Complete ovarian unresponsiveness to hMG stimulation after prolonged GnRH analogue administration

GnRH agonists (GnRH-a) have recently been shown to exert an inhibitory effect on human reproductive functions, the mechanism for this effect being attributed solely to the desensitization of the pituitary gonadotropin receptors to GnRH-a. We present two cases where chronic treatment with a GnRH-a caused complete suppression of ovarian activity in vivo. The effect could not be counteracted by large hMG doses and resulted in high FSH plasma concentrations. Normal ovarian activity was restored only after withdrawal of GnRH-a.     

Comparison of leuprolide acetate and triptorelin in assisted reproductive technology cycles: a prospective,randomized study

OBJECTIVE: To compare the use of two depot GnRH-a, leuprolide and triptorelin, in long-suppression GnRH-a protocols. DESIGN: Prospective, randomized study. SETTING: An IVF unit of an academic medical center.Fifty-two women who underwent controlled ovarian hyperstimulation and IVF. INTERVENTION(S): Patients were prospectively randomized to receive 3.75 mg depot formulations of either leuprolide or triptorelin on days 21-23 of the menstrual cycle. Stimulation with gonadotropins was initiated after pituitary desensitization was achieved. MAIN OUTCOME MEASURE(S): The stimulation pattern and cycle outcomes were compared between the two groups. RESULT(S): Twenty-six patients were included in each group. No significant differences were observed in the patient age, estrogen, and P levels on day of hCG administration, gonadotropin dosage, number of oocytes retrieved, fertilization rate, percentage of high-quality embryos, and number of embryos transferred. However, significantly higher clinical implantation and pregnancy rates were found in the leuprolide group compared with the triptorelin group. CONCLUSION(S): A depot preparation of leuprolide is associated with higher implantation and pregnancy rates than a depot preparation of triptorelin when it is used in the midluteal phase as part of the long-suppression GnRH-a protocol in IVF.     

Pituitary and ovarian suppression rate after high dosage of gonadotropin-releasing hormone agonist

Ten infertile menstruating women were treated with daily injections of gonadotropin-releasing hormone agonist (GnRH-a). The GnRH-a (Buserelin; Hoe 766, Hoechst-AG, Frankfurt/Main, West Germany) was administered subcutaneously (SC) from day 9 of the cycle for 6 days, and intranasally (1.2 mg) for 15 days. Before treatment, all ten women had a normal response to Buserelin challenge test and the GnRH test, and seven of the ten responded to estradiol (E2) benzoate test (2 mg intramuscularly). The SC administration of Buserelin (1.5 mg) for 6 days resulted in suppression of pituitary activity. Continuous treatment with Buserelin (1.2 mg for 3 weeks) was effective as demonstrated by decreasing serum E2 levels to below 20 pg/ml, and in the absence of ovarian follicles in ultrasonographic scanning. Three days after cessation of Buserelin treatment, the pituitary again responded to the GnRH test. Thus, the authors concluded that the administration of Buserelin in very high doses can induce medical hypophysectomy within 6 days, but over 3 weeks of suppression therapy are required to abolish ovarian findings. Desensitization of the pituitary was reversible within 3 days of cessation of the treatment.     

The relative success of gonadotropin-releasing hormone analogue, clomiphene citrate, and gonadotropin in 1,099 cycles of in vitro fertilization.

