A pharmacokinetic and endocrine comparison of recombinant follicle-stimulating hormone and human menopausal gonadotrophin in polycystic ovary syndrome

Elevated LH concentrations are frequently encountered in patients with polycystic ovary syndrome (PCOS) and increased LH (either endogenous or superimposed through the use of HMG) may have detrimental effects on reproductive function. In spite of this, FSH-only products and HMG have been used indiscriminately for ovulation induction - on the basis that the administration of HMG to patients with PCOS, who are not receiving GnRH agonists, does not result in significant increases in serum LH concentrations as judged by daily single blood samples. However, both endogenous and exogenous LH have a relatively short terminal half-life and studies have reported normal serum LH, but abnormal urinary LH and emphasized that early morning urinary measurements are more informative than those in serum because they reflect nocturnal LH secretion. Therefore, the present study was undertaken to perform a pharmacokinetic and endocrine comparison of recombinant human FSH and HMG in PCOS patients including LH measurements in the urine. Five PCOS patients receiving s.c. recombinant human FSH (rhFSH) and five PCOS patients receiving i.m. HMG for ovulation induction according to a chronic low-dose step-up regimen underwent blood and urine sampling at the following study points: Point 0 was the day of HCG injection; Points 1 to 5 corresponded to days HCG -1 to -2; -3 to -4; -5 to -6; -7 to -8; and -9 to -10; respectively. Serum hormone measurements included oestradiol, FSH, LH, progesterone, inhibin A, androstenedione, testosterone, and free testosterone index. FSH and LH were also measured daily in 8-h urine samples reflecting overnight renal urine secretion. Hormone concentrations calculated as the area under the curve showed that both FSH and LH concentrations in urine were significantly higher in HMG group than in group rhFSH. It is concluded that both LH and FSH concentrations significantly accumulate in the urine of PCOS patients receiving HMG for ovulation induction in a chronic low-dose protocol as compared with rhFSH treatment.     

LH improves early follicular recruitment in women over 38 years old

Although the capacity of recombinant FSH alone to induce folliculogenesis is undisputed, many believe that follicular recruitment in women over 38 years old could be improved by supplementing rFSH with human menopausal gonadotrophin (HMG). The present study sought to determine whether recombinant LH could reproduce the effect of HMG in women over 38 years during ovulation induction. Fifty-eight patients received rFSH (225 IU/day) supplemented with one ampoule of HMG (75 IU of FSH/75 IU of LH/HCG per day) for 5 days. Another 36 patients received rFSH (300 IU/day) supplemented with one ampoule of rLH (75 IU/day), also for 5 days. Both groups of patients received similar amounts of rFSH (1500 IU), LH/HCG (375 IU) and rLH (375 IU) and recruited a similar number of follicles as counted on day 6 (4.07 +/- 3.1 in the HMG group versus 3.7 +/- 3.2 in the LH group respectively) or on the day that human chorionic gonadotrophin (HCG) was indicated (6.5 +/- 2.7 versus 5.8 +/- 2.5 respectively). Ovarian stimulation was shorter, but not significantly so, in the group of patients receiving rFSH + HMG (10.5 +/- 1.7 days) than in the group of patients treated with rFSH +/- rLH (12 +/- 1.8 days). Significantly more MII oocytes were seen in the group treated with rFSH + rLH than in the group treated with rFSH + HMG (93.1 versus 75.3%, P < 0.05). With respect to pregnancy rates, 14/54 (26%) patients receiving rFSH + HMG and 16/34 (47%) patients receiving rFSH + rLH had a positive serum HCG. No significant difference in the number of miscarriages was observed between the two groups. In conclusion, the present results seem to indicate that rLH could be the HMG component that aids early follicular recruitment.     

Concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid and serum in relation to stimulation protocol and outcome of assisted reproduction treatment

