Subcutaneous Leuprolide Acetate Research Articles

Unstimulated Luteinizing Hormone for Assessment of Suppression during Treatment of Central Precocious Puberty with 6-Month Subcutaneous Leuprolide Acetate: Correlations with Clinical Response

Introduction: Phase 3 trial of 6-month subcutaneous leuprolide acetate (SC-LA) in children with central precocious puberty (CPP) demonstrated efficacy and safety. The aims of this secondary analysis were to evaluate unstimulated luteinizing hormone (LH) as efficacy measure, assess clinical suppression metrics, and present biochemical and clinical data for subgroups not achieving hormone suppression. Methods: Sixty-two children with treatment-naïve CPP received 2 doses of 45 mg SC-LA at 24-week intervals. Unstimulated and GnRH-stimulated LH, E2, and T concentrations were measured. Clinical measures included bone age (BA) and predicted adult height (PAH). Results: Eighty-four percentage and 86% of children achieved unstimulated LH <1 IU/L at weeks 24 and 48, respectively. Of 8 children not achieving unstimulated LH <1 IU/L at week 24 that completed the study, all showed a lack of pubertal stage progression and stable/decreased BA to chronological age ratio (BA/CA). Received operating characteristic (ROC) analyses suggested unstimulated LH is a good diagnostic predictor of GnRH-stimulated LH <4 IU/L at weeks 24 and 48 (AUC = 0.88). Across all children, mean BA/CA improved from 1.4 (screening) to 1.3 (week 48) and mean PAH increased by 3 cm. Of 7 girls not achieving stimulated LH <4 IU/L at week 24, all achieved E2 <10 pg/mL, showed a lack of pubertal stage progression, and had stable or decreased BA/CA by week 48. Additionally, 6/7 had increased PAH by week 48 and 4 had unstimulated LH <1 IU/L. Conclusion: Unstimulated LH has value as an efficacy measure and concentrations <1 IU/L may be an adequate surrogate of treatment response in children with CPP. All children who completed the study had evidence of pubertal suppression.

Long-Acting Gonadotropin-Releasing Hormone Analogues for Central Precocious Puberty, Including 45-Mg 6-Month Subcutaneous Leuprolide Acetate: Use for Treatment and Treatment Monitoring

Plain Language SummaryThe gonadotropin-releasing hormone analogue (GnRHa) stimulation test has historically been used for diagnosing and monitoring treatment efficacy in children with central precocious puberty (CPP). However, this test is not always practical due to costs related to lengthy hospital or clinical testing, and additional injections that may negatively impact the child’s therapeutic experience. Therefore, alternative methods of assessing therapeutic efficacy would be valuable. This manuscript presents an overview of the studies supporting the suitability of therapeutic dosing of CPP medications (intramuscular [IM] leuprolide acetate [LA], IM triptorelin pamoate, and subcutaneous [SC] LA) for treatment monitoring. Four studies of injectable CPP medications have demonstrated that these therapies achieved similar stimulated luteinizing hormone (LH) levels compared to a traditional GnRHa stimulation test. However, the effect of SC LA (approved by the US FDA for treatment in May 2020) on LH levels has not been directly compared to those measured as part of a traditional stimulation test. As several studies have shown that SC LA has similar efficacy on the physical characteristics of puberty as IM LA, we postulate that therapeutic SC LA may also be used to monitor the response to CPP treatment, in place of a traditional GnRHa stimulation test.

6-month Formulations of Androgen Deprivation Therapy for Advanced Prostate Cancer: Effectiveness and Rationale for Extended Dosing

Background: Luteinizing hormone-releasing hormone (LHRH) agonists and GnRH antagonists are the most widely used androgen deprivation therapy to achieve castration levels of serum testosterone (T). Adherence to dosing schedules is important to avoid treatment failure. A recent analysis found a high non-adherence rate of 84% for LHRH agonist injections based on dosing schedules used in pivotal trials. Method: Narrative review of LHRH therapy and evaluation of which offers optimal efficacy, safety, and practicality. Results: 6-month LHRH agonist formulations require fewer appointments for injections than shorter-acting formulations. Therefore, the frequency of late/missed doses and overall non-adherence may be reduced compared to options requiring frequent dosing (e.g., oral therapies and shorter-acting injections). This flexibility may be preferable for patients who live in multiple locations throughout the year, live long distances from clinics, and/or lack access to reliable transportation. 6-month formulations may also have cost benefits compared to shorter-acting doses. Despite similar levels of T suppression during the labeled dosing period, individual 6-month LHRH agonist formulations appear to have unique profiles, e.g., 6-month subcutaneous leuprolide acetate (LA) results in lower T escape rates compared to 6-month intramuscular LA, if dosing is late. Conclusion: The efficacy and practicality offered by 6-month LHRH formulations suggest these could reduce opportunities for late injections by requiring fewer office visits and provide greater confidence that efficacy will be maintained should there be extenuating circumstances leading to delays in therapy administration, as experienced during the recent pandemic.

