Case Report: First established pregnancy and birth after ovarian stimulation with recombinant human follicle stimulating hormone (Org 32489)

This case report describes the first established pregnancy andbirth after ovarian stimulation with Org 32489, pure recombinanthuman follicle stimulating hormone (recFSH, Organon International).A patient with tubal infertility participated in an open efficacystudy of recFSH evaluating the efficacy of combined gonadotrophin-releasinghormone (GnRH)agonist/recFSH treatment in women undergoing in-vitrofertilization (IVF) and embryo transfer. Ovarian stimulationwas induced by recFSH in association with buserelin (Suprecur^®,4 x 150 µg/day) using a short protocol. After 9 days ofrecFSH treatment (75 IU/day), six pre-ovulatory follicles (15mm) were observed and 10 000 IU human chorionic gonadotrophinwere administered. Nine mature oocytes were retrieved by oocytepuncture and after IVF, three embryos were replaced in the uterus.A viable singleton intra-uterine pregnancy was revealed at agestational age of 7 weeks. The pregnancy progressed normallyand ended with a vaginal delivery at a gestational age of 39.5weeks. A healthy girl was born and paediatric examination didnot demonstrate any abnormality.     

A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). The ganirelix dose-finding study group

A multicentre, double-blind, randomized dose-finding study of Org 37462 (ganirelix) was conducted in 333 women undergoing ovarian stimulation with recombinant follicle stimulating hormone (rFSH; Puregon) to establish the minimal effective dose preventing premature luteinizing hormone (LH) surges during ovarian stimulation. For ovarian stimulation, rFSH was given in a fixed daily dose of 150 IU for 5 days from days 2 to 6 of the menstrual cycle. From cycle day 7 onward, up to and including the day of human chorionic gonadotrophin (HCG), Org 37462 (dosages 0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/0.5 ml) was administered once daily by s.c. injection, and the rFSH dose was adjusted depending on ovarian response. The lowest (0.0625 mg) and highest (2.0 mg) dose groups were terminated prematurely on the advice of an external independent advisory committee. Serum Org 37462 concentrations increased in a linear dose-proportional manner, whereas serum LH and increases of oestradiol fell with increasing Org 37462 dose. During Org 37462 treatment, serum LH concentrations > or =10 IU/l were observed in the lowest dose groups with incidences of 16% (0.0625 mg), 9% (0.125 mg) and 1.4 % (0.25 mg). On the day of HCG, the number of follicles > or =11, > or =15 and > or =17 mm were similar in the six dose groups, whereas serum oestradiol concentrations were highest in the 0.0625 mg group (1475 pg/ml) and lowest in the 2 mg group (430 pg/ml). The median daily dose of rFSH was between 150 and 183 IU and the overall median duration of Org 37462 treatment was approximately 5 days in the six treatment groups. Overall, Org 37462 treatment appeared to be safe and well tolerated. The mean number of recovered oocytes and good-quality embryos was similar in all dose groups and ranged from 8.6 to 10.0 and 2.5 to 3.8, respectively. The mean number of replaced embryos in the different dose groups ranged from 2.3 to 2.7. The implantation rate was highest in the 0.25 mg group (21.9%) and lowest in the 2 mg group (1.5%). The early miscarriage rates (first 6 weeks after embryo transfer) were 11.9 and 13% in the 1 and 2 mg group respectively, whereas in the other dose groups this incidence was zero (0.0625%) up to a maximum of 3.7% (0.5 mg group). The vital pregnancy rate (with heart activity) at 5-6 weeks after embryo transfer was highest in the 0.25 mg group, i.e. 36.8 % per attempt and 40.3 % per transfer, and resulted in an ongoing pregnancy rate 12-16 weeks after embryo transfer of 33.8% per attempt and 37.1% per transfer. In conclusion, a daily dose of 0.25 mg Org 37462 prevented LH surges during ovarian stimulation and resulted in a good clinical outcome.      

