Subcutaneously administered Repronex in oligoovulatory female patients undergoing ovulation induction is as effective and well tolerated as intramuscular human menopausal gonadotropin treatment.

OBJECTIVE: To determine the efficacy and safety of Repronex SC as compared with Repronex IM and Pergonal IM in patients undergoing ovulation induction. DESIGN: Randomized, open-label, multicenter, parallel group study. SETTING: Ten academic and private fertility clinics with expertise in ovualtion induction. PATIENT(S): Premenopausal anovulatory and oligoovulatory females (n = 115) undergoing ovulation induction. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of treatment with gonadotropins and hCG administration and luteal phase progesterone support. MAIN OUTCOME MEASURE(S): Percentage of patients ovulating; percentage of cycles with follicular development meeting criteria for hCG administration; number of follicles recruited per cycle meeting hCG criteria; peak serum E(2) levels; rates of chemical, clinical and ongoing pregnancies; adverse events; injection-site pain scores. RESULT(S): There was no statistically significant difference in the percentage of women who ovulated among the treatment groups. However, Repronex SC was significantly more effective than Pergonal IM in producing follicular development in patients who met hCG criteria. There were no significant differences in clinical, ongoing, or continuing pregnancy rates or in multiple pregnancies among the treatment groups. No differences were found in the safety assessments, proportions or seriousness of adverse events or treatment discontinuations. Also, there were no differences between the three treatment groups in patient-recorded scores of injection-site pain or injection-site reactions. CONCLUSION(S): Repronex SC is as efficacious and well tolerated as Repronex IM or Pergonal IM in ovulation induction. Self-administration of Repronex SC provides a convenient treatment alternative to daily IM injections.     

Ovulation induction increases serum levels of insulin-like growth factor binding protein 1.

The effect of ovulation induction on serum insulin-like growth factor binding protein 1 (IGFBP-1) level in relation to sex hormone binding globulin (SHBG) levels was evaluated. Serum samples were collected 8 to 12 days after ovulation from 26 women undergoing ovulation induction with clomiphene citrate (CC), and from 58 women treated with CC in combination with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). In addition, serum samples were obtained from 63 spontaneously ovulating women and from 12 women during an anovulatory cycle. Luteal phase serum IGFBP-1 levels were 4.22 +/- 2.95 micrograms/L (P less than .05) in the CC group and 7.31 +/- 6.13 micrograms/L (P less than .001) in the CC/hMG/hCG group as compared to unstimulated ovulatory cycles (2.64 +/- 2.52 micrograms/L). No significant difference in IGFBP-1 levels was seen between spontaneously ovulatory and anovulatory cycles. The serum IGFBP-1 levels correlated positively to SHBG levels (r = .52, P less than .001). The data show that ovulation induction increases serum IGFBP-1 levels in parallel to SHBG levels, indicating that ovarian stimulation, which results in increased steroid hormone production, also induces changes in other factors known to modulate steroid hormone actions.     

The importance of human chorionic gonadotropin support of the corpus luteum during human gonadotropin therapy in women with anovulatory infertility

One hundred ten women with anovulatory infertility (World Health Organization [WHO] group I n = 50, WHO group II n = 60) were given 341 treatment courses with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). Additional hCG was given as single or repeated injections during the luteal phase in 205 ovulatory cycles. In WHO group I, the incidence of luteal phase defects was lower and the pregnancy rate higher in cycles with extra hCG administration during the luteal phase than in cycles with no extra hCG. In WHO group II, there was no such difference after supplemental hCG. The abortion rate was the same after cycles with or without extra hCG administration. It is suggested that during ovulation induction with hMG/hCG in anovulatory women with no evidence of endogenous estrogen activity, the luteal phase should be supplemented with additional hCG.     