THU195 6-Month Subcutaneous Leuprolide Acetate Achieved And Maintained Hormonal And Clinical Suppression In All Weight Groups Of Children With Central Precocious Puberty

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, Bristol Myers Squibb, BioMarin, Endo Pharmaceuticals, EMD Serono, Novo Nordisk, Pfizer, Tolmar Pharmaceuticals. Research Investigator; Self; Alexion, Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics, Sangamo Therapeutics. D. Boldt-Houle: Employee; Self; Tolmar Pharmaceuticals, Inc. S.N. Atkinson: Employee; Self; Tolmar Pharmaceuticals, Inc. Background: Childhood obesity is associated with an increased risk of central precocious puberty (CPP).1 Thus, data on whether weight status affects the treatment of children with CPP would be valuable to help clinicians ensure correct management. We present secondary analyses of hormone and height velocity (HV) data from the pivotal trial of the first small-volume, long-acting, subcutaneously administered gonadotropin-releasing hormone agonists (GnRHa) for CPP, with the goal of assessing if the study drug adequately suppresses hormones in overweight and obese children. Methods: 62 children with treatment-naïve CPP received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals over the 48-week study period. The BMI percentile for children was calculated based on the Center for Disease Control growth charts, accounting for height, weight, age, and gender. Luteinizing hormone (LH) concentrations were assessed using a validated central Cobas ECLIA assay with a lower limit of detection of 0.100 IU/L. Estradiol (E2) concentrations were assessed using liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS) with a lower limit of detection of 10 pg/mL. HV was calculated as the change in height between visits/((number of weeks between visits)/52). Results: Mean GnRH-stimulated LH concentrations at screening, week 24, and week 48 were 24.5, 2.1, and 2.5 IU/L in non-overweight children, 10.5, 3.2, and 2.2 IU/L in overweight children, and 31.5, 4.8, and 1.9 IU/L in obese children, respectively. In these same groups, mean E2 concentrations at screening, week 24, and week 48 were 28.2, 10.5, and 10.3 pg/mL in non-overweight children, 17.8, 10.4, and 10.4 pg/mL in overweight children, and 25.9, 11.0, and 11.1 pg/mL in obese children, respectively. Mean HV at week 4, week 24, and week 48 was 10.2, 5.6, and 5.7 cm/year in non-overweight children, 7.7, 5.5, and 6.2 cm/year in overweight children, and 8.2, 4.9, and 6.6 cm/year in obese children, respectively. Conclusions: Subcutaneous leuprolide acetate effectively treated all overweight children without any requirement for weight-based dosing. This is consistent with results from previous studies of GnRHa efficacy in obese and normal-weight children with CPP.2 Clinicians should consider providing counseling and interventions that support healthy diets and lifestyles to children with above-normal BMI and their caregivers. References Cited 1.Liu G, Guo J, Zhang X, Lu Y, Miao J, Xue H. Obesity is a risk factor for central precocious puberty: a case-control study. BMC Pediatr. 2021;21(1):509.2. Chen M, Eugster EA. Central precocious puberty: update on diagnosis and treatment. Paediatr Drugs. 2015;17(4):273-281. Presentation: Thursday, June 15, 2023

6-Month subcutaneous leuprolide acetate achieved and maintained hormonal suppression in overweight children

6-Month subcutaneous leuprolide acetate achieved and maintained hormonal suppression in overweight children

Clinical experience with 6-month subcutaneous leuprolide acetate for central precocious puberty

Clinical experience with 6-month subcutaneous leuprolide acetate for central precocious puberty

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

Phase 3 trial of a small-volume subcutaneous 6-month duration leuprolide acetate treatment for central precocious puberty