In this prospective, randomized study, concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid (FF) and serum were related to type of stimulation protocol as well as to the outcome of assisted reproduction in 280 women subjected to the long protocol gonadotrophin-releasing hormone (GnRH) agonist pituitary down-regulation and ovarian stimulation with either human menopausal gonadotrophin (HMG) or recombinant FSH. In the women treated with HMG, concentrations of LH, FSH, oestradiol and androstenedione in FF were significantly higher, and those of human chorionic gonadotrophin (HCG) and progesterone significantly lower, than in the women treated with recombinant FSH (rFSH). More women became pregnant and delivered in the HMG than in the rFSH group. These differences, however, were not statistically significant. Concentrations of FSH in serum and of FSH and LH in FF were significantly higher in conception than in non-conception cycles, whereas all other hormone concentrations in FF and serum were similar. The present study demonstrates that the pre-ovulatory follicular fluid hormone profile is significantly influenced by the gonadotrophin preparation used for ovarian stimulation, and suggests that ovarian stimulation with HMG results in an intra-follicular hormone profile more similar to that characterizing conception cycles than stimulation with rFSH. However, as the present data represent means of FF hormone profiles, they do not allow the conclusion of a direct correlation between the intra-follicular concentration of a certain hormone and the ability of the corresponding embryo to implant and establish an ongoing pregnancy.     

The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction

Purpose: The purpose of this prospective, randomized study was to compare ovarian response and oocyte and embryo yields in women undergoing ovulation induction for IVF/ICSI using recombinant human FSH (rhFSH) alone or in combination with recombinant human LH (rhLH).Methods: Patients were randomized to receive rhFSH alone (group F; n = 13) or rhFSH + rhLH (group L; n = 15). rhFSH was administered according to a step-down protocol; patients assigned to group L received rhLH at a fixed dose of 75 IU (1 ampoule) throughout the treatment period.Results: The total dose of rhFSH, number of growing follicles, and serum concentrations of estradiol (E₂) on the day of hCG administration were similar in both treatment groups. However, the percentage of metaphase II oocytes and fertilization rate were significantly higher in group F than in group L. The lower fertilization rates associated with rhLH were also seen in a subgroup of patients from group L who had undergone a previous ART cycle stimulated with FSH only and thus acted as their own controls. However, when in vitro fertilization (IVF) and intracytoplasmic sperm injection cycles were considered separately, differences in fertilization rates were statistically significant only for oocytes treated by conventional IVF.Conclusions: This study shows that the addition of recombinant LH to recombinant FSH in pituitary-suppressed women undergoing ART does not improve the ovarian response and even may have a negative impact on oocyte maturation and fertilization.     

Pregnancy after administration of high dose recombinant human LH alone to support final stages of follicular maturation in a woman with long-standing hypogonadotrophic hypogonadism

Traditionally, the roles of LH in folliculogenesis have been considered to be limited to stimulating theca cells androgen production, triggering ovulation and supporting the corpus luteum. However, in the late stages of follicle development, granulosa cells become receptive to LH stimulation and LH becomes capable of exerting its actions on both theca cells and granulosa cells. Thus, it has been postulated that once an appropriate (i.e. LH-responsive) stage of follicular development has been achieved in response to treatment with FSH, there are theoretical grounds for reducing or completely withdrawing FSH and maintaining tonic stimulation of the dominant follicle with exogenous LH. This hypothesis was tested in a woman with long-standing hypogonadotrophic hypogonadism, which is the best and only true model to investigate correctly any LH hypothesis. Ovulation induction treatment was carried out with daily s.c. injections of 150 IU recombinant human FSH (rhFSH) (increased to 225 IU daily on stimulation day 15) and 375 IU recombinant human LH (rhLH). When a 14-mm follicle was identified on stimulation day 26, rhFSH was discontinued and from treatment days 26 to 29 the patient was given only rhLH at the above-mentioned dose of 375 IU/day. On treatment day 30, the single dominant follicle measured 22 mm in diameter and oestradiol serum concentration was 148 pg/ml. Thus, an injection of 10,000 IU i.m. human chorionic gonadotrophin was given and sexual intercourse was advised. The patient conceived and a viable singleton intrauterine pregnancy was obtained.     

Increasing the dose of human menopausal gonadotrophins on day of GnRH antagonist administration: randomized controlled trial

