Ovulation triggering in clomiphene citrate-stimulated cycles: Human chorionic gonadotropin versus a gonadotropin releasing hormone agonist

Purpose To compare the use of human chorionic gonadotropin (hCG) to a gonadotropin releasing hormone (GnRH) agonist, nafarelin, in initiating ovulation and supporting the luteal phase after priming with clomiphene.Methods In 26 infertile women 50 mg clomiphene citrate produced a preovulatory-size follicle. Then, 11 women were randomized to receive two 400-g doses of nafarelin intranasally 16 h apart, and 15 women were injected intramuscularly with 5000 IU of hCG (luteal day 0 = LD0). Starting on LD6, 7 more 400-g doses of nafarelin were repeated on an every 16-h schedule or a single 2500 IU dose of hCG was given, respectively. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E₂), progesterone (P), and hCG were measured. On LD13, endometrium was evaluated with ultrasonography and biopsy in 19 nonpregnant women.Results As judged by a threefold rise in serum LH, an LH surge was detected on LD1 in all 11 nafarelin patients, but in only 8 hCG patients (P = 0.01). LH and FSH levels were significantly higher on LD1, 7, and 8 and were significantly suppressed on LD13 in the nafarelin group. All patients had mid-luteal P levels greater than 10 ng/ml and luteal phases longer than 13 days. Significantly different luteal E₂ or P levels were noted only on LD13, with lower values in the nafarelin group. Pregnancies were achieved in 3 of 11 nafarelin cycles and 2 of 15 hCG cycles. Luteal phase defects were also similar: 4 of 8 nafarelin patients and 7 of 11 hCG patients.Conclusion Nafarelin or hCG in conjunction with clomiphene can result in viable pregnancies, but is associated with low pregnancy rates and a high incidence of luteal phase defects.     

Comparison between nafarelin acetate andd-Trp6-LHRH for temporary pituitary suppression in in vitro fertilization (IVF) patients: A prospective crossover study

Purpose Nafarelin acetate is a new gonadotropin releasing (GnRH) agonist analogue with unique potency, intranasal administration, and convenient storage. Hence, nafarelin was considered as an alternative for temporary pituitary suppression in patients undergoing ovulation induction in IVF. A crossover treatment in a prospective study was performed including 40 women with bilateral obstructed tubes and normal ovarian function, treated in 80 ovulation induction cycles using the long protocol. Twenty patients used nafarelin acetate 600 g/daily in their first cycle and received d-Trp6-LHRH, 0.5 mg/daily, in their following cycle. The other 20 women used decapeptyl in their first cycle and received nafarelin in the second.Results Estradiol suppression was achieved by both d-Trp6-LHRH and nafarelin at equal time intervals. The average total number of ampoules (P=0.0005) and the length of administration of hMG required for ovarian stimulation (P=0.0002) and the time interval between GnRHa initiation to oocyte retrieval (P=0.04) was significantly lower in nafarelin cycles. The number and the distribution between large and small follicles as well as the average number of oocytes retrieved did not differ between the two GnRH analogues.Conclusion Our results demonstrate that nafarelin acetate is comparable to d-Trp6-LHRH for temporary pituitary suppression used for controlled ovarian stimulation in IVF patients. However, using nafarelin ovarian stimulation was achieved with fewer ampoules of hMG, administered for a shorter period of time, thus with a lesser cost.     

那法瑞林长效制剂对大鼠垂体功能影响

 目的:观察国产那法瑞林(nafarelin )长效制剂的长效作用及对大鼠垂体功能影响，并探讨其作用部位。方法:采用大鼠间质细胞睾酮 (RICT)法检测血清LH(luteinizing hormone)生物活性水平。结果:那法瑞林长效制剂在体内的持续释药时间为((40.0±6.8)d。单次理植3周后大鼠血LH的周期性分泌高峰及激发高峰均消失。预先理植长效制剂组大鼠血LH在切除双侧卵巢后变化不明显。结论:那法瑞林长效制剂确有长效作用，其通过作用于垂体而抑制大鼠垂体功能。     

