Gonadotropin-releasing Hormone Analogue Group Research Articles

Ultrasound-guided HIFU for uterine fibroids of hyperintense on T2-weighted MR imaging with or without GnRH-analogue-pretreated: A propensity score matched cohort study.

ObjectiveTo compare the therapeutic effect of high-intensity focused ultrasound (HIFU) ablation and HIFU pretreated with gonadotropin-releasing hormone analogue (GnRH-a) in the treatment of hyperintense uterine fibroids on T2-weighted magnetic resonance imaging (T2WI) by using propensity score matching.Materials and methods339 women with 368 hyperintense uterine fibroids on T2WI who underwent single-session HIFU ablation were enrolled, including 283 patients with 303 fibroids in the single-session HIFU (sHIFU) group and 56 patients with 65 fibroids in the HIFU pretreated with GnRH-a (Gn-HIFU) group. The signal intensity (SI) value and standard deviation (SD) value were measured based on T2WI, and the fibroids were further subdivided into heterogeneous hyperintense fibroids, slightly homogeneous hyperintense fibroids and markedly homogeneous hyperintense fibroids as 3 subgroups (HHF, sHHF and mHHF group respectively). Treatment time, sonication time, dose, non-perfused volume (NPV), NPV per sonication time, non-perfused volume ratio (NPVR), energy effect ratio (EEF) and adverse events were recorded.ResultsOut of 339 patients, the median NPVR was 75.2% (interquartile range,31.5%). After propensity score matching, the matched cohort included 91 (64.5%) patients in the sHIFU group and 48 (34.5%) patients in the Gn-HIFU group. The NPVR of sHHF in the Gn-HIFU group had significantly smaller than that in the sHIFU group (60.2% versus 74.9%, p = 0.005), and the NPVR of HHF in the Gn-HIFU group was higher than those in the sHIFU group (87.4% versus 72.9%, p = 0.002).ConclusionsCompared with HIFU alone, the therapeutic efficacy of the heterogeneous hyperintense fibroids may be enhanced by GnRH-a pretreated with HIFU, however it is important to rule out the slightly homogeneous hyperintense fibroids.

Comparison of outcomes in patients with luminal type breast cancer treated with a gonadotropin-releasing hormone analog or bilateral salpingo-oophorectomy: A cohort retrospective study

IntroductionPremenopausal patients with hormone receptor-positive breast cancer require ablation therapy via a pharmacological or surgical approach. Data comparing outcomes between treatment with gonadotropin-releasing hormone (GnRH) analogs and treatment with bilateral salpingo-oophorectomy (BSO) in Indonesia remains limited. Therefore, this study aimed to compare incidence of local recurrence and metastasis, and overall survival (OS) in patients with luminal type breast cancer treated using the two approaches. MethodsThis observational retrospective cohort study examined 100 premenopausal patients diagnosed with luminal type hormone receptor-positive breast cancer who registered at Dr. Wahidin Sudirohusodo Hospital and its networking hospitals in Makassar City from January to December 2017. ResultAmong the 100 study patients, 50 were given GnRH analogs and 50 underwent BSO. Incidence of local recurrence (P = 0.408) and metastasis (P = 0.419) did not significantly differ between the GnRH analog and BSO groups, although the incidence of local recurrence was higher in the GnRH analog group (68% vs. 58%) and incidence of metastasis was higher in the BSO group (24% vs 19%). The 5-year survival rate did not significantly differ between the GnRH analog and BSO groups. ConclusionIncidence of local recurrence and metastasis, and 5-year survival rate did not significantly differ between premenopausal breast cancer patients treated using a GnRH analog and those treated with BSO. Further large-scale studies to compare the efficacy and safety of both approaches are warranted.

The Effects of Gonadotropin-Releasing Hormone Analog and a Combination of Gonadotropin-Releasing Hormone Analog and Recombinant Human Growth Hormone on Adult Height in Girls with Early Puberty.