Luteinizing response to human chorionic gonadotropin does not predict outcome in gonadotropin releasing hormone agonist-suppressed/human menopausal gonadotropin-stimulated in vitro fertilization (IVF) cycles

Objective The purpose of this study was to determine if early luteinizing potential in gonadotropin releasing hormone agonist (GnRH-a)-suppressed/human menopausal gonadotropin (hMG)-stimulated IVF cycles is predictive of cycle outcome.Design, Patients The study was a prospective evaluation of 41 women beginning a GnRH-a-suppressed/hMG-stimulated IVF cycle.Setting The in vitro fertilization program of a tertiary care institution was the study setting.Main Outcome Measures The main outcome measures were (1) estradiol (E₂) and progesterone (P) levels on the day of human chorionic gonadotropin (hCG) administration and the following day and (2) the ovarian response to ovulation induction and clinical outcome.Results Ten of the 41 women achieved a clinical pregnancy (24.4%). There was no significant difference in progesterone (P) levels on the day of or the day following hCG administration between the pregnant and the nonpregnant groups. Both groups exhibited a significant rise in P level in response to hCG. There was no significant difference in E₂ levels on the day of hCG between the two groups. The serum E₂ did not rise significantly in response to hCG in either group. Patients who became pregnant had significantly more oocytes retrieved, fertilized, cleaved, and transferred.Conclusions Clinical response and outcome in GnRH-a-suppressed/hMG-stimulated IVF cycles are not predicted by early luteinizing potential as indicated by the response of E₂ or P to hCG.Presented at the 7th Annual World Congress of in Vitro Fertilization, Paris, France, June 30–July 3, 1991.     

Relationship of baseline ovarian volume to ovarian response in World Health Organization II anovulatory patients who underwent ovulation induction with gonadotropins

OBJECTIVE: To assess whether ovarian volume of World Health Organization II anovulatory patients in the early follicular phase predicts the response to ovulation induction with gonadotropins. DESIGN: Retrospective data analysis of two prospective, randomized, multicenter studies. SETTING: Clinical development unit of biotechnology company. PATIENT(S): Four hundred sixty-five World Health Organization II anovulatory patients undergoing ovulation induction. MAIN OUTCOME MEASURE(S): Ovarian response to stimulation, ovulation (mid-luteal serum progesterone > 30 nmol/L), cancellation rate, pregnancy rate, and incidence of the ovarian hyperstimulation syndrome (OHSS) according to baseline ovarian volume (day 2-5) before stimulation. RESULT(S): Mean ovarian volume was 11.55 +/- 6.0 cm(3) (range, 0.8-49.3 cm(3)). Small ovarian volume was associated with lower rates of cycle cancellation owing to risk for OHSS (3 vs. 29 patients [2.8% vs. 9%]). Patients with small ovarian volume (<7.25 cm(3)) required fewer ampules of FSH (1373 IU vs. 1629 IU) and shorter duration of stimulation (16 vs. 18.1 days) and had higher ovulation rate than did patients with mid-range and larger ovarian volume (84.3% vs. 69.1% and 68.8%, respectively). The clinical pregnancy rate per cycle of hCG administration was similar in the three groups (25.8%, 28.1%, and 27.5%). CONCLUSIONS: World Health Organization II anovulatory women with medium-sized or large ovaries who are undergoing low-dose gonadotropin stimulation for ovulation induction may have higher risk for OHSS than do women with small ovaries. Women with small ovaries who meet criteria for administration of hCG respond better to ovulation induction and have a similar likelihood of conceiving compared with women with larger ovaries.     

Successful induction of ovulation and conception with pulsatile intravenous administration of human menopausal gonadotropins in anovulatory infertile women resistant to clomiphene and pulsatile gonadotropin-releasing hormone therapy

Gonadotropins are released in a pulsatile fashion at a frequency of between 1 and 2 hours in the follicular phase of the menstrual cycle. Human menopausal gonadotropins are usually administered intramuscularly. We evaluated the gonadal response to intravenous human menopausal gonadotropins administered in a pulsatile fashion over nine treatment cycles in three anovulatory infertile women. Human menopausal gonadotropin pulses in doses up to 12 IU follicle-stimulating hormone at frequencies between 2 to 3 hours over 3 to 17 days resulted in ovulation in five cycles with one pregnancy being conceived. In the ovulatory cycles (5,000 to 10,000 IU of human chorionic gonadotropin was used to induce ovulation), the 17 beta-plasma estradiol level was 961 +/- 128 versus 326 +/- 95 pg/ml (mean +/- SEM) in the anovulatory cycles (p = 0.015). The dose of human menopausal gonadotropins (in ampules of Pergonal, 75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone) in the intravenous cycles needed to induce ovulation was 12.3 +/- 1.4 versus 20.4 +/- 0.9 for intramuscular cycles (n = 80 in 23 women, p = 0.008). Treatment was well tolerated and without complications. We are continuing to explore the use of this apparently more efficient mode of administering human menopausal gonadotropins to anovulatory patients resistant to other techniques of ovulation induction therapy.     