High dose gonadotrophin-releasing hormone antagonist (ganirelix) may prevent ovarian hyperstimulation syndrome caused by ovarian stimulation for in-vitro fertilization

This case report describes the first attempt to treat imminent ovarian hyperstimulation syndrome (OHSS) by using a gonadotrophin-releasing hormone (GnRH) antagonist. A 33 year old, normo-ovulatory woman undergoing in-vitro fertilization received daily subcutaneous injections of 150 IU of recombinant follicle-stimulating hormone (recFSH) from cycle day 2, together with GnRH antagonist (ganirelix) 0.125 mg from cycle day 7 onwards. On cycle day 10 the patient was found to have a serum oestradiol concentration of 16 500 pmol/l and, on ultrasound examination, four preovulatory (>16 mm) and nine intermediate sized (10-16 mm) follicles. RecFSH injections were discontinued, human chorionic gonadotrophin (HCG) withheld, whereas the ganirelix dose was increased to 2 mg/d. This regimen led to a rapid decrease in serum oestradiol concentrations and the decrease in ovarian size on ultrasound. Since GnRH antagonists will become clinically available for in-vitro fertilization programmes in the near future this suggested regimen might have a role in preventing severe OHSS.      

Mid-luteal endometrial intracrinology following controlled ovarian hyperstimulation involving use of a gonadotrophin releasing hormone antagonist

BACKGROUND: There are concerns of reduced pregnancy rates with the use ofgonadotrophin-releasing hormone antagonists (GnRH antagonists)in IVF/ICSI cycles. Sex steroids and their metabolizing enzymesin the endometrium may play a vital role in embryo implantation.This study has evaluated the levels and localization of sex-steroidreceptors and metabolizing enzymes, 3β-hydroxysteroid dehydrogenases(3βHSD) and selected 17β-HSD (17βHSD), in mid-lutealendometrium of women treated with GnRH antagonist (Cetrorelix)and recombinant FSH (rFSH; Gonal-F) with luteal phase progesteronesupplementation. METHODS: Mid-luteal phase endometrial biopsies were obtained from oocytedonors undergoing ovarian stimulation and from control womenwith regular periods. Immunohistochemistry and real-time quantitative–polymerasechain reaction (QRT–PCR) were used to compare proteinand mRNA expression of progesterone receptor (PR), estrogenreceptor (ER), estrogen receptor β (ERβ), androgenreceptor (AR), 3βHSD1, 3βHSD2, 17βHSD2 and 17βHSD5. RESULTS: Cetrorelix–rFSH treatment caused a mid-luteal suppressionof PR protein expression in the endometrial stroma, surfaceepithelium and glands, although expression in the glands ofcontrol samples was variable. In contrast, the treatment causedan increase in PR staining in perivascular cells. No other significantdifferences in protein expression were observed between thetwo groups. mRNA levels of AR, ER, 3βHSD1 and 17βHSD2were significantly reduced in the treatment group. PR mRNA levelswere also reduced by GnRH antagonist–rFSH treatment, butthe difference was not significant. CONCLUSIONS: Changes in the expression of sex-steroid receptors and metabolizingenzymes may lead to alterations in the activity and intracellularavailability of estrogens, progestogens and androgens in endometriumof women treated with Cetrorelix and rFSH. Their impact on embryoimplantation merits further evaluation.     

Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group

A multicentre, open-label, randomized study of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix (Orgalutran((R))/Antagon((TM))) was performed in women undergoing ovarian stimulation with recombinant FSH (rFSH: Puregon((R))). The study was designed as a non-inferiority study using a long protocol of buserelin (intranasal) and rFSH as a reference treatment. A total of 730 subjects was randomized in a treatment ratio of 2:1 (ganirelix:buserelin) using an interactive voice response system which stratified for age, type of infertility and planned fertilization procedure [IVF or intracytoplasmic sperm injection (ICSI)]. The median duration of GnRH analogue treatment was 5 days in the ganirelix group and 26 days in the buserelin group, whereas the median total rFSH dose was 1500 IU and 1800 IU respectively. In addition, in the ganirelix group the mean duration of stimulation was 1 day shorter. During ganirelix treatment the incidence of LH rises (LH >/=10 IU/l) was 2.8% versus 1.3% during rFSH stimulation in the buserelin group. On the day of triggering ovulation by human chorionic gonadotrophin (HCG), the mean number of follicles >/=11 mm diameter was 10.7 and 11.8, and the median serum oestradiol concentrations were 1190 pg/ml and 1700 pg/ml in the ganirelix and buserelin groups respectively. The mean number of oocytes per retrieval was 9.1 and 10.4 respectively, whereas the mean number of good quality embryos was 3.3 and 3.5 respectively. The fertilization rate was equal in both groups (62.1%), and the same mean number of embryos (2.2) was replaced. The mean implantation rates were 15.7% and 21.8%, and the ongoing pregnancy rates per attempt were 20.3% and 25.7% in the ganirelix and buserelin groups respectively. Evaluation of all safety data indicated that the ganirelix regimen was safe and well tolerated. The overall incidence of ovarian hyperstimulation syndrome was 2.4% in the ganirelix group and 5.9% in the reference group. The results of this study support a safe, short and convenient treatment regimen of ganirelix, resulting in a good clinical outcome for patients undergoing ovarian stimulation for IVF or ICSI.     

In-vitro biopotency and glycoform distribution of recombinant human follicle stimulating hormone (Org 32489), Metrodin and Metrodin-HP

In this study the in-vitro biopotency and glycoform distributionof human recombinant follicle stimulating hormone (FSH, Org32489) has been assessed. The biopotency of recombinant FSHwas studied using animal (rat Sertoli) and human (granulosa-lutein)cell models. Recombinant FSH, as measured in the rat Sertolicell assay, was more potent than the urinary preparations Metrodin,Metrodin-HP and IS 70/45 with half maximal stimulation (ED₅₀;mean ± SEM, n 3) occurring at 2.2 ± 0.5 IU/I (recombinantFSH), 4.7 ± 1.1 IU/I (Metrodin), 13.2 ± 0.7 IU/I(Metrodin-HP) and 6.4 ± 0.3 IU/I (IS 70/45); the pituitarypreparation IRP 83/575 had an EDM of 10.4 ± 0.1 IU/I.Using human granulosa-lutein cells, cultured for up to 4 daysin the absence of exogenous steroid precursors, recombinantFSH was either without effect (three out of five patients) orinhibited both oestradiol and progesterone secretion. FSH (83/575)was without effect on oestradiol with preparations from anyof the patients but slightly stimulated (134 ± 8%; mean± SEM, P < 0.05) progesterone production at the highestdose (80 IU/I). The distribution of FSH isoforms, assessed bypolyclonal radioimmunoassay, following chromatofocusing overthe ranges pH < 3.5 and pH 3.5–7.0 respectively wasrecombinant FSH, 12.4 and 87.6%; Metrodin, 19.8 and 80.2%; Metrodin-HP,50.2 and 49.8%; IS 70/45, 15.0 and 85.0%; IS 83/575, 70.9 and29.1%. All glycoforms were pi <7.0 for the five preparations.In conclusion: (i) the potency of FSH as measured in the ratSertoli cell assay increases in the order Metrodin-HP < pituitaryIRP 83/575 < < Metrodin < IS 70/45 < recombinantFSH; (ii) in contrast to 83/575, recombinant FSH inhibits steroidogenesisin human granulosa-lutein cells isolated from some patients;(iii) the glycoform distribution of recombinant FSH resemblesMetrodin more closely than Metrodin-HP which is far more acidicin nature. biopotency/glycoform/isoform/Metrodin/recombinant FSH     

Induction of superovulation in cyclic rats by administration of decreasing doses of recombinant follicle stimulating hormone (Org32489)

