Treatment with the GnRH antagonist ganirelix prevents premature LH rises and luteinization in stimulated intrauterine insemination: results of a double-blind, placebo-controlled, multicentre trial.

BACKGROUND: This study was designed to assess whether the use of ganirelix in women undergoing stimulated IUI could prevent the occurrence of premature LH rises and luteinization (LH+progesterone rises). METHODS: Women of infertile couples, diagnosed with unexplained or male factor infertility, were randomized to receive either ganirelix (n=103) or placebo (n=100) in a double-blind design. All women were treated with an individualized, low-dose rFSH regimen started on day 2-3 of cycle. Ganirelix (0.25 mg/day) was started if one or more follicles>or=14 mm were visualized. Ovulation was triggered by HCG injection when at least one follicle>or=18 mm was observed and a single IUI was performed 34-42 h later. The primary efficacy outcome was the incidence of premature LH rises (+/-progesterone rise). RESULTS: In the ganirelix group, four subjects had a premature LH rise (value>or=10 IU/l), one LH rise prior to the start of ganirelix and three LH rises during ganirelix treatment, whereas in the placebo group 28 subjects had a premature LH rise, six subjects prior to the start of placebo and 22 subjects during placebo treatment. The incidence of LH rises was significantly lower in ganirelix cycles compared to placebo cycles (3.9 versus 28.0%; P=0.003 for ITT analysis). When excluding subjects with an LH value>or=10 IU/l before the start of ganirelix/placebo the incidence of LH rises was also significantly lower in ganirelix cycles compared to placebo cycles (2.9 versus 23.4%; P=0.003 for ITT analysis). Premature luteinization (LH rise with concomitant progesterone rise>or=1 ng/ml) was observed in one subject in the ganirelix group and in 17 subjects in the placebo group of which three subjects had a premature spontaneous ovulation. Ongoing pregnancy rates per attempt were 12.6 and 12.0% for the ganirelix and placebo groups respectively. CONCLUSIONS: Treatment with ganirelix effectively prevents premature LH rises, luteinization in subjects undergoing stimulated IUI. Low-dose rFSH regimen combined with a GnRH antagonist may be an alternative treatment option for subjects with previous proven luteinization or in subjects who would otherwise require insemination when staff are not working.

Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial.

OBJECTIVE: To evaluate the effect of intravenous immunoglobulin (IVIG) on pregnancy outcome in couples with repeated unexplained in vitro fertilization (IVF) failure. DESIGN: Prospective, randomized, double blind, placebo-controlled clinical trial. SETTING: A university-based and a free-standing IVF program. PATIENT(S): Fifty-one couples with a history of repeated unexplained IVF failure who were preparing for another fresh IVF cycle or replacement of cryopreserved embryos. INTERVENTION(S): Eligible women underwent a standard IVF stimulation using a long luteal phase GnRH analog protocol. Cryopreserved embryos were replaced after endometrial preparation with oral micronized estradiol and subsequent vaginal progesterone. The women were randomly selected to receive IVIG (500 mg/kg) or an equivalent volume of normal saline. The first infusion was given on the day of embryo transfer or during the preceding 72 hours. The second infusion was given 4 weeks later if a clinical pregnancy was confirmed by ultrasound. MAIN OUTCOME MEASURE(S): Live-birth rates. RESULT(S): Overall, the live-birth rates were 4/26 (15%) for the IVIG group and 3/25 (12%) for the placebo group (P=0. 52). There were 39 fresh IVF cycles, which yielded a clinical pregnancy rate of 28%, with live-birth rates of 4/21 (19%) for the IVIG group and 3/18 (17%) for the placebo group (P=0.59). CONCLUSION(S): In this randomized clinical trial, IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure, stringently defined by known determinants of IVF outcome.

Rescue intracytoplasmic sperm injection (ICSI)-salvaging in vitro fertilization (IVF) cycles after total or near-total fertilization failure.

OBJECTIVE: To evaluate the effectiveness of delayed oocyte reinsemination by ICSI (rescue ICSI) after total or near-total fertilization failure (

An ounce of prevention: outpatient management of the ovarian hyperstimulation syndrome.