Background:Early puberty (EP) is due to the activation of gonadotropin-releasing hormone (GnRH) pulse generator in lower ages; EP may be a potential cause for impairment of adult height, leading to short stature. The aim of this study was to determine the effects of GnRH analog (GnRHa) and GnRHa plus recombinant human growth hormone (rhGH) treatment on final height in healthy girls with EP.Materials and Methods:Fifty EP girls (sexual maturity rating: 2–3) with chronological age (CA) 9.22 ± 0.56 and bone age (BA) 9.74 ± 0.59 years were treated with GnRHa (Triptorelin) at a dose of 100 μg/kg body weight (BW) as intramuscular every 28 days for 2.82 ± 0.57 years; 45 EP girls with CA 9.84 ± 0.57 and BA 10.14 ± 1.02 years were also treated with the same GnRHa plus rhGH (Norditropin) at a dose of 0.1 unit/kg BW daily for 6 days in a week for 2.55 ± 0.6 years. In the control group, 33 EP girls followed for the same period without treatment. Height, weight, and body mass index of girls and parents were assessed. Predicted adult height (PAH) at the start and the end of the study and target height were assessed.Results:PAH at the end of the study in the GnRHa group was not different with untreated girls. PAH at the end of the treatment in GnRHa plus rhGH group was significantly higher than both untreated and GnRHa group. PAH at the end of therapy in GnRHa plus rhGH group was significantly more than their target height.Conclusion:GnRHa therapy has a benefit effect in achievement of target height. Combination therapy with GnRHa plus rhGH increased their PAH more than both untreated and GnRHa groups.

Efficacy of levonorgestrel releasing intrauterine system as a postoperative maintenance therapy of endometriosis: A meta-analysis

ObjectiveTo compare the efficacy of levonorgestrel releasing intrauterine system (LNG-IUS) with other treatments as a postoperative maintenance therapy for endometriosis in terms of pain reduction, recurrence prevention, side effects and patients’ satisfaction. Study designWe searched MEDLINE, EMBASE, and the Cochrane Library from January 1986 until February 2018. Two evaluators independently extracted and reviewed prospective and retrospective articles based on pre-determined selection criteria. Outcomes were expressed as mean difference (MD), risk ratios (RR) or odds ratios (OR) in a meta-analysis model, using Revman software. ResultsAmong the 962 studies, 7 studies were selected: 7 studies included 4 randomized controlled trials with 212 patients, 1 prospective cohort study with 88 patients, and 2 retrospective studies with 191 patients. A meta-analysis showed that LNG-IUS was significantly effective in reducing pain after surgery (MD = 12.97, 95% confidence interval (CI): 5.55–20.39), with a comparable effect to gonadotropin-releasing hormone analogues (MD = −0.16, 95% CI: −2.02 to 1.70). LNG-IUS was also effective in decreasing the recurrence rate (RR = 0.40, 95% CI: 0.26–0.64), with an effect comparable to OC (OR = 1.00, 95% CI: 0.25–4.02) and danazol (RR = 0.30, 95% CI: 0.03–2.81). Furthermore, patients’ satisfaction with LNG-IUS was significantly higher than that with OC (OR = 8.60, 95% CI: 1.03–71.86). However, vaginal bleeding was significantly higher in the LNG-IUS group than in the gonadotropin-releasing hormone analogue group (RR = 27.0, 95% CI: 1.71–425.36). ConclusionOur meta-analysis found a positive effect of LNG-IUS as a postoperative maintenance therapy for endometriosis on pain relief, prevention of dysmenorrhea recurrence, and patients’ satisfaction.

Intraoperative Effect of Preoperative Gonadotropin-Releasing Hormone Analogue Administration in Women Undergoing Cold Loop Hysteroscopic Myomectomy: A Randomized Controlled Trial

