GnRH analogues in the treatment of endometriosis

Modifications of the native gonadotropin-releasing hormone (GnRH) decapeptide have led to longer-acting compounds with increased binding ability. Pharmacologic doses of agonists result in suppression of ovarian estradiol production to levels similar to oophorectomized patients. The resultant hypoestrogenism is associated with regression in endometrial implant size. Both subjective and objective clinical improvement have been reported. Recent studies document that a reversible state of hypogonadism is effective treatment for endometriosis.     

GnRH agonists in the treatment of endometriosis

GnRH agonists, synthetic peptide analogs of GnRH, desensitize pituitary receptors for the native molecule, thus causing reversible hypogonadotropic hypogonadism. Numerous clinical studies have suggested that these compounds are efficacious in the treatment of endometriosis, but it is not clear whether they are superior to the other drugs used in treatment of this disease. The frequency of recurrence of pain symptoms at the end of treatment is high and the data on recovery of fertility are conflicting. Long-term administration of GnRH agonists is a safe and well tolerated treatment but its role in the management of endometriosis is still not well defined.     

Indications for GnRH analogs in the treatment of genital endometriosis

Three GnRH agonists are currently available in France in clinical medicine with the indication: "Genital or extragenital endometriosis (from stage I to stage IV of the rAFS classification [4] )." The 2004 Cochran meta-analysis showed a significant improvement in the pain score in patients treated with GnRH compared with placebo, with the effect lasting 12 months after cessation of the medication, but few data are available on their advantages in the perioperative situation and in deep endometriosis. A. Audebert found an advantage to preoperative use of GnRHa in severe cases of endometriosis, with a significantly higher rate of patients having surgery that was considered optimal at the end of the intervention, both in terms of the endometriosis lesions and adherences. The benefits of GnRH treatment before medically assisted procreation are, however, supported by the literature.     

GnRH-拮抗剂对体外受精-胚胎移植中低反应患者有效性的系统性评价

目的:系统性评价GnRHA(GnRH-拮抗剂)在体外受精-胚胎移植(IVF-ET)低反应患者治疗中的有效性。方法:计算机检索CBMDISC(中国生物医学文献数据库1979~2010)、万方(1994~2010)、CNKI(中国学术期刊网专题全文数据库1994~2010)、维普(中国生物医学期刊数据库1989~2010);PUBMED(1997~2010)、ProQust MedicalLibraray(简称PML)(1997~2010)、《外文生物医学期刊文献数据库》英文缩写FMJS(2000~2010),并手检相关杂志9种。纳入GnRHA与GnRHa(GnRH激动剂)在体外受精-胚胎移植低反应患者治疗中有效性的随机对照实验,质量评价后进行Meta分析。结果:共9篇已发表研究符合纳入标准,合计731例。Meta分析结果显示,与GnRHA组比较,周期取消率两组差异无统计学意义[WMD1.04(0.70~1.55)];刺激天数GnRHA组较低,差异有统计学意义[WMD-0.97(-1.64~-0.30)];Gn量GnRHA组较低,差异有统计学意义[WMD-0.49(-7.32~2.48)];HCG日子宫内膜厚度GnRHA组较高,两组差异有统计学意义[WMD0.36(0.20~0.53)];HCG日E2值两组差异无统计学意义[WMD-102.49(303.57~98.59)];获卵数两组差异无统计学意义[WMD 0(-0.5~0.51)];GnRHA组妊娠率较高,差异无统计学意义[Peto OR1.35(0.92~1.99)]。结论:低反应患者在体外受精-胚胎移植卵巢治疗中,GnRHA方案较之GnRHa方案能显著缩短刺激天数及Gn量,两者临床结果相似。GnRHA方案为卵巢低反应患者治疗提供另外一种选择。由于纳入文献存在质量和数量的不足以及方法学的差异,建议本研究结论仅作为临床分析的参考,需要后效评价和不断更新。     

