Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens

OBJECTIVE: To investigate whether luteal E(2) administration reduces size discrepancies of early antral follicles. DESIGN: Prospective, crossover study. SETTING: ART unit, Clamart, France. PATIENT(S): Sixty women and 120 cycles. INTERVENTION(S): On cycle day 3 (baseline day 3), all women underwent measurements of early antral follicles by ultrasound and serum FSH and ovarian hormones. From day 20 until the next cycle day 2, 30 of them received oral 17beta-E(2), whereas the remaining women served as controls. The day after E(2) discontinuation (E(2) day 3) or on subsequent cycle day 3 (control day 3), participants were reevaluated as on baseline day 3. MAIN OUTCOME MEASURE(S): Magnitude of follicular size discrepancies. RESULT(S): Follicular size discrepancies and follicular diameters were significantly attenuated on E(2) day 3 (3.7 +/- 0.5 mm) as compared with baseline day 3 (4.9 +/- 1.0 mm), but not in controls (5.0 +/- 0.8 vs. 4.9 +/- 0.8 mm). FSH (4.3 +/- 1.9 vs. 7.3 +/- 3.3 mIU/mL) and inhibin B (34 +/- 28 vs. 71 +/- 32 pg/mL) levels were consistently lower on E(2) day 3 than on baseline day 3 but remained unchanged in controls. CONCLUSION(S): Luteal E(2) administration reduces the size and improves the homogeneity of early antral follicles on day 3. This approach may be instrumental in synchronizing follicular development during controlled ovarian hyperstimulation.     

Coordination of antral follicle growth: basis for innovative concepts of controlled ovarian hyperstimulation

Among the key objectives of controlled ovarian hyperstimulation (COH) is the achievement of adequate coordination of multiple follicular growth to trigger ovulation when most of follicles have reached concomitant maturation. However, during the early follicular phase, early antral follicles present noticeable size heterogeneities that may be amplified during COH. To challenge the hypothesis that this phenomenon results, at least in part, from the early exposure of antral follicles to gradient follicle-stimulating hormone (FSH) levels during the preceding late luteal phase, we conducted three clinical studies. First, we artificially lowered luteal FSH levels by administering estradiol (E (2)) and measured follicular characteristics on the subsequent day 3. Second, we verified whether luteal E (2) administration could promote the coordination of follicular growth during COH and improve its results. Third, we assessed the effects of premenstrual gonadotropin-releasing hormone (GnRH) antagonist administration on follicular characteristics during the early follicular phase. Our results showed that luteal FSH suppression by either E (2) or GnRH antagonist administration reduces the size and improves the homogeneity of early antral follicles during the early follicular phase, an effect that persists during COH. Coordination of follicular development may optimize ovarian response to short GnRH agonist and antagonist protocols, and constitutes an attractive approach to improving their outcome.     

Hormonal manipulations in the luteal phase to coordinate subsequent antral follicle growth during ovarian stimulation

During the early follicular phase in the menstrual cycle, antral follicle sizes are often markedly heterogeneous. These follicular size discrepancies may, at least in part, result from the early exposure of FSH-sensitive follicles to gradient FSH concentrations during the preceding luteal phase. In addition, they potentially affect the results of ovarian stimulation. Indeed, pre-existing follicle size discrepancies may encumber coordinated follicular growth during ovarian stimulation, thereby reducing the number of follicles that reach maturation at once. To investigate this issue, three clinical studies were conducted to test the hypothesis that luteal FSH suppression could coordinate follicular growth. First, luteal FSH concentrations were artificially lowered by administering physiological oestradiol doses and measured follicular characteristics on the subsequent day 3. Second, it was verified whether luteal oestradiol administration could promote the coordination of follicular growth during ovarian stimulation and improve its results. Third, the effects of premenstrual gonadotrophin-releasing hormone (GnRH) antagonist administration on follicular characteristics were assessed during the early follicular phase. The results showed that luteal FSH suppression by either oestradiol or GnRH antagonist administration reduces the size and improves the homogeneity of early antral follicles during the early follicular phase, an effect that persists during ovarian stimulation. Coordination of follicular development may optimize ovarian response to short GnRH agonist and antagonist protocols, and constitutes an attractive approach to improving their outcome.     

