Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation

OBJECTIVE: To assess the efficacy, safety, and local tolerance of ganirelix acetate for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH). DESIGN: Phase III, multicenter, open-label randomized trial. SETTING: In vitro fertilization (IVF) centers in North America. PATIENT(S): Healthy female partners (n = 313) in subfertile couples for whom COH and IVF or intracytoplasmic sperm injection were indicated. INTERVENTION(S): Patients were randomized to receive one COH cycle with ganirelix or the reference treatment, a long protocol of leuprolide acetate in conjunction with follitropin-beta for injection. OUTCOME MEASURE(S): Number of oocytes retrieved, pregnancy rates, endocrine variables, and safety variables. RESULT(S): The mean number of oocytes retrieved per attempt was 11.6 in the ganirelix group and 14.1 in the leuprolide group. Fertilization rates were 62.4% and 61.9% in the ganirelix and leuprolide groups, respectively, and implantation rates were 21.1% and 26.1%. Clinical and ongoing pregnancy rates per attempt were 35.4% and 30.8% in the ganirelix group and 38.4% and 36.4% in the leuprolide acetate group. Fewer moderate and severe injection site reactions were reported with ganirelix (11.9% and 0.6%) than with leuprolide (24.4% and 1.1%). CONCLUSION(S): Ganirelix is effective, safe, and well tolerated. Compared with leuprolide acetate, ganirelix therapy has a shorter duration and fewer injections but produces a similar pregnancy rate.     

Gonadotropin-releasing hormone agonist improves the efficiency of controlled ovarian hyperstimulation/intrauterine insemination

OBJECTIVE: Leuprolide acetate (LA) has improved the efficiency of human menopausal gonadotropins (hMG) in in vitro fertilization cycles. We hypothesized that the combination of LA/hMG/intrauterine insemination (IUI) would be more efficacious than hMG/IUI cycles. DESIGN: During an 18-month period, all patients completing either a hMG/IUI cycle (group I) or a LA/hMG/IUI cycle (group II) had the characteristics and outcomes of their stimulation cycles assessed. The groups were not prospectively randomized. SETTING: Referral center at a tertiary care hospital. PATIENTS: One hundred twenty three patients in group I completed 219 cycles, and 64 patients in group II completed 102 cycles. Twenty-eight of the patients who failed to conceive with hMG/IUI were advanced to group II. MAIN OUTCOME MEASURES: Pregnancy/IUI is compared between the two groups. RESULTS: Group II demonstrated significantly greater clinical pregnancy/IUI than group I (26.5% and 16.0%, respectively, P less than 0.05), as well as a higher live birth/IUI (21.6% and 12.8%, respectively, P less than 0.05). No difference was present in the rate of fetal wastage or multiple births. CONCLUSIONS: In our patients with recalcitrant infertility, the addition of a gonadotropin-releasing hormone agonist to hMG/IUI improved the pregnancy rate, without increasing the rate of multiple births or fetal wastage.     

Gonadotropin-releasing hormone agonist trigger: the way to eliminate ovarian hyperstimulation syndrome--a 20-year experience

Gonadotropin-releasing hormone agonist (GnRHa) trigger instead of human chorionic gonadotropin in the context of ovarian hyperstimulation syndrome (OHSS) prevention has been used for >20 years. In its first decade it did not gain popularity because it cannot work in GnRHa-based ovarian stimulation protocols. The introduction of GnRH antagonists has revolutionized our ability to eliminate OHSS completely because patients at high risk for OHSS can be triggered with GnRHa. This has been documented in randomized prospective studies, in which none of the patients randomized to the agonist trigger arm developed OHSS. In other words, GnRHa proved to be a potent tool that, truly remarkably, never fails. Although there is some debate concerning the clinical outcome of these cycles, data so far indicate that aggressive luteal support can ensure a good outcome. Moreover, the large number of frozen embryos in these cycles results in excellent per-oocyte retrieval pregnancy rates. In summary, GnRHa ovulatory trigger is the ultimate tool for complete OHSS prevention. GnRH antagonist-based ovarian stimulation protocols should be considered in OHSS high-risk patients so GnRHa trigger can be used if needed.     

Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome

OBJECTIVE: To review the available knowledge on the use of GnRH agonist for ovulation triggering as a means to prevent ovarian hyperstimulation syndrome (OHSS). DESIGN(S): Review of pertinent English language studies published over the past 15 years. RESULT(S): The available literature suggests that while GnRH agonist effectively induces final oocyte maturation and ovulation, it also completely and reliably prevents clinically significant OHSS. The mechanism of action in the context of OHSS prevention involves complete, quick, and irreversible luteolysis CONCLUSION(S): Controlled ovarian stimulation protocols based on GnRH antagonist to prevent premature LH rise and GnRH agonist for ovulation triggering provide a safe and OHSS-free clinical environment. Adequate luteal support compensates for luteolysis and assures good clinical outcome. The fertility community is urged to adopt these protocols. This will make OHSS a disease of the past.     