OBJECTIVE: To evaluate a protocol of active outpatient management, including outpatient paracentesis and albumin administration, in women at risk for severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective cohort. SETTING: Freestanding IVF program. PATIENT(S): Thirteen women progressing from moderate to severe OHSS. INTERVENTION(S): Bed rest and home monitoring with intermittent outpatient paracentesis and albumin administration. MAIN OUTCOME MEASURE(S): Procedural outcomes and time to resolution of OHSS symptoms. RESULT(S): The initial paracentesis occurred 14.1 +/- 3.3 days after oocyte retrieval, removing 1,735 +/- 506 mL of ascitic fluid. Eleven women required a second paracentesis and five women required a third paracentesis over the next 8 days. Six women received albumin on seven occasions because of hypoalbuminemia. The onset of diuresis occurred 2.8 +/- 1.9 days and recovery occurred 7. 4 +/- 3.0 days after the first paracentesis. There were no hospitalizations for OHSS symptoms and no complications. All 13 women had viable intrauterine pregnancies. CONCLUSION: Active outpatient intervention in the early stages of OHSS, including paracentesis and albumin administration, can avoid hospitalization while minimizing the progression and complications of OHSS.

Diagnostic laparoscopy in infertile women with normal hysterosalpingograms.

OBJECTIVE: To assess the value of laparoscopy in infertile women with normal hysterosalpingograms, with and without risk factors suggesting pelvic disease. STUDY DESIGN: We retrospectively reviewed 1,022 consecutive charts from a tertiary infertility practice. In 265 women, laparoscopies were performed after normal hysterosalpingograms. RESULTS: Laparoscopies were normal in 136 (51%) women, whereas 129 (49%) had one or more abnormal laparoscopic findings, including minimal or mild endometriosis (n = 85), moderate or severe endometriosis (n = 11), adnexal adhesions (n = 27), subserosal myomas (n = 17), ovarian neoplasms (n = 5), distal phimosis (n = 1) and salpingitis isthmica nodosa (n = 1). Only 7% of cases had findings that might require standard operative laparoscopy or laparotomy, although not all were causally related to infertility. A history of dysmenorrhea or dyspareunia increased the likelihood of detecting endometriosis from 41% to 64% and 69%, respectively. The presence of both symptoms increased the likelihood to 83%. CONCLUSION: In the presence of a normal hysterosalpingogram, laparoscopy identified other pelvic disease in about half of patients. Because most abnormalities were mild, this knowledge can be used to plan a micro-laparoscopic approach for many women, reserving traditional or operative laparoscopy for women with an abnormal hysterosalpingogram or extensive disease following micro-laparoscopy. Alternately, knowledge of the nature and severity of the expected laparoscopic findings might lead to bypassing laparoscopy in favor of assisted reproduction when the perceived benefit of surgical intervention is small.

Withholding gonadotropins ("coasting") to minimize the risk of ovarian hyperstimulation during superovulation and in vitro fertilization-embryo transfer cycles.

OBJECTIVE: To evaluate superovulation (SOV) and IVF-ET cycles in which E2 levels were allowed to decrease to restrain rapid follicular growth and minimize the risk of ovarian hyperstimulation syndrome. DESIGN: Retrospective series. SETTING: Tertiary care infertility practice. PATIENT(S): Women who underwent SOV (n = 51) and IVF-ET (n = 93) treatment and who were at risk for OHSS. INTERVENTION(S): In SOV cycles, hMG was withheld (coasting) for >3 days before hCG administration, until follicular maturity was attained (> or = 3 follicles of > or = 18 mm) and E2 levels decreased. In IVF-ET cycles, either follicular maturity was attained before coasting (n = 63), allowing hCG administration after E2 levels decreased by >25%, or coasting occurred before follicular maturation (n = 30), necessitating the administration of additional hMG after coasting. MAIN OUTCOME MEASURE(S): Estradiol concentrations, follicle size, and pregnancy rates. RESULT(S): Estradiol concentrations usually rose for > or = 1 day after coasting began, then fell by > or = 25% while follicle numbers and mean diameters increased. No spontaneous LH surges occurred, although four SOV cycles were canceled because of excessive follicular development. Of the women who received hCG,11 of 47 (23% per cycle) conceived during SOV and 35 of 93 (37.6% per cycle) conceived during IVF-ET. Severe ovarian hyperstimulation syndrome developed in 1 woman who underwent IVF-ET. CONCLUSION(S): Coasting can safely rescue overstimulated SOV and IVF-ET cycles characterized by an excessive rise in E2 levels and/or numerous incompletely mature follicles.