Study ObjectiveTo evaluate the intraoperative effects of gonadotropin-releasing hormone (GnRH) analogue pretreatment in patients undergoing cold loop hysteroscopic myomectomy. DesignRandomized controlled trial (Canadian Task Force classification I). SettingArbor Vitae Center for Endoscopic Gynecology, Rome, Italy. PatientsA total of 99 patients were randomized and subsequently allocated to the GnRH analogue group or to the nonpharmacologic treatment control group. Fifteen patients were lost after allocation, and 42 patients per group underwent hysteroscopic myomectomy. InterventionsCold loop hysteroscopic myomectomy. Measurements and Main ResultsThe control group accomplished the treatment in a 1-step procedure more frequently than the GnRH analogue group (92.85% and 73.8% of cases, respectively; p = .040). The completion of the treatment was more unlikely in case of G2 myomas (p = .006), whereas no differences were recorded for G1 and G0 myomas. The multivariate analysis showed a significant correlation between the multiple-step treatment and the use of GnRH analogue (odds ratio, 5.365; 95% confidence interval [CI], 1.018–28.284; p = .048), grading (odds ratio, 4.503; 95% CI, 1.049–19.329; p = .043), and size of myomas (odds ratio, 1.128; 95% CI, 1.026–1.239; p = .013). ConclusionsPreoperative GnRH analogue administration did not facilitate the completion of cold loop hysteroscopic myomectomy in a single surgical procedure in G2 myomas and was correlated with a longer duration of the surgery. No significant benefits were found for G0 and G1 myomas. (ClinicalTrials.gov: NCT01873378.)

Failure of Ovarian Suppression With Gonadotropin-Releasing Hormone Analogs to Preserve Fertility: An Assessment Based on the Quality of Evidence.

The proximate cause of menopause, whether natural or induced, is ovarian primordial follicle oocyte reserve depletion. This reserve is established inutero and cannot be replenished. Specific chemotherapeutics, particularly alkylatingagents and topoisomerase inhibitors, induce DNA double strand breaks in primordial follicle oocytes, thereby triggering apoptotic death.1 It is by this reduction of the ovarian folliclereservethatthereproductive life span is shortened andmenopause is facilitated. Ovarian failure is the last manifestation of chemotherapy-induced infertility. Hence, ovarian follicle depletion and infertility due to cancer treatments are not independent processes. In the meta-analysis by Munhoz et al,2 the authors conclude that gonadotropin-releasing hormone analog (GnRHa) suppression preserves menstruation but not fertility in premenopausalwomenwithearly-stagebreast cancer.Howdowe explain this contradiction?As the authors indicate,menstruation is not a surrogate of fertility. In fact, the commonly accepteddefinitionof premature ovarian failure (POF) is irregular periods or amenorrhea with 2 serum follicle-stimulating hormone (FSH) values greater than 40mIU/mL (to convert to IU/L,multiplyby1.0).Prior studies incorrectlyapplied thedefinition of natural menopause (ie, a retrospective absence of menses for 12months inwomen>40years) to chemotherapyinduced POF.2 Irregular menstruation is more common than amenorrhea inwomenexperiencingearlymenopause. In a recent 18-month longitudinal follow-up of women with breast cancer receiving chemotherapy, we found that approximately one-third of women with severely diminished and/or undetectable ovarian reserves by serum antimullerian hormone (AMH) levels were still menstruating.3 This brings up a major weakness of all studies that show some benefit in preserving menstruation by GnRHa. Each used different criteria and none reported on the frequency of periods and whether theprechemotherapymenstrualpatternwaspreserved.Moreover, many included women close to menopausal age. Given that at least one-third ofwomen in early POFmay bemisclassified as having normal ovarian function, the use of resumptionof periods afterGnRHa treatments as a gaugeof effectiveness of ovarian suppression is questionable. Furthermore, tamoxifen isanovarianstimulantandcanaltermenstrual functionandcause amenorrhea.Only 3 studies, 2withnegative results, excludedwomen receiving tamoxifen. Studiesmeasuring menstrual regularity postchemotherapy did not find a benefit of GnRHa in ovarian protection.4 In addition,no trial usedblindingand/orplacebo.Theparticipantswho are aware of theGnRHa treatmentmaybemore likely to report anybleeding asmenstruation. Ideally, short of using long-term fertility rates, theovariannormalcy shouldbe assessed by quantitative biomarkers. Some studies randomly measured serumFSHandestradiol, and this is not reliableunless performed on cycle days 2 to 3 as the FSH and estradiol serum values fluctuate throughout the cycle. Antral follicle count (AFC) is amore reliablemeasure,which is likewisecycledaydependent. Finally, serumAMH is thought to be themost reliableand lesscycle-dayspecificmarkerbecauseofbeingproduced from early-stage follicles. Only 2 randomized studies employed ovarian reserve markers appropriately. Demeestere et al5 used the widely accepted criterion of FSH level greater than 40 mIU/mL to determine POF in GnRHa-treated women with lymphomas after 12months. Elgindy et al,4 in addition to regularmenstrual status, followed women with breast cancer measuring AFCs andAMHlevels forup to 12months.Neither study foundabenefit from GnRHa treatments. The currentmeta-analysiswas limited to premenopausal women with early-stage breast cancer only.2 Given that the mechanismof ovarian damage by gonadotoxic agents is similar regardless of theunderlyingmalignancy type, a diagnosisbased segregation is not needed to assess the efficacy of GnRHa. The prospective studies in women with hematological malignancies, which were left out from the current metaanalysis, found ovarian suppression to be ineffective in preserving ovarian function.4 Ameta-analysis doesnot remove flaws, andas the authors indicated, amajority of patients originated from3studieswith the aforementioned inherent weaknesses. In the study by Badawy et al,6 receptor status, tamoxifen use, and the definition for resumption of menses were not mentioned. Whether this studywasactually randomizedwasalsoquestioned.7 Inanotherstudy,8authorsobservedhigherpregnancyrateswithGnRHa, thoughthiswasnot theprimaryoutcomemeasure.When recalculated based on those who were attempting pregnancy and not the total number of women in each group, there was nostatisticaldifference.Moreover, attesting to thepositivebias amongwomen receivingGnRHa, there appeared to be a trend, though not statistically significant, for a higher number of women attempting pregnancy in the GnRHa group (P = .13). In a recent meta-analysis5 that included 10 eligible trials and907womenwith theprimaryoutcomedefinedas theproportion of women with resumed ovarian function at the longest follow-upafter the endof chemotherapy,GnRHa cotreatment did not favor ovarian function resumption (320/468 Related article page 65

