Results and limitationsThe cumulative incidence rate of testosterone recovery to >280 ng/dl at 90 d following drug discontinuation was significantly higher in the relugolix cohort (n = 137) than in the leuprolide acetate cohort (n = 47; 54% vs 3.2%; nominal p = 0.002). The median time to testosterone recovery was faster following relugolix treatment than with leuprolide acetate treatment (86.0 vs 112.0 d). Compared with leuprolide acetate, more men treated with relugolix achieved ≥80% of baseline testosterone levels (39% vs 2.1%). Men ≤65 yr and those with baseline testosterone greater than the median had a higher incident rate of testosterone recovery. Adverse events were generally similar between treatment groups. One limitation is the short testosterone recovery follow-up period. ConclusionsOral relugolix had faster and more complete recovery of testosterone to normal levels after treatment discontinuation than leuprolide acetate in a subset of men from the HERO study. The clinical implications of a faster testosterone recovery with relugolix may be significant for men being treated with androgen deprivation therapy and influence treatment decisions. Patient summaryThe male hormone testosterone is reduced during androgen deprivation therapy for prostate cancer. Reduced testosterone levels cause side effects, impacting patient quality of life. When treatment is stopped, the side effects lessen over time as the levels of testosterone come back to pretreatment range (testosterone recovery). In this study, we found that the time to testosterone recovery was faster with relugolix than with leuprolide acetate.

Effects of Combined Laparoscopic Cystectomy and Leuprolide Acetate Therapy on Anti-Mullerian Hormone Level and Antral Follicle Count Profile in Endometriosis

Objective: This study examines the effectiveness of combined laparoscopic cystectomy and leuprolide acetate therapy on AMH level and AFC profile in endometriosis. Method: This study is a randomized controlled clinical trial with open label form. The subjects were divided into control and therapy groups, with the therapy group receiving leuprolide acetate injection following laparoscopic cystectomy. In both groups, the AMH levels and AFC were examined prior to the surgery and six weeks after before they were compared. Results: There were significant pre-post differences of AMH levels(p = 0.000) and AFC (p = 0.000) in the therapy group but not in the control group. In the therapy group, the mean increases of AMH level and AFC were 0.94 (95% CI: 0.63-1.25) and 9.53 (95% CI: 6.83-12.24), respectively. Linear regression model found that AFC level prior to intervention was a significant predictor of endometriosis ASRM grade (p = 0.001) with an R-value of 0.633, suggesting strong correlation. Conclusion: The combined therapy of laparoscopic cystectomy and leuprolide acetate injection for endometriosis provided better outcome concerning ovarian reserve, as opposed to the therapy with laparoscopic cystectomy alone.

FRI312 Diplopia And Headache After Treatment With GnRH Agonist

Abstract Disclosure: A.A. Zakkar: None. M. Al Mushref: None. M. Fadanelli: None. Case Report: The Patient is a 46-year-old male with past medical history of hypertension and prostate cancer, currently undergoing treatment with leuprolide acetate injections, who presented to the emergency department with a complaint of worsening headache. He received his second injection 3 days prior to admission and within hours he developed a headache in the frontal area that was continuous and worsening over time, increasing with positional changes of his head. One day after the treatment he developed persistent double vision. The patient reported that he has had worsening vision over the last year and was to see an ophthalmologist but was diagnosed with prostate cancer at the same time so he became more focused on the oncologic care. He also reported poor balance, excessive thirst and increased urination of large volumes of urine every hour with nocturia several times. On exam the vital signs were normal, he was A&amp;Ox4 and in no distress. He had left abducens and oculomotor nerve palsy but an otherwise benign exam. MRI of the brain revealed a sellar mass measuring 2.2 x 1.7 x 2.3 cm consistent with pituitary macroadenoma extending into the suprasellar cistern, compressing the pituitary stalk and the optic chiasm. Patient was evaluated by ophthalmology who noted +2 optic nerve edema of the left eye. Laboratory evaluation revealed low ACTH of 6 pg/mL at 5:30AM along with corresponding cortisol level of only 1.6 mcg/dL. FSH was low and LH undetectable as expected with GnRH agonist therapy. Growth hormone level, IGF-1, l and prolactin levels were all normal. The TSH was 0.50 microunits/mL with a freeT4 of 1.0. Urinalysis revealed dilute urine with specific gravity &amp;lt;1.006. Serum sodium on admission was 137 mmol/L and after overnight fasting was 140 mmol/L. The patient was started on desmopressin 0.1 mg po at bedtime and on intravenous dexamethasone 4 mg q6hrs. He was evaluated by neurosurgery and ENT who recommended trans-sphenoidal resection of the mass. Pathology report of the specimen was consistent with a pituitary adenoma with infarction without hemorrhage. The patient reported an improvement in his left eye vision and lateral rectus palsy. He was transitioned to oral hydrocortisone 20 mg daily and 10 mg every afternoon prior to discharge. On follow up with endocrinology several months later he was found to have persistent adrenal insufficiency and developed central hypothyroidism that required treatment. Conclusion: Patients with an undiagnosed pituitary adenoma are at risk of tumor expansion and mass effect as well as pituitary apoplexy during treatment with GnRH agonists. In our case clinical presentation was consistent with pituitary apoplexy without evidence of pituitary hemorrhage soon after GnRH agonist. A full ophthalmologic exam may be an appropriate screening prior to initiation of such therapy. Presentation: Friday, June 16, 2023