Perinatal and neonatal outcomes in multiple gestations: assisted reproduction versus spontaneous conception.

OBJECTIVE: Our purpose was to test the hypothesis that multiple pregnancies resulting from assisted reproductive therapy have a better outcome than those resulting from spontaneous conception. STUDY DESIGN: This was a retrospective cohort study. Cases came from pregnancies from assisted reproductive techniques. Controls were identified from spontaneous multiple pregnancies delivered in the same time period. Matching was done for maternal age, parity, fetal number, and presence of maternal medical problems. A total of 72 cases (56 twins and 16 triplets) and 124 controls (108 twins and 16 triplets) were studied. The primary outcome was perinatal mortality. Secondary outcomes were preterm delivery, birth weight, maternal complications, neonatal morbidity, and length of hospitalization. RESULTS: Perinatal mortality is significantly increased in spontaneous twin gestations compared with twins resulting from assisted reproductive techniques (24 vs 2, P =.003). No difference is seen in the perinatal mortality in triplets. Mean gestational age at diagnosis was lower for twins and triplets resulting from assisted reproductive techniques (9.4 vs 13.3; P <.001 and 8.8 vs 15. 8; P <.001, respectively). Rate of cerclage and number of prenatal visits was higher for triplets in the assisted reproductive techniques group (P =.05 and.02, respectively). Mean gestational age at delivery, birth weight, rate of preterm labor, preterm premature rupture of membranes, pregnancy-induced hypertension, and incidence of gestational diabetes were not significantly different between the groups. No significant differences in neonatal morbidity were detected. CONCLUSIONS: Assisted reproductive techniques-associated twins have lower perinatal mortality than spontaneously conceived twins. Perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by assisted reproductive techniques, even with closer surveillance and earlier gestational age at diagnosis in this group. Differences may be due to a higher frequency of monochorionic placentation in the spontaneously conceived group.

An extended 10-day course of clomiphene citrate (CC) in women with CC-resistant ovulatory disorders.

OBJECTIVE: To evaluate the effectiveness of extended duration clomiphene citrate (CC) (100 mg for 10 days) as an alternative to complex ovulation induction strategies for women who fail to ovulate despite standard incremental doses of CC of > or = 150 mg for 5 days. DESIGN: Retrospective case series. SETTING: University-based infertility practice. PATIENT(S): Thirty women with CC-resistant World Health Organization group II ovulatory disorders. INTERVENTION(S): At least one cycle of 100 mg CC from days 3 to 12. RESULT(S): Fourteen patients (47%) ovulated during 31 of their 48 cycles (65%). Five women (17%) conceived a total of seven singleton pregnancies, including five term deliveries and two spontaneous abortions. Weight, body mass index, and the presence of hyperandrogenism did not predict responsiveness to the extended duration CC. Side effects were similar to those reported during standard CC treatment. CONCLUSION(S): An extended 10-day course of CC provides a simple, noninvasive, and inexpensive alternative for a subset of women with ovulatory disorders that are refractory to standard CC treatment.

Laparoscopic oophoropexy for recurrent adnexal torsion.