The objective of this study was to set up a superovulation protocol in adult cyclic rats by using recombinant human follicle stimulating hormone (rhFSH; Org32489). Good results were obtained by treatment with decreasing doses of rhFSH (2.5 to 0.5 IU) during the dioestrus period. The number of corpora lutea (CL) found in rats treated with this protocol was 43.5 +/- 3.4; this is more than three times the number in saline-treated control rats (13.0 +/- 0.4). Fertilization of oocytes after superovulation was as good as after normal ovulation in terms of number of 2-cell stage embryos found 2 days after mating. The absolute number of implantations was twice the number observed in saline-treated control rats (23.3 +/- 1.8 versus 10.6 +/- 0.5); therefore the number of implantations per CL was lower in superovulated rats. The serum concentrations of luteinizing hormone (LH), endogenous FSH and oestradiol-17beta were decreased during rhFSH treatment, while the inhibin serum concentration was increased. The progesterone serum concentration was increased on the days of pro-oestrus and oestrus after treatment. No difference was observed in the testosterone serum concentration. Pretreatment with 10 IU rhFSH at oestrus before giving the decreasing doses of rhFSH during dioestrus reduced the ovulatory response. Finally, treatment with a constant low dose of rhFSH instead of a decreasing dose of rhFSH did not result in spontaneous ovulation. However, ovulation induction by means of a human chorionic gonadotrophin bolus resulted in superovulation in six out of eight rats. It is concluded that superovulation in cyclic rats can be achieved using rhFSH treatment. However, it was found that the type of rhFSH regimen was very important to achieve appropriate stimulation. The optimal protocol was treatment with decreasing doses of rhFSH during dioestrus. The oocytes retrieved could be fertilized as well as oocytes of saline-treated control rats. The results also indicate that treatment with higher doses of rhFSH might induce a desensitization for FSH and LH.      

Obstetrical and neonatal outcome after controlled ovarian stimulation for IVF using the GnRH antagonist ganirelix

BACKGROUND: To establish long-term safety, follow-up data on pregnancy, birth and neonatal outcome were collected during clinical development trials with ganirelix (Orgalutran) in women undergoing controlled ovarian stimulation for conventional IVF or ICSI. METHODS: Results of an analysis of the pooled data of all follow-up data of the phase 2 and 3 programme for the development of ganirelix are presented. Obstetrical data on 340 ongoing pregnancies ( vertical line16 gestational weeks) after ganirelix treatment and 134 pregnancies after GnRH agonist treatment in a long protocol are shown. Furthermore, the neonatal outcome of 432 children [258 (75.9%) singletons, 72 (21.2%) twins and 10 (2.9%) triplets] born in the ganirelix group is presented and compared with 184 children [91 (67.9%) singletons, 36 (26.9%) twins and seven (5.2%) triplets] in the agonist group. RESULTS: There were no differences between the two groups in pregnancy loss after 16 weeks gestation. Incidence and nature of complications during pregnancy and delivery did not differ between the two groups. The overall mean gestational age was approximately 38.0 weeks, ranging from an average of 39 weeks for singletons to 34 weeks for triplets. No major differences were observed in neonatal characteristics of infants in the ganirelix and agonist groups, who had an overall mean birth weight of on average 3200 g for singletons, 2300 g for twins and 1800-1900 g for triplets. Congenital malformations were observed in 32 of 424 (7.5%) fetuses vertical line26 gestational weeks in the ganirelix group and in 10 of 181 (5.5%) in the agonist group. When applying a broad definition of major malformation (a major congenital malformation is a condition that causes functional impairment or requires surgical intervention) the rates were 4.5 versus 3.3 (odds ratio 1.37, 95% confidence interval 0.54-3.48) for the ganirelix and agonist group respectively. CONCLUSIONS: Reviewing the presented data and the literature on obstetric and neonatal outcome after conventional IVF or ICSI, we conclude that a controlled ovarian stimulation protocol including the novel GnRH antagonist ganirelix has been shown to be safe for pregnant women and their newborn babies.     