OBJECTIVES: To evaluate the effectiveness of and analyze the factors influencing the outcome of three ovarian stimulation protocols used during in vitro fertilization (IVF) in a large population. DESIGN: Retrospective file review. SETTING: In vitro fertilization program in one center during the years 1985 to 1990. PATIENTS AND PROTOCOLS: Three hundred forty-one patients received clomiphene citrate (CC) and human menopausal gonadotropin (hMG), 365 received hMG alone, and 393 received gonadotropin-releasing hormone analogue (GnRH-a) for pituitary suppression followed by hMG stimulation. MAIN OUTCOME MEASURE: Rates of cancellation, total pregnancies, and ongoing pregnancies, with breakdown by age of patients. RESULTS: The cancellation rate because of early luteinization following GnRH-a/hMG was significantly reduced compared with the other two protocols: 3.6% versus 9.4% and 13.7% for CC/hMG and hMG, respectively. However, in women over 40 years of age, GnRH-a/hMG resulted in the highest rate of poor ovarian response. Significantly more oocytes were retrieved, fertilized, and cleaved after the use of GnRH-a/hMG compared with the other two protocols. Despite this, clinical pregnancy rate (PR) was the highest with CC/hMG compared with GnRH-a/hMG and hMG:31.4% versus 16.9% and 15.7%, respectively. Ongoing PRs were 20.5%, 9.7%, and 11.6%, respectively. CONCLUSIONS: Although the use of GnRH-a for pituitary suppression before ovarian stimulation for IVF reduced the cancellation rate and increased the number of retrieved oocytes, it was not found to result in higher PRs than those achieved by stimulation with CC/hMG. This suggests that treatment by GnRH-a/hMG should be reserved mainly for the prevention of early luteinization.     

Serum luteinizing hormone,follicle-stimulating hormone and oestradiol pattern in women undergoing pituitary suppression with different gonadotrophin-releasing hormone analogue protocols for assisted reproduction

Gonadotrophin-releasing hormone analogues (GnRH-a) are used widely in controlled ovarian stimulation (COS) cycles for assisted reproduction. At present, there is great debate about the influence of exogenous hormone activity on the hypothalamus–pituitary axis following pituitary desensitization. The objective of this comparative study was to investigate the pattern of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol in women undergoing ovarian stimulation with different GnRH-a preparations. We retrospectively analysed 201 women, aged between 27 and 43 years, who were referred consecutively to our infertility clinic between January 2002 and January 2003. All women had no endocrinopathies or occult ovarian failure as assessed by day-3 hormone profile. Women were enrolled in one of the following COS protocols: depot triptorelin long protocol (n?=?38), buserelin long protocol (n?=?101) or buserelin short protocol (n?=?62). Recombinant FSH was used to induce ovulation. Treatment was monitored by transvaginal ultrasound scan and serum measurement of FSH, LH and oestradiol. Among the women initially included, 30 had cancelled cycles due to poor ovarian response. Serum LH levels were significantly higher in the short-protocol group compared with the long-protocol groups (p?<?0.001). The number of follicles, oocyte yield, number of grade-I embryos and fertilization rate were significantly lower in the short-protocol group than in the long-protocol groups. These findings showed that LH concentrations are significantly higher in women undergoing reversible medical hypophysectomy with a GnRH-a short protocol than in women treated with a long protocol. The hypothesis of an LH ceiling is confirmed.     

Relationship between gonadotropin releasing hormone agonist dosage and in vitro fertilization outcome.

A prospective study in 132 women undergoing in vitro fertilization was performed in order to assess whether lower doses of gonadotropin releasing hormone agonists (GnRH-a) may ensure adequate oocyte retrieval and pregnancy rate, without pituitary oversuppression. Forty-five patients received subcutaneous tryptorelin depot (Decapeptyl 3.75, IPSEN SpA), 41 received subcutaneous tryptorelin acetate daily (Decapeptyl 0.1 mg, IPSEN SpA) and 46 received 0.05 mg tryptorelin acetate daily from day 21 of the cycle. From day 3 of the new cycle, if the estradiol levels were < 30 pg/ml, patients received two or three ampules of gonadotropin daily. In the group receiving subcutaneous tryptorelin acetate depot, the mean number of total gonadotropin ampules was significantly higher (p < 0.05), otherwise estradiol levels and the number of oocytes retrieved, fertilized and cleaved were significantly lower (p < 0.05). Pituitary oversuppression induced by GnRH-a causes an increase in the gonadotropin requirement for assisted reproductive techniques (ART) and a reduction in the number of oocytes retrieved and fertilized. There is a high risk of oversuppression in normal-weight or underweight women, because there is greater bioavailability of the peptide, hence elevated circulating levels of GnRH-a. Thus, ovarian stimulation in ART cycles depends on many factors, not least the identification of the best GnRH-a dose.     