CONTEXT Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration. OBJECTIVE Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP. DESIGN Phase 3 multicenter, open-label, single-arm study. SETTING 25 sites in 6 countries. SUBJECTS 64 GnRHa-naive children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study. INTERVENTION(S) 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks. MAIN OUTCOME MEASURE(S) Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24. RESULTS 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation. CONCLUSIONS A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

Abstract #973797: 6-Month Subcutaneous Leuprolide Acetate Effectively Suppressed Rate of Bone Maturation and Increased Predicted Adult Height Without Significant Increase in BMI in Children with Central Precocious Puberty

Abstract #973797: 6-Month Subcutaneous Leuprolide Acetate Effectively Suppressed Rate of Bone Maturation and Increased Predicted Adult Height Without Significant Increase in BMI in Children with Central Precocious Puberty

6-Month Subcutaneous Leuprolide Acetate Effectively Suppresses Clinical Signs of Puberty in Children With Central Precocious Puberty

Objective: Gonadotropin-releasing hormone (GnRH) agonists, such as intramuscular leuprolide acetate, triptorelin and the subcutaneous histrelin implant, are standard treatment for central precocious puberty (CPP). Implants require surgery and sometimes anesthesia, while frequent intramuscular injections can be painful. A shift to longer acting-formulations and subcutaneous injections has been proposed for the treatment of CPP. Therapies with convenient administration, prolonged duration of action and favorable safety profile may be beneficial, improving patient adherence. 87% of subjects achieved stimulated LH suppression to <4 IU/L by Week (W) 24 in a Phase III trial evaluating the efficacy and safety of the first6-month subcutaneous injectable in situ gel leuprolide acetate for CPP. We present secondary analyses of bone age (BA) advancement, weight, BMI, and pubertal maturation from this trial. Methods: 62 children (60 girls, 2 boys) with CPP (naïve to treatment) received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals, constituting the intent-to-treat population. Radiographs of the left hand and wrist were used to determine BA using the Greulich and Pyle method. BA was assessed by a blinded central reader. Rate of BA advancement was determined by the ratio of BA to chronological age (CA, BA/CA). Pubertal maturation was categorized with the Tanner staging system using breast development, external genitalia, and pubic hair. Safety outcomes were measured. Results: Mean age at onset of treatment was 7.5 ± 0.9 (SD) (range 4-9) years. BA/CA consistently declined throughout treatment, from 1.4 ± 0.2 at baseline, to 1.3 ± 0.1 at W24 and 1.3 ± 0.1 at W48. Although mean weight increased 8.7% from screening to W24 (34.8 kg vs 37.7 kg) and 16.9% from screening to W48 (40.4 kg), mean BMI remained stable throughout the study. The proportion of girls with early breast Tanner stage development (stage 1 and 2) increased from 9% at baseline to 37% at W48. The proportion of girls with late breast Tanner stage development (stage 4 and 5) decreased from 18% at baseline to 5% at W48. Both boys regressed from Tanner stage 3 to stage 2 for external genitalia development by W48. Tanner staging for pubic hair development remained stable for approximately 80% and decreased for 7% of children by W48. 52/53 treatment emergent adverse events were mild or moderate. Conclusions: 6-month 45 mg subcutaneous leuprolide acetate is a promising treatment for CPP. It effectively suppressed LH, suppressed clinical signs of pubertal maturation and demonstrated a good safety profile. It also has the beneficial features of subcutaneous administration, small injection volumeand twice a year dosing. This may be a welcome addition to the armamentarium given the proposed shift in CPP therapies towards longer-acting formulations and subcutaneous injections.

6-Month Subcutaneous Leuprolide Acetate Effectively Suppresses Clinical Signs of Puberty in Children with Central Precocious Puberty

Gonadotropin-releasing hormone (GnRH) agonists are standard treatment for central precocious puberty (CPP). Implants require surgery and sometimes anesthesia, while frequent intramuscular injections can be painful. A shift to longer acting-formulations and subcutaneous injections has been proposed for the treatment of CPP. Therapies with convenient administration, prolonged duration of action and favorable safety profile may be beneficial. 87% (54/62) of children achieved LH < 4 IU/L by Week 24 (W24) in a Phase III trial evaluating the efficacy and safety of the first 6-month subcutaneous injectable in situ gel leuprolide acetate for CPP.4 7/8 children who did not achieve the primary efficacy endpoint achieved LH < 5 IU/L by W48 and showed signs of effective clinical suppression.