Torsion of the adnexa has traditionally been treated by adnexectomy because of the fear of emboli departing from thrombosed ovarian veins. Several recent reports have described successful conservative management with unwinding of the twisted adnexa. As the trend toward conservative management progresses, the incidence of recurrent adnexal torsion may increase. We present a case of a 33 year old gravida 3, para 2 Caucasian female who presented at 7 weeks gestation complaining of symptoms similar to those experienced during an episode of right ovarian torsion treated by laparoscopic unwinding 6 years earlier. Colour Doppler sonography revealed absent flow in the right adnexa. The twisted right adnexa containing the presumed corpus luteum of pregnancy was laparoscopically unwound. Using an extracorporeal suturing technique, a laparoscopic oophoropexy was performed to prevent any further rotatory movement. This appears to be the first reported case of laparoscopic oophoropexy for a recurrent ovarian torsion; we encourage the use of this simple, minimally invasive procedure in cases of recurrent adnexal torsion.

Successful pregnancy following zygote intrafallopian transfer for congenital cervical hypoplasia.

BACKGROUND: Congenital cervical atresia and hypoplasia are rare abnormalities that generally require reconstructive or extirpative procedures to relieve outflow tract obstruction. Infertility is a common sequel, and only four previous pregnancies have been reported. In selected cases, zygote intrafallopian transfer (ZIFT) or other assisted reproductive techniques may offer alternatives for conception. CASE: A 21-year-old amenorrheic woman experienced a spontaneous gush of vaginal bleeding following an 11-year history of cyclic lower abdominal pain. Regular but prolonged and painful menses ensued. After another 8 years of primary infertility, transcervical and transfundal hysteroscopy demonstrated congenital cervical hypoplasia and a normal endometrial cavity. Conception was achieved during her third cycle of ZIFT. Delivery occurred by elective cesarean at 39 weeks for a persistent oblique fetal lie. CONCLUSION: A successful pregnancy was established following ZIFT in a woman with congenital cervical hypoplasia. The endometrial cavity was evaluated by a previously unreported technique, transfundal hysteroscopy. The use of appropriate surgical or assisted reproductive techniques in conjunction with individualized post-conception management may permit successful pregnancy and delivery in selected women with congenital cervical hypoplasia and atresia.

Contrasting effects of a gonadotropin-releasing hormone agonist and antagonist on the secretion of free alpha subunit.

Gonadotropin-releasing hormone agonists and antagonists have initial divergent effects on the pituitary secretion of intact biologically active gonadotropins and long-term divergent effects on the secretion of free alpha-subunit. The antagonists appear to function as true competitive inhibitors, blocking the stimulatory effects of endogenous GnRH without evoking any known postreceptor activity. The agonists, in contrast, initially stimulate pituitary secretion and then incompletely desensitize the gonadotrope, resulting in suppression of intact gonadotropin, but not free alpha-subunit, secretion. The mechanisms by which GnRH-a produce this incomplete gonadotrope desensitization and facilitate limited postreceptor activity remain to be elucidated.

Exogenous gonadotropin therapy in World Health Organization groups I and II ovulatory disorders.

OBJECTIVE: To analyze cumulative conception rates and the prognostic factors influencing them during exogenous human menopausal gonadotropin (hMG) therapy for World Health Organization (WHO) group I or II ovulatory disorders. METHODS: A retrospective review was conducted of 468 treatment cycles in 146 women with ovulatory disorders refractory to conventional therapy. Cumulative conception rates were calculated, and the effects of diagnostic group, age, gravidity, and duration of infertility were examined using the Cox proportional hazards model. RESULTS: The cumulative proportion pregnant following six hMG cycles in WHO group I (0.89) was significantly greater than in the hyperandrogenic subgroup of WHO group II (0.30) (95% confidence interval [CI] 0.2-0.7, P = .006) or the luteal phase defect subgroup (0.35) (95% CI 0.07-0.6, P = .02). Conception rates in WHO group I did not differ significantly from those in the normoandrogenic oligo-ovulatory subgroup of WHO group II (0.63) (95% CI 0.3-1.3, P = .6). Conception rates were not influenced by duration of infertility or primary versus secondary infertility. Women 35 years or older had significantly lower conception rates than those aged 27 years or less (P = .04, hazard ratio 0.3, 95% CI 0.1-0.8). CONCLUSIONS: Cumulative conception rates following exogenous gonadotropin therapy for women with refractory ovulatory disorders were both diagnosis- and age-dependent. Treatment with hMG approximated or surpassed normal fertility rates in women with WHO group I and normoandrogenic WHO group II oligo-ovulation, but was significantly less successful at correcting the underlying defect in women with hyperandrogenic anovulation and luteal phase defects.

