Prolonged Gonadotropin-releasing Hormone Agonist Research Articles

Comparison of two gonadotropin-releasing hormone agonist suppression protocols for in vitro fertilization in young patients with low body mass index.

To evaluate two different gonadotropin-releasing (pituitary downregulating) hormones used in in vitro fertilization (IVF) on the live birth rate in young patients with low body mass index (BMI) undergoing their first IVF cycle. In a retrospective study in a single public medical center, 555 long gonadotropin-releasing hormone agonist (GnRH-a) protocols were compared with 431 prolonged GnRH-a protocols between 2016 and 2018. All analyses were performed using the SPSS version 22.0. The primary measured outcome was live birth rate. Compared with the long protocol, the prolonged protocol required more doses of gonadotropin and a longer duration of ovarian stimulation. Lower levels of serum luteinizing hormone and serum estrogen were detected on the day of chorionic gonadotropin administration, and a lower fertilization rate was found in the prolonged protocol. Although more oocytes were retrieved and more frozen embryos were recorded in the prolonged protocol, the live birth rate per fresh cycle was comparable between the two protocols (P= 0.057). The incidence of ovarian hyperstimulation syndrome was higher in the prolonged protocol group. In the subgroup of women with antral follicle count (AFC) of 12 or less, there was no difference in the live birth rate between the two protocols (P= 0.688). However, for women with AFC > greater than 12, the prolonged protocol was still a positive predictor of live birth rate. The odds ratio was 1.73 (95% confidence interval 1.04-2.89). The prolonged protocol might not increase the live birth rate in women with low BMI who are undergoing their first IVF cycle. However, for women with AFC greater than 12, a prolonged protocol could be a good choice to improve the live birth rate.

Prednisone combined with letrozole reduced risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing long-term gonadotropin-releasing hormone analog treatment.

Ovarian hyperstimulation syndrome (OHSS) is a severe disease that can lead to serious complication. Letrozole has been applied during controlled ovarian hyperstimulation (COH) to reduce the rate of OHSS in women undergoing long-term Gonadotropin-releasing Hormone Analog (GnRHa) treatment for assisted fertility. Prednisone can prevent vasodilatation and increased vascular permeability, which is common during OHSS. However, few studies have evaluated the combined effect of letrozole and prednisone in preventing severe OHSS and is the aim of our retrospective study of patients receiving GnRHa treatment. A total of 296 women who accepted autologous in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included in this retrospective study. There were three groups: 146 women had letrozole, including letrozole alone (LE group, n=60) and letrozole with prednisone (LE + Pre group, n=86), and 150 women had no treatment (C group). Severe OHSS was diagnosed according to clinical evidence of hydrothorax, severe dyspnea, oliguria/anuria, and intractable nausea/vomiting. The addition of prednisone to letrozole successfully reduced the occurrence rate of severe OHSS than those women administered letrozole alone (55.0% vs. 70.6%, P=0.022). However, the ongoing pregnancy rate was lower in the LE + Pre group than that in the LE-alone group (64.3% vs. 87.0%, P=0.025). Surprisingly, progesterone level on the trigger day (>0.895 ng/mL) is a strong predictor for pregnancy failure with a specificity of 68.3% and sensitivity of 65.7% in the LE-alone group. Treatment with a combination of letrozole and prednisone may lower the rate of severe OHSS in women with prolonged gonadotropin-releasing hormone agonist protocol during assisted fertility treatment. When the progesterone level on trigger day is over 0.895 ng/mL, letrozole treatment may negatively affect clinical pregnancy.