Sex ratio and birth weights of infants born as a result of blastocyst transfers compared with early cleavage stage embryo transfers

OBJECTIVE: To investigate relations between dose of GnRH antagonist and follicular phase characteristics. DESIGN: Randomized controlled multicenter trial. SETTING: Tertiary referral fertility centers. PATIENT(S): Three hundred and twenty-nine IVF patients. INTERVENTION(S): Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist. MAIN OUTCOME MEASURE(S): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations. RESULT(S): In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E(2) levels showed a GnRH antagonist dose-related decrease (P<0.05). Late follicular phase E(2) levels correlated with total follicular surface area, AD, LH, and FSH (all P<0.001). Increasing GnRH antagonist doses exhibited additional suppressive action on E(2) levels. CONCLUSION(S): Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E(2) levels could not be exclusively attributed to suppression of LH.     

A novel protocol of ovulation induction with delayed gonadotropin-releasing hormone antagonist administration combined with high-dose recombinant follicle-stimulating hormone and clomiphene citrate for poor responders and women over 35 years

OBJECTIVE: To evaluate the efficacy of a novel protocol of ovulation induction for poor responders. DESIGN: Prospective, controlled, clinical study. SETTING: Research institute's reproductive unit. PATIENT(S): One hundred forty-five infertile women, aged 27-39 years, candidates for assisted reproductive techniques (ART). INTERVENTION(S): Before undergoing ART, 85 patients received clomiphene citrate, high-dose recombinant human FSH, and a delayed, multidose GnRH antagonist, whereas 60 patients underwent a standard long protocol. MAIN OUTCOME MEASURE(S): Estradiol levels (pg/mL), cancellation rate, oocyte retrieval, embryo score, and fertilization and pregnancy rates. RESULT(S): Patients undergoing the study protocol obtained lower cancellation rates (4.7% vs. 34%) and higher E(2) levels (945.88 +/- 173.2 pg/mL vs. 169.55 +/- 45.07 pg/mL), oocyte retrieval (5.56 +/- 1.13 vs. 3.36 +/- 1.3), and pregnancy (22.2% vs. 15.3%) and implantation rates (13.5% vs. 7.6%) compared with those receiving the long protocol. Age negatively correlated with ovarian response in the latter, whereas the ovarian outcome results were comparable in younger (<35 yrs) and older (>35 yrs) women treated with the study protocol. CONCLUSION(S): The proposed protocol of ovulation induction can be usefully administered in poor responders as well as in aged woman, probably because the delayed administration of GnRH antagonist prevents its adverse effects on ovarian paracrine activity and on oocyte maturation.     

Elevated early follicular gonadotropin levels in women with unexplained infertility do not provide evidence for disordered gonadotropin-releasing hormone secretion as assessed by luteinizing hormone pulse characteristics

OBJECTIVE: To determine whether women with rigorously defined unexplained infertility demonstrated altered GnRH secretion, as reflected by serum LH secretion patterns. DESIGN: Prospective observational study. SETTING: National Center for Infertility Research at Michigan. PATIENT(S): Nine women with rigorously defined unexplained infertility and 11 healthy, parous age-matched control women.Gonadotropin-releasing hormone (25 ng/kg) as a bolus injection. MAIN OUTCOME MEASURE(S): Daytime pulse patterns of LH secretion measured every 10 minutes; mean serum concentrations of LH, FSH, E(2), P, PRL, and cortisol; and response to a physiologic dose of GnRH in the early follicular, late follicular, mid-luteal, and late luteal phases of the same menstrual cycle. RESULT(S): Serum LH pulse frequency and pulse amplitude and LH secretion in response to a physiologic bolus of GnRH were not significantly different in unexplained infertility patients at any phase of the cycle. Luteinizing hormone pulse frequency and amplitude, as well as response to GnRH, varied significantly across the cycle. Mean early follicular serum LH and FSH concentrations were significantly higher in unexplained infertility patients than in fertile control subjects (LH: 5.31 +/-.51 vs. 4.03 +/-.33 [mIU/mL +/- SEM]; FSH: 5.81 +/-.63 vs. 3.80 +/-.45) but were not different at any other phase of the cycle. CONCLUSION(S): These data do not support the hypothesis that unexplained infertility is caused by an abnormality in pulsatile GnRH secretion or abnormal pituitary sensitivity to GnRH. However, the results are consistent with a difference in negative feedback from the ovary to the pituitary in unexplained infertility patients that is suggestive of diminished ovarian reserve.     