Human gonadotropin therapy. I. Serum estradiol and progesterone patterns during conceptual cycles

Hormone patterns during 43 conceptual cycles induced by human gonadotropins in 37 women with anovulatory infertility were analyzed. The treatment was monitored by daily determinations of estradiol (E2) in serum. The incidence of both multiple pregnancies and abortions during the gonadotropin therapy was high (30%). When the hormone patterns during the human menopausal gonadotropin-induced conceptual cycles were compared with spontaneous conceptual cycles, it became evident that the ovaries were hyperstimulated during the follicular and luteal phases of the induced cycle. The mean serum E2 level at induction of ovulation did not differ between treatment courses resulting in single or multiple pregnancies. The endogenous estrogen secretion at the initiation of treatment was lower in the multiple pregnancy group than in the single pregnancy group. The active phase, i.e., when the estrogens progressively increase during the late follicular phase of the induced cycle, was found to be prolonged in the multiple pregnancy group. The prolonged follicular stimulation by human menopausal gonadotropin might explain why multiple ovulations and pregnancies occur. Thus, both the duration of the active phase of follicular stimulation and the E2 level at the day of induction of ovulation by human chorionic gonadotropin should be determined for optimal monitoring of human gonadotropin therapy.     

Follicular Development and Hormonal Levels Following Highly Purified or Recombinant Follicle-Stimulating Hormone Administration in Ovulatory Women and WHO Group II Anovulatory Infertile Patients

Purpose: Our purpose was to compare ovarian performance and hormonal levels, after ovulation induction, in both normal ovulatory women undergoing intrauterine insemination (group 1) and World Health Organization (WHO) group II anovulatory infertile patients (group 2), using two different gonadotropin drugs. Methods: Patients (n = 20 per group) were treated during consecutive cycles, using the same stimulation protocol, with highly purified urinary FSH (HP-FSH) in the first treatment study cycle and recombinant FSH (rFSH) in the second one. Patients in group 1 were treated according to a late low-dose technique, and WHO group II anovulatory patients (group 2) received chronic low-dose FSH therapy. Results: Compared with HP-FSH, treatment with rFSH in group 2 required significantly less ampules of drug to induce follicular development but resulted in significantly higher plasma levels of estradiol and inhibin A on the day of human chorionic gonadotropin injection. No differences were found when both treatment modalities were compared in group 1. Conclusions: rFSH is more efficacious than urinary HP-FSH for ovulation induction in WHO group II anovulatory infertile patients as assessed by follicular development, hormonal levels, and the amount of FSH required.     

Human gonadotropin therapy. II. Serum estradiol and progesterone patterns during nonconceptual cycles

Hormone patterns during 113 nonconceptual gonadotropin-induced cycles of 65 infertile anovulatory women were analyzed. All but one women ovulated, i.e., the ovulation rate was 98%. Signs of defective corpus luteum function were observed during 8 cycles, and anovulation occurred in 11 treatment cycles. The duration of the active phase of the follicular stimulation was shorter during cycles with defective luteal phases and anovulatory cycles. The mean estradiol level at induction of ovulation by human chorionic gonadotropin did not differ between the groups. Premature ovulation was observed in six treatment cycles. No case of severe hyperstimulation was encountered. The hormone pattern during gonadotropin-induced conceptual cycles did not differ in comparison with gonadotropin-induced nonconceptual ovulatory cycles.     