Ovarian response in World Health Organization group II anovulatory women during consecutive human menopausal gonadotropin cycles.

While ovulation induction with human menopausal gonadotropins (hMG) is commonly used to treat refractory ovulatory disorders, little is known about the characteristics of multiple consecutive treatment cycles. Since such cycles may be required to achieve pregnancy, it is important to ensure that the ovarian response is not compromised during consecutive cycles. We examined the ovarian response and cycle characteristics of 25 women with World Health Organization (WHO) group II ovulatory disorders who underwent three consecutive ovulatory hMG cycles. The total hMG dose and duration of treatment increased significantly between the first and third consecutive hMG cycles, although the final estradiol levels remained similar. While the mean numbers of follicles > or = 14 mm in diameter were comparable, the size of the largest follicle was significantly greater during the third cycle as compared to the first. These results suggest that while the ovary required more vigorous stimulation during subsequent cycles, the ultimate hormonal and follicular response did not appear to be compromised during this series of three consecutive cycles.

Cycle characteristics and outcome in relation to ovarian response during in vitro fertilization.

PURPOSE: This retrospective analysis of 148 non-male factor couples sought to determine whether oocyte or embryonic quality was compromised by the magnitude of the ovarian response following clomiphene citrate/human menopausal gonadotropin stimulation for in vitro fertilization. METHODS: Increased oocyte numbers were associated with decreased fertilization rates (r = -0.36, P < 0.001) and estradiol/follicle ratios (r = -0.443, P < 0.001), although the quality of the resulting embryos was not affected. Despite reduced fertilization, higher oocyte numbers yielded additional healthy embryos (r = 0.70, P < 0.001) for immediate replacement or cryopreservation. Implantation rates did not differ among groups and no predictive variables were identified. RESULTS: These results suggest that endometrial receptivity and implantation were not adversely affected by increasing estradiol levels. The decline in oocyte quality associated with the retrieval of larger numbers of oocytes appeared to be offset by the availability of additional embryos for immediate replacement and cryopreservation.

A prospective randomized comparison of zygote intrafallopian transfer and in vitro fertilization-embryo transfer for nontubal factor infertility.

OBJECTIVE: To evaluate the efficacy of zygote intrafallopian transfer (ZIFT) versus standard IVF-ET for the treatment of nontubal factor infertility. DESIGN: A prospective randomized trial. PARTICIPANTS: Fifty-nine couples undergoing oocyte retrieval for nontubal infertility in a university hospital-based IVF-ET program. INTERVENTIONS: A maximum of four cleaving embryos were transferred into the fallopian tube or uterine cavity 48 or 55 hours after oocyte retrieval, respectively. MAIN OUTCOME MEASURES: Rates of implantation, pregnancy, and spontaneous abortion (SAB) were compared. RESULTS: Clinical pregnancies occurred after 26.5% versus 12% of retrievals and 29% versus 14.3% of transfers in IVF-ET versus ZIFT cycles, respectively. Pregnancy, implantation, and SAB rates did not differ between the groups. CONCLUSIONS: This prospective randomized trial failed to demonstrate any therapeutic improvement associated with the increased complexity of ZIFT as compared with standard IVF-ET.

Exogenous gonadotropin therapy in combined anovulatory and male factor infertility.

This retrospective study evaluated conception rates in 18 women with refractory anovulatory infertility undergoing hMG ovulation induction in the presence of persistent mild to moderate semen abnormalities. Logistic regression analysis showed no relationship between conception (9.6% cycle) and the age of either partner, primary versus secondary infertility, or lowest sperm count, motility or morphology. In summary, this study demonstrates that a coexisting mild to moderate male factor does not preclude pregnancy during hMG therapy for anovulation. While semen abnormalities should not be ignored, aggressive treatment of concomitant ovulatory disorders and the resulting timed ovulation of several oocytes may minimize the effects of semen abnormalities.

The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.