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.

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 &amp;lt;40 pg/mL after 4 mg bid po, and &amp;lt;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.

O-307 Cannabidiol as a potential novel treatment for endometriosis by its anti-inflammatory and anti-oxidative effects in an experimental rat model

Abstract Study question Can cannabidiol (CBD) - a nonpsychoactive constituent of the cannabis plant – be used in the treatment of endometriosis by its anti-inflammatory and anti-oxidative effects? Summary answer CBD appears to be a potential novel therapeutic agent in the treatment of endometriosis through inhibiting inflammation and decreasing oxidative stress in a dose-dependent manner. What is known already The endocannabinoid system (ECS) consists of various bioactive lipids that are produced endogenously which activate cannabinoid 1-2 receptors (CB1-2). Alterations in ECS are associated with many physiological and pathological conditions throughout the body including endometriosis. The events that play role in the development and growth of ectopic endometriotic implants are proliferation, angiogenesis, and inflammation. By their anti-inflammatory and anti-oxidative effects, phyto and synthetic cannabinoids had been investigated and started being used for diseases with similar mechanisms. CBD is a nonpsychoactive constituent of the cannabis plant which acts indirectly upon the CB-1 receptor and as an inverse agonist of CB-2 receptor. Study design, size, duration Endometrial implants were surgically induced in 36 female Wistar-Albino rats in the first surgery. After confirmation of endometriotic foci in the second surgery, the rats were randomized into four groups. Group 1 (leuprolide acetate group) was given a single 1 mg/kg subcutaneous injection of leuprolide acetate. Groups 2,3 and 4 were 5 mg/kg CBD, saline solution (control group), and 20 mg/kg CBD injected groups, respectively, and daily intra-peritoneal (i.p.) injections were applied for seven days. Participants/materials, setting, methods After 21 days from the second surgery, the rats were sacrificed and histopathological analysis of endometriotic lesions, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-a) measurements in blood and peritoneal fluid samples, and immunohistochemical staining for TNF-a expression in endometriotic tissue were evaluated. Main results and the role of chance After treatment, significant reductions in TOS, OSI, IL-1, IL-6 and TNF-α levels in the blood and peritoneal fluid samples and TNF-α expression of endometriotic implants (p &amp;lt; 0.01) and increased TAS (p &amp;lt; 0.01) were found in the CBD 5mg/kg and leuprolide acetate groups. Limitations, reasons for caution The limitation is that this is an experimental rat model study. Wider implications of the findings This is the first study in the literature that evaluates the effects of a phytocannabinoid -CBD- on endometriosis in a rat model. With its anti-inflammatory and anti-oxidative effects and favorable safety and tolerability profile, it might be a candidate for a novel treatment in endometriosis. Trial registration number not applicable