Serum luteinizing hormone, follicle-stimulating hormone and oestradiol pattern in women undergoing pituitary suppression with different gonadotrophin-releasing hormone analogue protocols for assisted reproduction.

Gonadotrophin-releasing hormone analogues (GnRH-a) are used widely in controlled ovarian stimulation (COS) cycles for assisted reproduction. At present, there is great debate about the influence of exogenous hormone activity on the hypothalamus-pituitary axis following pituitary desensitization. The objective of this comparative study was to investigate the pattern of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol in women undergoing ovarian stimulation with different GnRH-a preparations. We retrospectively analysed 201 women, aged between 27 and 43 years, who were referred consecutively to our infertility clinic between January 2002 and January 2003. All women had no endocrinopathies or occult ovarian failure as assessed by day-3 hormone profile. Women were enrolled in one of the following COS protocols: depot triptorelin long protocol (n = 38), buserelin long protocol (n = 101) or buserelin short protocol (n = 62). Recombinant FSH was used to induce ovulation. Treatment was monitored by transvaginal ultrasound scan and serum measurement of FSH, LH and oestradiol. Among the women initially included, 30 had cancelled cycles due to poor ovarian response. Serum LH levels were significantly higher in the short-protocol group compared with the long-protocol groups (p < 0.001). The number of follicles, oocyte yield, number of grade-I embryos and fertilization rate were significantly lower in the short-protocol group than in the long-protocol groups. These findings showed that LH concentrations are significantly higher in women undergoing reversible medical hypophysectomy with a GnRH-a short protocol than in women treated with a long protocol. The hypothesis of an LH ceiling is confirmed.     

Simplification of the clinical phase of IVF and ICSI treatment in programmed cycles.

OBJECTIVE: To evaluate the success of a protocol for controlled ovarian hyperstimulation allowing patient self-selection into groups for ovulation stimulation planned 8 weeks and more in advance following cycle synchronization, drug self-administration as well as a reduced number of folliculometries. METHODS: A total of 714 patients received the same stimulation protocol. In 260 cases GnRH-a was applied daily and in 454 as depot. In all patients FSH-HP was self-administered subcutaneously for ovarian stimulation. In 316 patients IVF and in 398 patients ICSI was performed. RESULTS: The delivery rate per started cycle was higher in patients receiving depot GnRH-a in the IVF and ICSI group (30.2 vs. 23.4) than in those receiving subcutaneous GnRH-a (20.2 vs. 22.1). CONCLUSION: Programming of the IVF/ICSI cycle greatly simplifies treatment. A comparison of pregnancy rate and delivery rate per cycle between depot and subcutaneous daily application of GnRh-a did not confirm any statistically significant difference.     

Oral contraception: disadvantages of estrogen reduction

New oral contraceptives (OCs) include formulations with reduced estrogen and progestin doses intended to reduce cardiovascular risk and triphasic pills that allow maximum steroid concentrations to coincide with the luteinizing hormone LH surge. The risk of administering low steroid doses is that the antigonadotropic effect will be insufficient to inhibit endogenous estrogen secretion in some women. Individual receptivity to sex steroids is known to be highly variable. Incomplete ovarian inhibition poses risks over the short and long terms of functional ovarian cysts and loss of the protective effects of higher dosed pills against ovarian and endometrial cancers and benign breast disease. It is impossible to compare the different OC formulations because no truly comparative prospective studies have yet been done, the number of subjects in existing trials has been small, and the methods of measuring the different hormones and overall evaluation criteria have differed. Follow-up of subjects is variable, usually ranging from 1 to 12 months, but hormone levels vary at different durations of usage. Most studies have contained no statistical data. Available studies indicate that low-dose formulations in general provide a sufficient ovarian blockage. The hypothalamopituitary axis is not as strongly inhibited except by OCs containing 50 mcg of ethinyl estradiol (EE). Formulations containing the 3rd generation progestins have the strongest inhibiting effect. When EE doses decline from 30 to 20 mcg, the suppressive effect on ovarian activity usually persists, but 20 mcg of EE is not enough for some women. Unfortunately, no studies have examined the efficacy of a formulation with 30 mcg of EE in women insufficiently responding to 20 mcg. Results concerning the effect of 20 mcg formulations on the hypothalamopituitary axis are contradictory; a crossover, double-blind, comparative study on a sufficient number of women will be required to evaluate definitively the effect of reduction from 30 to 20 mcg. From a practical standpoint, it is more interesting to compare clinical tolerance to the 30 and 20 mcg formulations. Available studies on breast effects and cycle control, the incidence of ovarian cysts, metabolic effects, and the persistence of other beneficial effects of higher-dosed OCs suggest that the disadvantages of reducing estrogen doses are minor. The most important is the reduced protection against ovarian cysts observed in 2nd generation formulations. Because of the strong inhibition of ovarian activity and the powerful progestomimetic activity of the 3rd generation progestins, it is probable that ongoing studies will demonstrate that the beneficial effects of higher-dosed OCs persist. Cycle disturbances have not been observed with formulations containing at least 20 mcg of EE. Until definitive results become available, however, it is recommended that low-dose OCs be avoided in women requiring complete blockage of ovarian activity.     