促性腺激素释放激素类似物那法瑞林对人乳腺癌细胞BCaP-37生长的影响

目的：观察促性腺激素释放激素(LHRH)类似物那法瑞林对体外培养的人乳腺癌细胞BCaP-37生长的影响。方法：培养的BCaP-37细胞,经下列条件作用4 d后进行细胞计数：(1) 加入10-5-10-9mol/L的那法瑞林;(2)加入10-7-10-10mol/L的雌二醇(E2);(3)在含10-8mol/L E2的条件下,加入10-6-10-8mol/L的那法瑞林或他莫昔芬;(4)加入10ng/ml或50ng/ml的表皮生长因子(EGF);(5)在含10ng/ml EGF的条件下,加入10-5-10-7mol/L的那法瑞林。结果：那法瑞林在10-5-10-9mol/L浓度下对BCaP-37培养细胞的生长无显著抑制作用,在10-6-10-8mol/L浓度下可拮抗10-8mol/L E2对BCaP-37细胞的生长促进作用,对10ng/ml EGF抑制BCaP-37细胞生长的作用无显著影响。他莫昔芬拮抗E2促进BCaP-37生长的作用与那法瑞林相似。结论：那法瑞林对人乳腺癌细胞BCaP-37体外培养生长无显著抑制作用,但能拮抗E2对BCaP-37细胞的生长促进作用。     

Endocrinology: A prospective randomized single-blind comparative trial of nafarelin acetate with buserelin in long-protocol gonadotrophin-releasing hormone analogue controlled in-vitro fertilization cycles

The use of gonadotrophin-releasing hormone (GnRH) agonists tocontrol ovulation induction cycles for in-vitro fertilization(IVF) has been shown to increase the pregnancy rate and livebirth rate compared with non-analogue cycles. Different formulationsof GnRH agonist are available with different routes and frequenciesof administration. In this prospective study, the efficacy andsafety of intranasal nafarelin and buserelin as adjunctive therapyduring IVF were assessed. A total of 240 female patients wererecruited to the study and in the first phase patients wererandomized to receive either intranasal nafarelin 200 µgtwice daily or buserelin 200 µg five times daily. In thesecond phase, patients received either nafarelin 400 µgtwice daily or buserelin 200 µg five times daily. Nafarelin400 µg and buserelin 200 µg both produced clinicalpregnancy rates of 31% per recruit and 39% per embryo transfer.The rates for nafarelin 200 ug were 23 and 37% respectively.There was no statistically significant difference in pregnancyrates, by either drug or dosage. The time taken for pituitarydown-regulation to be achieved was significantly longer on nafarelin200 µg than on either nafarelin 400 µg or buserelin.The total number of days stimulation with human menopausal gonadotrophinrequired to reach criteria for human chorionic gonadotrophin(HCG) administration was significantly longer on buserelin thanon either dose of nafarelin. Median serum oestradiol concentrationson the day of HCG administration were significantly higher oneither dose of nafarelin than on buserelin.     

A comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist-treated patients

BACKGROUND: This randomized controlled trial was designed to assess the impact of oral contraceptive (OC) scheduling with a GnRH antagonist (ganirelix) regimen on the ovarian response of women undergoing recombinant FSH (rFSH) stimulation for IVF, compared with a non-scheduled ganirelix regimen and a long GnRH agonist (nafarelin) protocol. METHODS: A total of 110 women was treated with an OC and ganirelix, 111 with ganirelix alone and 111 with nafarelin. The OC (containing 30 microg ethinylestradiol/150 microg desogestrel) was taken for 14-28 days and stopped 2 days prior to the start of rFSH treatment. Primary efficiency parameters were the number of cumulus-oocyte complexes (per attempt) and the number of grade 1 or 2 embryos (per attempt). RESULTS: In terms of follicular growth and hormone profiles, the OC-scheduled antagonist regimen mimicked the agonist regimen rather than the (non-scheduled) GnRH antagonist regimen. In the OC-scheduled GnRH antagonist group and the nafarelin group (versus the non-scheduled antagonist group), pituitary suppression was more profound at the start of stimulation (P < or = 0.001), there was a slower start of follicular growth (P < or = 0.001), longer stimulation was required (11.7 and 10.3 days respectively versus 9.4; P < or = 0.001), and more rFSH was used (2667 and 2222 IU versus 1966 IU; P < or = 0.001). In the three groups, the number of oocytes was similar (13.1, 12.9 and 11.5 respectively; not significant) as well as the number of good quality embryos (5.1, 5.7 and 5.0 respectively; not significant). CONCLUSION: OC treatment prior to the rFSH/ganirelix regimen can be successfully applied to schedule patients, although more days of stimulation and more rFSH are required than with a non-scheduled GnRH antagonist regimen.     