A significantly lower pregnancy rate following the gonadotrophin-releasing hormone (GnRH) antagonist protocol as compared with the long GnRH agonist protocol has been reported. The objective of this study was to investigate whether increasing the dose of gonadotrophins on the day of antagonist administration would increase the pregnancy rate. This study is an open labelled, randomized controlled trial and allocation was done using sealed envelopes. One hundred and fifty-one subfertile couples undergoing IVF/intracytoplasmic sperm injection (ICSI) cycles were included in the study. Ovarian stimulation was started on day 3 of the cycle, using 150-300 IU human menopausal gonadotrophin (HMG)/day. From day 8 onward, daily vaginal ultrasound and daily urinary LH estimation were performed. If a premature LH rise was detected, the cycle was cancelled. The antagonist (0.25 mg daily) was started when the leading follicle reached 15 mm in mean diameter and LH testing in urine was negative up to and including the day of human chorionic gonadotrophin (HCG) injection. Patients were randomized on the day of starting the antagonist into two groups: group A, 72 patients with no increase in HMG dose, and group B, 79 patients in whom the dose of HMG was increased by 75 IU on the day of antagonist administration, and continued till the day of HCG administration. The results showed no statistically significant difference between the groups regarding number of oocytes retrieved, embryos obtained, implantation rate, clinical pregnancy rate and multiple pregnancy rate. It was concluded that there is no clinical evidence for increasing the dose of HMG on the day of antagonist administration.     

Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF

A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150 μg corifollitropin alfa versus daily 200 IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ≥11 mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (Cl) 0.5-1.8; P < 0.01) and on the day of HCG injection (difference, 2.1; 95% Cl 1.4-2.8; P < 0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar.     

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.     

Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism

The aim of this observational preliminary trial was to estimate the association between the most common polymorphism of LH (LH-β variant: v-βLH), with different profiles of ovarian response to recombinant human FSH (rhFSH). A total of 60 normogonadotrophic patients undergoing a gonadotrophin-releasing hormone analogue long down-regulation protocol followed by stimulation with recombinant human FSH (rhFSH) for IVF/intracytoplasmic sperm injection, and in whom at least five oocytes were retrieved were retrospectively included. On the basis of the total rhFSH consumption, patients were divided into three groups: Group A: 22 women requiring a cumulative dose of rhFSH >3500 IU; Group B: 15 patients requiring 2000-3500 IU; Group C (control): 23 women requiring <2000 IU. The presence of v-βLH was evaluated using specific immunoassays. Peak oestradiol concentrations were significantly lower in Group A when compared with both groups B (P < 0.05) and C (P < 0.001). Group A had a significantly lower (P < 0.05) number of oocytes retrieved (7.3 ± 1.5, 11.7 ± 2.4 and 14.7 ± 4.1 in the three groups, respectively). Seven carriers (31.8%) of v-βLH were found in Group A, whereas only one variant (6.7%) was observed in Group B; no variant was detected in Group C. These preliminary results suggest that v-βLH is more frequent in women with ovarian resistance to rhFSH.     

Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF

A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150 μg corifollitropin alfa versus daily 200 IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ?11 mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (CI) 0.5–1.8; P < 0.01) and on the day of HCG injection (difference, 2.1; 95% CI 1.4–2.8; P < 0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar.A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. The objective of this study was to compare the pharmacokinetics and pharmacodynamics of corifollitropin alfa versus daily rFSH. A total of 1509 patients were randomized in a double-blind, controlled trial to either a single injection of 150 μg corifollitropin alfa or to daily injections of 200 IU rFSH for the first 7 days of ovarian stimulation. Serum levels of FSH immunoreactivity were analysed (pharmacokinetic analysis), together with the number and size of growing follicles and serum inhibin B and oestradiol concentrations as biomarkers of the ovarian response (pharmacodynamic analysis). Serum FSH immunoreactivity levels were higher up to stimulation day 5 for corifollitropin alfa compared with the daily rFSH regimen but were similar from day 8 onwards, when patients started rFSH if the criteria for human chorionic gonadotrophin were not yet reached. Corifollitropin alfa treatment resulted in a similar growth rate of follicles though a slightly higher number of follicles were recruited compared with daily rFSH. It is concluded that the pharmacokinetics of corifollitropin alfa and rFSH are quite different but their induced pharmacodynamic effects at the dosages used are similar.     

Compositional analyses of a human menopausal gonadotrophin preparation extracted from urine (menotropin). Identification of some of its major impurities

Recently, a highly purified human menopausal gonadotrophin preparation (HMG) was launched. The composition and purity of this HMG (Menopur); Ferring Pharmaceuticals) with a claimed 1:1 ratio of FSH and LH was determined. Three gonadotrophins were observed: FSH, LH and human chorionic gonadotrophin (HCG). The immunoactivity for HCG was three-fold higher than the immunoactivity for LH. Because of the longer half-life of HCG as compared with LH, about 95% of the in-vivo LH-receptor-mediated bioactivity is attributable to the presence of HCG. This is substantiated by biochemical analyses. To the best of the authors' knowledge, this relatively high amount of HCG can only be explained by assuming the addition of HCG from external sources, which is a well established practice for standardization purposes. In addition to gonadotrophins, a number of other proteins were detected. The amount of these impurities, as determined by reversed-phase high-performance liquid chromatography on a peak-area basis, is at least 30%. Therefore, it is concluded that this HMG preparation contains at most 70% gonadotrophins. Via a proteomics approach three major impurities were identified: leukocyte elastase inhibitor, protein C inhibitor, and zinc-alpha(2)-glycoprotein. On the basis of the results obtained in this study, a comparison is made with recombinant FSH.     