Ovarian hyperstimulation in polycystic ovary syndrome during therapy with leuprolide acetate

Continuous exposure to GnRH eliminates the pituitary as a source of gonadotropins and may have direct suppressive effects on the ovary. A woman with PCO syndrome received leuprolide acetate (1 mg/d SC) for 4 weeks before and simultaneously with hMG stimulation. Human chorionic gonadotropin (5,000 IU) was administered IM on the 8th day of hMG therapy. There were 10 follicles greater than 15 mm and a polycystic appearance to the ovaries with 25 follicles measuring less than 10 mm. The serum E2 concentration was 2,280 pg/mL. She developed severe ovarian hyperstimulation and required hospitalization for 12 days for fluid management. A viable intrauterine pregnancy was present. Four weeks of pretreatment with leuprolide did not prevent hyperstimulation in the presence of an intrauterine pregnancy.     

Gonadotroph adenoma causing ovarian hyperstimulation syndrome in a premenopausal woman

Introduction: Gonadotroph adenomas occur commonly in middle-aged adults without any specific endocrinological symptoms. To date, only 30 cases of gonadotropinoma causing ovarian hyperstimulation syndrome in pre-menopausal women have been reported.

Case report: A 37-year old woman with pituitary macroadenoma and hyperprolactinaemia was admitted to the Department of Endocrinology, Diabetology and Isotope Therapy. She presented with recurrent ovarian cysts, menstrual disturbances, headaches, visual impairment and galactorrhea. Her endocrine profile showed normal values of FSH, elevated concentrations of estradiol and suppressed LH levels. Transsphenoidal resection of the tumor tissue resulted in normalization of the hormone values and improvement in the clinical picture.

Conclusions: Gonadotroph adenomas should be considered in the differential diagnosis in premenopausal women with OHSS.     

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.     

Gonadotropin-releasing hormone agonist analog therapy effective in ovarian granulosa cell malignancy

Ovarian granulosa cell tumor lung metastases regressed, and symptoms were relieved, during gonadotropin-releasing hormone (GnRH) agonist analog therapy after the failure of operative treatment and cytotoxic chemotherapy, indicating the hormone dependence of the malignancy. The response was transient, but the largest metastasis did not relapse. This case report suggests that GnRH analogs may offer a new approach to the treatment of ovarian stromal cell malignancies.     

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.     

Dose of GnRH agonist (nafarelin acetate) affects intrafollicular PAPP-A expression in controlled ovarian hyperstimulation cycle

OBJECTIVE: To determine the effect of dose of GnRH agonist on the follicular environment in controlled ovarian hyperstimulation (COH) cycles. STUDY DESIGN: Twenty-eight IVF patients with normal ovarian function were divided into three groups: group I received GnRHa (nafarelin acetate/Synarel) intranasally at 200 microg daily, group II received 400 microg daily until hCG injection, and group III was given 400 microg daily before the initiation of ovarian stimulation, then 200 microg daily before the day of hCG injection. Serum estradiol, progesterone, and leptin levels were measured on the day of hCG injection. After aspiration, expression of pregnancy-associated alpha-plasma protein (PAPP)-A in the follicular fluid of dominant follicles (>20 mm) was determined by Western blot analysis. RESULTS: No significant difference was noted in serum estradiol, progesterone, and leptin levels. But intrafollicular PAPP-A expression was significantly higher in group II compared to other groups (P<0.05). CONCLUSION: The dose of GnRHa may have an impact on the intrafollicular environment of dominant follicles in COH cycles.     

Fibroid and myometrial steroid receptors in women treated with gonadotropin-releasing hormone agonist leuprolide acetate

The reduction in uterine and fibroid volume associated with the chronic administration of a gonadotropin-releasing hormone agonist (GnRH-a) is thought to be secondary to the analogue induced hypoestrogenic state. Our hypothesis was that the concentration of bioactive estrogen receptors (ER) and progesterone receptors (PR) may be important in the regulation of fibroid growth. The purpose of this study was to determine ER and PR content in fibroids and myometria from women pretreated with GnRH-a compared with controls. Tissue was obtained from 20 premenopausal women with uterine fibroids who were randomized to receive either leuprolide acetate depot, 3.75 mg intramuscularly every 28 days for four injections (n = 10) or placebo (n = 10) before myomectomy. The mean fibroid ER and PR content was significantly greater than the mean myometrial ER and PR content. The mean fibroid ER content for GnRH-a-treated patients was significantly greater than in placebo-treated patients (143.3 +/- 22.8 versus 36.1 +/- 14.3 fmol/mg). The mean fibroid PR and the mean myometrial ER and PR content were not significantly different between treatment groups. Clinically, the significant increase in fibroid ER may be an explanation for the rapid regrowth of fibroids observed after the cessation of GnRH-a therapy.