Ovarian stimulation by a combination of a gonadotropin-releasing hormone agonist and gonadotropins for in vitro fertilization

In the first of two studies, 20 patients were selected on the basis of tubal infertility and were randomly assigned to two groups receiving different ovarian stimulation protocols. In group A, 10 patients were given follicle-stimulating hormone (FSH), FSH was continued until the criteria for human chorionic gonadotropin (hCG) administration were satisfied. In group B, 10 patients received Buserelin (0.3 ml twice a day subcutaneously) for 14 days to induce pituitary desensitization. Stimulation with FSH was then started, and Buserelin treatment was continued until hCG administration. In the second study, patients were included if they had had at least two previous attempts at ovarian stimulation that failed to reach the stage of follicular aspiration. Ovarian stimulation was conducted with a combination of Buserelin and human menopausal gonadotropin. Use of the gonadotropin-releasing hormone (GnRH) agonist in in vitro fertilization increased the number of oocytes collected, the fertilization rate, the length of the luteal phase and the pregnancy rate. The GnRH agonist also contributed to a generally better ovarian response in patients whose estradiol production had previously responded poorly to conventional ovarian stimulation protocols.     

Hormonal changes induced by short-term administration of gonadotropin-releasing hormone agonist during ovarian hyperstimulation for in vitro fertilization and their consequences for embryo development

Several regimens have been developed to administer gonadotropin-releasing hormone agonists in association with human menopausal gonadotropins (hMG) during follicular growth stimulation for in vitro fertilization. The aim of this study was to characterize hormonal changes induced by short-term administration of agonist, and to evaluate a putative impact of the flare-up effect on follicular recruitment and subsequent IVF. Eighteen highly selected patients were randomely divided in two groups. Nine patients received a short-term administration of Buserelin (Hoechst, AG, Franfurt/Main, FRG) (day 1). They were compared with 9 patients who were exposed to a long-term protocol (day 21), and 13 control patients. Agonist-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increase, in early follicular phase, stimulated follicular growth, shortened follicular phase, and induced a transient rise in progesterone. This was followed by a phase of reduced LH secretion associated with a significant modification of LH immunoreactivity. The short-term regimen did not improve the follicular recruitment, and appeared to reduce the oocytes fertilization rate and embryo quality when compared with prolonged administration of peptide.     

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.     

Ovarian stimulation for in vitro fertilization using pure follicle-stimulating hormone with and without gonadotropin-releasing hormone agonist in high-responder patients

There is a distinct pattern of response to gonadotropin stimulation in some patients marked by high peak estradiol (E₂) levels, multifollicular ovarians response, and elevated basal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios. We reviewed the stimulation profiles of five such high-responder patients who failed to conceive during in vitro fertilization with ovarian stimulation using pure FSH. All patients had baseline LH/FSH >1.5 and peak E₂>800 pg/ml. One cycle was canceled prior to hCG administration because of marked ovarian response (E₂>2500 pg/ml, multiple small follicles). In a subsequent cycle, all patients were pretreated with the gonadotropin releasing-hormone agonist (GnRHa) leuprolide acetete for 10–14 days prior to initiation of FSH for ovarian stimulation. Leuprolide was continued until the day of hCG administration. During cycles using GnRHa, there was a statistically significant decrease (P <0.05) in serum FSH on day 3 (<5 vs 8.3 mIU/ml), serum E₂ on day 3 (14.6 vs 34.6 pg/ml), and peak serum E₂ (1197.6 vs 1923.0 pg/ml). Patients during cycles with GnRHa had a greater number of preovulatory (8.6 vs 3.0) and total (12.4 vs 6.0) oocytes retrieved (P<0.05). The fertilization rate of preovulatory oocytes was also higher during cycles using GnRHa (83 vs 64%). Two pregnancies occurred in the cycles pretreated with GnRHa. These preliminary data indicate that in high-responder patients, a combination of GnRHa and pure FSH results in lower E₂ levels during the stimulation cycle and a greater number of total and mature oocytes retrieved and fertilized.     