English

BACKGROUND We wanted to compare the effectiveness of the treatment and the adverse effects of ulipristal acetate and leuprolide acetate in the medical management of symptomatic uterine fibroids. METHODS This is a randomised controlled study conducted in the the Department of Obstetrics and Gynaecology in Chalmeda Anand Rao Institute of Medical Sciences from January 2019 to January 2020. 60 patients with symptomatic fibroids and excessive uterine bleeding were randomly divided. They were given daily therapy of ulipristal acetate 10 mg orally for 3 months or monthly injection leuprolide acetate 3.75 mg intramuscularly for 3 months. RESULTS Controlled uterine bleeding was observed in 98 % of patients who received oral therapy of ulipristal acetate of 10 mg, and 89 % of patients who received injections of leuprolide acetate, for differences in comparison with leuprolide acetate of 8.8 % points (95 % CI, 0.4 to 18.3) for ulipristal acetate of 10 mg. Median time of amenorrhea for those taking ulipristal acetate of 10 mg was 5 days, and 21 days for leuprolide acetate. 10 % of patients receiving ulipristal acetate reported moderateto-severe hot flashes and 40 % of patients receiving leuprolide acetate reported moderate to severe hot flashes (P &lt; 0.0010 for each dose of leuprolide acetate vs. ulipristal acetate). CONCLUSIONS Daily therapy of 10-mg ulipristal acetate was considered non inferior when compared to monthly injections of leuprolide acetate in control of uterine bleeding, moreover ulipristal acetate therapy was also significantly less likely to cause hot flashes. KEY WORDS Ulipristal Acetate; Leuprolide acetate; Abnormal Uterine Bleeding; Leiomyoma

Uterine Artery Clipping at the Level of the Ureteric Tunnel for Reduction of Blood Flow

Study Objective Though cervical myomas comprise only 5% of total uterine myomas, they present unique surgical challenge due to proximity to the uterine vessels and ureters. We aim to highlight an approach to robotic-assisted hysterectomy with a large cervical fibroid, with minimal blood loss and clear visualization of the displaced anatomy. Design Video Case Presentation. Setting A robotic-assisted hysterectomy (RAH) was performed under general anesthesia in dorsal lithotomy position at a university-affiliated hospital. Patients or Participants 41-year-old G0 with abnormal uterine bleeding in the setting of 5 × 4 × 5 cm subserosal fibroid of the left posterior cervix. The patient was pretreated with leuprolide acetate injections then letrozole to reduce the fibroid volume, however, no change in size was observed. The patient desired definitive management of the fibroid. Interventions Once in the operating room, a uterine manipulator could not be placed due to displacement of the cervix by the fibroid. Careful retroperitoneal dissection was performed to identify the uterine artery coursing over the ureter at the ureteric tunnel of Wertheim. Laparoscopic clips were applied to the uterine artery to decrease blood supply to the fibroid. After completion of the hysterectomy, the fibroid capsule was entered and myomectomy was completed, resulting in separation of the fibroid from the vagina. Measurements and Main Results Estimated blood loss was 50 cc. Final specimen were uterus, fallopian tubes, and cervix weighing 54 g and cervical fibroid weighing 99 g. The patient had an uncomplicated postoperative course and was discharged home on postoperative day 1. Conclusion This case demonstrates the use of minimally-invasive surgical approach to safely complete a hysterectomy in the context of a large, cervical myoma. Our video demonstrates improved hemostasis and visualization of the ureters throughout the case due to placement of vessel clips at the level of the ureteric tunnel. Though cervical myomas comprise only 5% of total uterine myomas, they present unique surgical challenge due to proximity to the uterine vessels and ureters. We aim to highlight an approach to robotic-assisted hysterectomy with a large cervical fibroid, with minimal blood loss and clear visualization of the displaced anatomy. Video Case Presentation. A robotic-assisted hysterectomy (RAH) was performed under general anesthesia in dorsal lithotomy position at a university-affiliated hospital. 41-year-old G0 with abnormal uterine bleeding in the setting of 5 × 4 × 5 cm subserosal fibroid of the left posterior cervix. The patient was pretreated with leuprolide acetate injections then letrozole to reduce the fibroid volume, however, no change in size was observed. The patient desired definitive management of the fibroid. Once in the operating room, a uterine manipulator could not be placed due to displacement of the cervix by the fibroid. Careful retroperitoneal dissection was performed to identify the uterine artery coursing over the ureter at the ureteric tunnel of Wertheim. Laparoscopic clips were applied to the uterine artery to decrease blood supply to the fibroid. After completion of the hysterectomy, the fibroid capsule was entered and myomectomy was completed, resulting in separation of the fibroid from the vagina. Estimated blood loss was 50 cc. Final specimen were uterus, fallopian tubes, and cervix weighing 54 g and cervical fibroid weighing 99 g. The patient had an uncomplicated postoperative course and was discharged home on postoperative day 1. This case demonstrates the use of minimally-invasive surgical approach to safely complete a hysterectomy in the context of a large, cervical myoma. Our video demonstrates improved hemostasis and visualization of the ureters throughout the case due to placement of vessel clips at the level of the ureteric tunnel.