Long-term remission of ovarian hyperandrogenism after short-term treatment with a gonadotropin-releasing hormone agonist

OBJECTIVE: To assess the long-term effects of GnRH agonist (GnRH-a) therapy in a patient with benign ovarian hyperandrogenism. DESIGN: Case report. SETTING: University Hospital endocrine outpatient's clinic. PATIENT(S): A 55-year-old postmenopausal woman with hirsutism and virilization of ovarian origin. INTERVENTION(S): Treatment with a course of GnRH-a (triptorelin 3.75 mg IM every 28 days for 4 months). Follow-up for 3 years. MAIN OUTCOME MEASURE(S): Serum gonadotropin and androgen levels, clinical assessment using the Ferriman-Gallwey score, and assessment of ovarian morphology by ultrasonography. RESULT(S): Administration of triptorelin resulted in suppression of serum testosterone and gonadotropin values and relief of the hyperandrogenic symptoms. Upon discontinuation of treatment, the patient's serum gonadotropin levels returned to the postmenopausal range, but the testosterone levels remained normal and the patient was asymptomatic for an observation period of 3 years. CONCLUSION(S): This case is the first example of long-term remission of ovarian hyperandrogenism in a postmenopausal woman, after short-term treatment with GnRH-a. This supports the view that GnRH-a therapy could be used, even in short courses, for the long-term suppression of benign ovarian hyperandrogenism.     

Gonadotropin-releasing hormone agonist-induced ovarian hyperstimulation: low-dose side effects in women and monkeys

OBJECTIVE: To determine whether low (subtherapeutic) doses of gonadotropin-releasing hormone agonists (GnRH-a) can cause ovarian hyperstimulation. DESIGN: The study is in two parts: a preliminary clinical trial of women and a follow-up study in laboratory primates. SETTING: Normal human volunteers were studied in an academic research environment; primates were in a conventional laboratory setting. PATIENTS, PARTICIPANTS: Human volunteers were selected on the basis of apparent normal health. The monkeys were believed to be of normal reproductive status. INTERVENTIONS: Gonadotropin-releasing hormone agonists were administered at subtherapeutic doses. MAIN OUTCOME MEASURES: After observing ovarian hyperstimulation in two of five women receiving low doses of GnRH-a, a study was specifically designed to test the hypothesis that at low (subtherapeutic) doses of GnRH-a the "flare-effect" can be sustained without achieving down regulation. RESULTS: The data in women and monkeys suggest that a highly individualized response to low GnRH-a doses can be manifested as ovarian hyperstimulation. CONCLUSION: Four points of interpretation are offered: (1) that subtherapeutic doses of GnRH-a can cause ovarian hyperstimulation and related sequelae; (2) this may be a unique observation in that, typically, lower doses of medications have a lower incidence of negative side effects; (3) the findings suggest that GnRH-a prescribed in self-administration regimens may be more prone to such problems in noncompliant patients; and (4) the hyperstimulation response of the ovaries to low GnRH-a doses may indicate a new approach to controlled ovulation induction, although wide individualism was found.     