Testosterone (T) suppression by weight and age groups in four pivotal trials of in-situ forming polymer-delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).

172 Background: In-situ forming polymer-delivered, subcutaneous leuprolide acetate (SC-LA) has previously been shown to suppress serum T levels to ≤20ng/dL in advanced PCa patients. Currently, luteinizing hormone releasing hormone agonists are dosed independently of body weight (BW) or age. Reaching nadir T&lt;20ng/dL within the first year of androgen deprivation therapy (ADT) is associated with improved clinical outcomes such as time to progression and disease specific survival (Klotz 2015). As maintaining castrate T levels during ADT is important, it is of interest to understand if factors such as BW or age should be considered when selecting a therapy. This study aims to determine if patient BW and age correlate with the pharmacodynamic profile of all SC-LA formulations. Methods: In 4 open-label, prospective single-arm, fixed dose, pivotal studies, 438 PCa patients were treated with either 7.5, 22.5, 30, or 45mg SC-LA lasting 1, 3, 4, or 6 months. Blood was sampled at screening, baseline, 2, 4, 8 hours post dosing, day 1, 2, 3, 7, and every other week until end of study and assayed for total T by radioimmunoassay. Results: Mean BW of 86 kg (range 49-146) and age of 73 years (range 40-86) was similar across the 4 studies. &gt;90% of patients in all age groups (including 100% of those &lt;60 years) and ≥92% of patients in all BW groups (including 97% of those ≥90 kg) achieved T≤50ng/dL by week 4. When pooled, all age and BW groups achieved median T≤20ng/dL by week 4 and maintained until the end of the study (Table). Conclusions: The results demonstrate that all SC-LA dose formulations consistently achieve and maintain T≤20ng/dL across all BW and age subgroups, including those with the highest BW (&gt;90 kg) and youngest age (&lt;70 years). BW and age do not appear to have an impact on consistent drug delivery and T suppression by SC-LA. Consistent achievement of T ≤20ng/dL may have implications for improved clinical outcomes and progression free survival in PCa patients. [Table: see text]

Polymer-delivered subcutaneous leuprolide acetate formulations achieve and maintain castrate concentrations of testosterone in four open-label studies in patients with advanced prostate cancer.

To determine whether luteinising hormone-releasing hormone (LHRH) agonist, ATRIGEL® polymer-delivered, subcutaneous, leuprolide acetate (ADSC-LA), formulations suppressed serum testosterone to concentrations of ≤20ng/dL. Data from four open-label, fixed-dose studies were evaluated. Male patients aged 40-86years with advanced prostatic adenocarcinoma, whom had not undergone prior androgen-deprivation therapy (ADT), were treated with a depot formulation of ADSC-LA: 7.5mg (1-month, 120 patients), 22.5mg (3-month, 117 patients), 30mg (4-month, 90 patients), or 45mg (6-month, 111 patients). Serum testosterone was sampled at screening, baseline, 2, 4, 8h after dosing, 1, 2, 3, and 7days, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24weeks for 1- and 3-month formulations, 32weeks for 4-month, and 48weeks for the 6-month). The primary analyses were mean serum testosterone concentrations and proportion of patients who achieved concentrations of ≤20ng/dL. The mean (SE) serum testosterone concentrations at the end of study were consistently ≤20ng/dL in each study, at 6.1 (0.4), 10.1 (0.7), 12.4 (0.8), and 12.6 (2.1)ng/dL for the 1-, 3-, 4-, and 6-month formulations, respectively. A high proportion of patients (94%, 90%, 92%, 96% for the 1-, 3-, 4-, and 6-month formulations, respectively) achieved testosterone concentrations of ≤20ng/dL within 6weeks, and 90-97% of patients in all studies maintained concentrations of ≤20ng/dL from weeks 6-24. Recent studies have shown improved outcomes in patients with prostate cancer who consistently attained a more rigorous level of testosterone suppression (≤20ng/dL) with ADT than the historical standard (≤50ng/dL). All doses of ADSC-LA rapidly achieved and maintained mean serum testosterone to the more rigorous target concentration of ≤20ng/dL. These data suggest that ADSC-LA delivers equivalent testosterone suppression as achieved by surgical castration.