The regulation of the follicular synchronization and sensitivity of rats with PCOS by AMH during prolonged pituitary downregulation

The modified prolonged gonadotropin-releasing hormone agonist (GnRH-a) protocol lessens the ovarian hyperstimulation syndrome (OHSS) effect and improves the clinical pregnancy rate of women with polycystic ovary syndrome (PCOS) compared with the standard long GnRH-a protocol. However, the molecular basis of this process needs to be elucidated. Sprague Dawley (SD) female rats with letrozole-induced PCOS were divided into GnRH-a and blank groups. Rats in the GnRH-a group were given triptorelin for 11 days, whereas those in blank group were given an equal volume of 0.9% NaCl. Meanwhile, the changes in estrus cycle, hormonal profile, ovary index, ovarian histopathology and body weight were measured. The expressions of anti-mullerian hormone (AMH), type II receptor of AMH (AMHRII), and FSH receptor (FSHR) were taken as the indicators of follicular sensitivity. Changes of follicular counting and differences in antral follicle diameter at each stage were evaluated. The number of follicles from primordial to antral stages increased during downregulation and the differences in antral follicle diameter were reduced in the GnRH-a group, whereas no significant difference was found in the blank group. The results of Western blotting and ELISA indicated that the level of AMH in ovarian total protein and serum had a similar dynamic change in the GnRH-a group. The results of immunohistochemistry showed that follicular AMH, AMHRII, and FSHR significantly decreased in the GnRH-a group. Prolonged GnRH-a protocol can improve synchronization and sensitivity of follicular development by balancing the expressions of AMH, AMHRII, and FSHR among follicles at all levels, thereby achieving better therapeutic effect.

Effect of Prolonged GnRH Agonist Downregulation on ICSI Outcome in Patients With Endometriomas of Less Than 5 cm: A Randomized Controlled Trial.

To evaluate the effect of prolonged Gonadotropin releasing hormone (GnRH) agonist downregulation in patients with endometriomas of less than 5 cm on the outcome of the proceeding Intracytoplasmic sperm injection (ICSI) trial. In a randomized controlled trial at a university teaching hospital, 90 patients indicated for ICSI and having unilateral single endometrioma of less than 5 cm in diameter were randomized into 2 groups. Group A (45 patients) received the standard long protocol; whereas group B (45 patients) received 3 consecutive Intramuscular (IM) injections of triptorelin 3.75 mg 28 days apart followed by the standard long protocol 28 days after the last injection. There were no significant differences in the clinical and hormonal characteristics between the 2 groups. All ICSI cycle characteristics including number of retrieved oocytes, fertilized oocytes, and transferred embryos were also not significantly different. However, patients who received prolonged GnRH agonist therapy showed significantly higher chemical ( P = .011), clinical ( P = .018), and ongoing ( P = .028) pregnancy rates. Prolonged GnRH agonist downregulation improves the pregnancy rates in patients with small endometriomas undergoing ICSI.

Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists

This was a preliminary study to determine the effect of aromatase inhibitors in preventing the flare induced by GnRH agonist (GnRH-a) in women with endometriosis (n = 9) or leiomyomata (n = 4) who were given letrozole on the first 5 days of the GnRH-a therapy. Serum LH and FSH levels showed the typical flare 1 day after the injection of the GnRH-a; however, E(2) declined immediately after letrozole administration and was notably suppressed at 1, 2, and 4 days after GnRH-a. No patients complained of clinical symptoms typical of the GnRH-a flare phenomenon.

Prolonged gonadotropin-releasing hormone agonist therapy reduced expression of nitric oxide synthase in the endometrium of women with endometriosis and infertility

To determine whether endometrial expression of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS) protein in women with endometriosis-associated infertility is different from that in the fertile controls, whether GnRH agonist (GnRH-a) regulates the endometrial expression of NOS in women with endometriosis-associated infertility, and whether there is a correlation between serum E2 or P levels, and the endometrial expression of eNOS or iNOS. Prospective controlled study. University hospital for reproductive medicine and gynecologic endocrinology. Thirty patients with endometriosis-associated infertility and 19 patients with carcinoma in situ of the cervix. Endometrial biopsy specimens and blood samples. Endometrial eNOS and iNOS protein relative levels and serum concentrations of E2 or P. By Western blot analysis, iNOS was not detected, and a unique menstrual cycle-dependent expression of eNOS was observed. Eutopic endometrium in women with endometriosis-associated infertility before GnRH-a treatment showed higher levels of eNOS than that of the control group. After 3 months of GnRH-a therapy, eNOS levels in the endometrium were reduced. In addition, a significant positive correlation was found between serum E2 or P concentrations, and the endometrial expression of eNOS. The GnRH-a treatment attenuated the endometrial expression of eNOS in women with endometriosis-associated infertility. Endogenous ovarian steroids influence endometrial eNOS expression.

