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.     

The results of GnRH analog treatment of endometriosis

Our study consisted of 146 patients with endometriosis diagnosed during laparoscopy. The age of those women varied from 19 to 43. Pathological changes were classified according to Revised American Fertility Society scale. Numeric scale was also used to evaluate clinical symptoms characteristic to this disease. During the initial laparoscopy biopsies were taken, endometrial implants were coagulated, pelvic adhesions deliberated and endometriomas were enucleated or their wall cut out and coagulated. When endometriosis was histopathologically confirmed the hormonal treatment was undertaken during a period of time from 3 to 6 months depending on the severity of the disease. The patients were treated with 3.6 mg gosereline and 3.75 mg triptorelin monthly or with 400 mcg of naphareline daily. The hormonal therapy was monitored by the concentration of estradiol in blood serum. After full cycle of GnRH analogues treatment laparoscopy was repeated. The mean of The Symptom Severity Scores decreased from 7.1 to 2.1 after the treatment which is a 70% decrease. In the group of women with pain complains 96% of patients noticed improvement, in the group suffering from infertility there were 26.3% of patients who got pregnant. GnRH analogues were good tolerated by patients during the treatment.     

Low-dose GnRH agonist therapy for the management of endometriosis.

OBJECTIVE: In order to examine whether treatment with a GnRH agonist alone can maintain estrogen levels within the "estrogen window" that inhibits endometriosis without influencing bone-mineral density, we studied the effects of GnRH agonist therapy and changes in bone-mineral density. METHODS: Buserelin acetate nasal spray was administered 3 times a day for 8 weeks (daily dose, 900 micrograms) to 21 women with endometriosis. The drug was then given twice a day for 16 weeks (daily dose, 600 micrograms). The total duration of treatment was 24 weeks. The bone-mineral density of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry before treatment (baseline), at the end of treatment, and 24 weeks after the end of treatment. RESULTS: The bone-mineral density of the lumbar vertebrae at the end of treatment was 2.44% +/- 0.46% (mean +/- standard error) lower than the baseline value. The value at 24 weeks after the end of treatment was 1.10% +/- 0.64% lower than the baseline value. More than 80% of the patients had serum-estradiol levels of 45 pg/ml or less. During treatment, more than 90% of the patients had serum-estradiol levels of 60 pg/ml or less. Genital bleeding was inhibited in 90% of the patients. After 8 weeks of treatment, the clinical symptoms improved in 75% of the patients; such improvement persisted for the duration of the treatment. CONCLUSION: Decreasing the dose of GnRH agonist during treatment can minimize the loss of bone-mineral density without lessening the beneficial effects on endometriosis. This technique might be useful in the management of endometriosis.     

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.     

Treatment of endometriosis with the GnRH agonist nafarelin acetate.

Additional details of a multicenter study of nafarelin acetate with particular attention to a unique endometriosis scoring system utilized are reviewed. Additional information regarding the relapse of symptoms of 10 patients treated with nafarelin and danazol during a 6- to 12-month follow-up interval is described. Transient decreases in leukocytes previously reported by other investigators were observed in 3 of 8 patients, but appear to represent a laboratory artifact.     

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.     

The efficacy and tolerability of short-term low-dose estrogen-only add-back therapy during post-operative GnRH agonist treatment for endometriosis

Objective

To evaluate the efficacy and tolerability of a low-dose estrogen-only regimen as a short-term add-back therapy during post-operative GnRH agonist (GnRHa) treatment of patients with endometriosis.

Study design

Retrospective cohort study. One hundred seventeen women of reproductive age who were treated with post-operative GnRHa after conservative laparoscopic surgery for endometrioma were eligible for this study. The patients were divided into two groups: group A (n = 56) received tibolone (2.5 mg) between 2002 and 2004 and group B (n = 61) received estradiol valerate (1 mg) between 2005 and 2007 as an add-back therapy for five months, beginning at the time of the second injection of a GnRHa. The incidence of hypoestrogenic symptoms and the degree of pelvic pain according to a verbal rating scale (VRS) scoring system, the incidence and patterns of uterine bleeding during add-back therapy, the endometrial thickness by ultrasonography two months after the last GnRHa treatment, and the serum CA-125 level were evaluated.