Comparison of the hemostatic effects of a levonorgestrel-releasing intrauterine system and leuprolide acetate in women with endometriosis: A randomized clinical trial

IntroductionThe hemostatic and inflammatory systems may activate each other. Endometriosis is a chronic inflammatory disease affecting 10% of women. The objective of this study was to compare the hemostatic effects of two treatments widely prescribed to women with endometriosis: the levonorgestrel intrauterine system (LNG-IUS) and the gonadotropin-releasing hormone analog (GnRHa) leuprolide acetate. Materials and MethodsIn this randomized open-label controlled trial, 44 women with endometriosis were randomly allocated to one of two groups: 22 women were assigned to use LNG-IUS and 22 to use GnRHa. The assessed variables were D-dimers, fibrinogen, prothrombin time, activated partial thromboplastin time, coagulation factors (F) II, V, VII, VIII, IX, X, and XI, antithrombin (AT), protein C, free protein S, tissue plasminogen activator (t-PA), α2-antiplasmin, thrombin-antithrombin complex, and prothrombin fragment 1+2. All variables were assessed before treatment and six months after treatment onset. ResultsIn the LNG-IUS group, FVIII decreased 10% after six months of use. In the GnRHa group, there was a 6% increase in AT, 29% reduction in D-dimers, and 19% increase in t-PA. The LNG-IUS users exhibited a significantly greater reduction of FVIII than the GnRHa users (LNG-IUS: −6.4±14.3% vs. GnRHa: 4.2±12.3%, p=0.02). The women in the GnRHa group exhibited a greater increase of AT than the LNG-IUS users (LNG-IUS: −0.7±9.5% vs. GnRHa: 6.5±10.1%, p=0.02). ConclusionBoth hormonal treatments for endometriosis exhibited no association with a procoagulant profile.

