Leuprolide acetate induces structural and functional recovery of injured spinal cord in rats

Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5^th week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1^st week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury.     

醋酸亮丙瑞林原位注射制剂的制备及其体内外释放性能的研究

目的：合成mPEG/PLA比例为10/90,5/95,2/98的3种聚合物并对其进行结构表征。用合成的mPEG-PLA为载体材料和有机溶剂N-甲基比咯烷酮（NMP）制备醋酸亮丙瑞林（LA）的原位注射剂并对其物理化学性质和体内外释放试验进行研究。方法：采用mPEG2000和外消旋-丙交酯（DL-LA）,以开环聚合法合成比例为10/90,5/95,2/98的聚合物mPEG-PLA,并通过1H-NMR对产物进行结构确证。然后将mPEG-PLA和LA置于两个注射器中,制成A/B系统,在使用前将药物加入聚合物溶液中并混合均匀,制备醋酸亮丙瑞林的原位注射剂。利用显微镜和SEM分析制剂结构。其次进行药物的体外释放试验,对释放曲线进行模型拟合,最后以大鼠为动物模型进行试验,考察药物在SD大鼠体内的释放行为,并考察体内外相关性。结果：成功合成且验证了不同比例的mPEG/PLA聚合物,并以此为载体材料成功制备出LA原位注射制剂。体外释放试验表明,药物以接近零级的方式释放,释放速率和聚合物mPEG/PLA比例,载药量和加入有机溶剂的量有关,且聚合物中PLA比例越高释放越慢,载药量增加则释放速率增加;选用黏度大的溶剂则药物释放减慢,溶剂的用量增加释放速率减小;大鼠体内实验也表明该制剂在体内能够达到缓释的效果,药物在前10 d内释放较快,30 d释放药物能达到90%。结论：醋酸亮丙瑞林原位注射制剂物理化学性质稳定,体内外实验均证明该制剂具有良好的释放性能。     

Leuprolide acetate elevates prolactin during ovarian stimulation with gonadotropins

Objective The purpose of this study was to determine whether gonadotropin-releasing hormone agonist further increases the prolactin rise accompanying ovarian stimulation.Design Serum prolactin concentrations were compared between cycles with and cycles without the use of leuprolide acetate (LA) matched for estradiol levels. Relationships of prolactin levels to cycle outcomes were examined.Setting The study took place at a private fertility center.Patients Patients were women receiving stimulation for oocyte retrieval using human menopausal gonadotropins.Interventions No interventions were used.Main Outcome Measures Serum prolactin level, fertilization rate, embryo quality, and pregnancy were the main outcome measures.Results Higher serum prolactin was associated with both higher estradiol levels and use of LA but did not have any effects on fertilization rate, embryo quality, or occurrence of pregnancy.Conclusion LA stimulates prolactin release during ovarian stimulation but without apparent consequence.     

In Vitro Characterization and in Vivo Testosterone Suppression of 6-Month Release Poly(D,L-Lactide) Leuprolide Microspheres

Pharmaceutical Research -     

Effect of the Concurrent LHRH Antagonist Administration with a LHRH Superagonist in Rats

Purpose. The purpose of this study was to investigate the effect of anovel LHRH antagonist, Orntide acetate, on the initial testosteroneelevation in rats during treatment with a LHRH superagonist,Leuprolide acetate.Methods. Thirteen groups of a rat animal model were administeredeither liquid Orntide or Orntide PLGA microspheres before or simultaneouslywith Leuprolide injections. Serum levels of testosterone weremonitored during the time course of the study using a radioimmunoas say method.Results. Administration of a single daily dose of liquid Orntide resultedin testosterone suppression within 6 h to levels below 0.5 ng/ml(castration level). However, combined administration of liquid Orntide andliquid Leuprolide did not have a significant effect on the initialtestosterone elevation in studied rats. Similarly, there was no effect when liquidOrntide was co-administered with Leuprolide microspheres. Administrationof Orntide microspheres 48 h before Leuprolide microspheressuppressed testosterone levels below the castration level within 24 h,however, did not prevent a rise in testosterone serum concentration uponadministration of Leuprolide microspheres. Also, a second testosteronepeak was observed between days 3 and 15 in the animals which weresimultaneously treated with Orntide microspheres and Leuprolidemicrospheres.Conclusions. Orntide acetate was found to be an effective LHRHantagonist with a rapid onset of pharmacological action and a shortbiological half-life. Administration of a single dose of liquid Orntideor Orntide microspheres, resulted in rapid testosterone suppressionwithout an initial elevation, as seen with LHRH superagonists. However,combined administration of Orntide and Leuprolide did not havean effect on the initial testosterone elevation in rats.     