Ovarian hyperstimulation syndrome following the sole administration of injectable gonadotropin-releasing hormone agonist (triptorelin) for the pituitary down-regulation and in vitro fertilization treatment: report of two cases

This report is to illustrate two cases of ovarian hyperstimulation syndrome following the sole administration of injectable mid-luteal gonadotropin-releasing hormone agonists (triptorelin) for pituitary down-regulation. Both women underwent egg retrieval, and despite the transfer of good quality embryos, no pregnancy was achieved. The possible mechanism and management of the condition were discussed.     

Endometriosis-associated infertility treated by long-term gonadotropin-releasing hormone agonist administration and assisted fertilization

Summary Two patients with long-lasting infertility associated with moderate and severe symptomatic endometriosis were treated with long-term GnRH-agonist suppression of ovarian function. Both patents were relieved of their endometriosis-related abdominal pains during the first treatment month. After an additional treatment period of 3 to 5 months, assisted fertilization was performed, resulting in an ongoing pregnancy for both patients.     

Short-term use of gonadotropin-releasing hormone agonist (Leuprolide) for in vitro fertilization

A common problem encountered by in vitro fertilization (IVF) programs is the premature occurrence of the spontaneous lutenizing hormone (LH) surge during ovarian stimulation cycles. Administration of gonadotropin-releasing hormone agonists (GnRH-a) for 2 to 3 weeks produces a state of hypogonadotropic hypogonadism, thus allowing ovarian stimulation to proceed uncomplicated by a spontaneous LH surge. We have elected to treat seven patients with GnRH-a in a short-term protocol, with GnRH-a initiated on cycle day 3 along with exogenous gonadotropins. In this series, we found that the spontaneous LH surge was abolished, while ovarian responsiveness seemed to be improved. These results suggest that the initial surge of gonadotropins elicited by GnRH-a administration may enhance ovarian stimulation and that spontaneous LH surge is blocked when GnRH-a and exogenous gonadotropins are initiated concomitantly.     

Value of suppression with a gonadotropin-releasing hormone agonist prior to gonadotropin stimulation for in vitro fertilization

This study examined the use of gonadotropin-releasing hormone agonist (GnRHa) suppression before gonadotropin stimulation in 26 patients with failed prior in vitro fertilization (IVF) attempts and variable basal serum gonadotropin levels. Leuprolide, 1 mg subcutaneously per day, was administered from the midluteal phase of the cycle before IVF treatment. Concomitantly, stimulation was initiated on cycle day 3 with human menopausal gonadotropin (hMG) and follicle stimulating hormone (FSH). Based on their prior IVF attempts and serum gonadotropin levels on cycle day 3, 9 patients were high responders with elevated mean basal luteinizing hormone (LH)/FSH, 8 were low responders with elevated mean basal FSH/LH, 7 were intermediate responders with normal mean basal FSH/LH and a history of premature LH surge, and 2 had elevated (perimenopausal) mean FSH and LH. Leuprolide was discontinued on the day of human chorionic gonadotropin (hCG) administration. Prior IVF attempts in the same patients with the same protocol, but without GnRHa suppression, were used as controls. The mean number of ampules of hMG and FSH was significantly higher in leuprolide cycles than in controls. The mean day of hCG administration was also higher for leuprolide cycles than for controls. The mean LH and progesterone levels on the day of hCG were significantly lower in leuprolide cycles. The mean number of preovulatory oocytes aspirated and transferred was higher in leuprolide cycles. Cancellation and pregnancy rates were improved in leuprolide cycles. It is concluded that prior GnRHa suppression is beneficial for follicular recruitment for IVF. More patients with variable basal serum gonadotropin levels need to be studied before definite recommendations are made.     