Efficacy of nafarelin in assisted reproductive technology: a meta-analysis

A systematic review identified nine randomized, controlled trials (both published and unpublished) which assessed the efficacy of nafarelin during IVF compared with other gonadotrophin-releasing hormone (GnRH) agonists. The trials included 1,014 women (nafarelin n = 597) in protocols employing three different dosage regimens, long and short stimulation protocols, and three comparative GnRH agonists (buserelin n = 348; triptorelin n = 14, and leuprolide n = 55). The meta-analysis of the data showed that pregnancy rates per embryo transfer with nafarelin were equivalent to those obtained with other GnRH agonists. Nafarelin and other agonists were also comparable in terms of several intermediate IVF outcomes, including fertilization rates, number of oocytes retrieved, peak oestradiol concentrations, and cycle cancellations. Women treated with nafarelin required fewer ampoules of human menopausal gonadotrophin (HMG)/FSH for ovarian stimulation and fewer days of stimulation. Safety results from both the meta-analysis and a qualitative analysis of 12 additional reports suggested that adverse effects were within the accepted tolerance range; the most frequent adverse effects were hypo-oestrogenic symptoms. In conclusion, the overall efficacy of nafarelin was equivalent to that of other GnRH agonists. The possibility that the reduced gonadotrophin requirements in women taking nafarelin will translate into cost savings per IVF treatment cycle requires further study.     

Temporary serine protection in solid phase synthesis of LH-RH analogs

Methodology for the large-scale, solid-phase synthesis of nafarelin, I, an LH-RH agonist and RS-26306, III, and LH-RH antagonist, is described. N^α-Boc protected amino acids were used in the synthesis. The only side-chain-protected amino acids required were BocHis(Tos)-OH and BocSer(t-Bu)-OH. The use of temporary protection on serine eliminates the formation of bis-serine derivatives (II and IV), which presents a major limitation to the use of minimal protection schemes for large-scale synthesis. Using this approach, the side-chain protecting groups are cleaved during the synthesis, and HF deprotection in a separate step is not required.     

The choice of a gonadotropin-releasing hormone analog influences outcome of in vitro fertilization treatment

OBJECTIVE: Our purpose was to determine if there is a difference in outcome associated with choice of gonadotropin-releasing hormone analog in in vitro fertilization treatment cycles. STUDY DESIGN: A retrospective analysis of 510 consecutive in vitro fertilization cycles with patient-selected use of either nafarelin (Synarel) or leuprolide (Lupron) was performed. RESULTS: Of 510 consecutive patient cycles, 284 patients (56%) chose nafarelin and 226 (44%) chose leuprolide. In the nafarelin group 64 cycles (34% of retrievals) resulted in deliveries. In the leuprolide group 37 (24%) resulted in delivery (p < 0.05). There were 260 patients in their first cycle of treatment, with 157 (60%) choosing nafarelin, resulting in 33 deliveries (34% per retrieval). Leuprolide, used in 103 (40%) of first cycles, resulted in 12 deliveries (20% per retrieval), (p = 0.052). CONCLUSIONS: In a large population of unselected patients undergoing in vitro fertilization the choice of nafarelin was associated with a significantly better outcome in terms of successful pregnancies achieved. (AM J Obstet Gynecol 1994;170:1629-34.)     

促性腺激素释放激素类似物那法瑞林对人乳腺癌细胞BCaP—37生？…

目的：观察促性腺激素释放激素（ＬＨＲＨ）类似物那法瑞林对体外培养的人乳腺癌细胞ＢＣａＰ－３７生长的影响。方法：培养的ＢＣａＰ－３７细胞。经下列条件作用４ｄ后进行细胞计数：（１）加入１０＾－５￣１０＾－９ｍｏｌ／Ｌ的那法瑞林;（２）加入１０＾－７￣１０＾－１０ｍｏｌ／Ｌ的雌二醇（Ｅ２）;（３）在含１０＾－８ｍｏｌ／ＬＥ２的条件下,加入１０＾－５￣１０＾－８ｍｏｌ／Ｌ的那法瑞林或他莫昔芬;（４）加入１