Ovulation induction with low dose alternate day recombinant follicle stimulating hormone (Puregon)

We investigated whether a recombinant follicle stimulating hormone (FSH) (Puregon) can be administered less frequently and at lower doses during ovulation induction than is current practice. Patients (20-35 years, body mass index <30 kg/m(2)) with infertility and chronic anovulation secondary to polycystic ovarian syndrome and resistant to previous clomiphene treatment received (Puregon); 100 IU, n = 17 patients, or 50 IU, n = 10 patients) on alternate days. After 2 weeks and in the absence of follicular recruitment, doses were increased stepwise at weekly intervals (50 IU/alternate days). Twenty-two cycles out of 27 were ovulatory. There were six pregnancies, five from Puregon (100 IU) and one from Puregon (50 IU); four pregnancies proceeded to term. The duration of stimulation (mean, range) with Puregon (100 IU) was 16.4, 7-29 and Puregon (50 IU) 19.1, 8-38 days. The gonadotrophin doses administered (mean; range) were 689, 200-1800 IU (Puregon 50 IU) and 939, 400-2300 IU (Puregon 100 IU). We conclude that low dose alternate day Puregon treatment is suitable for this difficult patient group.     

Recombinant hormones: In-vitro biopotency and glycoform distribution of recombinant human follicle stimulating hormone (Org 32489), Metrodin and Metrodin--HP

In this study the in-vitro biopotency and glycoform distributionof human recombinant follicle stimulating hormone (FSH, Org32489) has been assessed. The biopotency of recombinant FSHwas studied using animal (rat Sertoli) and human (granulosa—lutein)cell models. Recombinant FSH, as measured in the rat Sertolicell assay, was more potent than the urinary preparations Metrodin,Metrodin—HP and IS 70/45 with half maximal stimulation(ED₅₀; mean ± SEM, n > 3) occurring at 2.2 ±0.5 IU/I (recombinant FSH), 4.7 ± 1.1 IU/I (Metrodin),13.2 ± 0.7 IU/I (Metrodin—HP) and 6.4 ±0.3 IU/I (IS 70/45); the pituitary preparation IRP 83/575 hadan ED₅₀ of 10.4 ± 0.1 IU/I. Using human granulosa—luteincells, cultured for up to 4 days in the absence of exogenoussteroid precursors, recombinant FSH was either without effect(three out of five patients) or inhibited both oestradiol andprogesterone secretion. FSH (83/575) was without effect on oestradiolwith preparations from any of the patients but slightly stimulated(134 ± 8%; mean ± SEM, P < 0.05) progesteroneproduction at the highest dose (80 IU/I). The distribution ofFSH isoforms, assessed by polyclonal radioimmunoassay, followingchromatofocusing over the ranges pH < 3.5 and pH 3.5–7.0respectively was recombinant FSH, 12.4 and 87.6%; Metrodin,19.8 and 80.2%; Metrodin—HP, 50.2 and 49.8%; IS 70/45,15.0 and 85.0%; IS 83/575, 70.9 and 29.1%. All glycoforms werepl <7.0 for the five preparations. In conclusion: (i) thepotency of FSH as measured in the rat Sertoli cell assay increasesin the order Metrodin—HP < pituitary IRP 83/575 <<Metrodin < IS 70/45 < recombinant FSH; (ii) in contrastto 83/575, recombinant FSH inhibits steroidogenesis in humangranulosa—lutein cells isolated from some patients; (iii)the glycoform distribution of recombinant FSH resembles Metrodinmore closely than Metrodin—HP which is far more acidicin nature.     

First established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone in polycystic ovary syndrome

This case report describes the first established pregnancy andbirth after induction of ovulation with recombinant human follicle-stimulatinghormone (FSH) in a woman suffering from chronic clomiphene-resistantanovulation due to polycystic ovary syndrome (elevated serumluteinizing hormone and testosterone concentrations togetherwith polycystic ovaries). Starting on day 3 of a progestagenwithdrawal bleeding, 75 IU of rFSH was administered i.m.dailyuntil a single preovulatory follicle was seen upon transvaginalultrasound examination at day 13. Ovulation was induced by asingle i.m. administration of 10 000 IU of human chorionic gonadotrophin,after which aviable singleton pregnancy was revealed at a gestationalage of 6 weeks. The course of pregnancy and labour was uneventfuland no abnormalities were found upon a paediatric examination.     