Pituitary desensitization for eight weeks after the administration of two distinct gonadotrophin-releasing hormone agonists

OBJECTIVE(S): The objective was to evaluate the duration of pituitary desensitization after the administration of 3.5 mg of triptorelin (T) and leuprolin (L) depot preparations in patients with endometriosis. STUDY DESIGN: Two groups of 30 patients received, on 21st day of the cycle, 3.75 mg i.m. of triptorelin (T group), and of leuprolin acetate (L group). From the first to the eighth week following gonadotrophin-releasing hormone agonists (GnRH-a) administration both groups underwent pelvic ultrasound and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) evaluation. Statistical analysis was performed using the ANOVA test and the median test. A p-value < 0.05 was considered significant. RESULTS: Pituitary suppression was achieved from two to six and from two to seven weeks after the administration of 3.75 mg of leuprolin and triptorelin, respectively. FSH and LH serum levels were significantly higher in the L group than in the T group after the fourth week. CONCLUSIONS: Leuprolin and triptorelin depots (3.75 mg) promote satisfactory ovarian suppression lasting for six and seven weeks, respectively, after administration, with significantly different ambient levels of endogenous LH.     

Ovarian protection with gonadotropin-releasing hormone agonists during cyclophosphamide therapy in systemic lupus erythematosus

Administration of cyclophosphamide (CYC), an alkylating agent used to treat malignancies and severe rheumatic diseases, creates a risk of ovarian insufficiency that is related to the intensity and duration of therapy and the age of the patient. To preserve reproductive capacity in the appropriate clinical setting, oocyte, embryo, and/or ovarian tissue cryopreservation are recommended. Medical protection with depot gonadotropin-releasing hormone agonists (GNRHa) has emerged as a potential means to preserve both fertility and ovarian function through the suppression of ovarian activity during treatment with alkylators. We review the trials of GNRHa for ovarian protection in both cancer and rheumatic disease patients. Trials in cancer patients receiving CYC alone, or in combination with other gonadotoxic agents that have employed several different GNRHa have yielded mixed results. Trials in lupus patients receiving lower doses of CYC alone utilizing depot leuprolide acetate have tended to show favorable results.     

Significance of an abnormal response during pituitary desensitization in an in vitro fertilization and embryo transfer program

Purpose: Our purpose was to evaluate the IVF-ET outcome in patients who did not achieve timely pituitary-ovarian suppression following long-protocol GnRH agonist (GnRH-a) administration. Methods: A retrospective analysis was done on 96 IVF treatment cycles characterized by a delayed response (DR) to long-protocol GnRH-a treatment. The study included those patients who either achieved ovarian suppression (E₂ 110 pM) despite an elevated LH level (group DR-A) or had pituitary desensitization (LH 1.5 IU/L) without ovarian suppression (group DR-B) on day 12 of GnRH-a treatment but needed an extended course of GnRH-a treatment to achieve complete suppression. These patients had gonadotropin stimulation either from day 12, despite an elevated level of LH (subgroup DR-A1; n=13) or elevated E₂ levels (subgroup DR-B1; n=9), or after achieving a complete hypogonadotropic-hypopgonadal state following an extended course of GnRH-a treatment [subgroups DR-A2 (n=46) and DR-B2 (n=28)]. The outcome was compared with that of 88 cycles of normal responders (group NR) who had pituitary-ovarian suppression by day 12 of GnRH-a administration. Results: Ovarian response and pregnancy rates in subgroups DR-A1 and DR-A2 were statistically not different and comparable to those in the NR group. In subgroups DR-B1 and DR-B2, E₂ response and rates of oocyte retrieval and pregnancy were significantly lower than those in the other groups, but fertilization and cleavage rates were similar. The requirement of gonadotropin for ovarian stimulation was comparatively higher in subgroup DR-A2 and both DR-B subgroups. Conclusions: There was no treatment cancellation in group NR and both DR-A subgroups, but 22% of the cycles in DR-B1 and 14% of the cycles in DR-B2 were canceled due to poor ovarian response. It therefore appears that during long-protocol pituitary desensitization, the post-GnRH-a level of serum E₂, rather than LH, better predicts IVF-ET outcome.Presented in part at the XIth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Successful management of an ovarian enlargement resembling ovarian hyperstimulation in a premenopausal breast cancer patient receiving tamoxifen with cotreatment of GnRH-agonist.