De novo postmenopausal endometriosis during tibolone treatment: a case report and review of the literature

Endometriosis is uncommon before puberty and after menopause as it is an estrogen-dependent disease. A case is presented of postmenopausal endometriosis encountered in a patient who had received tibolone (Livial, Organon, Cambridge, UK) 1 year before the diagnosis of the adnexal mass for 3 months for relief from vasomotor symptoms and had the medication stopped because of fibrocystic disease of the breast. Transvaginal ultrasonography showed homogeneous cystic adnexal mass of 36 × 26 mm with no internal echoes in the right ovary. Laparoscopic right salpingooophorectomy was performed and the histopathological examination of the cyst showed an endometriotic cyst. Most of the cases with postmenopausal endometriosis are associated with the use of hormone replacement therapy (HRT). However, tibolone is recommended in hormone replacement therapy of postmenopausal symptomatic women who have a past history of hormone-dependent tumors such as endometriosis. There is restricted data in the literature about tibolone use and recurrence or de novo formation of endometriosis.     

Use of GnRH antagonists in the treatment of endometriosis

Endometriosis is an oestrogen-dependent disease that is treatable by oestrogen withdrawal, a therapy that has been effectively provided by the use of a gonadotrophin-releasing hormone (GnRH) agonist. Complete oestrogen withdrawal results in unacceptable side-effects, in particular in accelerated bone density loss. This problem has been effectively overcome with 'add-back therapy' using low-dose oestrogens and progestins in combination with a GnRH agonist to limit these side-effects, while still allowing regression of endometriotic lesions. The aim of this study was to determine the feasibility of using a subcutaneous injection of GnRH antagonist in the treatment of endometriosis. All patients (15/15; 100%) reported a symptom-free period during GnRH antagonist treatment, including mood changes, hot flushes, loss of libido, vaginal dryness and other symptoms. Serum oestradiol oscillated around a mean concentration of 50 pg/ml during therapy. Diagnostic laparoscopy before GnRH antagonist administration showed a mean stage III of disease. Regression occurred in 60% of cases (9/15) and the degree of endometriosis declined to stage II. Sequential administration of the GnRH antagonist cetrorelix (Cetrotide) in a 3 mg dosage once weekly over 8 weeks creates a new opportunity for medical treatment of symptomatic endometriosis. Preserving basic oestrogen production during the course of treatment apparently does not influence regression of disease, and has no major side-effects.     

Association between endometriosis and gynecological cancers: a critical review of the literature

Endometriosis is one of the most common benign gynecological diseases with an occurrence approximately 10% in reproductive age. Endometriosis has been proposed as a possible precursor of certain ovarian carcinomas such as clear cell and endometrioid ovarian carcinomas. In addition to this pathogenic link, the association with other gynecological tumors and breast cancer has been studied on an epidemiological basis in several studies. The aim of this review was to critically present the recent published evidence on the association of endometriosis with gynecological cancer, and with a special emphasis on ovarian cancer. A search for eligible studies was conducted in three electronic databases, MEDLINE, EMBASE and CINAHL, for original research in humans published in any language. The present review includes studies examining the association between endometriosis and different types of gynecological cancer (i.e., 25 studies on ovarian cancer, 8 studies on breast cancer, 8 studies on endometrial cancer and 2 studies on cervical cancer). The present literature supports the pre-existing evidence suggesting an association between ovarian cancer and endometriosis and specifically its two histologic subtypes (endometrioid and ovarian clear cell cancer). The most recent population-based epidemiological studies cannot provide a clear association between endometriosis and endometrial, cervical or breast cancer.     

Polypoid endometriosis of the cervix: a case report and review of the literature

Background

Giant and multilobular endocervical polyps are rare and need to be differentiated from cervical neoplastic lesions.

