Lessons learned from the preclinical drug discovery of asoprisnil and ulipristal for non-surgical treatment of uterine leiomyomas

Introduction: Uterine leiomyoma is the most common benign tumor in women during the reproductive years. Menorrhagia is the common symptom and accounts for the most frequent indication for hysterectomy. Thus, development of a novel drug for non-surgical treatment of uterine leiomyoma is needed for the betterment of women's health. Area covered: This review introduces a translational research initiated by use of the levonorgestrel-releasing intrauterine system (LNG-IUS) for contraceptive purposes. During follow-up, a patient informed that heavy menstrual bleeding caused by uterine myoma was strikingly reduced after the insertion of device. The patient's unexpected comment led the authors to perform clinical trials of LNG-IUS for the management of menorrhagia in women with uterine myomas and striking reduction in menorrhagia was obtained by the use of LNG-IUS. MRI examination, however, revealed that the volume of myomas decreased in some, but increased in the other instances. This unexpected finding with MRI directed the authors to characterize the effects of progesterone (P4) and progesterone receptor modulators (PRMs) on uterineleiomyoma cell growth in vitro. Expert opinion: In consistence with the in vitro data obtained, randomized controlled clinical trials of PRMs in patients with uterine leiomyomas at several institutions have demonstrated that oral administration of PRMs (asoprisnil and ulipristal) for 3 months reduced leiomyoma volume, resulting in a significant improvement of the associated symptoms. However, a novel pattern of PRM-associated endometrial changes was recognized in the endometrial pathology, demonstrating unusual epithelial types not seen in the normal menstrual cycle of a premenstrual woman. Thus, follow-up studies to determine whether the novel endometrial changes remain, disappear or progress to something else are needed for the possible long-term use of PRMs for the treatment of uterine leiomyoma.     

Cost-utility of levonorgestrel intrauterine system compared with hysterectomy and second generation endometrial ablative techniques in managing patients with menorrhagia in the UK

ABSTRACT

Objective: To estimate the cost-utility of levonorgestrel intrauterine system (LNG-IUS; Mirena) compared to second generation endometrial ablative techniques [i.e. microwave endometrial ablation (MEA) and thermal balloon endometrial ablation (TBEA)] and hysterectomy in the UK.

Methods: Clinical and utility data from a 5-year randomised controlled trial comparing LNG-IUS with hysterectomy were combined with further data from published studies to construct a state-transition (Markov) model. The model depicted the movement of patients between health states over 5 years following treatment for menorrhagia. The model was used to estimate the cost-utility of LNG-IUS followed by ablation (L-A); LNG-IUS followed by hysterectomy (L-H); immediate ablation (MEA or TBEA) and immediate hysterectomy in the UK at 2004/2005 prices, from the perspective of the UK's National Health Service (NHS).

Main outcome measures and results: The expected 5-yearly cost of treating menorrhagia with L-A, L-H, TBEA, MEA and hysterectomy was estimated to be £828, £1355, £1679, £1812 and £2983 per patient respectively and the expected level of health gain to be 4.14, 4.12, 4.13, 4.13 and 4.01 QALYs per patient respectively. LNG-IUS followed by ablation dominated all the alternative treatments. Hysterectomy was dominated by the alternative treatments. Sensitivity analysis found the model to be sensitive to the quality of life data used.

Conclusion: Within the model's limitations, LNG-IUS followed by ablation appears to offer the NHS a cost-effective treatment for menorrhagia, when compared to immediate surgery, affording the NHS a less expensive treatment modality without detrimental effects on resulting health gain.     

Vilaprisan for treating uterine fibroids

Introduction: The medical strategy to antagonize myoma size and related-symptoms is to reduce estrogen and progesterone activity on myomas. This can be obtained with the GnRH agonist (GnRHa) or with compounds that antagonize progesterone stimulatory activity on myomas. Selective progesterone receptor modulators (SPRMs) bind progesterone receptor (PR), leading to both agonist and antagonist effects. The result of SPRMs’s action is tissue-specific and it depends on the particular affinity and strength of each SPRM.

Area covered: Ulipristal acetate (UPA) is the first SPRM registered for myoma treatment. UPA reduces heavy uterine bleeding within 7 days from the onset of treatment, whereas a longer time is required with GnRHa treatment. Vilaprisan is a novel powerful SPRM. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids.

Expert opinion: It is fundamental to underline the rapidity of action (only 3 days) in the control of myoma-related bleeding.     