Aromatase inhibitors in ovarian stimulation for IVF/ICSI: a pilot study

This prospective randomized pilot study was aimed at investigating the effect of the novel addition of aromatase inhibitors to an ovarian stimulation protocol for IVF or intracytoplasmic sperm injection, on endocrine parameters including serum androgen, oestrogen, progesterone, LH and FSH concentrations. The patients were randomized to receiving letrozole (group A; n = 10), versus no letrozole (group B; n = 10) in an ovarian stimulation protocol with recombinant FSH 150 IU/day starting on day 2 of the cycle, and gonadotrophin-releasing hormone antagonist 0.25 mg/day starting on day 6 of the cycle. Median LH concentrations were significantly higher (P < 0.01) in group A versus group B during letrozole administration. Median serum oestradiol concentrations were lower in group A versus group B, and median serum FSH, testosterone and androstenedione concentrations were higher in group A versus group B, throughout the follicular phase, without reaching significance. Median endometrial thickness was significantly higher (P < 0.05) in group A versus group B on the day of human chorionic gonadotrophin administration. Pregnancies were achieved. This pilot study supports the idea that aromatase inhibitors can contribute to normal potential of implantation and follicular response, without having negative anti-oestrogenic effects.     

Recombinant human follicle-stimulating hormone as a pretreatment for idiopathic oligoasthenoteratozoospermic patients undergoing intracytoplasmic sperm injection

OBJECTIVE: To evaluate the efficacy of recombinant human FSH pretreatment in improving fertilization and pregnancy rates in oligozoospermic patients who are undergoing ICSI. DESIGN: Prospective, controlled, clinical study. SETTING: A research institute's reproductive unit. PATIENT(S): Thirty-three subjects with idiopathic oligoasthenoteratozoospermia who failed to conceive after previous ICSI attempts. INTERVENTION(S): Treatment with recombinant human FSH 150 IU for 3 months (23 patients) or no treatment (10 patients); clinical, hormonal, and seminal evaluation before and after treatment. MAIN OUTCOME MEASURE(S): Testicular volume, sperm parameters, FSH, LH, T, E(2), and inhibin B plasma levels, E/T ratio, and fertilization and pregnancy rates. RESULT(S): Treatment with 150 IU of FSH induced a significant increase in testicular volume and sperm parameters. The mean fertilization rate (FR) after ICSI cycles was higher, although not significantly, in treated patients when compared with controls (62.3 +/- 22.4 vs. 47.2 +/- 20.4). A strong negative correlation was observed between FR and serum FSH, inhibin B and E/T ratio in controls, whereas in treated patients, FR correlated with posttreatment inhibin B levels. The pregnancy rate in the entire treated group was 30.4%. No pregnancies were recorded in the control group. CONCLUSION(S): Recombinant human FSH may be a valuable pretreatment for oligozoospermic patients undergoing ICSI and may influence testicular paracrine activity.     

HMG versus recombinant FSH plus recombinant LH in ovarian stimulation for IVF: does the source of LH preparation matter?

Studies on the role of LH supplementation in patients undergoing assisted reproductive technique use different sources of LH bioactivity-containing preparations, daily doses and modes of administration. This review aims to critically present the available evidence comparing the effect of the two commercially available LH preparations (human menopausal gonadotrophin [HMG] and recombinant FSH + recombinant LH) with different sources of intrinsic LH bioactivity (HCG versus LH, respectively) on ovarian stimulation characteristics and IVF cycle outcomes. A literature review was conducted for all relevant articles reporting on IVF and intracytoplasmic sperm injection treatment outcome after ovarian stimulation using HMG or recombinant FSH plus recombinant LH. The available studies are mostly observational, using different daily doses and modes of administration. No statistically significant differences were observed in ovarian stimulation variables and clinical pregnancy and live birth rates when HMG was compared with recombinant FSH + recombinant LH. Moreover, combined analysis of all the available prospective and retrospective studies produced no firm conclusions in favour of either source of LH bioactivity. Further large randomized controlled studies are needed to investigate the effect of the LH source on IVF outcome and to identify patients who are most likely to benefit from the addition of LH bioactivity supplementation.     