Effect of single-dose depot leuprolide acetate on embryonal implantation: an experimental rat model

The objective of this article is to investigate the effect of single-dose depot leuprolide acetate in rat embryonal implantation and its association with glycodelin A, mucin-1 and leukemia inhibitory factor expression. Thirty-two pregnant Wistar Albino rats were divided into four equal groups: untreated control rats in group I (n = 8) and untreated pregnant rats in group II (n = 8) were injected intraperitoneally with single dose of normal saline, treated rats in group III (n = 8) and treated pregnant rats in group IV (n = 8) were given single 1 mg/kg subcutaneous injection of leuprolide acetate at day 8 of pregnancy. The dams were sacrificed on the 15th day of gestation, uterine horn samples were removed. Immunohistochemical examination of the tissue samples prepared from the control and experimental groups, a statistically significant difference was observed between the groups in the luminal-glandular-decidualized epithelium of the uterus with glycodelin A, mucin-1 and leukemia inhibitory factor. A statistically significant difference was observed between the groups for the concentration of glycodelin A but no statistically significant difference was found for the other two molecules. In light of our findings, leuprolide acetate adversely affected expression and concentration of all three molecules in embryonal implantation model.

SAT-292 Superimposed Peripheral Precocious Puberty Caused by Autonomous Ovarian Follicular Cyst in Being Treated Central Precocious Puberty Patient: Underlying Condition of Herlyn-Werner-Wunderlich Syndrome

Autonomous ovarian follicular cysts are known as the most common cause of peripheral precocious puberty(PPP) in prepubertal girls, and relapses of autonomous ovarian cysts resulting in prolonged estrogen exposure can precipitate early maturation of the hypothalamic-pituitary-gonadal axis, resulting in progression from PPP to central precocious puberty(CPP), which is called “combined precocious puberty”, an evolution which may require GnRH therapy. In present case, PPP caused by autonomous ovarian follicular cyst was developed concomitantly during the treatment course of CPP, with suppressed status of hypothalamic-hypophyseal-axis. In addition, a rare congenital Müllerian anomaly known as Herlyn-Werner-Wunderlich syndrome(HWWS), consisting of uterus didelphys, obstructed hemivagina and unilateral renal agenesis was incidentally diagnosed as an underlying condition. A 7-year-old girl was presented to our clinic with the development of breast buds which was examined as Tanner stage 2-3. Right renal agenesis was diagnosed in infancy. Her bone age was advanced as 10 years of age, and Luteinizing hormone(LH) showed pubertal response in LHRH stimulation test. The pelvic US revealed absence of right kidney and uterine enlargement. Brain MRI showed no specific abnormalities. Based on these results, We diagnosed idiopathic central precocious puberty. Thereafter, we commenced the treatment with Leuprolide acetate 3.75mg every 4 weeks. After the 11th injection of Leuprolide acetate, however, the patient complained of sudden breast engorgement and vagnal bleeding. Being considered as unsuccessful suppression of HPG axis, Leuprolide acetate was boosted. Hormonal analysis results revealed an extremely elevated level of estradiol and suppressed baseline gonadotropin levels. The pelvic US revealed double uterus, which had not been detected to that point. Abdominopelvic MRI demonstrated right renal agenesis and uterus didelphys with clearly separated uterine body, cervix and vagina. About 3cm sized cystic lesion with several internal daughter cysts is also discovered in left adnexa area. Based on all examinations, we concluded that PPP caused by autonomous ovarian cyst was superimposed on treatment course of CPP and HWWS was incidentally found as underlying disease. Maintaining GnRH agonist treatment, the progression of secondary sexual characteristics was halted and left ovarian cyst disappeared. In couclusion, clinician should be aware of possibility of autonomous ovarian follicular cyst when sudden progression of secondary sexual characteristics is shown in being treated CPP patients, and discriminate PPP from unsuccessfully treated CPP. Additionally, careful suspicion for HWWS that is tied to indications of renal agenesis in children may be the key for successful early diagnosis and immediate treatment intervention, which could prevent long-term complications.