Tamoxifen use in breast cancer patients may cause ovarian cysts. This report presents a case of complex cyst resembling ovarian hyperstimulation in a premenopausal breast cancer patient receiving tamoxifen which resolved by administering monthly depot GnRH-agonist (GnRH-a) without abandoning the tamoxifen treatment.     

The effect of gonadotropin-releasing hormone agonist on the ovarian response and in vitro fertilization results in polycystic ovarian syndrome: a prospective study.

OBJECTIVE: To assess the effect of gonadotropin-releasing hormone agonist (GnRH-a) on pituitary suppression, subsequent ovarian response, and results of in vitro fertilization (IVF) treatments in polycystic ovarian syndrome (PCOS) patients. DESIGN: Randomized prospective study. SETTING: In vitro fertilization program and endocrinologic institute. PATIENTS: Thirty patients with PCOS; 16 received GnRH-a, and 14 did not receive GnRH-a. INTERVENTIONS: Ovum pick-up and embryo transfer. MAIN OUTCOME MEASURES: Response to GnRH-a test, serum and follicular fluid (FF) hormonal measurements, steroid levels, and aromatse activity in granulosa cell (GC) culture, and results of IVF. RESULTS: Pituitary responsiveness was abolished in all patients 14 days after GnRH-a administration, and early luteinization was prevented. Steroid levels in FF did not differ between the two groups. In GC culture, progesterone (P) levels were higher in patients without the GnRH-a (3,704 +/- 1,232 nmol/L versus 2,117 +/- 235 nmol/L; P less than 0.05) as were androstenedione (A) levels (5.3 +/- 1.0 nmol/L versus less than 3.5 nmol/L; P less than 0.05). However, aromatase activity and IVF results were similar in the two groups. CONCLUSIONS: Administration of GnRH-a in patients with PCOS decreases P and A production by the GC cells and prevents early luteinization. It does not affect the IVF results.     

Ovarian stimulation protocol for in vitro fertilization with gonadotropin-releasing hormone agonist widens the implantation window

Pregnancy rates vary considerably with the type of ovarian stimulation used for in vitro fertilization and embryo transfer (IVF-ET). The window of implantation may represent one of the rate-limiting steps in IVF success. We therefore investigated estimated implantation times of 10 consecutive IVF singleton pregnancies, achieved using pituitary suppression with gonadotropin-releasing hormone agonist (GnRH-a) before and during ovarian stimulation with human menopausal gonadotropins (hMG), and compared those with 9 consecutive IVF pregnancies achieved by hMG stimulation only. Estimated implantation times were calculated by regression analysis of serial human chorionic gonadotropin (hCG) measurements between days 7 and 16 after ET. The GnRH-a/hMG pregnancies implanted between days 7 and 11, whereas hMG pregnancies implanted between days 7 and 9 after ET. The hCG regression curve for the GnRH-a/hMG pregnancies revealed a delay of 1.5 days in estimated implantation time compared with the hMG only group. There were no significant differences in pretransfer in vitro embryos development between the two groups. Thus, the delay in hCG rise probably reflects a delay in embryo implantation. We therefore conclude that a GnRH-a/hMG stimulation protocol appears to widen the implantation window in comparison with a hMG only protocol. This observation may at least in part explain the improved IVF pregnancy success with GnRH-a/hMG stimulation protocols.     

A preliminary study on reduced dose (33 or 25 microg) gonadotropin-releasing hormone agonist long protocol for multifollicular ovarian stimulation in patients with high basal serum follicle-stimulating hormone levels undergoing in vitro fertilization-embryo transfer.