Estimation of the follicle-stimulating hormone (FSH) threshold for initiating the final stages of follicular development in women with elevated FSH levels in the early follicular phase

OBJECTIVE: To test the hypothesis that the follicle-stimulating hormone (FSH) threshold in patients with elevated FSH levels in the early follicular phase (EFP) is higher than in controls. DESIGN: Pilot study. SETTING: Academic hospital. PATIENT(S): Six patients with elevated EFP FSH (>10 IU/L) and 13 controls. INTERVENTION(S): Treatment with a GnRH agonist in the midluteal phase before IV administration of recombinant FSH was started in an ultra-low-dose step-up protocol. The FSH threshold was determined by the mean of FSH levels of the above threshold value and the below threshold value. MAIN OUTCOME MEASURE(S): Follicle-stimulating hormone threshold, FSH screening value, E(2), number of follicles. RESULT(S): The FSH threshold in the elevated EFP FSH group was 6.75 IU/L and was significantly higher than the FSH threshold of the controls (4.65 IU/L). The FSH screening value on day 3 was 12.0 IU/L in the patient group and 5.0 IU/L in the controls. Estradiol was significantly lower on the day that the largest follicle was 18 mm in the elevated EFP FSH group compared with controls (277 vs. 491 pmol/L, respectively). On the day of hCG administration, the number of smaller (10-13 mm) follicles was equal but the number of larger (>14 mm) follicles was higher in the control group compared with the elevated FSH group. In the control group, the basal FSH levels correlated highly with the FSH threshold levels (r = 0.8), but in the patients with elevated EFP FSH this correlation was absent. CONCLUSION(S): In normal women, basal FSH day 3 values represent the ovarian threshold for FSH. In women with elevated day 3 FSH, the FSH threshold is higher but not as high as basal FSH values. We postulate that the FSH threshold in patients with elevated EFP FSH is higher because of intraovarian factors. Basal FSH overshoots the threshold, probably because of the limited feedback by the ovary.     

Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment

OBJECTIVE: To determine the preferred treatment modality in patients with PCOS who experienced premature luteinization during CC treatment. DESIGN: Prospective randomized study. SETTING: Tertiary medical center. PATIENTS: Twenty-two infertile women with PCOS demonstrating premature luteinization during at least two consecutive CC cycles. INTERVENTIONS: Randomized induction of ovulation either with FSH alone or with GnRH agonist combined with FSH for a single treatment cycle. MAIN OUTCOME MEASURES: Premature luteinization was defined as serum progesterone >1.5 ng/mL before hCG administration. RESULTS: Premature luteinization occurred in eight of the 10 patients (80%) in group A and in two of the 12 patients in group B (16.6%). This result corresponds to the higher mean (+/-SD) progesterone level present in group A patients as compared to those in group B (2.0 +/- 1.2 ng/mL vs. 1.2 +/- 0.6 ng/mL, P=0.03). No pregnancies were achieved in group A, whereas the pregnancy rate per cycle observed in group B was 33.3% (4/12). On the day of hCG administration, the maximum mean (+/-SD) estradiol level was significantly lower (P<0.0001) in group A (210.6 +/- 37.9 pg/mL) than in group B (600.3 +/- 253.8 pg/mL). The treatment duration and the number of FSH ampules used did not differ between the groups.Conclusions: Pituitary desensitization with GnRH analog in combination with FSH is superior to FSH-only treatment in PCOS patients who demonstrate premature luteinization during CC treatment.     

Luteal estradiol administration strengthens the relationship between day 3 follicle-stimulating hormone and inhibin B levels and ovarian follicular status

OBJECTIVE: To investigate whether the prevention of early follicular growth by luteal E(2) administration improves the relationship between day 3 hormone measurements and the ovarian follicular status. DESIGN: Prospective, cohort study. SETTING: Assisted reproductive technology unit in Clamart, France. PATIENT(S): One hundred sixty-two infertile women. INTERVENTION(S): Participants received oral 17beta-E(2), 4 mg/day, from day 20 to the next cycle day 1 (n = 81) or served as controls (n = 81). Serum E(2), inhibin B, and FSH were measured during the 3 days after E(2) discontinuation (FD1, FD2, and FD3) in E(2)-treated women and on cycle day 3 (CD3) in controls. Early antral follicles were counted at ultrasound scans on FD3 and CD3. MAIN OUTCOME MEASURE(S): Hormonal-follicular correlations on FD3 and CD3. RESULT(S): As expected, after E(2) withdrawal, inhibin B and FSH increased from FD1 to FD3 whereas E(2) decreased. Correlations between FSH and inhibin B and follicular counts were stronger on FD3 than on CD3. CONCLUSION(S): Luteal E(2) administration notably strengthens the relationship between serum FSH and inhibin B levels and the number of antral follicles on day 3. This approach may represent an alternative test of ovarian follicular status.     

Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin

OBJECTIVE: To investigate the effect of triggering oocyte maturation with GnRH agonist on corpus luteum function by measuring luteal phase levels of inhibin A and pro-alphaC. DESIGN: Prospective randomized trial. SETTING: In vitro fertilization (IVF) program at a university hospital. PATIENT(S): Infertile women undergoing IVF-ET treatment. INTERVENTION(S): Controlled ovarian hyperstimulation with FSH and GnRH antagonist, triggering of final oocyte maturation with either hCG (n = 8) or GnRH agonist (n = 8), IVF-ET, and collection of blood samples every 2-3 days during the luteal phase. MEASUREMENTS AND MAIN RESULTS: Luteal phase serum levels of inhibin A and pro-alphaC, P, and E(2). RESULT(S): Levels of inhibin A, pro-alphaC, estrogen, and P were significantly lower from day 4 to day 14 after triggering final oocyte maturation by GnRH agonist compared with hCG. Maximal luteal serum inhibin A and pro-alphaC levels were 91.5 +/- 23.6 and 184.1 +/- 23.5 pg/mL in the GnRH agonist-treated women compared with 464.7 +/- 209.1 and 7,351.6 +/- 934.3 pg/mL in women treated with hCG. CONCLUSION(S): Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.     

Effect of an oral contraceptive pill on follicular development in IVF/ICSI patients receiving a GnRH antagonist: a randomized study

This randomized controlled study compared the effectiveness of a gonadotrophin releasing hormone (GnRH) antagonist protocol with or without oral contraceptive (OC) pretreatment on the number of oocytes retrieved in IVF or intracytoplasmic sperm injection (ICSI) patients. Sixty-four patients were randomized to start recombinant human FSH (r-hFSH) on day 2 or 3 after OC withdrawal (OC group) or on day 2 of a natural cycle (control group). From stimulation day 6 onwards, all patients were treated with daily (0.5 mg/ml) GnRH antagonist (Antide). OC pretreatment resulted in significantly lower starting concentrations of FSH, LH and oestradiol (P < 0.001) and a thinner endometrium (P < 0.0001). In the early stimulation period, fewer large follicles were found after OC pretreatment, leading to a significantly extended stimulation period (11.6 versus 8.7 days, P < 0.0001) with more follicles on the day of recombinant human chorionic gonadotrophin administration (15.4 versus 12.5, P = 0.02) and more oocytes retrieved (13.5 versus 10.2, P < 0.001) as compared with the control group. GnRH antagonist regimen, pretreated with OC, prevented the early endogenous FSH rise and improved follicular homogeneity, resulting in more oocytes. As a consequence of the extended treatment period, more rhFSH was required.     

Stimulation quality in IVF

Quality control in IVF stimulation requires first establishing the ovarian follicle status, then a hormone strategy, and finally monitoring follicle maturation. The ovary examination includes an ultrasound examination to evaluate the number of follicles and their size and hormone tests measuring FSH, E2, but most particularly AMH levels. The hormone strategy during COH mainly seeks to obtain a large number of antral follicles of a homogeneous size and quality, using either FSH suppression at the end of the luteal phase or the administration of a GnRH antagonist in the premenstrual phase. Follicle maturation during COH is usually monitored using ultrasound, with three-dimensional and/or software measurements to evaluate follicle volume.     

Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome

OBJECTIVE: To determine the prevalence and the effect of premature luteinization in GnRH antagonist IVF-ET cycles. DESIGN: Prospective observational study. SETTING: In vitro fertilization-embryo transfer (IVF-ET) program at the Instituto Valenciano de Infertilidad. PATIENT(S): Eighty-one infertile patients undergoing controlled ovarian hyperstimulation with gonadotropins and GnRH antagonist for IVF-ET. INTERVENTION(S): Gonadotropin-releasing hormone (GnRH) antagonist was administered from stimulation day 6. Serum P, E(2), and LH were determined on the day of hCG administration. MAIN OUTCOME MEASURE(S): Cycles were grouped according to serum P level on the day of hCG administration (<1.2 ng/mL or > or =1.2 ng/mL). Clinical pregnancy and implantation rates were determined. RESULT(S): The incidence of premature luteinization was 38.3%. Total recombinant FSH dose and stimulation days differed significantly between the groups. Pregnancy rate (25.8% vs. 54.0%) and implantation rate (13.8% vs. 32.0%) were significantly lower in the premature luteinization group. CONCLUSION(S): Premature luteinization during GnRH antagonist IVF-ET cycles is a frequent event that is associated with lower pregnancy and implantation rates. Progesterone elevations are not related to serum LH levels and may reflect the mature granulosa cell response to high FSH exposure.     

GnRHa flare and IVF pregnancy rates.

OBJECTIVES: GnRH agonist administered early in the menstrual cycle (flare) causes an endogenous discharge of FSH and LH. Flare has been used in conjunction with gonadotropin ovarian stimulation for IVF 'poor responders'. There is an ongoing controversy regarding whether flare protocols improve pregnancy rates in 'poor responders'. The current study was designed to compare a GnRHa flare protocol with long suppression GnRHa IVF in 'poor responders'. METHODS: Seventy-three newly diagnosed poor responders who failed long GnRHa suppression IVF attempts were compared retrospectively with 128 age-matched IVF patients previously known poor ovarian responders treated with a long GnRHa suppression protocol. 'Poor responders' consisted of patients with peak E(2) less than 1000 pg/ml and/or less than five mature follicles with diameter >15 mm on the day of hCG administration. Student's t-test was used to analyze the data and the chi-squared test was used to compare fertilization and pregnancy rates. RESULTS: The flare protocol produced higher peak E(2) levels (1647+/-747 vs. 720+/-258 mIU/ml, P<0.05) and a larger number of mature follicles (5.8+/-2.2 vs. 4.0+/-1.0 P<0.05) in the study vs. the control group. A 30% pregnancy rate was achieved during this second IVF attempt using GnRHa flare protocol in the study group vs. 37 in the control group (P>0.05, NS). CONCLUSIONS: A comparison between the flare protocol group and the age-matched control group of poor ovarian responders subject to down regulation protocol, revealed higher peak E(2) levels and more mature follicles, respectively. However, both groups yielded comparable pregnancy rates. The use of high dose gonadotropin treatment in our study groups seems to be the only explanation for their subsequent successful outcome. We concluded that GnRH agonist flare protocol does not result in better IVF outcome compared with long GnRH agonist suppression protocol in IVF poor responders.     

Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer.

AIM: The combination of gonadotropin-releasing hormone (GnRH) antagonist and gonadotropin represents a valid alternative to the classical protocol with GnRH agonist for ovulation induction in patients with polycystic ovary syndrome (PCOS). The use of metformin is of benefit to women with PCOS. The aim of the present study was to compare the stimulation characteristics and in vitro fertilization (IVF)-embryo transfer (ET) outcomes of the standard short GnRH antagonist protocol for ovarian stimulation with or without metformin. MATERIALS AND METHODS:We recruited 40 PCOS patients. The population studied was divided into two groups (A and B). Group A was pretreated for 2 months with metformin 1.5 g/day (Glucophage(R); Merck Pharm), and then stimulated with recombinant follicle-stimulating hormone (rFSH) 150 UI/day (Gonal F(R) 75 UI; Serono). GnRH antagonist, cetrorelix acetate 0.25 mg/day (Cetrotide(R); Serono), was started when the leading follicle reached 14 mm diameter on ultrasound scan. Group B was treated only with rFSH 150 UI/day and GnRH antagonist 0.25 mg/day when the leading follicle was >or=14 mm in diameter. RESULTS: In group A we found a statistically significant (p < 0.05) decrease in the number of ampoules of rFSH (A vs. B: 18+/-6 vs. 24+/-8) and estradiol levels (A vs. B: 2400+/-600 vs. 3370+/-900 pg/ml) (all values mean+/-standard deviation). Group A had significantly fewer cancelled cycles (A vs. B: 1 vs. 3; p < 0.05). The incidence of ovarian hyperstimulation syndrome was 5% in group A and 15% in group B (p < 0.05). In patients treated with metformin, the total number of follicles on the day of human chorionic gonadotropin treatment (23+/-1.2 vs. 33+/-2.6) was decreased with no change in the number of follicles >or=14 mm in diameter (A vs. B: 18+/-1.2 vs. 19+/-1.7). However, the mean number of mature oocytes (A vs. B: 8.4+/-1.5 vs. 5.0+/-1.5) was increased with metformin treatment (p < 0.05). No difference was found in the number of cleaved embryos (A vs. B: 2.5+/-0.5 vs. 2.2+/-0.3). CONCLUSIONS: The use of metformin with GnRH antagonist improves the outcome of ovarian stimulation in IVF-ET cycles in PCOS patients.     

Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy

OBJECTIVE: To compare ongoing implantation rates under two different GnRH antagonist protocols. DESIGN: Randomized controlled trial. SETTING: Tertiary referral center. PATIENT(S): One hundred eleven women undergoing ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). INTERVENTION(S): Ovarian stimulation with 150 IU recombinant-FSH (rec-FSH) starting on day 2 of the cycle and GnRH antagonist starting either on day 6 of stimulation (fixed group) or when a follicle of > or = 15 mm was present after at least 5 days of stimulation (flexible group). In the flexible group, the rec-FSH dose was increased to 250 IU when the antagonist was initiated. MAIN OUTCOME MEASURE(S): Ongoing implantation and pregnancy rate. RESULT(S): In patients with no follicle of > or = 15 mm present on day 6 of stimulation, a significantly lower ongoing implantation rate was observed if the flexible scheme was applied as compared with the fixed scheme of administration (8.8% vs. 23.9%, respectively). Exposure of the genital tract to LH or E2 from initiation of stimulation to antagonist administration was able to distinguish between pregnant and nonpregnant patients in the population studied. CONCLUSION(S): High exposure of the genital tract to LH and E2 in the early follicular phase is associated with a reduced chance of pregnancy in cycles stimulated with recombinant FSH and GnRH antagonist for IVF/ICSI.     

Preferred treatment of infertile women older than 37 years of age who demonstrate premature luteinization in the first evaluation cycle

OBJECTIVE: To evaluate the efficacy of various treatments in abolishing premature luteinization in infertile women over 37 years old who are undergoing ovulation induction. DESIGN: Prospective, nonrandomized study. SETTING: Tertiary care medical clinic. PATIENT(S): Seventeen infertile women >37 years old in whom premature luteinization was detected during their evaluation (pretreatment) cycle. INTERVENTION(S): The patients underwent three consecutive treatment cycles with clomiphene citrate (group A), hMG (group B), and a GnRH agonist plus hMG (group C). MAIN OUTCOME MEASURE(S): Premature luteinization, defined as a progesterone/E2 ratio of >1 on the day of hCG administration. RESULT(S): Fifteen (88%) of the 17 patients in group A and 13 (76%) of the 17 patients in group B demonstrated premature luteinization. In contrast, only 1 (6%) of the 17 patients in group C had a progesterone/E2 ratio of >1 on the day of hCG administration. The mean (+/-SD) E2 level on the day of hCG administration was significantly higher in group C (1.236 +/- 772.7 pg/mL) than in group A (214.02 +/- 104.46 pg/mL) or group B (412.5 +/- 337 pg/mL). CONCLUSION(S): Pituitary desensitization with a GnRH agonist in conjunction with hMG may be of benefit for older infertile women who demonstrate early luteinization in their first evaluation cycle.     

Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment

Pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) challenge test before, during, and after GnRH antagonist administration was compared in four ovariectomized female monkeys receiving GnRH antagonist intramuscularly (IM) at increasing doses of 0.3, 1.0, and 3.0 mg/kg/day over 9 days. Three days before and 3 days after treatment, monkeys received vehicle alone. On experiment days 4, 7, 10, 13, and 16, 100 micrograms of GnRH was administered intravenously (IV) and blood drawn at 0 and 30 minutes. Before treatment, tonic follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were 248 +/- 105 and 178 +/- 31 ng/ml, respectively; after 0.3 mg/kg/day of GnRH antagonist, FSH and LH decreased to 30 +/- 6 and 41 +/- 4 ng/ml, respectively. After treatment with either 1 mg/kg/day or 3 mg/kg/day of GnRH antagonist, both gonadotropins were undetectable in serum. Monkeys with lower initial levels of gonadotropins were suppressed by 48 hours after GnRH antagonist, while those with higher tonic gonadotropins were suppressed 6 days later (FSH: r = 0.992; LH: r = 0.833). The data show that initial physiologic status is predictive of the rapidity of the suppression response induced by a GnRH antagonist and that, after achieving pituitary suppression, responsivity to an IV GnRH challenge test may be restored before normal tonic FSH/LH secretion is regained.     