Internal carbohydrate complexity of the oligosaccharide chains of recombinant human follicle stimulating hormone (Puregon(R), Org 32489): a comparison with Metrodin and Metrodin-HP

Glycoforms of recombinant human follicle stimulating hormone(rhFSH) (Org 32489, Puregon^®) were characterized using concanavalinA lectin affinity chromatography to reveal information aboutthe internal carbohydrate complexity (extent of carbohydrateside-chain branching) of the preparations. The rhFSH glycoformswere measured by radioimmunoassay and a two-site immunoradiometricassay and compared with those in two urinary preparations (Metrodinand Metrodin-HP) used in assisted reproduction programmes anda urinary FSH international standard 70/45 (uFSH IS 70/45).Similar data were obtained with both assays; rhFSH had 6% complexinternal carbohydrate structures compared with 22–27%for Metrodin, Metrodin-HP and uFSH. The proportion of simplecarbohydrate structures was also different, with rhFSH having18.5 compared with 4.5–9.3% for Metrodin, Metrodin-HPand uFSH. A linear relationship was observed between the percentageglycoforms with an isoelectric point (pl) <4 and the logpercentage simple forms (logarithmic regression; r = 0.93) indicatinga direct relationship between carbohydrate complexity and chargeheterogeneity. In summary, rhFSH contains fewer complex formsand an increased proportion of simple carbohydrate structuresin comparison with Metrodin, Metrodin-HP and IS 70/45. concanavalin A/glycoform/immunoreactivity/lectin affinity chromatography/rhFSH     

Increasing the daily dose of recombinant follicle stimulating hormone (Puregon) does not compensate for the age-related decline in retrievable oocytes after ovarian stimulation

A prospective, randomized, double-blind, multicentre (n = 6) study was conducted to compare the influence of either a 150 or 250 IU daily fixed-dose regimen of recombinant follicle stimulating hormone (FSH, Puregon) on the number of oocytes retrieved and the total dose used in down-regulated women between 30 and 39 years of age undergoing ovarian stimulation. In all, 138 women were treated with recombinant FSH, 67 with 150 IU and 71 with 250 IU. The number of oocytes retrieved in the low-dose group was 9.1 compared to 10.6 in the high-dose group (not significant). In the 30-33 years of age class receiving the 250 IU dose, a surplus of 4.2 oocytes (14.8 versus 10.6) was found, whereas in the 37-39 age class nearly one oocyte more was retrieved in the 150 IU group (8.1 versus 7.4). The total dose used to reach the criterion for human chorionic gonadotrophin (HCG) administration was 1727 IU for the women treated with 150 IU daily and 2701 IU for the 250 IU treated women (P < 0. 001). No significant relationships were found between serum FSH concentrations as obtained in the early follicular phase and the number of oocytes collected, or the total dose. It is concluded that in women between 30 and 39 years of age, the decline in number of oocytes retrieved with increasing age cannot be overcome by augmenting the daily dose of recombinant FSH from 150 to 250 IU.     

The effect of recombinant follicle stimulating hormone (Gonal-F) on endogenous luteinizing hormone secretion in women

Parenteral administration of follicle stimulating hormone (FSH) has been shown to lower luteinizing hormone (LH) concentrations in women undergoing ovulation induction. This study was designed to explore the physiological mechanism of this effect. Seven healthy women were recruited into a double-blind placebo-controlled study. LH secretion, after the administration of variable i.v. boluses (37.5, 75 and 150 IU) of recombinant FSH (Gonal-F), was evaluated. LH was measured at 10 min intervals for 2 h before and 4 h after the FSH/placebo infusion. LH pulse frequency and amplitude were evaluated and there was no significant difference between control and trial cycles for each subject. A linear regression analysis revealed that in the group receiving 150 IU FSH, the mean plasma LH concentration decreased significantly due to a reduction tonic LH secretion. This could be a result of the suppression of secretion or an alteration of clearance. This decrease was not seen in the other dosage groups, revealing that above a dosage threshold, FSH reduced non-pulsatile LH secretion. Therefore the effect of FSH in this study exposed the likely presence of two components of LH concentration: an FSH-sensitive, non-pulsatile tonic secretion and a gonadotrophin-releasing hormone-stimulated, pulsatile release that is unaffected by FSH. Although an indirect effect involving ovarian regulation is not excluded, the rapidity of the effect suggests that FSH acts directly on the pituitary gland.      