Results

The incidence of uterine bleeding, hypoestrogenic symptoms such as hot flashes and sweating, and pelvic pain did not differ significantly between the two treatment groups. However, the endometrium was thicker in group A than group B (p = 0.022). In group B, the frequency of uterine bleeding was lower from the second month after starting add-back therapy than in group A, but without statistical significance (at the sixth month, p = 0.086).

Conclusion

The low-dose estrogen-only regimen was efficacious and tolerable as a short-term add-back therapy during post-operative GnRHa treatment after surgery for endometriosis.     

Bone density in adolescents treated with a GnRH agonist and add-back therapy for endometriosis

STUDY OBJECTIVE: To evaluate the bone density of adolescents with endometriosis treated with a GnRH-agonist and "add-back" therapy with norethindrone acetate. DESIGN: Retrospective chart review. SETTING: Pediatric gynecology clinic at a tertiary care center. PARTICIPANTS: 36 adolescents, ages 13 to 21 years, with endometriosis. MAIN OUTCOME MEASURES: Bone mineral density (BMD, g/cm(2)) by dual energy x-ray absorptiometry (DXA); BMD Z-scores of hip and spine. RESULTS: The mean BMD Z-score at the total hip was -0.24 +/- 1.0, with a range of -2.4 to 1.7. At this site, 6 subjects had a BMD Z-score between -1.0 and -2.0 SD, while 2 had a Z-score < or = -2.0 SD. The mean BMD Z-score at the lumbar spine was 0.55 +/- 1.1, with a range of -2.8 to 1.4. At the spine, 11 subjects had a BMD Z-score between -1.0 and -2.0 SD, while 3 had a Z-score < or = -2.0 SD. There was no correlation noted between duration of therapy with the GnRH-agonist plus add-back and BMD at the hip or spine. CONCLUSION: BMD at the hip was normal in most adolescents with endometriosis who were receiving a GnRH-agonist plus add-back therapy with norethindrone acetate. Almost one third of subjects exhibited skeletal deficits at the spine. These data suggest that BMD should be carefully monitored in adolescents receiving treatment with GnRH agonists.     

Bone mass in endometriosis patients treated with GnRH agonist implant or danazol.

Before treatment, the trabecular bone mineral content of the lumbar spine and femoral neck was not significantly different between endometriosis patients and age-matched controls (N = 26). In 17 subjects treated with a monthly goserelin implant, serum estradiol (E2) levels were suppressed into the menopausal range. Mean decreases from pre-treatment values in the lumbar spine and femoral neck were -5.7 and -3.8% at 3 months and -8.2 and -7.7% at 6 months of treatment, respectively; lumbar spine values were significantly different (P less than .05) from those of the control group, whose values changed little during the same period. Significant increases over baseline values were also observed in urinary calcium-creatinine ratio and serum alkaline phosphatase. In nine danazol-treated subjects, serum E2 levels were generally within the early follicular-phase range. There were no significant changes in bone assessments. Normal menses returned within 2 months after cessation of either medication. Six months after goserelin treatment, the lumbar spine and femoral neck bone mineral content was still reduced but to values not significantly different from the pre-treatment and control values; urinary calcium-creatinine ratio was decreased, whereas serum alkaline phosphatase was still elevated. The rapid and deep suppression of ovarian steroidogenesis by a monthly goserelin implant induced significant bone loss compared with the control and danazol groups. This loss was not reversed completely 6 months after cessation of treatment, but bone densities at that time were not different from those of controls. Studies of larger numbers of patients followed for longer periods will be required to resolve the question of complete reversibility.     

子宫内膜异位症诊治中有争议的几个问题

子宫内膜异位症(EM)是一种雌激素依赖的慢性疾病,在育龄期女性中发病率达10％～15％.其病因不明,保守治疗后容易复发,难以根治,有恶变的风险.因此,EM需要长期管理. 国内外EM诊治指南中的很多建议都是基于专家共识[1],缺乏高质量的证据支撑.在EM患者的诊治中,很多问题还存在争议,需进一步明确.