A New Sustained-release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer

PurposeThis clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. MethodsA Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28–168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. FindingsAll 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28–168 in 96.8% (95% CI, 92.5%–98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively. ImplicationsLeuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

Clinical Effect of Leuprolide Acetate, an Agonist of GnRH, on Sensitive and Motor Function in a Patient With Chronic Spinal Cord Injury

The spinal cord is the major conduct through which sensory and motor signals pass between brain and body. Spinal cord injury (SCI) results in a disruption of these pathways and dramatic functional losses. There are different experimental approaches to counteracting the effects of SCI, such as the use of neurotrophic factors. It has been demonstrated that GnRH and its agonist leuprolide acetate (LA) have neurotrophic properties in SCI experimental model animals. Here, we report our findings from a patient suffering chronic SCI, who had undergone treatment with LA therapy. Treatment consisted of intramuscular injection of LA each month during 12 months. An important improvement in sensitive and motor functions was seen in the patient after treatment with LA. Further research is necessary to elucidate the mechanism of action of LA in SCI patients. J Neurol Res. 2016;6(5-6):111-113 doi: https://doi.org/10.14740/jnr403w

The impact of postnatal leuprolide acetate treatment on reproductive characteristics in a rodent model of polycystic ovary syndrome

In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS.

Clinical Effect of Leuprolide Acetate, an Agonist of GnRH, on Sensitive and Motor Function in a Patient With Chronic Spinal Cord Injury

The spinal cord is the major conduct through which sensory and motor signals pass between brain and body. Spinal cord injury (SCI) results in a disruption of these pathways and dramatic functional losses. There are different experimental approaches to counteracting the effects of SCI, such as the use of neurotrophic factors. It has been demonstrated that GnRH and its agonist leuprolide acetate (LA) have neurotrophic properties in SCI experimental model animals. Here, we report our findings from a patient suffering chronic SCI, who had undergone treatment with LA therapy. Treatment consisted of intramuscular injection of LA each month during 12 months. An important improvement in sensitive and motor functions was seen in the patient after treatment with LA. Further research is necessary to elucidate the mechanism of action of LA in SCI patients. J Neurol Res. 2016;6(5-6):111-113 doi: https://doi.org/10.14740/jnr403w

Improved implantation and live delivered pregnancy rates following transfer of embryos derived from donor oocytes by single injection of leuprolide in mid-luteal phase

To determine if the use of a single injection of one-mg leuprolide acetate in mid-luteal phase can increase pregnancy rates in donor oocyte recipients.Prospective study where couples were made aware of a study using the gonadotropin releasing hormone agonist (GnRHa) triptorelin that in the mid-luteal phase found improved pregnancy rates following embryo transfer in donor oocyte recipients. They were given the option of a single one-mg injection of the GnRHa leuprolide acetate. Pregnancy outcome was compared according to whether leuprolide was given or not. Also compared were the average first serum beta-hCG level in those who conceived according to taking leuprolide or not.Chi-square analysis showed a significantly higher clinical and live delivered pregnancy rate (63.9% and 52.8%) in those supplementing with leuprolide than those who did not (39.5% and 32.9%). Similarly implantation rates were significantly higher (44.2% vs. 25.2%). The average first serum beta-hCG level for those conceiving and taking leuprolide was 294 mIU/mL vs. 325 mIU/mL for those who did not.Similar to triptorelin the mid-luteal injection of leuprolide acetate improves pregnancy outcome in donor oocyte recipients.