The role of ultrasound in ovulation induction: a critical appraisal

Twenty-five cycles induced by human menopausal gonadotropin (hMG) were serially studied by ultrasound. The developing follicles were observed up to and beyond human chorionic gonadotropin (hCG) administration. Ovulation as determined by subsequent pregnancy or a sustained elevation of basal temperature was seen in 18 of these cycles. Among these patients the follicular size ranged between 24 and 13 millimeters. No pregnancies occurred where the follicular size was below 15 mm. A shortened luteal phase was noted in three cycles where the follicular size was either 13 or 14 mm. Multiple follicles greater than 10 mm were observed in 14 of the ovulating cycles, but in no case did a multiple pregnancy occur. Fifteen millimeters is therefore suggested as a minimum size for satisfactory ovulation, but it does not appear that an optimum size exists. We conclude that ultrasound can play an important role in the monitoring of ovulation induction but does not replace the present methods.     

First demonstration of induction of ovulation with a hybrid human chorionic gonadotropin compound (AB1ER-CR-2XY)

This study presents the first demonstration of the ability of a hybrid human chorionic gonadotropin (hCG) compound, AB1ER-CR-2XY, to induce ovulation in humans. Thirteen patients with primary infertility were treated for 16 cycles with varying dosages of human menopausal gonadotropin (hMG), and 10,000, 5000, and 2500 IU of the hybrid hCG. Presumptive occurrence of ovulation was recorded in 15 courses of medication. Echographic studies did not indicate overt follicular or ovarian enlargement. Two singleton pregnancies occurred, one during the first treatment course and the other following the second course of hMG/hybrid hCG therapy. Due to its specific characteristics, the hybrid hCG may provide equal or greater effectiveness and a better margin of safety than commercial hCG used for ovulation induction in patients pretreated with hMG.     

促排卵周期PCOS妇女子宫内膜纤维粘连蛋白及层粘连蛋白的表达

目的:了解促排卵药物氯米酚(CC)、hMG及GnRH-a对黄体中期子宫内膜内膜纤维粘连 蛋白(FN)及层粘连蛋白(LN)表达的影响。方法:应用单克隆抗体,采用免疫组织化学技术检测50 例正常妇女自然周期以及50例正常妇女,45例多囊卵巢综合征妇女应用CC／hCG,CC／hMG／hCG 及GnRH-a／hMG／hCG方案促排卵治疗后黄体中期子宫内膜FN和LN的表达。结果:子宫内膜FN 和LN表达在正常妇女自然周期着床窗口时呈现强阳性;而CC、hMG抑制FN和LN的表达,使 其阳性强度减弱,有显著性统计学差异P<0．01;GnRH-a对FN和LN抑制不明显。同时妊娠者较 未妊娠者FN和LN表达强度高。结论:CC／hCG及CC／hMG／hCG方案促排卵后黄体中期子宫内膜 中FN和LN表达下降或缺失,内膜容受性下降,妊娠率降低。     

Human menopausal gonadotropin/human chorionic gonadotropin follicular maturation for oocyte aspiration: phase I, 1981

Thirty-one human menopausal gonadotropin and human chorionic gonadotropin (hMG/hCG) ovulation induction cycles from 25 normally ovulating patients who applied to a program for the Vital Initiation of Pregnancy (VIP) are discussed. Three different categories of serum estradiol (E2) response were found. Serum E2 and progesterone responses were inversely related to the amount of hMG, indicating a patient sensitivity rather than a dosage relationship. Luteinizing hormone levels were suppressed by gonadotropins. Daily evaluation of vaginal smear, cervical mucus, serum E2 determinations, and pelvic ultrasound are necessary for an optimum ovulation induction with gonadotropins. Two successful pregnancies are reported.     