A study of the controlled ovarian hyperstimulation using GnRH agonist and pure FSH in in vitro fertilization-embryo transfer and gamete intrafallopian transfer program

The present study was undertaken to examine controlled ovarian hyperstimulation (COH) during an IVF-ET/GIFT program with GnRH agonist (GnRH-a) and pure FSH and with the conventional method. Pituitary desensitization was induced with a subcutaneous injection of GnRH agonist (leuprolide acetate) in 20 patients undergoing COH for oocyte recovery. These 20 patients had previously dropped out of our IVF-ET/GIFT program because of a low estradiol response or premature LH surge. Comparisons were made among the menstrual cycles of 20 drop-out patients, the same patients' cycles after GnRH-a and pure FSH administration (GnRH-a group), and the cycles of 20 non-drop-out patients (control group). After treatment with GnRH-a and pure FSH, Estradiol levels were increased (GnRH-a cycles:previous cycles, 1,520 +/- 416 pg/ml:416 +/- 209.1 pg/ml), while the premature LH surge was decreased (GnRH-a cycles:previous cycles, 2:12). Moreover, the number of follicles at the day of hCG injection was increased (GnRH-a group: control group, 4.6 +/- 1.3:3.4 +/- 1.5). However, the fertilization rates for the GnRH-a group and the control group did not differ markedly, though the pregnancy rate was increased slightly in the former (GnRH-a group:control group, 25%:15%). In conclusion, it was seen that COH using GnRH-a and pure FSH contributed to a better ovarian response and suppression of LH surge in patients who had previously dropped out of the IVF-ET/GIFT program using conventional ovarian stimulation.     

Inhibition of gonadotropin surge by a brief mid-cycle regimen of ethinyl estradiol and norethindrone: possible role in in vitro fertilization.

Various methods to prevent premature luteinizing hormone (LH) surge and improve cycle control during hyperstimulation for in vitro fertilization (IVF) are standard of care. The purpose of the present study was to determine the influence of a 5-day regimen of ethinyl estradiol (EE) and norethindrone (NET) on folliculogenesis, gonadotropin surge, and ovulation. In a prospective randomized and comparative study, ten patients were assigned to two groups. A combination of 50 micrograms of EE and 1 mg of NET was used in groups I and II from days 6 through 10, and days 8 through 12, respectively. Blood samples and transvaginal ultrasound imaging were carried out throughout a 28-day cycle. Follicular diameter, plasma levels of LH, follicle-stimulating hormone (FSH), estradiol and progesterone, and endometrial thickness were determined. No LH surge or ovulation was detected in any patient studied. Peak estradiol concentrations were not significantly different between the groups (152.04 +/- 107.1 pg/ml vs 162.1 +/- 56.1 pg/ml [mean +/- SD] for groups I and II, respectively). No differences were noted between the groups for serum concentrations of FSH (range: 2-9 mIU/ml) or LH (range: 2-10 mIU/ml) for any given cycle day. Mean follicular diameters were not different between groups I and II (20.5 +/- 8.1 mm2 vs 20.6 +/- 14.2 mm2). Ultrasound assessment of mid-cycle follicular growth revealed diameters ranging from 18.5 mm2 to 34.0 mm2. Endometrial thickness ranged from 8 to 10 mm. There was no evidence of ovulation on ultrasound examination and either persistence or gradual resolution of follicles through the luteal phase. Peak serum concentrations at mid-luteal phase were < or = 2 ng/ml. In this pilot study, the combination of EE and NET restricted to a 5-day course beginning on day 6 or 8 permitted folliculogenesis but effectively inhibited midcycle LH surge and ovulation. Such regimens may have a role in IVF cycles for prevention of premature LH surges, especially as stimulation regimens evolve toward decreased gonadotropin use for stimulation and strict FSH preparations with the potential need for less complete pituitary suppression.