屈螺酮炔雌醇联合左炔诺孕酮宫内缓释系统治疗子宫腺肌病的疗效观察及相关激素水平检测

目的 探讨屈螺酮炔雌醇联合左炔诺孕酮宫内缓释系统（LNG-IUS）治疗子宫腺肌病的疗效,并检测相关激素水平。方法 选取2009年6月-2013年6月浚县人民医院就诊的子宫腺肌病患者150例,随机分为治疗组（75例）和对照组（75例）,对照组患者在月经期第3天由专门的医务人员放置LNG-IUS。治疗组患者在此基础上口服屈螺酮炔雌醇片,放置LNG-IUS当天开始服用,1片/d,每个周期21 d,服用一个周期后停用7 d。两组患者均连续治疗3个周期。比较两组患者痛经、经量、子宫体积以及阴道点滴出血时间的发生情况。并测定两组治疗前后孕激素（PRL）、雌二醇（E₂）、卵泡刺激素（FSH）、黄体生成素（LH）的水平。结果 治疗后,两组患者痛经、经量评分均较治疗前得到显著改善,同组治疗前后差异有统计学意义（P<0.05）;治疗组随访1、3个月痛经评分、月经失血图（PBAC）评分均显著低于对照组,两组比较差异有统计学意义（P<0.05）。治疗后,两组患者子宫体积均显著减小,同组治疗前后差异有统计学意义（P<0.05）;治疗组随访1、3、6个月的子宫体积显著小于对照组,两组比较差异有统计学意义（P<0.05）;治疗后治疗组子宫点滴出血时间显著低于对照组（P<0.05）。治疗后,治疗组E₂较治疗前显著升高,FSH、LH较治疗前显著降低,治疗前后差异有统计学意义（P<0.05）;治疗后,治疗组这些指标与对照组相比差异有统计学意义（P<0.05）。结论 屈螺酮炔雌醇联合LNG-IUS治疗子宫腺肌病有较好的临床疗效,能够显著改善患者痛经症状、减少月经量和阴道点滴出血时间,值得临床推广应用。     

妇科止血灵胶囊联合去氧孕烯炔雌醇治疗功能失调性子宫出血的疗效观察

目的 探讨妇科止血灵胶囊联合去氧孕烯炔雌醇片治疗功能失调性子宫出血的临床疗效。方法 选取2022年6月—2023年8月佳木斯市妇幼保健院收治的104例功能失调性子宫出血患者,按照随机数表法将104例功能失调性子宫出血患者分为对照组（52例）和治疗组（52例）。对照组口服去氧孕烯炔雌醇片,于月经周期第5天开始,初始剂量为1片/次,2次/d,连用3 d后改为1片/次,1次/d,连续治疗3周。治疗组患者在对照组治疗基础上口服妇科止血灵胶囊,4粒/次,3次/d。两组均连续治疗3周。观察两组的临床疗效和中医症候改善时间,比较两组治疗前后子宫内膜厚度、血红蛋白、激素指标的变化情况。结果 治疗后,治疗组患者的总有效率为94.23%,显著高于对照组80.77%（P＜0.05）。治疗后,两组子宫内膜厚度降低,而血红蛋白水平升高（P＜0.05）;与对照组比较,治疗后治疗组子宫内膜厚度减小,而血红蛋白水平更高（P＜0.05）。与对照组比较,治疗组腰膝酸软、面色晦黯、小便频数改善时间更短（P＜0.05）。与治疗前比较,治疗后两组雌二醇、促卵泡激素、孕酮水平均显著降低（P＜0.05）;与对照组比较,治疗后治疗组患者雌二醇、促卵泡激素、孕酮水平更低（P＜0.05）。结论 妇科止血灵胶囊联合去氧孕烯炔雌醇治疗功能失调性子宫出血可获得较好的治疗效果,能有效改善患者的中医症状,降低子宫内膜厚度、提高血红蛋白水平,改善机体激素紊乱的状态,且不良反应少。     

散结灵胶囊联合亮丙瑞林治疗子宫肌瘤的临床研究

目的 探讨散结灵胶囊联合亮丙瑞林治疗子宫肌瘤的临床疗效.方法 选择2018年1月—2020年12月天津市宁河区医院收治的102例子宫肌瘤患者,按照随机数字表法分为对照组和治疗组,每组各51例.对照组患者皮下注射注射用醋酸亮丙瑞林微球,月经周期第1天给药,1支/次,每28天1次,共治疗3次;在对照组治疗的基础上,治疗组餐...     