Preservation of Ovarian Function and Minimizing Premature Ovarian Failure during Chemotherapy Using Gonadotropin-Releasing Hormone Analogs

Evaluation of: Del Mastro L, Boni L, Michelotti A et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA 306(3), 269-276 (2011). This study is a randomized, open-label, Phase III trial, conducted in 16 Italian centers that enrolled 281 patients between 2003 and 2008. The recruited patients were prospectively and randomly allocated to either chemotherapy alone or combined with monthly triptorelin gonadotropin-releasing hormone analog, started before chemotherapy and repeated every month throughout chemotherapy. The clinical and tumor characteristics of the patients in the control or treatment groups were similar. A total of 12 months after ending chemotherapy, the premature ovarian failure rate was 25.9% in the chemotherapy-alone group versus 8.9% in the chemotherapy and gonadotropin-releasing hormone analog group, an absolute difference of -17% (95% CI: -26 to -7.9%; p < 0.001). The odds ratio for treatment-induced premature ovarian failure was 0.28 (95% CI: 0.14-0.59; p < 0.001). The authors concluded that use of gonadotropin-releasing hormone analog chemotherapy in premenopausal breast cancer patients can significantly reduce the occurrence of chemotherapy-induced early menopause.

Prospective Randomized Trial Comparing Gonadotropin-Releasing Hormone Analogues With Triple Tourniquets at Open Myomectomy

The primary treatment for preservation of fertility in women with large fibroids―open myomectomy―is complicated by significant intraoperative bleeding. In a recent survey, over 85% of gynecologists in the United Kingdom reported use of gonadotropin-releasing hormone (GnRH) analogues before myomectomy to reduce operative hemorrhage at myomectomy. In contrast to pretreatment with GnRH analogues, less than 25% of gynecologists of the United Kingdom reported use of tourniquets to myomectomy-associated bleeding. Although evidence for reduction of bleeding by pretreatment with GnRH analogues has been shown in many studies, other studies have found no benefit. In a previous randomized, controlled trial, triple tourniquets (tourniquets applied to the uterine and ovarian vessels) were highly effective to temporarily occlude the uterine blood supply and reduce myomectomy-associated bleeding. This randomized, controlled trial compared the effectiveness of triple tourniquets and preoperative treatment with GnRH analogues in reducing blood loss in a population of 40 women undergoing open myomectomy for symptomatic fibroids. The study subjects were randomized to either 3 months pretreatment with a GnRH analogue or intraoperative application of triple tourniquets. To occlude the uterine blood supply, a number 1 polyglactin suture was threaded through the broad ligament incisions on each side and tied around the cervix above the level of the bladder and size 10 suction catheter tubing was also passed through the incisions and tied around the infundibulopelvic ligaments. Women randomized to tourniquets received no pretreatment. No significant differences between the 2 groups were found in the numbers of fibroids removed or in the total weight of fibroids (P = 0.13). Compared with triple tourniquets, intraoperative blood loss was significantly greater with the GnRH analogue group (GnRH analogues: median 2482 mL, 95% confidence level, 1744 to 3151 vs. tourniquets: mean 640 mL, 95% confidence level, 418 to 881, respectively, P < 0.001), and significantly more women in the GnRH analogue group required blood transfusion (70% vs. 30%, P < 0.025). The frequency of postoperative complications was similar among the 2 groups; most were minor. Two women from the tourniquet group sustained major complications that appeared to be unrelated to the use of tourniquets. There was no difference between the 2 groups in the length of the postoperative hospital stay and none of the women in either group was readmitted to hospital in the early postoperative period (<6 weeks). These data are consistent with previous findings that triple tourniquets are more effective than preoperative treatment with GnRH analogues or other available intraoperative techniques at reducing intraoperative blood loss at open myomectomy.