Case report

The authors report a 29-year-old sexually inactive woman presenting with a prolapsed giant endocervical polyp, associated with malodorous discharge and menorrhagia. The wide-based polyp originated in part from the posterior lip of the exocervix and in part from the endocervix. This trilobular pedunculated mass (90 × 50 × 35 mm) had small cysts on the surface and focal areas of haemorrhage. Microscopic examination revealed areas with classic endocervical mucosal polyp histology intimately mixed with expanses of endometrial stroma and occasional endometrial glands. Immunohistochemically the endometrial stroma showed strong CD10 positivity, glands were oestrogen and progesterone receptor positive and Ki-67 proliferation index was low.

Conclusion

Polypoid endometriosis of the cervix is a distinct form of endometriosis that may be mistaken for a neoplasm. Five earlier reports of this entity have not described a prolapsed polyp assuming gigantic proportions. We conclude that this condition be considered in the differential diagnosis of polypoid lesions of the cervix.     

Reproductive outcome using a GnRH antagonist (cetrorelix) for luteolysis and follicular synchronization in poor responder IVF/ICSI patients treated with a flexible GnRH antagonist protocol

To investigate the possible beneficial effect of a new stimulation protocol (termed 'CRASH') on the outcome of poor responder patients, a multicentre, prospective longitudinal study including a total of 36 women undergoing 72 IVF/intracytoplasmic sperm injection (ICSI) cycles with patients serving as their own controls, was conducted. A poor responder patient was defined as a patient with four or fewer oocytes extracted from five or fewer follicles and with a total FSH consumption exceeding 2000 IU in a preceding long agonist down-regulation protocol. The CRASH protocol included 3 mg of the gonadotrophin-releasing hormone (GnRH) antagonist cetrorelix given in the late luteal phase on cycle day 23. Stimulation with recombinant human FSH (rhFSH) started on cycle day 2, followed by a flexible GnRH antagonist protocol. The results showed significantly more follicles (5.4 versus 3.5), oocytes (4.3 versus 2.4) and transferable embryos (1.8 versus 0.8) with the CRASH protocol as compared with the preceding long protocol (P < 0.005 in all cases). The implantation rate and pregnancy rate per transfer was 18.4 and 38.5% respectively, approaching the clinical outcome of normal responder patients. The CRASH protocol thus may constitute an attractive alternative to conventional protocols for low responder patients, improving their clinical outcome.     

Depot GnRH agonist versus the single dose GnRH antagonist regimen (cetrorelix, 3 mg) in patients undergoing assisted reproduction treatment

The objective of this study was to compare, in a centre with previous experience of gonadotrophin-releasing hormone (GnRH) antagonist use, single administration of a GnRH antagonist [cetrorelix (Cetrotide) 3 mg] with a single administration of a GnRH agonist [Decapeptyl Retard 3.75 mg] in patients undergoing assisted reproduction treatment (n = 307 and 364 respectively). GnRH agonist was administered on the first day of menses, while cetrorelix was administered when the largest follicle reached 14 mm. Ovarian stimulation was performed with recombinant human FSH (r-hFSH; 150-225 IU/day). Human chorionic gonadotrophin (HCG, 10,000 IU) was administered when at least two follicles reached a mean diameter > or =18 mm. Over 90% of patients in both groups reached the criteria for HCG administration and underwent oocyte retrieval and embryo transfer. Duration of FSH therapy (9.95 versus 11.25 days) and cumulative dose of r-hFSH (1604 versus 1980 IU) were significantly reduced (P < 0.01) in the cetrorelix 3 mg group. The number of oocytes retrieved was lower (8.5 versus 11.2; P < 0.01) with cetrorelix, but the number of embryos replaced was similar (2.2 versus 2.3; NS). The pregnancy rates per oocyte retrieval were the same, 24.5%, in the antagonist and agonist groups. This study indicates that although fewer oocytes are recovered, similar pregnancy rates can be achieved with a GnRH antagonist compared with a GnRH agonist. Additionally, a single dose of 3 mg cetrorelix was administered in 84% of patients, thus being simpler and more convenient for patients. Cetrorelix 3 mg may thus be proposed as a first choice for preventing both a premature LH surge and detrimental rises in LH during ovarian stimulation prior to assisted reproduction treatment.     