雌、孕激素对子宫肌瘤细胞EGF表达的调节作用

目的：探讨孕酮、雌二醇对体外培养的子宫肌瘤细胞表皮生长因子（EGF）表达的调节作用。方法：用胶原酶消化分离肌瘤细胞进行培养，待细胞汇合成片时，分别加入3种浓度的孕酮和3种浓度的雌二醇，加药后3d用免疫细胞化学的方法检测各组细胞EGF蛋白表达的情况。结果：镜下观察肌瘤细胞呈梭形或不规则三角形，细胞在生长时多呈放射状、火焰状或旋涡状走行；P4^-4组和E2^-5组肌瘤细胞与对照组相比生长较旺盛，相对细胞数量多、密度大。P4^-4组与对照组相比肌瘤细胞EGF蛋白的表达显著增加（P〈0．05）。结论：生理浓度的孕酮或雌二醇促进体外培养的子宫肌瘤细胞的增殖分裂；其中孕酮升调节体外培养的子宫肌瘤细胞EGF蛋白的表达。     

Selective progesterone receptor modulators (SPRMs): progesterone receptor action,mode of action on the endometrium and treatment options in gynecological therapies

Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention.

Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered.

Expert Opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action.     

Emerging treatment options for uterine fibroids

Introduction: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by patient age and desire to preserve fertility or avoid ‘radical’ surgery such as hysterectomy.

Areas covered: There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, leading to increasing use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate. We searched all published studies on medical management of fibroids with SPRMs.

Expert opinion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.     

桂枝茯苓胶囊治疗大鼠子宫肌瘤及其机制研究

目的探讨桂枝茯苓胶囊对子宫肌瘤大鼠的治疗作用及其机制。方法采用注射苯甲酸雌二醇和黄体酮复制大鼠子宫肌瘤模型,造模大鼠按体质量随机分为模型组、他莫昔芬(枸橼酸他莫昔芬片3.6 mg/kg)组以及桂枝茯苓胶囊0.14、0.27、0.54 g/kg组,另设对照组。连续给药8周后处死大鼠,取子宫、脾脏、胸腺并计算其脏器系数,比较子宫病理评分和组织形态,放射免疫分析方法检测血清中雌二醇(E2)、孕酮(P)及子宫组织中表皮生长因子(EGF)水平。结果桂枝茯苓胶囊显著降低大鼠子宫系数,减轻子宫壁平滑肌增生,显著降低血清E2和子宫组织EGF水平。结论桂枝茯苓胶囊对大鼠子宫肌瘤具有治疗作用,其作用机制可能与降低血清E2、子宫组织EGF水平有关。     

左炔诺孕酮宫内缓释系统治疗子宫内膜增生症的临床观察

目的探讨左炔诺孕酮宫内节育系统(LNG-IUS)对子宫内膜增生症的治疗作用。方法 2011年1月至2012年1月我院收治的100例子宫内膜增生症患者,随机分为对照组(孕激素组)和试验组(LNG-IUS组)各50例。对照组于诊断性刮宫术后第5天给予孕激素(醋酸甲羟孕酮),试验组于诊断性刮宫术后第5天宫腔内置入LNG-IUS,比较两组治疗前、后月经量改变情况、血红蛋白水平、子宫内膜厚度及不良反应发生情况。结果对照组治疗1个疗程后,月经量过多者21例,治愈率58%;试验组月经过多者4例,治愈率92%,两组比较差异具有统计学意义(P<0.05)。试验组治疗1个疗程后,血红蛋白水平高于对照组,且子宫内膜厚度低于对照组。对照组不良反应为体重增加、恶心、头晕及肝肾功能损害,而试验组仅有子宫不规则的点状出血。结论左炔诺孕酮宫内缓释系统对子宫内膜增生症的治疗效果优于常规口服孕激素,且不良反应少。     

Levonorgestrel-releasing intra-uterine systems as female contraceptives

Introduction: The availability and use of long-acting reversible contraceptives (LARCs), such as levonorgestrel intrauterine systems (LNG-IUSs), have increased in recent times.

Areas covered: The authors provide a narrative review of the LNG-IUSs currently available worldwide as female contraceptives (LNG-IUS 13.5, 19.5 and 52 mg). Specific features of the devices and their parameters of efficacy and tolerability were considered as outcomes.