Prolonged use of gonadotropin-releasing hormone agonist and tibolone as add-back therapy for the treatment of endometrial hyperplasia

Objectives: To investigate the response of the various hyperplastic disorders of the endometrium to a prolonged treatment with leuprolide acetate, a gonadotropin-releasing hormone agonist (GnRH-a), plus tibolone, as add-back therapy, and further to study if the tibolone addition reduces the hypoestrogenic actions of the GnRH-analogue. Methods: We treated 26 women with histologically confirmed simple ( n=9), complex ( n=15) or atypical ( n=2) endometrial hyperplasia (EH) for 12 months with monthly injections of 1Ampulle/3.75 mg of leuprolide acetate, followed by tibolone, 2.5 mg per day per os. Every woman unterwent a hysteroscopic evaluation and biopsy of the endometrium after 3 (in cases with atypical EH), 6 and 12 months of treatment, as well as after 12 and 24 months of follow-up. The clinical, paraclinical and laboratory course of the disease was followed-up by using of a climacteric scoring system and by testing of various parameters. Results: The histopathologic evaluation of the endometria revealed regression of EH in all women after 12 months of treatment, however, during the first 2 years of follow-up EH reappeared in four women (4/21, 19%). Bone mineral density and serum parameters did not show significant changes during treatment, whereas only a mild suffering from hypoestrogenic side-effects was noted. Conclusions: It seems that the combined GnRH-a/tibolone treatment in women with EH is a potent alternative, so far as the endometrial status and the clinical course of the disease are concerned, whereas tibolone appears to act sufficiently as add-back therapy to prolonged GnRH-a treatment. The probability of relapse of the disease during the follow-up period makes the close monitoring of the endometrium after cessation of the treatment absolutely necessary.

Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of rapid ICSI-ZIFT in patients with endometriosis

Objective: We presented 4000 cases of intrafallopian transfer of ova immediately after intracytoplasmic sperm injection (RAPID ICSI-ZIFT) for treatment of severe male factor infertility in 57th annual meeting of ASRM 2001, in the present study we want to evaluate the effect of a 3 month course of GNRH agonist administered immediately before RAPID ICSI-ZIFT in infertile patients with endometriosis. Design: Prospective randomized trial in a private and university ART center. Materials and Methods: 50 patients received three courses of a long-acting GNRH agonist. Triptorelin lactide (Decapeptyl Pharma Biotech-sines France) 3.75 mg IM every 28 days followed by standard controlled ovarian hyperstimulation. Fifty two patients received standard controlled ovarian hyperstimulation with midluteal phase GNRH agonist down regulation. Candidates were infertile patients with endometriosis and at least one patent fallopian tube documented at laparoscopy within 60 months of cycle initiation (Range 2–55 months). All patients had regular menses (every 26–33 days). Patients with early follicular phase greater than 12 mIU/ml and evidence of ovarian endometrioma were excluded. Patients were randomized into two groups by using a computer generated random number (IRB approved). Group 1 consisted of 50 patients who received a depot preperation of the GNRH agonist Decapeptyl 3.75 mg IM. every 28 days for three injections. The first injection was administered during the early follicular phase. Controlled ovarian hyperstimulation consisted of standard GNRH agonist down-regulation using LH/RH agonist buserlin (suprefact) HMG combinations in the form of a long protocol and transvaginal ultrasound guided oocyte retrieval, ICSI and laparoscopic tubal transfer within 45 days of the last decapeptyl injection. Group 2 consisted of 52 controls with endometriosis who did not receive the long-acting GNRH agonist but instead underwent standard controlled ovarian hyperstimulation regimens. Results: Baseline clinical data did not differ significantly in terms of age (Y), group I, 33.12 ± 0.67 (Range 28–39) group II, 32 ± 0.56 (Range 27–39) early follicular phase serum FSH group I, 6.17 ± 0.54 mIU/ml group II, 7.32 ± 0.32. Estradiol group I, 36.26 ± 5.37 (pg/ml) group II, 30.33± 4.84. Interval between the most recent surgical intervention and cycle onset group I, 14.52 ± 2.45 (MO) group II, 17.58 ± 2.4 (MO) surgical technique used, however significantly greater proportion of group I patients than group II patients had stages III or IV endometriosis. Group I, 21 and group II, 15 (p<0.05). The groups did not differ with regard to total Gonadotropin dose. Group I, 42 ± 3.21 (75 IU Ampules) or days of administration. Group I, 10.12 ± 0.43 and group II, 10.08 ± 0.21, number of oocytes obtained, group I, 14.84 ± 1.5, group II, 15.23 ± 1.56 number of embryo transferred. Group I, 3.28 ± 0.19 and group II, 3.04 ± 0.2. The implatation rate in group I, was 38.7% and only 20.2% in group II (p-value = 0.002). The clinical pregnancy rates were 45.5% and 18.6%, respectively (p-value = 0.007). Conclusion: The pregnancy and implantation rates were significantly higher in prolonged gonadotropin-releasing hormon agonist therapy on the outcome of Rapid ICSI-ZIFT in patients with endometriosis.

Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis

Objective: To evaluate the effect of a 3-month course of GnRH agonist administered immediately before IVF-ET in infertile patients with endometriosis. Design: Prospective, randomized trial. Setting: Three tertiary care assisted reproductive technology programs. Patient(s): IVF-ET candidates with surgically confirmed endometriosis. Intervention(s): Twenty-five patients received three courses of a long-acting GnRH agonist, 3.75 mg i.m. every 28 days, followed by standard controlled ovarian hyperstimulation. Twenty-six patients received standard controlled ovarian hyperstimulation with mid-luteal phase GnRH agonist down-regulation or microdose flare regimens. Main Outcome Measure(s): Response to controlled ovarian hyperstimulation, ongoing pregnancy rates per cycle, group implantation rates, and implantation rate per embryo transfer procedure. Result(s): The extent of surgically confirmed endometriosis was greater in patients who received the long-acting GnRH regimen for 3 months before IVF-ET. The groups did not differ significantly in terms of dose or duration of gonadotropin stimulation, number of oocytes retrieved, fertilization rate, or number of embryos transferred. Patients who received the long-acting GnRH regimen had significantly higher ongoing pregnancy rates (80% vs. 53.85%) and a trend toward higher implantation rates (42.68% vs. 30.38%). Conclusion(s): Prolonged use of GnRH agonist before IVF-ET in patients with endometriosis resulted in significantly higher ongoing pregnancy rates than did standard controlled ovarian hyperstimulation regimens. No deleterious effect on ovarian response was observed.

Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone “add-back” therapy

To examine the safety and efficacy of combining cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH agonist (GnRH-a) for prolonged therapy of symptomatic endometriosis. Prospective randomized open label study. Tertiary care university-affiliated reproductive medicine program. Nineteen regularly cycling women with laparoscopically diagnosed symptomatic endometriosis and 18 regularly cycling untreated controls without endometriosis. All patients received a depot preparation of the GnRH-a leuprolide acetate IM monthly for 48 weeks. Group I patients (n = 10) received supplemental sodium etidronate cycled with calcium carbonate as well as 2.5 mg norethindrone daily. Group II patients (n = 9) received only supplemental 10 mg norethindrone daily. Group III volunteers (n = 18) were untreated and followed for bone density changes. Disease extent at follow-up laparoscopy; pain, vasomotor, and vaginal symptom scores; bone mineral density (serial dual-energy roentgenogram absorptiometry scans); serum estrogens, lipids, and glucose and insulin response to glucose challenge. Painful symptoms and extent of endometriosis were reduced in both treatment groups. Despite maintenance of a chronically hypoestrogenic state for 48 weeks, no changes in bone density over time or in comparison to group III untreated controls were noted. Similarly, no evidence of significant vasomotor symptoms were reported in either treatment group. However, adverse changes over time in circulating low-density lipoprotein (LDL) cholesterol and apolipoprotein A1 levels as well as the ratio of high-density lipoprotein to LDL were noted only in group II. The combination of cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH-a served to safely prolong medical therapy of symptomatic endometriosis. Clinical efficacy was preserved while prophylaxis against significant hypoestrogenic side effects was achieved.