体外受精超促排卵治疗中单用促性腺激素和拮抗剂方案临床结局的比较

目的探讨体外受精(IVF)治疗中单用促性腺激素(Gn)对妊娠结局的影响。方法月经第3日开始给予重组卵泡刺激素(rFSH)促排卵,促排卵第6日开始监测血激素水平和阴道超声监测卵泡大小。将达到思则凯添加标准者[黄体生成素(LH)5 IU/L,或LH/基础LH≥3]设为对照组,每日给予思则凯0.125 mg直至人绒毛膜促性腺激素(hCG)注射日;以未达到标准不使用思则凯者设为研究组。结果研究组(n=31)和对照组(n=49)患者在Gn剂量、促排卵天数、hCG注射日血清内分泌水平、获卵数、受精率、着床率、临床妊娠率和活产率方面均无统计学差异(P0.05)。结论在IVF促排卵治疗中,通过对血清LH的监测,如果LH维持在低水平可以不给予拮抗剂治疗,单纯使用Gn是一种经济有效的促排卵方案。     

Efficacy and safety of human menopausal gonadotrophins versus recombinant FSH: a meta-analysis

LH activity has been proposed to influence treatment response and outcome. In order to assess its clinical profile and efficacy, human menopausal gonadotrophin (HMG) was compared with recombinant FSH (r-FSH) in IVF/intracytoplasmic sperm injection (ICSI) cycles. Computerized and hand searches were conducted for relevant citations. Primary outcome measures were live-birth and OHSS rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage rates and cycle characteristics. The live-birth rate was significantly higher with HMG [odds ratio (OR) = 1.20, 95% CI = 1.01-1.42] versus r-FSH, but OHSS rates (OR = 1.21, 95% CI = 0.78-1.86) were not significantly different. As for the secondary outcomes, there was statistical significance with regard to the clinical pregnancy rate also in favour of the HMG group. Even so, there were significantly fewer treatment days, total dose and embryos produced in the r-FSH group compared with the HMG group. The other secondary outcomes were not different between the two groups. In conclusion, HMG has been demonstrated to be superior to r-FSH with regard to the clinical outcomes, with equivalent patient safety during assisted reproduction.     

Results of controlled ovarian stimulation for ART in poor responders according to the short protocol using different gonadotrophins combinations

Introduction Improving pregnancy rates in intricate cases of ovarian stimulation remains a challenge during IVF and intracytoplasmic sperm injection (ICSI). Different protocols of ovulation induction have been proposed.Methods The short protocol of ovarian stimulation using recombinant follicle-stimulating hormone (rFSH) with or without the use of luteinizing hormone (LH) in IVF or ICSI outcome in patients with many failed attempts and maternity age 37 years was investigated. The prognostic significance of high but normal values of day 3 serum FSH concentrations was also evaluated.Results Results show that FSH levels of >9 mIU/ml are associated with poor results even with the use of human menopausal gonadotrophin (HMG). Results were generally comparable when rFSH was used alone or in combination with HMG, except for the quality and the number of embryos transferred, the later being better in the rFSH + HMG group.Conclusion In conclusion intricate cases have good chances for achieving a pregnancy using the short protocol and the outcome is further improved when LH is added from the beginning of ovarian stimulation. A slight elevation of day 3 FSH seems to be a strong prognostic factor for a poor outcome.     

Replacing HMG/FSH by low-dose HCG to complete corifollitropin alfa stimulation reduces cost per clinical pregnancy: a randomized pragmatic trial