Mid-luteal phase injection of subcutaneous leuprolide acetate improves live delivered pregnancy and implantation rates in younger women undergoing in vitro fertilization-embryo transfer (IVF-ET)

Purpose: To determine if a single injection of one-mg leuprolide acetate three days after embryo transfer (ET) in younger women causes an increase in pregnancy rates, and if so, is it associated with a higher initial serum hCG level? Materials and Methods: A prospective study was initiated where women aged ≤ 35 years were offered the option of taking the leuprolide or not. Results: Though a significant difference was not found, there was a trend for higher live delivered pregnancy rates in those taking the leuprolide supplement (47.8%) vs. those not taking it (38.6%). There was no difference in the first serum beta hCG level. Conclusions: The trends is interesting enough to continue with a higher powered study.

Mid-luteal phase injection of subcutaneous leuprolide acetate improves live delivered pregnancy and implantation rates in younger women undergoing in vitro fertilization-embryo transfer (IVF-ET)

Purpose: To see if the single injection of one mg of the gonadotropin releasing hormone agonist (GnRHa) leuprolide acetate given in the mid-luteal phase can increase live delivered pregnancy and implantation rates. Furthermore the purpose was to determine if improvement was found, did the mechanism involve increased secretion of human chorionic gonadotropin (hCG). Materials and Methods: A prospective study was conducted in women aged ≤ 35 who were undergoing in vitro fertilization-embryo transfer (IVF-ET). They were advised of data from Tesarik et al. and a previous pilot study conducted in the present IVF center showing improved pregnancy rates with the injection of a GnRHa three days after embryo transfer. They were offered the option of returning for a one-mg injection s.c. of leuprolide acetate or not. Clinical and live delivered pregnancy rates were compared according to those taking or not the leuprolide acetate one-mg injection. Chi-square analysis was used for statistical comparisons. Serum beta-hCG levels were compared between those conceiving with or without the extra injection of leuprolide. Results: There was a non-significant trend for higher live delivered pregnancy rates in those taking leuprolide (47.8%, 64/134) vs. those not taking it (38.6%, 76/197). For those pregnant there was no difference in hCG levels according to taking the GnRHa or not. Conclusions: The 25% increased live delivered pregnancy rate per transfer was insufficiently powered to detect a significant difference. The results do justify continuing the study. Perhaps the difference could be wider using a slightly older age group whose embryos are frequently less hearty.

Continuous release, solid depot, subcutaneous leuprolide acetate formulations to achieve and maintain castrate level serum testosterone levels below 20ng/dL in 4 open label, fixed dose studies.

e16062 Background: Growing evidence (eg, Klotz et al, EAU Congress 2014) suggest that prostate cancer patients undergoing androgen deprivation therapy who attained castrate levels of testosterone (...

Effect of the non-specific matrix metalloproteinase inhibitor Doxycycline on endometriotic implants in an experimental rat model.

The aim of this study was to investigate the possible therapeutic effects of Doxycycline (Dox) on endometriotic lesions in an experimental rat model. Thirty-seven female Wistar albino rats with surgically induced endometriosis were randomized and divided into four groups. The rats were administered 5 mg/kg/day oral Dox in Group 1 (low-dose Dox group, n=9), 20 mg/kg/day oral Dox in Group 2 (high-dose Dox group, n=10) and 1 mg/kg single dose, subcutaneous leuprolide acetate in Group 3 (leuprolide acetate group, n=9). The rats in Group 4 (control group, n=9) were given no medication. The rats received medication for three weeks and were then sacrificed to evaluate the morphological and histological features of the implants. Matrix metalloproteinase (MMP)-9 immunoreactivity of the implants was also evaluated. The size of the endometriotic implants decreased in Groups 1-3 but statistically significant differences were not observed among the groups. The mean surface area of the endometriotic implants decreased from 69.3±30.8 to 52.1±27.0 mm² in Group 1 (P>0.05), from 60.2±18.9 to 38.6±28.7 mm² in Group 2 (P>0.05) and from 58.1±33.1 to 26±9.0 mm² in Group 3 (P=0.03). The epithelial MMP-9 immunohistochemical score was significantly higher in Group 1 and lower in Group 3 when compared with the control group (Group 4) (P=0.042 and P=0.014, respectively). When the stromal MMP-9 immunohistochemical and histopathological scores of the endometriotic implants were compared, no statistically significant differences were found among the groups. Although there was no statistically significant difference, Dox reduced the endometriotic implant area in the rat endometriosis model. Further studies are required to investigate the potential efficacy of Dox in endometriosis due to its widespread use and tolerability.