The use of ovarian ultrasonography in monitoring ovulation induction

Ovarian ultrasonography is a new diagnostic technique which has become almost essential in monitoring ovulation. Recent improvements in ultrasound technology have allowed for accurate assessment of the number and size of the developing follicles and their rate of growth, as well as ovulation and postovulatory events. In the non-stimulated cycle follicular size correlates well with optimal maturation and there is a linear correlation between follicular diameter and plesma estradiol (E₂ levels). In stimulated cycles, because of asynchrony of various recruited coliorts of follicles, these rules are not as steadfast, These observations indicate that when there is endogenous gonadotropic activity, follicular growth stimulated by human menopausal gonadotropins (hMG) does not develop synchronously. The aim should be, therefore, not only to improve the monitoring system but mainly to synchronize the cohorts of follicles recruited for development in any one cycle by a better regimen for ovalation induction. In view of the high success rate of hMG treatment in patients without endogenous gonadotropin secretion, it is tempting to speculate that inducing similar conditions in women with endogenous gonadotropin production may have a significant change in the pattern of follicular development in their conception rate.     

Regulation of ovarian follicular and luteal function during treatment with exogenous gonadotropins in anovulatory infertility

The dosage, duration of treatment, and plasma hormone levels were analyzed statistically between and within groups of treatment cycles with (n = 46) and without (n = 10) ovulation. A significant difference was observed in the dosage of human menopausal gonadotropins (hMG) over various days of treatment, but not in the mean dosage of hMG and human chorionic gonadotropin (hCG) administered per cycle. Follicle-stimulating hormone (FSH):luteinizing hormone (LH) ratios, prolactin (PRL) levels, and the magnitude and the duration of the estradiol response were greater in the ovulatory cycles. Additionally, in the ovulatory cycles, the dose of hMG correlated with the plasma levels of estradiol, FSH, and LH, while in the anovulatory cycles, hMG dosage correlated only with the LH concentrations. After administration of hCG, the mean plasma concentrations of its beta subunit peaked within 1 day and remained detectable for up to 10 days thereafter. In the ovulatory cycles, the mean progesterone level was maximal 6 days following hCG administration. In these cycles, luteal phase progesterone levels correlated positively with the preovulatory estradiol and inversely with concentrations of the beta subunit of hCG. The data demonstrate that, in contrast to anovulatory follicles, ovulatory follicles were exposed to a relative "dominance" of FSH over LH, with higher concentrations of estradiol and PRL for several days before hCG was administered. Apart from hMG dosage, the endogenous discharge of LH appeared to be an important determinant of the ovarian response. A single 10,000 IU dose of hCG was adequate for inducing ovulation and maintaining luteal function.     

Endocrine modifications associated with final oocyte maturation with gonadotropin-releasing hormone agonists vs. human chorionic gonadotropin in women undergoing intrauterine insemination

OBJECTIVE: To compare the hormonal profile when using triptorelin vs. human chorionic gonadotropin (hCG) to trigger ovulation in intrauterine insemination (IUI) cycles. STUDY DESIGN: Twenty-five patients who underwent 48 cycles were enrolled in a prospective, randomized, crossover study. After ovulation induction with recombinant follicle-stimulating hormone (FSH), couples were randomly allocated to a first cycle with a single dose of 0.2 mg of triptorelin or 5,000 IU of urinary hCG to trigger ovulation; if pregnancy did not occur, a second cycle was carried out, and the patient was crossed over to the other treatment group. Blood was collected the day of hCG/triptorelin administration and both days after IUI. RESULTS: Patients treated with triptorelin showed a significantly higher FSH and luteinizing hormone (LH) rise 24 hours after the injection when compared to hCG. Serum progesterone was significantly increased 48 hours after hCG administration, although estradiol levels were comparable between the groups. CONCLUSION: A higher LH and FSH peak than that induced by hCG was observed. Considering that serum progesterone levels were suboptimal in both protocols and taking into account the lower progesterone production in gonadotropin releasing hormone analogue cycles, corpus luteum supplementation in the luteal phase should be recommended for these patients.     