The aim of the present study was to evaluate the clinical efficacy of half-dose (50 mug) and further reduced dose (33 or 25 mug) gonadotropin-releasing hormone agonist (GnRH-a; triptorelin) long protocols for multifollicular ovarian stimulation (MFOS) for patients with high basal serum follicle-stimulating hormone (FSH) level undergoing in vitro fertilization and embryo transfer (IVF-ET). One hundred and two IVF-ET cycles performed in 84 infertile patients with high basal serum FSH (>10.0 mIU/ml) were included in this retrospective study. Study subjects were assigned to two groups: continuous half-dose GnRH-a long protocol (group A, n = 63) vs. further reduced dose GnRH-a long protocol (group B, n = 39) from half-dose at the start of GnRH-a to one-third or one-quarter dose after pituitary downregulation. Exogenous FSH or human menopausal gonadotropin was administered for MFOS in step-down mode, four or fewer embryos were transferred, and the outcomes of MFOS were compared between the two groups. Serum estradiol (E(2)) level on the day of human chorionic gonadotropin administration was significantly higher in group B (mean +/- standard deviation (SD): 1318.3 +/- 1120.4 vs. 2054.9 +/- 1773.5 pg/ml, p = 0.015). The number of transferable and good-quality embryos was also significantly higher in group B (mean +/- SD: 2.9 +/- 1.7 vs. 3.7 +/- 2.0, p = 0.027; 1.8 +/- 1.4 vs. 2.7 +/- 2.0, p = 0.020). No statistically significant difference in the outcomes was observed with respect to the dose of gonadotropins administered, the number of oocytes retrieved or the clinical pregnancy rate. In conclusion, GnRH-a long protocol with a reduced dose, tapered from the starting half-dose to a third or a quarter of the normal dose after pituitary suppression, may be beneficial for MFOS in IVF-ET patients with a high basal serum FSH level. A further prospective randomized controlled study on a larger scale is needed to confirm these findings.     

IVF-ET中促性腺激素释放激素激动剂的超促排卵应用与剂量研究

促性腺激素释放激素激动剂(GnRH-a)是体外受精-胚胎移植(IVF-ET)技术中重要用药。GnRH-a与GnRH受体结合后,早期"突发"作用可刺激垂体促性腺激素急剧释放,持续应用后使垂体受抑制,内源性促性腺激素(Gn)水平下降,即所谓的降调节作用。利用这种生物学特性,GnRH-a联合Gn超促排卵可预防早发黄体生成素(LH)峰,避免卵泡过早黄素化。另外,GnRH-a代替人绒毛膜促性腺激素诱发排卵可降低卵巢过度刺激综合征(OHSS)发生率。探索既能有效抑制LH峰,又不使垂体过度抑制的GnRH-a有效低剂量对于超促排卵有重要意义。     

The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the efficacy of gonadotropin-releasing hormone agonists (GnRH-a) used in ovulation induction for in vitro fertilization and embryo transfer (IVF-ET) and gamete intrafallopian transfer (GIFT). DESIGN: Meta-analysis of 10 trials comparing treatment cycle outcomes after GnRH-a (n = 914) with other ovulation induction protocols (n = 722) and 7 trials comparing outcomes after short flare-up (n = 368) with longer suppression (n = 476) GnRH-a protocols. MAIN OUTCOME MEASURES: The outcome of primary interest was clinical pregnancy rate (PR) per treatment cycle commenced. Data describing the amount of gonadotropin used, cycle cancellation rate, clinical pregnancy per ET, and multiple pregnancy and abortion rates were also analyzed. RESULTS: Clinical PR per cycle commenced was significantly improved after GnRH-a use for IVF (common odds ratio [OR] 1.80, 95% confidence interval [CI] 1.33 to 2.44) and GIFT (common OR 2.37, 95% CI 1.24 to 4.51). Clinical PR per embryo transfer was also significantly improved with GnRH-a use (common OR 1.40, 95% CI 1.01 to 1.95). Cycle cancellation was decreased (common OR 0.33, 95% CI 0.25 to 0.44), whereas spontaneous abortion rate was similar with and without GnRH-a use. Cycle cancellation and PRs after short flare-up and longer suppression protocols were similar between groups. CONCLUSIONS: This meta-analysis supports the routine use of GnRH-a for IVF and GIFT. Further research is needed, however, to assess the potential for increased rates of multiple pregnancy and ovarian hyperstimulation syndrome, which may be associated with this treatment.