两种不同剂量生长激素在体外受精超排卵中的作用比较

目的　探讨不同剂量生长激素 (GH)在体外受精 -胚胎移植 (IVF -ET)中 ,对低反应患者超排卵周期的作用。方法　前一IVF周期卵巢低反应的患者 30例 ,她们在前一周期采用促性腺激素释放激素激动剂 (GnRH -a)和促性腺激素(Gn)治疗 ,本周期采用GnRH -a、Gn、GH(两种不同剂量 )治疗 ,比较两种不同剂量生长激素的作用。结果　两种剂量生长激素均可提高受精率 ,增加优质胚胎数 ,提高妊娠率 ,且不同剂量生长激素间的作用无显著差异。结论　生长激素在IVF超排卵中有辅助作用 ,且不同剂量作用无显著差异     

Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report

BACKGROUND: Gonadotrophin-releasing hormone (GnRH) antagonists have been proven safe and effective, with no adverse effects on offspring in animal studies. Careful study of pregnancy outcome in humans is mandatory. METHODS AND RESULTS: This preliminary report includes follow-up data of patients treated with the GnRH antagonist, ganirelix, during ovarian stimulation for IVF or ICSI. In total, 333 patients were randomized in a multicentre, double-blind, dose-finding study of ganirelix, at six different doses ranging from 0.0625 to 2 mg. In total, 68 vital intrauterine pregnancies were established that resulted in the birth of 46 singletons, 12 twins and one triplet. Follow-up of the 67 pregnant patients (one subject was lost to follow-up) revealed six miscarriages (9%). Of the 61 subjects with an ongoing pregnancy, two with a singleton pregnancy did not give birth to a live-born infant (one spontaneous abortion in week 19, and one intrauterine death in week 27). The mean gestational age was 39.4 weeks for singleton pregnancies, and 36.6 weeks for multiple pregnancies. In total, 73 infants (33 boys, 40 girls) were born. A birth weight <2500 g was reported for 8.7% and 54.2% of the infants resulting from singleton and twins delivery respectively. One major congenital malformation was diagnosed; a boy with Beckwith-Wiedemann syndrome (exomphalos and macroglossia). Seven minor malformations were reported among five infants. CONCLUSIONS: In this first follow-up study, the incidence of adverse obstetrical and neonatal outcome was comparable with reported incidences for IVF-embryo transfer pregnancies.     

Successful induction of ovulation and completed pregnancy using recombinant human luteinizing hormone and follicle stimulating hormone in a woman with Kallmann's syndrome

The induction of ovulation in women with hypogonado-trophichypogonadism requires follicle stimulating hormone (FSH) forfollicular growth and both FSH and luteinizing hormone (LH)to induce optimal follicular steroidogenesis. The developmentof human recombinant FSH and LH means that individually tailoreddoses of both hormones can be used with the aim of inducingunifollicular ovulation. This report describes the use of recombinanthuman FSH and LH for the induction of ovulation and conceptionin the second cycle of treatment, and subsequently a successfullycompleted pregnancy in a woman with Kallmann's syndrome.     