Preoperative administration of GnRH-a plus tibolone to premenopausal women with uterine fibroids: evaluation of the clinical response, the immunohistochemical expression of PDGF, bFGF and VEGF and the vascular pattern

Aim of the study is to compare the effects of preoperative therapy with tibolone plus gonadotropin-releasing hormone analogue (GnRH-a) in premenopausal women with those of GnRH-a alone on clinical response, uterine volume, immunohistochemical expression of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and vascular features of myomas. Seventy women with symptomatic uterine fibromatosis were treated for four months with leuprorelin acetate alone or plus tibolone. Untreated patients were submitted to uterine surgery directly. Uterine volume, hematological data, BMD, myoma-related symptoms and hot flushes were evaluated at the admission and before surgery. Immunohistochemical expression of PDGF, bFGF and VEGF, vascular changes and CD105 expression, as a marker of angiogenesis, were evaluated in myomas obtained after surgery. Uterine volume and myoma-related symptoms reduced and hematological variables increased in treated patients. BMD decreased in patients treated with GnRH-a alone. Hot flushes were less in GnRH-a plus tibolone group than in GnRH-a group. Immunohistochemical expression of PDGF, bFGF and VEGF, vascularization and angiogenesis reduced in treated patients in comparison with untreated ones. In conclusion, the administration of tibolone plus GnRH-a before uterine surgery does not change the clinical and immunohistochemical effects of GnRH-a alone.

Induction and synchronisation of spawning in cultivated turbot ( Scophthalmus maximus L.) broodstock by implantation of a sustained-release GnRH-a pellet

Cultivated turbot were successfully spawned using sustained-release pellets containing a gonadotropin-releasing hormone analogue (GnRH-a), [ d-Ala 6–Pro 9-Net]-luteinising hormone releasing hormone. Significant synchronisation of females was obtained, reducing the spawning season by about half. The number of spawning females was increased, and all sexually mature females ovulated. The delay between ovulations decreased from more than 2 days in controls to about 36 h in GnRH-a treated fish. The mean batch volume increased from 144 to 214 ml, but total volume of eggs for the whole spawning season did not change. At a production scale, fertilisation rate was significantly lower in the GnRH-a group than in the control (76.6 and 89.5%, respectively). Hatching rates were not significantly different between experimental groups.

Endometrial Na +, K +-ATPase pump function and vasopressin levels during hysteroscopic surgery in patients pretreated with GnRH agonist

To investigate the effects of gonadotropin-releasing hormone (GnRH) analog pretreatment on endometrial Na+, K+-adenosine triphosphatase (ATPase) pump function and peripheral blood vasopressin levels, and their role in fluid absorption and mechanisms of hyponatremia in patients undergoing hysteroscopic endometrial ablation. Prospective, randomized, placebo-controlled study (Canadian Task Force classification I). University-affiliated hospital. Seventeen women with dysfunctional uterine bleeding. Nine women received a GnRH analog and eight received saline approximately 6 to 8 weeks before hysteroscopic ablation by electrosurgery. Both before randomization and immediately before surgery, endometrial biopsy samples were obtained and numbered consecutively without patient identification. Operative hysteroscopy was performed with glycine 1.5% mixed with 2% alcohol. The amount of irrigant and irrigant deficit; blood levels of albumin and ethanol; hematocrit and hemoglobin; changes in sodium levels; and central venous pressure were compared. The Na+, K+-ATPase pump activity was significantly increased in the GnRH analog group compared with the saline group and correlated with decreased estradiol levels (0.4 +/- 0.08 vs 0.26 +/- 0.06 micro mol/min/ml). Vasopressin levels were significantly lower in the GnRH group (3.2 +/- 0.9 vs 7.6 +/- 1.7 micro mol/L). Mean volume of irrigant used and operating time were similar in both groups. Volume deficit, decrease in protein, and hematocrit were less in GnRH than in the saline group. Blood ethanol levels, decrease in sodium, and irrigant deficit were significantly lower in GnRH group. Pretreatment with GnRH analogs may prevent the adverse effects of estradiol on endometrial Na+, K+-ATPase and creates a protective mechanism against iatrogenic hyponatremia, which is more critical in women than men in case of absorption of irrigating fluid. Moreover, created hypoestrogenism may enhance Na+, K+-ATPase activity in brain as well as endometrium, thus decreasing women's susceptibility to hyponatremic complications and brain damage. Suppressed vasopressin levels may be protective against fluid absorption in GnRH analog-treated patients.