Ultrashort gonadotropin-releasing hormone agonist combined with flexible multidose gonadotropin-releasing hormone antagonist for poor responders in in vitro fertilization/embryo transfer programs

To evaluate the appropriate controlled ovarian hyperstimulation (COH) protocol in poor responders, we compared the stimulation characteristics of 21 cycles, which included the ultrashort gonadotropin-releasing hormone (GnRH) agonist combined with the flexible multidose GnRH antagonist, to the patients' previous failed in vitro fertilization attempts. The use of an ultrashort GnRH-agonist/GnRH-antagonist COH protocol resulted in a statistically significantly greater number of follicles larger than 14 mm on the day of hCG administration, a higher number of oocytes retrieved and embryos transferred, and a reasonable clinical pregnancy rate (14.3%).     

Ovarian hyperstimulation syndrome prevention strategies: oral contraceptive pills-dual gonadotropin-releasing hormone agonist suppression with step-down gonadotropin protocols

The identification of patients at high risk for excessive responses to ovarian stimulation for in vitro fertilization and embryo transfer is essential in the tailoring of safe and effective treatment strategies. Known factors associated with increased sensitivity to gonadotropins include polycystic ovary syndrome, young age, prior ovarian hyperstimulation syndrome (OHSS), high baseline antral follicle count, and high baseline ovarian volume. Although several treatment strategies have been proposed for these patients, this report describes the experience using the dual suppression with gonadotropin step-down protocol. This protocol uses oral contraceptive pretreatment in combination with a long gonadotropin-releasing hormone agonist followed by a programmed step-down in gonadotropin dosing. Hormonal characteristics of dual suppression include an improved luteinizing hormone-to-follicle-stimulating hormone ratio and lower serum androgens, particularly dehydroepiandrosterone sulfate. Clinical characteristics of the protocol include a lower cancellation rate and favorable clinical and ongoing pregnancy rates per initiated cycle while mitigating the risk of OHSS.     

Ovarian cyst formation: a complication of gonadotropin-releasing hormone agonist therapy

Since gonadotropin-releasing hormone (GnRH) analogs were introduced into clinical therapeutic use, several side effects directly related to the hypoestrogenic state have been reported. The authors have encountered a rather infrequent complication, namely ovarian cystic formations, when using these compounds for selected in vitro fertilization and embryo transfer (IVF-ET) cases. In 7 of 24 patients with Decapeptyl (D-Trp6-luteinizing hormone-releasing hormone [LH-RH], Ferring, Kiel, FRG) treatment, and in 5 of 22 patients treated with Buserelin (Superfact, Hoechst A.G., Frankfurt, FRG), solitary ovarian cysts developed during the down-regulation phase. Their growth did not change during ovulation induction with menotropins. Although the mechanism of ovarian cyst formation during GnRH agonist treatment is not clear, their presence does not appear to interfere with the fertility of these women.     

Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization

In 143 cycles of in vitro fertilization the ovarian hyperstimulation syndrome (OHSS) occurred in 12 (8.4%) cycles. Six were in the moderate form and 6 severe. Ovarian stimulation by menotropins was preceded by induction of hypopituitary hypogonadism using D-Trp6-LH-RH microcapsules. The OHSS cycles are characterized by improved ovarian response expressed by the increased serum levels of estradiol, number of follicles, oocytes, embryos and pregnancy rate as compared to cycles with no OHSS. All patients recovered uneventfully. The follicular puncture did not have the suggested protective effect against OHSS. It is suggested that the substantial incidence of OHSS is probably related to the excessive ovarian stimulation not interrupted by early luteinization which is practically abolished by this protocol. The role of the given luteal hCG doses in the genesis of OHSS is questioned.     

Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention

Severe ovarian hyperstimulation syndrome (OHSS) was recorded in 8 of 413 patients after the use of gonadotropin-releasing hormone agonists (GnRH-a) associated with gonadotropins for in vitro fertilization. Seven of the 8 patients were pregnant. Common factors associated with the development of OHSS were high serum estradiol values on the day of ovulation induction and many follicles greater than or equal to 12 mm. Based on this experience, a new therapeutic schedule was used in a group of 10 patients who, after GnRH-a and gonadotropin stimulation, were judged to be at high risk of OHSS on the day of human chorionic gonadotropin (hCG). No hCG was administered and gonadotropins were stopped. The administration of GnRH-a was continued and, after a further period of pituitary desensitization, follicular stimulation was recommended with a lower dose of gonadotropins. No cases of OHSS occurred and 3 patients became pregnant.     

Ovarian hyperstimulation syndrome prevention strategies: use of gonadotropin-releasing hormone antagonists

The most serious complication of ovarian stimulation for in vitro fertilization is severe ovarian hyperstimulation syndrome (OHSS), a rare but potentially life-threatening condition. The present review discusses the place of gonadotropin-releasing hormone antagonists (GnRH-ant) in primary, secondary, and tertiary prevention of OHSS. Sound evidence indicates that the routine use of GnRH-ant instead of GnRH agonists (GnRHa) during ovarian stimulation drastically reduces the relative risk of OHSS. GnRH-ant are therefore useful for primary OHSS prevention, and an increased use of antagonists should help reduce the overall incidence of severe OHSS with its associated risks and complications. In patients on antagonist protocols identified to be at risk of developing severe OHSS, replacing human chorionic gonadotropin with GnRHa as a trigger of final oocyte maturation has been proposed as an effective measure of secondary prevention. A concept of combining GnRHa triggering with cryopreservation of all oocytes or embryos has yielded promising results as far as total avoidance of OHSS is concerned while providing a good chance of pregnancy for the patient in later frozen-thawed embryo transfers. In patients with early onset of OHSS, reinitiation of GnRH-ant in the luteal phase as a measure of tertiary prevention might lead to rapid regression of the syndrome; however only limited data on this new concept are available in the literature.     

Mini-dose long gonadotropin-releasing hormone (GnRH) agonist versus agonist flare stimulation protocol for in vitro fertilization poor responders

ObjectivesTo compare 2 stimulation protocols, mini-dose long gonadotropin releasing hormone (GnRH) agonist versus agonist flare for in vitro fertilization poor responders.DesignProspective comparative nonrandomized clinical trial.SettingDr. Samir Abasss IVF center, Jeddah, Kingdom of Saudi Arabia from april 2012 to December 2012 on 50 women undergoing IVF/ICSI fulfilling the criteria of poor responders.Material and methodsPatients were allocated into 2 groups, group 1 (n = 25) received mini-dose long agonist and group 2 (n = 25) received agonist flare protocol.Main outcomeNumber of oocytes retrieved (primary outcome), duration of stimulation (days), peak E2 level on the day of hCG injection, number of fertilized oocytes, number of transferred embryos and pregnancy rate/cycle.ResultsBoth groups were comparable regarding age, body mass index and duration of infertility (years). The difference in basal FSH and duration of stimulation (days) does not reach statistical significance (p value 0.833 and 0.373 respectively). There was a high statistical difference between both groups regarding peak E2 on day of hCG injection, number of oocytes retrieved, number of fertilized oocytes, number of transferred embryos; which is higher in the mini-dose agonist group (p value 0.00).Pregnancy rate/cycle was higher in the mini-dose agonist group (9/25 vs. 6/25) however this difference does not reach statistical significance (p value 0.355) which may be attributed to small sample size or advanced maternal age.ConclusionMini-dose long GnRHa stimulation protocol appears to be more beneficial for poor responders than GnRHa agonist flare.     

Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist

OBJECTIVE: To use gonadotropin-releasing hormone agonist (GnRH-a) instead of human chorionic gonadotropin (hCG) to induce oocyte maturation for in vitro fertilization (IVF). DESIGN: Pituitary and ovarian responses to GnRH-a and the outcome of IVF were studied prospectively. Data from patients injected with hCG were analyzed retrospectively. SETTING: Program of IVF at the Rambam (Governmental) Hospital, Haifa, Israel. PATIENTS AND INTERVENTIONS: One or two doses of buserelin acetate 250 to 500 micrograms were administered to six patients with moderate response (Estradiol [E2], 1,494 +/- 422 [+/- SD] pg/mL) and 8 patients with exaggerated response (E2, 7,673 +/- 3,028 pg/mL) to gonadotropin stimulation. Progesterone (P) and E2 were administered for luteal support. MAIN OUTCOME MEASURES: Gonadotropin-releasing hormone agonist effectively triggered luteinizing hormone (LH)/follicle-stimulating hormone (FSH) surge. Mature oocytes were recovered in all patients. Luteal E2 and P were lower than in patients injected with hCG. No signs of ovarian hyperstimulation syndrome were observed. RESULTS: Serum LH and FSH rose over 4 and 12 hours, respectively, and were significantly (P less than 0.05) elevated for 24 hours. Of all mature oocytes, 67% fertilized and 82% cleaved. Four pregnancies were obtained. CONCLUSIONS: A bolus of GnRH-a is able to trigger an adequate midcycle LH/FSH surge, resulting in oocyte maturation and pregnancy. Our preliminary results also suggest that it allows a more accurate control of ovarian steroid levels during the luteal phase and may prevent the clinical manifestation of ovarian hyperstimulation syndrome.     

Ovarian hyperstimulation syndrome after gonadotropin-releasing hormone agonist triggering and “freeze-all”: in-depth analysis of genetic predisposition

PurposeWe report on the results of the whole-genome analysis performed in a patient who developed severe ovarian hyperstimulation syndrome (OHSS) following gonadotropin-releasing hormone (GnRH) agonist triggering in a “freeze-all” protocol.MethodsA 30-year-old patient with polycystic ovary syndrome who developed severe early-onset OHSS with clinical ascites, and slight renal and hepatic dysfunction was admitted for monitoring and treatment with cabergoline and intravenous albumin. Exome sequencing to assess for any known genetic predisposition for OHSS was performed.ResultsNo known genetic variants associated with OHSS predisposition were found.ConclusionsCase reports of severe OHSS following a “freeze-all” strategy are starting to arise, showing that OHSS has not been completely eliminated with this approach. Further studies should be conducted to confirm if such cases may be due to genetic predisposition or not.     

The long protocol of administration of gonadotropin-releasing hormone agonist is superior to the short protocol for ovarian stimulation for in vitro fertilization.

OBJECTIVE: To investigate whether pituitary desensitization with the gonadotropin-releasing hormone agonist (GnRH-a), buserelin acetate, before the administration of human menopausal gonadotropin (hMG) for ovarian stimulation in in vitro fertilization (IVF) is superior to the simultaneous administration of both hormones at the beginning of the treatment cycle. DESIGN: Prospective randomized study. PATIENTS: Ninety-one patients having their first attempt at IVF. INTERVENTIONS: Patients in group 1 (long protocol) were administered subcutaneous (SC) buserelin acetate 200 micrograms/d from day 1 of the menstrual cycle, and hMG was started only after pituitary desensitization had been achieved at least 14 days later. Patients in group 2 (short protocol) were administered SC buserelin acetate 200 micrograms/d from day 2 and the same dose of hMG used in the long protocol from day 3 of the menstrual cycle. RESULTS: The median total amount of hMG required in both groups was comparable. There were significantly more follicles (P = 0.0001), oocytes (P = 0.0008), fertilized oocytes (P = 0.0001), and cleaved embryos (P = 0.0001), and a higher fertilization rate (P = 0.0047) in patients in group 1. The pregnancy rates per initiated cycle and per embryo transfer were 19.57% and 25.71% in group 1 compared with 8.89% and 16.67% in group 2. CONCLUSIONS: The long protocol is superior in terms of significantly greater follicular recruitment, oocyte recovery and fertilization rates, and significantly greater number of embryos available for transfer. In general, it is the preferred method when GnRH-a are used for ovarian stimulation in IVF.