Endocrinology and Paracrinology: Interference with follicle stimulating hormone regulation of human ovarian function

This review summarizes observations on the background and potentialclinical significance of interference with follicle stimulatinghormone (FSH) regulation of human ovarian function. This interferencemay occur at the level of the pituitary by the secretion ofFSH isoforms with reduced or absent bioactivity. In addition,interference with FSH may occur in the circulation, or withinthe ovarian follicular compartment. Although the full rangeof its significance remains to be elucidated, there are distinctindications that these mechanisms may be involved in normalovarian physiology, as well as in abnormal response of the ovaryto stimulation by endogenous FSH or by exogenously-administeredgonadotrophin preparations. Moreover, recent advances in thedetermination of the structure-function relationship of FSHand FSH-receptor interaction, in combination with new developmentsin recombinant DNA technology, will allow the production ofmodified FSH-or FSH receptor-like molecules with altered bioactivity.The availability of FSH agonists and antagonists in the nearfuture should provide a challenge for clinicians to improvetreatment outcome and to find new indications for the use ofthese compounds. anti-FSH/bioactivity/FSH/follicle development/gonadotrophins ^*Presented as an invited plenary lecture during the 11th AnnualMeeting of the European Society for Human Reproduction and Embryology,Hamburg, 1995.     

A randomized comparative study of highly purified follicle stimulating hormone and human menopausal gonadotrophin for ovarian hyperstimulation in an oocyte donation programme

A randomized comparative study of highly purified human follicle-stimulatinghormone (FSH-HP), administered s.c, and human menopausal gonadotrophin(HMG), administered i.m., was carried out in 41 volunteer oocytedonors. The response to ovarian hyperstimulation was similarin both groups. One cycle in both groups was cancelled. Thenumber of oocytes recovered was 16.0 ± 7.9 (mean ±SD) following stimulation with 32.8 ± 103 ampoules ofFSH-HP (n = 19) over 12.3 ± 1.7 days. Following stimulationwith 29.8 ± 10.6 ampoules of HMG over 11.5 ± 1.6days, the number of oocytes collected was 18.4 ± 12.7(n = 20). The oocyte recipients were allocated 9.2 ±3.6 oocytes in the FSH-HP group (n = 33) and 9.6 ± 4.6oocytes in the HMG group (n = 37). The fertilization rate (2PN/cell)was significantly higher in the HMG group (48%, 170/355) thanin the FSH-HP group (36%, 109/304) (P < 0.01). The numberof embryos transferred per recipient was 2.0 ± 0.4 inthe FSH-HP and 2.0 ± 03 in the HMG group. The pregnancyrate per embryo transfer was 25% in the FSH-HP (5/20) and 26%(8/31) in the HMG group. Fertile donors with body mass index£25 made up a poor responder group to s.c FSH-HP, possiblyindicating reduced absorption of the drug.     

The value of basal serum follicle stimulating hormone, luteinizing hormone and oestradiol concentrations following pituitary down-regulation in predicting ovarian response to stimulation with highly purified follicle stimulating hormone.

The value of gonadotrophin and oestradiol concentrations following pituitary down-regulation with leuprolide acetate in predicting ovarian response to stimulation was evaluated in three groups of women undergoing ovarian stimulation for in-vitro fertilization with highly purified follicle stimulating hormone (FSH). Leuprolide acetate was started in the midluteal phase, and either stopped at menses (IVF-SL group, n = 3), or continued throughout stimulation (IVF-LL group, n = 38; oocyte donors, n = 58). Ovarian stimulation was started on cycle day 3, after blood was drawn for down-regulated FSH, luteinizing hormone (LH) and oestradiol. Higher down-regulated LH was predictive of higher oestradiol on day 5 of stimulation in both IVF groups, and of need for fewer ampoules in the IVF-LL group, but not of oestradiol on day of human chorionic gonadotrophin (HCG) administration or number of oocytes retrieved. Higher FSH after down-regulation predicted yield of fewer oocytes in the donor and IVF-LL groups, and higher oestradiol on day 5 of stimulation, need for fewer ampoules and a shorter duration of therapy in both IVF groups. Higher oestradiol after down-regulation was associated with higher oestradiol on day 5 of stimulation and on day of HCG administration, a shorter duration of therapy and need for fewer ampoules in all groups. Whereas these results do not ascribe any predictive significance to LH, they suggest that oestradiol and FSH concentrations after down-regulation are predictive of the pattern of ovarian response to stimulation and of oocyte yield.