OBJECTIVE: To assess the outcome of in vitro fertilization and embryo transfer (IVF-ET) in women with refractory polycystic ovarian syndrome (PCOS). DESIGN: Retrospective case series with an age-matched control group. SETTING: Ovulation induction and IVF programs in a tertiary referral center. PATIENTS AND INTERVENTIONS: Nine patients with PCOS who failed standard ovulation induction treatment (clomiphene citrate plus greater than or equal to 6 ovulatory human menopausal gonadotropin [hMG] cycles) underwent 19 cycles of IVF-ET. Forty age-matched tubal factor patients who completed 40 cycles of IVF-ET served as a control group. OUTCOME MEASURES: Demographic features and IVF-ET cycle characteristics were compared using Student's t-test and Fisher's exact test. RESULTS: Cycles of IVF-ET in patients with PCOS were associated with higher estradiol levels (5,222 versus 4,009 pmol/L), lower hMG requirements (15.8 versus 19.6 vials), greater numbers of oocytes (7.6 versus 5.6), and lower fertilization rates (56% versus 75%) compared with tubal factor cycles (P less than 0.05). However, the number of embryos transferred (3.9 versus 4.0) and the clinical pregnancy rate per embryo transfer (24% versus 25%) did not differ significantly between the two groups. CONCLUSION: These results suggest that conception failure after six or more ovulatory hMG cycles in patients with PCOS does not adversely affect subsequent IVF performance.

Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, alpha subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix).

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P less than 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix.(ABSTRACT TRUNCATED AT 400 WORDS)

Variable ovarian response to gonadotropin-releasing hormone antagonist-induced gonadotropin deprivation during different phases of the menstrual cycle.

The gonadotropin dependence of ovarian follicular maturation and corpus luteum function can now be examined in women using antagonistic analogs of GnRH. We studied the responses of three groups of women throughout a control cycle and during the administration of a potent GnRH antagonist, detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] GnRH, Syntex Research). Detirelix (10 mg, sc) was administered for 3 consecutive days during the midfollicular phase (n = 4), preovulatory phase (n = 4), and early luteal phase (n = 4). The pituitary response to detirelix was similar throughout the three phases of the menstrual cycle. Immunoreactive LH concentrations decreased to 35% (mean +/- SEM) of pretreatment values within 8 h after the initial injection and remained suppressed for 72 h after discontinuance of treatment. Immunoreactive FSH concentrations decreased to 73 +/- 3% of pretreatment levels within 8 h and returned to baseline within 24 h after the third injection. In contrast, the ovarian response to detirelix varied markedly during different phases of the cycle. Midfollicular phase treatment was associated with a decline in estradiol (E2) levels from pretreatment values of 246 +/- 48 to 81 +/- 15 pmol/L within 24 h of the last injection. Vaginal bleeding ensued in three of four women. Follicular recruitment was then reinitiated, and an ovulatory LH surge occurred 18.2 +/- 2.9 days after the last injection. Similarly, treatment during the early luteal phase produced a decline in E2 concentrations from 286 +/- 29 to 70 +/- 7 pmol/L and a decline in progesterone concentrations from 20 +/- 1.6 to 1.9 +/- 0.3 nmol/L within 24 h after the last injection. Luteolysis was associated with menstrual bleeding in all four women. The subsequent ovulatory LH surge occurred 16.5 +/- 1.0 days after discontinuance of treatment. In contrast, treatment during the preovulatory phase resulted in a decline in E2 concentrations from 844 +/- 66 to 429 +/- 132 pmol/L during the first 48 h of treatment. Gonadotropin and E2 concentrations subsequently recovered from suppression, growth of the dominant follicle resumed, and a LH surge occurred 5.8 +/- 1.4 days after the last injection. These data indicate that the GnRH antagonist detirelix produces rapid and consistent suppression of pituitary gonadotropin secretion. The magnitude of suppression and preferential suppression of LH vs. FSH are similar throughout the cycle. In contrast, the ovarian response to gonadotropin deprivation varies during the menstrual cycle.(ABSTRACT TRUNCATED AT 400 WORDS)