Leuprolide Acetate Suppresses Pedophilic Urges and Arousability

Cognitive–behavioral psychotherapy was compared with cognitive–behavioral psychotherapy augmented by leuprolide acetate (LA) for suppression of pedophilic behavior. Five male pedophiles (M age, 50 years; range, 36–58) were administered LA by Depo injection for 12 months, followed by saline placebo for 12 months. Testosterone levels, sexual interest preference by visual reaction time (Abel Assessment), penile tumescence (Monarch Penile Plethysmography, PPG), as well as strong sexual urges toward children and masturbatory frequency involving thoughts of children (polygraph), were measured every 3 months. On LA, testosterone decreased to castrate levels. Penile tumescence was significantly suppressed compared with baseline, but sufficient response remained to detect pedophilic interest. Pedophilic interest was also detected by visual reaction times. When asked about having pedophilic urges and masturbating to thoughts of children, all subjects self-reported a decrease. Polygraph responses indicated subjects were not deceptive. On placebo, testosterone and physiologic arousal eventually rose to baseline. As noted by polygraph, at baseline and on placebo, subjects were deceptive regarding increased pedophilic urges and masturbatory frequency. Interest preference, as measured by Abel Assessment and Monarch PPG, was generally unchanged throughout the study. Cognitive–behavioral psychotherapy augmented with LA significantly reduced pedophilic fantasies, urges, and masturbation; however, pedophilic interest did not change during 1 year of therapy. Deceptive responses by polygraph suggested that self-report was unreliable. Follow-up utilizing objective measures is essential for monitoring efficacy of treatment in pedophilia. Our study supports the premise that suppression of pedophilic behavior is possible. LA may augment cognitive–behavioral psychotherapy and help break the sequence leading to a re-offense.     

Prevention of rat mammary carcinoma utilizing leuprolide as an equivalent to oophorectomy

A clinical trial is currently under way to examine the effectiveness of leuprolide as a breast cancer chemopreventive agent and contraceptive. This trial, as well as similar proposed studies, is based on the assumption that leuprolide is as effective as surgical castration in preventing the onset of mammary tumors; however, this has not been well documented in the DMBA animal model. We directly compared leuprolide and oophorectomy in this model and examined a combined therapy of leuprolide/bromocriptine. Twenty-seven day old female Sprague-Dawley rats were randomly allocated into one of eight groups. All rats received a 20-mg dose of DMBA at the age of 55 days. Group 1 (n=10), no treatment; Group 2 (n=9), leuprolide (100g/kg/day) for eight weeks beginning four weeks prior to DMBA; Group 3 (n=10), oophorectomy four weeks prior to DMBA with replacement estrogen beginning four weeks following DMBA. Estrogen replacement was achieved with a 0.05-mg estradiol tablet releasing 0.833g/day over a 60-day period. Group 4 (n=10), leuprolide (100g/kg/day) initiated two weeks prior to DMBA and continuing for two weeks following DMBA; Group 5 (n=9), oophorectomy two weeks prior to DMBA with 0.05mg of estradiol in depot form, releasing 0.833g/day, beginning four weeks following DMBA and continuing until week 16 of the study; Group 6 (n=10), leuprolide (100g/kg/day) beginning two weeks prior to DMBA and continuing for the duration of the experiment; Group 7 (n=10), leuprolide (100g/kg/day) for eight weeks beginning two weeks prior to DMBA; Group 8 (n=9), leuprolide (100g/kg/day) and bromocriptine (83g/day) for eight weeks beginning two weeks prior to DMBA. At nineteen weeks (15 weeks post DMBA), animals were sacrificed and autopsies performed. One hundred percent of untreated animals developed tumors. No animals undergoing oophorectomy four weeks prior to DMBA or receiving leuprolide four weeks prior to and simultaneously with DMBA developed tumors. In animals pretreated two weeks prior to DMBA with leuprolide or oophorectomy, each group had one animal with tumor development. No tumors developed in the animals receiving ongoing injections of leuprolide. However, one tumor developed in those receiving leuprolide for the first eight weeks beginning two weeks prior to DMBA administration. One animal receiving both leuprolide and bromocriptine developed one tumor. We conclude that chemical oophorectomy (with leuprolide) is as effective as surgical oophorectomy in inhibiting DMBA induced carcinogenesis.     

Sexual Behaviors in Autism: Problems of Definition and Management

Surveys of sexual behavior in autism suggest a variety of behavioral expression. However, the course of sexual development in autism is unplotted, leaving questions about the normalcy of specific behaviors. Even less is known about deviations of sexual development and the incidence of paraphilias in this population. We explore the problems of definition of sexual behaviors and describe a case report that highlights the difficulties of management. An application of a testosterone-suppressing medication and its effect on sexual behavior are reported. After failure of behavioral and educational programs, leuprolide, an injectable antiandrogen, resulted in suppression of behaviors and retention of the participants' community placement. Follow-up for almost 3 years shows no abnormal physical effects. Dosage has been tapered over that period to a low but effective dose. Directions for research are discussed.     

Endocrinology: Follicle cyst formation after administration of different gonadotrophin-releasing hormone analogues for assisted reproduction

The aim of this study was to examine the occurence of ovariancysts during the administration of three different gonadotrophin-releasinghormone analogues (GnRHa) in the long protocol as well as theircharacteristics, management and outcome compared with patientswith no cyst formation. A total of 172 in-vitro fertilization(IVF) cycles in which GnRHa was administered at menstruationwere analysed. Group B consisted of 72 cycles in which buserelinwas used. Of these, 10 (13.9%) were with cysts (group B1) and62 (86.1%) without cysts (group B2). Group T included 49 cyclesin which triptorelin was injected. Of these, seven (14.2%) werewith cysts (group T1) and 42 (85.7%) without cysts (group T2).Group L comprised 51 cycles in which leuprolide was administered.Of these, eight (15.7%) were with cysts (group L1) and 43 (84.3%)without cysts (group L2). All women with ovarian cysts had higherserum oestradiol concentrations and all except five underwentcyst aspiration with no complication. No differences were observedin the number of follicles and oocytes between groups B, T andL or between the groups with cysts and those without cysts.The pregnancy rate was similar in all groups. In conclusion,follicle cyst formation does not seem to be related to the useof a specific GnRHa, its short- or long-acting form or to themode of administration. In addition, follicle cyst aspirationis a safe and successful solution to the problem of functionallyactive ovarian cysts.