Clarithromycin regresses endometriotic implants in rat endometriosis model

The aim of this study was to investigate the effect of clarithromycin in rat endometriosis and its association with matrix metalloproteinase-9 (MMP-9) expression. After surgical induction of endometriosis, 27 rats were randomised into three groups. Size of endometriotic implants were evalutated and rats in group I (n = 9) were given 100 mg/kg/day of oral clarithromycin, rats in group II (n = 9) were given single 1 mg/kg s.c. injection of leuprolide acetate and rats in group III (n = 9) were not given any medication for 21 days. At the end of 21 days of medication, remaining 23 rats were sacrificed to evaluate morphological and histological features of implants. There was a significant difference between the groups in implant volumes (p = 0.004) before and after medication. Regression of implants were significantly higher in groups I and II than that in control group (p = 0.009 and p = 0.011, respectively). After medication, in group I the implant volume decreased from 62 (12–166) mm3 to 26 (3–87) mm3 (p = 0.012) and in group II the volume decreased from 224 (76–1135) mm3 to 62 (26–101) mm3 (p = 0.028). There was a significant difference between groups in histopathological score (p = 0.024). The epithelial immunohistochemical score of MMP-9 was significantly lower in group II than that in control group (p = 0.014). In conclusion, clarithromycin regresses endometriotic implants in rats, but not via MMP-9.

The effect of captopril on endometriotic implants in a rat model

ObjectiveTo determine the effects of captopril on experimentally induced endometriosis in a rat model. Study designTwenty-four adult, mature female Wistar-Albino rats in which endometriotic implants were induced by transplanting autologous uterine tissue to ectopic sites on the peritoneum. After the endometriotic implants were formed surgically, the 24 rats were randomly divided into three groups. Group 1 (captopril group, eight rats) were given 50mgkg−1d−1 of oral captopril for 21d. Group 2 (leuprolide acetate group, eight rats) were given a single 1mgkg−1 subcutaneous injection of leuprolide acetate. Group 3 (control) were given no medication and served as controls (eight rats). The surface area of the endometriotic implants and the score of histologic analysis. Also, VEGF and MCP-1 levels in peritoneal fluids and bloods were analyzed. ResultsAt the beginning of the medical treatment, the mean surface areas of the endometriotic implants were comparable in all three groups. At the end of the treatment the mean implant surface area in the captopril group and leuprolide acetate group was less than that in the control group. Mean histopathological examination score for the implants post treatment was lower in the captopril and leuprolide acetate groups. Peritoneal fluids VEGF level in the captopril and leuprolide acetate groups was lower than that in the control group. The post-treatment MCP-1 level was also lower in the captopril and leuprolide acetate groups than in the control group. The serum VEGF and MCP-1 levels post treatment were significantly lower in the captopril and leuprolide acetate groups than in the control group. ConclusionAdministration of captopril reduced the size and progression of endometriotic lesions in a rat model.

Effects of Chemical Castration on Sex Offenders in Relation to the Kinetics of Serum Testosterone Recovery: Implications for Dosing Schedule

A growing number of countries are adopting chemical castration as treatment and penalty for sex offenders. The aim of this study is to evaluate the outcome of chemical castration of sexual offenders with a focus on the kinetics of serum testosterone (T) recovery. This prospective analysis included 56 sex offenders imprisoned for sexual offenses at the National Forensic Hospital. Thirty-eight and 18 patients who received 3 and 6 months of leuprolide acetate injections were assigned to group A and group B, respectively. To evaluate treatment efficacy according treatment duration, psychobehavioral assessments and serum T levels were serially measured during the on-cycle and the following observational 12-month off-cycle. Chemical castration and the associated decrease in serum T levels reduced the frequency and intensity of sexual thoughts in 76% and 71% of group A patients and in 78% and 72% of group B patients, respectively. Reductions in masturbation frequency were observed in 74% of group A and 83% of group B patients. The median Wilson's Sex Fantasy Questionnaire (SFQ) scores were also significantly reduced in both groups. In group A, an upsurge of serum T to the flare level was observed during the first 2 months of the off-cycle, accompanied by an intense sexual drive and fantasy. In group B, serum T gradually recovered to the baseline level and continued to upsurge beyond baseline levels during the observational period. SFQ scores of group A returned to pretreatment levels following the observational period; however, SFQ scores of group B remained suppressed. Lack of objective assessments for psychobehavioral outcomes was a limitation. The efficacy of chemical castration varied according to the treatment duration. Regarding the kinetics of serum T recovery, maintaining at least 6 months of treatment warranted stable control of an excessive sexual drive following treatment cessation.