Expert opinion: The one-handed 3.8-mm-diameter inserter of LNG-IUS 13.5 mg and 19.5 mg may be particularly suitable in nulliparous women. While LNG-IUSs 13.5, 19.5 mg and LNG 52 mg should be used by women simply looking for an effective contraceptive method for up to 3, 4 or 5 years, LNG-IUS 52 mg has also been approved for the treatment of heavy menstrual bleeding and endometrial protection during hormone replacement therapy. LNG-IUS 52 mg is ideal for women who are experiencing a certain hyperestrogenic hormonal environment, with heavy menstrual bleeding due to hormonal imbalances, adenomyosis or fibroids, in the case of symptomatic endometriosis or for endometrial protection during hormone estrogenic replacement therapy in non-hysterectomized women.     

红金消结片联合戈舍瑞林治疗子宫肌瘤的临床疗效观察

目的探讨红金消结片联合醋酸戈舍瑞林缓释植入剂治疗子宫肌瘤的临床疗效。方法选取2016年7月—2017年12月成都中医药大学附属医院妇科收治的子宫肌瘤患者74例为研究对象,采用随机数字表法分为对照组和治疗组,每组各37例。对照组在月经周期第1~7天内经腹部前壁皮下注射醋酸戈舍瑞林缓释植入剂,3.6 mg/次,每隔28天注射1次。治疗组在对照组治疗的基础上口服红金消结片,4片/次,2次/d。两组患者均连续治疗3个月。观察两组的疗效,比较两组的血液流变学指标、性激素水平、子宫体积和子宫肌瘤体积。结果治疗后,对照组和治疗组的总有效率分别为78.38%、94.59%,两组比较差异有统计学意义(P0.05)。治疗后,两组血浆比黏度、纤维蛋白原、红细胞聚集指数明显降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组血液流变学指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组血清LH、FSH、P、E_2水平明显降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组性激素水平明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组子宫体积和子宫肌瘤体积明显减小,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显小于对照组,两组比较差异具有统计学意义(P0.05)。结论红金消结片联合醋酸戈舍瑞林缓释植入剂治疗子宫肌瘤具有较好的临床疗效,可改善患者血液流变学,调节性激素水平,缩小患者子宫体积和子宫肌瘤体积,安全性较好,具有一定的临床推广应用价值。     

Superiority of liquid crystalline cubic nanocarriers as hormonal transdermal vehicle: comparative human skin permeation-supported evidence

ABSTRACT

Objectives: The aim of this investigation was to explore the feasibility of various nanocarriers to enhance progesterone penetration via the human abdominal skin.

Methods: Four progesterone-loaded nanocarriers; cubosomes, nanoliposomes, nanoemulsions and nanomicelles were formulated and characterized regarding particle size, zeta potential, % drug encapsulation and in vitro release. Structural elucidation of each nanoplatform was performed using transmission electron microscopy. Ex vivo skin permeation, deposition ability and histopathological examination were evaluated using Franz diffusion cells.

Results: Each nanocarrier was fabricated with a negative surface, nanometric size (≤ 270 nm), narrow size distribution and reasonable encapsulation efficiency. In vitro progesterone release showed a sustained release pattern for 24 h following a non-Fickian transport diffusion mechanism. All nanocarriers exhibited higher transdermal flux relative to free progesterone. Cubosomes revealed a higher skin penetration with transdermal steady flux of 48.57.10^–2 ± 0.7 µg/cm² h. Nanoliposomes offered a higher percentage of skin progesterone deposition compared to other nanocarriers. Based on the histopathological examination, cubosomes and nanoliposomes were found to be biocompatible for transdermal application. Confocal laser scanning microscopy confirmed the ability of fluoro-labeled cubosomes to penetrate through the whole skin layers.

Conclusion: The elaborated cubosomes proved to be a promising non-invasive nanocarrier for transdermal hormonal delivery.     

Selective progesterone receptor modulators: an update

Introduction: Several selective progesterone receptor modulators (SPRMs) show promise in several areas of medicine and this work has been summarized by us in 2008.

Areas covered: Since the publication of our reviews, several developments have taken place in the field of reproductive medicine. The first is emergency contraception (EC). Two SPRMs are clinically utilized today: mifepristone (MFP) and ulipristal acetate (UPA). MFP is available for EC in up to 120 h following unprotected intercourse. A dose of 10 mg is significantly more effective than levonorgestrel (LNG). In a metanalysis of the use of UPA versus LNG up to 72 h after unprotected intercourse, failure rates of 1.4 versus 2.2% were reported. The second is contraception. A daily dose of 2 mg MFP can block ovulation and several MFP regimens are being tested, including a vaginal ring releasing MFP. The third is the preoperative administration in women harboring leiomyomas, where clinical testing of several SPRM has shown that they can decrease uterine leiomyomas' size and substantially reduce uterine bleeding. SPRM can induce unusual, specific endometrial appearances. Many believe that these changes should not cause concern, but the issue remains controversial.