Protection of ovarian function and fertility using a combination of gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist during cancer treatment in young females

Cytotoxic treatment can cause early loss of ovarian function associated with loss of fertility in younger women. To investigate if co-treatment with a combination of gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist may be useful in preserving ovarian function and fertility in younger women during chemotherapy, we prospectively observed nine young patients receiving different chemotherapies for various malignant diseases and other severe medical conditions who also received simultaneous GnRH agonist and GnRH antagonist. Mean age of the patients was 26.56 ± 8.78 years, all were ≤35 years old. Eight (88.9%) patients regained normal basal hormonal profile within 3 – 6 months after the completion of chemotherapy. Median level of follicle-stimulating hormone, luteinizing hormone and estradiol was 6.3 ± 8.8 U/l, 8.2 ± 25.4 U/l and 118.0 ± 130.8 pg/ml, respectively. Eight (88.9%) patients resumed spontaneous menses within 3 – 11 months following discontinuation of chemotherapy. Two (22.2%) patients conceived: one spontaneously, and the second following induction of ovulation by injection of gonadotropins. It seems that combined usage of GnRH agonist and GnRH antagonist during chemotherapy may be useful in preserving ovarian function and fertility in a group of young females receiving chemotherapy treatment.     

GnRH antagonist in the adjuvant treatment of a recurrent ovarian granulosa cell tumor: a case report

BACKGROUND: Ovarian granulosa cell tumors (GCT) are usually treated by surgery and chemotherapy. Successful response to GnRH agonists as an adjuvant therapy has previously been reported. In this case of recurrent GCT, we used a GnRH antagonist. CASE: A 78-year-old woman underwent surgery for an ovarian granulosa cell tumor (pT1a N0 Mx). Six months later, laparotomy revealed an inoperable recurrence of the tumor. Experimental treatment with a GnRH antagonist was not clearly successful. This is in contrast to the previously proven benefit of GnRH agonist therapy in this type of malignancy and to the positive response elicited by GnRH antagonists in epithelial ovarian tumors. CONCLUSION: GnRH antagonist therapy had no demonstrable efficacy in the treatment of a poorly differentiated and aggressive recurrent granulosa cell tumor.     

拮抗剂方案添加GnRH-α黄体支持治疗后妊娠结局研究

目的:探讨拮抗剂方案添加促性腺激素释放激素激动剂(GnRH-α)行黄体支持对临床结局的影响。方法:回顾分析兰州大学第一医院生殖医学专科医院2017年1月至2017年12月252个拮抗剂方案新鲜周期移植后获临床妊娠的患者的临床资料。根据黄体支持方法不同,将患者分为黄体酮+地屈孕酮组128例,添加GnRH-α组124例(常规黄体酮+地屈孕酮支持的基础上于取卵后第6天加用1次曲普瑞林0.1mg)。比较两组的妊娠率、临床妊娠率、持续妊娠率、早期流产率、异位妊娠率、多胎妊娠率、胚胎种植率、卵巢过度刺激综合征(OHSS)发生率及活产率。结果:两组患者的平均年龄、不孕年限、基础内分泌情况、移植日子宫内膜厚度、移植胚胎数及移植胚胎级别均无统计学差异(P0.05)。添加GnRH-α组的妊娠率、临床妊娠率及胚胎种植率均高于黄体酮+地屈孕酮组(P0.05);两组的早期流产率、持续妊娠率、异位妊娠率、多胎妊娠率、OHSS发生率及活产率比较,差异均无统计学意义(P0.05)。两组妊娠患者的血HCG、E2、PGN比较,差异无统计学意义(P0.05)。结论:GnRH拮抗剂方案中,添加GnRH-α黄体支持方案可提高临床妊娠率及胚胎种植率,黄体期添加GnRH-α可作为黄体支持的新选择。