Research questionThe cost of IVF treatment remains high, among other factors because of the medication needed for ovarian stimulation. This study investigated the effect of using low-dose human chorionic gonadotrophin (HCG) for the second phase of follicular maturation after corifollitropin alfa induction, to replace the more expensive, either recombinant or human menopausal gonadotrophin (HMG), on the cost of ovarian stimulation.DesignOne hundred and five patients were randomly divided into two groups: patients in the HCG group (n = 50) received low-dose HCG from Day 7 until the diameter of at least three follicles reached 17 mm or more, while patients in the FSH group (n = 55) received conventional ovarian stimulation with highly purified HMG injections.ResultsThe clinical pregnancy rate in the HCG group was 38% higher than in the FSH group (number needed to treat, NNT = 13). The cost per pregnancy needed for ovarian stimulation was reduced from €4902 in the FSH group to €2684 in the HCG group. Hence, the cost of ovarian stimulation medication to obtain 10 pregnancies using the conventional FSH protocol is sufficient to attain 18 pregnancies when applying the low-dose HCG protocol.ConclusionThis study provides evidence that using HCG instead of HMG/FSH for ovarian stimulation results in a significant reduction in the cost of IVF with, at least, an equivalent pregnancy rate.     

Are follicle stimulating hormone measurements predictive of ovarian response to hyperstimulation with human menopausal gonadotrophin?

Previous studies have suggested that elevated serum follicle stimulating hormone (FSH) concentrations are associated with a poor ovarian response to hyperstimulation with human menopausal gonadotrophin (HMG) in in vitro fertilisation (IVF) programmes. We have used the day 2 serum FSH concentration to determine the dose of HMG administered in women under 40 years. If the FSH concentration was below 9 IU/l, a constant dose of 150 IU HMG were administered; if above 9 IU/l a constant dose of 300 IU HMG was used. Women over the age of 40 years were given 300 IU HMG regardless of their serum FSH concentration. This retrospective study was undertaken to assess whether this approach was beneficial for the younger women and also whether the FSH concentration was predictive of outcome in older women. The study included all women < 40 years (n = 143) and > 40 years (n = 32) having their first IVF treatment cycle during 1994. In the younger women, there was no difference in the number of cancelled treatment cycles (9.7% vs. 7.5%); the number of follicles present (9.6 vs. 8.2); serum oestradiol concentration (6971 pmol/l vs. 6686 pmol/l); number of eggs collected (7.9 vs. 5.7); number of embryos created (3.7 vs. 3.6); and pregnancy rate (13.5% vs. 15%) between women with normal (n = 103) or elevated (n =40) FSH concentrations. By using the serum FSH concentration to select women in whom a poor response was expected, and administering a higher dose of HMG, a similar ovarian response was produced and the pregnancy rate was similar to those in women with normal FSH concentrations. Women over 40 years with elevated serum FSH concentrations (n = 17) had a significantly (P < 0.05) higher cancellation rate (17.6% vs. 0%) and fewer number of eggs collected (6.9 vs. 2.5) than the group with normal FSH concentrations (n = 15). One woman conceived in each group. These findings confirmed previous studies showing that the serum FSH is predictive of ovarian response. This study confirmed the value of measuring the day 2 serum FSH concentration as a predictor of response; and it provides a scientific approach to determine the dose of HMG administered for IVF stimulation. A satisfactory response to induction of ovulation will be achieved using 150 IU HMG in women with FSH < 9 IU/l but if the FSH is raised i.e. above 9 IU/l, 300 IU is required to achieve a similar response.     

Ovarian Response to Purified FSH in Infertile Women with Long-standing Hypogonadotrophic Hypogonadism

EDITORIAL COMMENT: We accepted this paper to illustrate an important point, namely that purified FSH preparations may not be appropriate for ovulation induction in -women lacking adequate levels of endogenous luteinizing hormone. Furthermore, if these preparations are used then reliance on oestradiol determinations alone may lead to inappropriate conclusions about the number of preovulatory follicles. However, there is probably a place for preparations of purified FSH in women with high circulating levels of endogenous luteinizing hormone.
Summary: It has previously been proposed that all anovulatory women requiring exogenous gonadotrophin therapy could be treated by purified FSH alone in the follicular phase. We have studied the ovarian response to purified FSH in 5 amenorrhoeic women with low endogenous LH production as a result of longstanding hypothalamic amenorrhoea. Follicles developed in all of the women but the rise in oestradiol was very slow. As a consequence of the HCG injection being delayed to allow the follicles to become functionally mature, too many follicles attained a preovulatory size. After the treatment was changed to more conventional preparations containing bom FSH and LH, the women had improved ovarian responses and 3 of them conceived. It is clear that FSH alone will promote follicular growth but that LH is needed to stimulate follicular function. We conclude that LH does play an important role in follicular maturation and that it is a critical component of exogenous gonadotrophin therapy for women with prolonged hypogonadotrophic hypogonadism.