Expert opinion: SPRMs are very effective in EC and for the preoperative treatment of uterine leiomyomas.     

The potential role of elagolix for treating uterine bleeding associated to uterine myomas

ABSTRACT

Introduction

Uterine myomas represents a widespread gynecological disease of women in reproductive age. Although surgery remains the first choice for treating most patients, in the last years, new medical approaches have been considered in order to ameliorate heavy menstrual bleeding (HMB) related to their presence. Elagolix is a second-generation gonadotropin-releasing hormone (GnRH) antagonist under investigation for the long-term treatment of uterine myomas.     

Selective progesterone receptor modulators 2: use in reproductive medicine

Background: Synthetic compounds can bind to progesterone receptors and these progesterone receptor ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. These substances have been classified as antiprogestins or as selective progesterone receptor modulators. Objective: There are several hundred selective progesterone receptor modulators available, although only a dozen or so have been evaluated to any significant extent. The best-known selective progesterone receptor modulators are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex^? (CDB 4124), ORG 33628 and ORG 31710. Methods: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone, but also on those other selective progesterone receptor modulators for which data are available. Results/conclusions: Outside pregnancy, selective progesterone receptor modulators are used or have been tested clinically for a number of indications in reproductive medicine: as oral contraceptives, alone or in combination with a progestin, to improve cycle control in users of progestin-only contraceptives, as emergency contraceptives, for the medical treatment of uterine fibroids, in cases of endometriosis and premenstrual syndrome and to improve ovarian stimulation prior to in vitro fertilisation. In the authors' opinion, as of today, few applications outside pregnancy seem worthy of large-scale use: emergency contraception and long-term medical management of uterine fibroids and possibly of endometriosis.     

Thiolated Polymers: Development and Evaluation of Transdermal Delivery Systems for Progesterone

Purpose. To evaluate the possible use of polycarbophil-cysteine (PCP-Cys) as polymeric matrix for transdermal progesterone application. Methods. Thiolated polycarbophil was synthesised by the covalent attachment of cysteine to the basis polymer. The adhesive properties of PCP-Cys in comparison to polyvinylpyrrolidone/hydroxypropyl- methylcellulose (PVP/HPMC) and polyvinylpyrrolidone/polyvinyl- alcohol (PVP/PVA) were investigated by testing the total work of adhesion (TWA) on porcine skin. Release studies in Franz diffusion cells and standard in vitro permeation experiments with porcine skin were performed analysing the progesterone content by high-per- formance liquid chromatography.Results. Films based on PCP-Cys displayed very high cohesive properties due to the formation of interchain disulfide bonds. The TWA of the thiolated polymer on porcine skin was significantly (P <0.05) the highest. In addition progesterone permeation was also the highest from PCP-Cys compared with PVP/HPMC and PVP/PVA within 24 hours. Conclusion. PCP-Cys—a partly thiolated polymer—might be a novel polymer matrix for transdermal progesterone delivery with excellent adhesiveness on porcine skin.     

补血益母丸联合甲羟孕酮治疗药物流产后阴道不规则出血的疗效观察

目的 探讨补血益母丸联合甲羟孕酮治疗药物流产后阴道不规则出血的疗效。方法 选取2021年2月—2023年2月海口市第四人民医院收治的80例药物流产后阴道不规则出血患者,随机分为对照组（40例）和治疗组（40例）。对照组患者口服醋酸甲羟孕酮片,4 mg/次,2次/d。在对照组的基础上,治疗组口服补血益母丸,12 g/次,2次/d。两组患者服用7 d。观察两组患者临床疗效,比较治疗前后两组患者流产后阴道出血情况,子宫内膜厚度和子宫容积,孕酮（P）、促卵泡生成素（FSH）、人绒毛膜促性腺激素（HCG）、黄体生成素（LH）水平。结果 治疗后,治疗组临床有效率为97.50%,明显高于对照组有效率（85.03%,P<0.05）。治疗后,治疗组阴道出血持续时间、阴道出血量均明显少于对照组（P<0.05）。治疗后,两组患者子宫内膜厚度、子宫容积比治疗前明显增加（P<0.05）,且治疗组患者子宫内膜厚度、子宫容积均优于对照组（P<0.05）。治疗后,两组性激素HCG、FSH、P、LH水平比治疗前明显降低（P<0.05）,且治疗组患者明显低于对照组（P<0.05）。结论...