Mid-luteal phase injection of subcutaneous leuprolide acetate improves live delivered pregnancy and implantation rates in younger women undergoing in vitro fertilization-embryo transfer (IVF-ET)

Purpose To see if the single injection of one mg of the gonadotropin releasing hormone agonist (GnRHa) leuprolide acetate given in the mid-luteal phase can increase live delivered pregnancy and implantation rates. Furthermore the purpose was to determine if improvement was found, did the mechanism involve increased secretion of human chorionic gonadotropin (hCG). Materials and methods A prospective study was conducted in women aged 35 who were undergoing in vitro fertilization-embryo transfer (IVF-ET). They were advised of data from Tesarik et al. and a previous pilot study conducted in the present IVF center showing improved pregnancy rates with the injection of a GnRHa three days after embryo transfer. They were offered the option of returning for a one-mg injection s.c. of leuprolide acetate or not. Clinical and live delivered pregnancy rates were compared according to those taking or not the leuprolide acetate one-mg injection. Chi-square analysis was used for statistical comparisons. Serum beta-hCG levels were compared between those conceiving with or without the extra injection of leuprolide. Results There was a non-significant trend for higher live delivered pregnancy rates in those taking leuprolide (47.8%, 64/134) vs. those not taking it (38.6%, 76/197). For those pregnant there was no difference in hCG levels according to taking the GnRHa or not. Conclusions The 25% increased live delivered pregnancy rate per transfer was insufficiently powered to detect a significant difference. The results do justify continuing the study. Perhaps the difference could be wider using a slightly older age group whose embryos are frequently less hearty.

Acute manic and psychotic symptoms following subcutaneous leuprolide acetate in a male patient without prior psychiatric history: A case report and literature review

Leuprolide acetate is usually used in the treatment of advanced prostate cancer. The adverse events associated with administration of leuprolide acetate include fatigue, hot flashes, loss of libido, impotence, and depression. These side effects can be treated conservatively. Acute manic and psychiatric symptoms following leuprolide acetate injection are very rare. Few case reports have been published documenting these symptoms. Here, we describe the case of a 62-year-old male with metastatic prostate cancer, who developed acute manic and psychiatric symptoms 2 months after subcutaneous leuprolide acetate injection. These symptoms were relieved after administration of neuroleptic drugs, such as risperidone. Administration of leuprolide acetate was eventually stopped. The exact mechanism causing the manic and psychiatric adverse events is unclear. Some experts have theorized that estrogen withdrawal following leuprolide acetate therapy may induce psychiatric symptoms. Manic episodes may arise from a deficit in central serotonergic neurotransmission. Based on these hypotheses, risperidone, lithium, and some anticonvulsants, such as divalproex sodium and carbamazepine, have been used effectively in the treatment and prophylaxis of manic episodes. Although psychiatric adverse events are rare following administration of leuprolide acetate, clinicians should be aware of the possibility.

Massive ascites and hydrothorax after leuprolide acetate administration in a down-regulated woman undergoing assisted reproduction

To present an atypical case of massive ascites and hydrothorax after leuprolide acetate administration in a down-regulated woman undergoing assisted reproduction. Case report. Centre for Reproductive Medicine, Department of Obstetrics, Gynaecology, and Neonatology, University of Parma, Parma, Italy. A 41-year-old, nulliparous, white woman who developed massive ascites and hydrothorax after administration of 0.50 mg/day of subcutaneous leuprolide acetate, beginning at the midluteal phase. Down-regulation with the gonadotropin-releasing hormone analogue was discontinued, and therapy was started with furosemide 50 mg/day for 10 days. Successful medical reduction of ascites and hydrothorax. Resolution of symptoms. A comprehensive MEDLINE search revealed this to be the first reported case of massive ascites and hydrothorax after leuprolide acetate administration (0.5 mg daily) in a down-regulated woman undergoing assisted reproduction. This case can be explained by an increase in capillary permeability, which resulted in a rapid fluid shift from the intravascular space into the third space. We believe that ascites in our patient resulted from an increase in estradiol in the ovaries, due to a direct action of the gonadotropin-releasing hormone analogue on the corresponding ovarian receptors in the first few days after the start of therapy.