Luteal dysfunction in ovulation induction: the role of repetitive human chorionic gonadotropin supplementation during the luteal phase

Several studies have indicated that ovulation induction with human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defect. To assess the efficiency of luteal support by hCG to an infertile population undergoing ovulation induction, with CC/hCG or hMG/hCG, we have randomly administered 2500 IU hCG intramuscularly on days 3, 6, and 9 after ovulation induction by 10,000 IU of hCG to 74 patients on 265 treatment cycles. As controls served 357 ovulation induction cycles in the same 74 patients. The treatment cycles were randomly alternated with control cycles so that each patient served as her own control. However, the mean +/- standard deviation (SD) midluteal P was 38.1 +/- 10.8 ng/ml in the study group versus 15.7 +/- 10.5 ng/ml in the control group (P less than 0.001). Luteal phase length was 15.4 +/- 1.5 days in the treatment group versus 12.1 +/- 1.7 in the control group (P less than 0.01). In the treatment group, 64.8% of the patients achieved pregnancy (27% pregnancies/treatment cycle) versus 47.3% in the control group (11.5% pregnancies/control cycle) (P less than 0.01). The pregnancy wastage rates (including abortions and "chemical" pregnancies) were 30.6% in the treatment group versus 56% in the control group (P less than 0.01). We conclude that repetitive hCG administration may be an efficient luteal support in infertile patients undergoing ovulation induction.     

IVF outcome in anovulatory infertility (WHO group 2)--including polycystic ovary syndrome--following previous unsuccessful ovulation induction

This follow-up study represents IVF treatment characteristics and outcomes in women with World Health Organization (WHO) group 2 anovulatory infertility after previous unsuccessful ovulation induction compared with controls. Furthermore, the possibility of initial screening parameters of these anovulatory women to predict IVF outcome was examined. Twenty-six patients with WHO 2 anovulatory infertility who failed to achieve a live birth following previous induction of ovulation (using clomiphene citrate as first line and exogenous FSH as second line) were compared with 26 IVF patients with tubal infertility matched for age, treatment period and treatment regimen. The WHO 2 patients underwent 49 IVF cycles, whereas the normo-ovulatory controls underwent 46 cycles. In WHO 2 patients 15 cycles were cancelled compared with six cycles in controls (P = 0.04). Cycles were predominantly cancelled due to insufficient response (P = 0.04). In cases in whom the cycle was cancelled, body mass index (BMI) was significantly higher (P < 0.001) in WHO 2 women compared with controls. Overall live birth rates were comparable (P = 0.9). Obese women suffering from WHO 2 anovulatory infertility are at an increased risk of having their IVF cycle cancelled due to insufficient response. Once oocyte retrieval is achieved, live birth rates are comparable with controls.     

The impact of high progesterone levels in the follicular phase of in vitro fertilization (IVF) cycles: A comparative study

Estrogen (E₂) and plasma progesterone (P₄) levels are valuable parameters for follicular development in in vitro fertilization (IVF) cycles. Furthermore, the progesterone concentration prior to, during, and following human chorionic gonadotropin (hCG) administration is an important marker for the detection of early luteinization and premature ovulation. The pattern of hormonal profile in relation to the number of oocytes retrieved, fertilized, and cleaved and the fate of the pregnancies achieved were compared in three groups of patients treated by the same protocol. Group I included 22 women who conceived with high progesterone levels on day hCG+1 (P_4'>2.5 ng/ml). Group II included 43 women who conceived with low P₄ values (P_4'<2.5 ng/ml), while group III included 46 patients in whom no pregnancies occurred. A significant decrease in fertilization, cleavage, and pregnancy rates was observed in patients with high progesterone levels on day hCG+1, compared to those with normal levels. Nevertheless, it is suggested that cycles with high P₄ levels in the preovulatory phase should not be canceled, as a fair chance for pregnancy still exists.     

促排卵治疗对多囊卵巢综合征患者子宫内膜整合素αv,β3表？…

目的 了解促排卵药物对多囊卵巢综合征（ＰＣＯＳ）患者黄体中期子宫内膜整合素αｖ、β３表达的影响。方法 应用单克隆抗体,采用免疫组织化学技术对２２例正常妇女、４０例无排卵ＰＣＯＳ患者促排卵治疗后黄体中期的子宫内膜整合素αｖ、β３进行测定。结果正常妇女子宫内膜整合素αｖ、β３表达在“着床窗口期”呈现强阳性;而氯米芬（ＣＣ）及绝经期促性腺激素（ｈＭＧ）抑制αｖ、βｂ的表达,使其表达呈弱阳性;而促性腺素释