Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.

STUDY QUESTION: Does a single oral dose of nolasiban 900 mg administered 4 h before embryo transfer (ET) increase pregnancy rates in women undergoing IVF? SUMMARY ANSWER: In an individual patient data (IPD) meta-analysis of three clinical trials, a single oral dose of nolasiban 900 mg was associated with an increased ongoing pregnancy rate of an absolute 5% (relative 15%). WHAT IS KNOWN ALREADY: Several clinical studies have shown that blocking activation of oxytocin receptors by an oxytocin receptor (OTR) antagonist has the potential to decrease uterine contractions, increase endometrial perfusion and enhance endometrial decidualisation and other parameters of endometrial receptivity. It has been hypothesised that antagonism of oxytocin receptors could improve the likelihood of successful embryo implantation and thus increase pregnancy and live birth rates following ET. STUDY DESIGN, SIZE, DURATION: This is an analysis of three randomised, double-blind, placebo-controlled trials, which randomised 1836 subjects between 2015 and 2019. We describe the results of a meta-analysis of individual participant data (IPD) from all three trials and the pre-specified analyses of each individual trial. PARTICIPANT/MATERIAL, SETTING, METHODS: Participants were patients undergoing ET following IVF/ICSI in 60 fertility centres in 11 European countries. Study subjects were below 38 years old and had no more than one previously failed cycle. They were randomised to a single oral dose of nolasiban 900 mg (n = 846) or placebo (n = 864). In IMPLANT 1, additional participants were also randomised to nolasiban 100 mg (n = 62) or 300 mg (n = 60). Fresh ET of one good quality embryo (except in IMPLANT 1 where transfer of two embryos was allowed) was performed on Day 3 or Day 5 after oocyte retrieval, approximately 4 h after receiving the study treatment. Serum hCG levels were collected at 14 days post oocyte retrieval (Week 2) and for women with a positive hCG result, ultrasound was performed at Week 6 post-ET (clinical pregnancy) and at Week 10 post-ET (ongoing pregnancy). Pregnant patients were followed for maternal (adverse events), obstetric (live birth, gestational age at delivery, type of delivery, incidence of twins) and neonatal (sex, weight, height, head circumference, Apgar scores, congenital anomalies, breast feeding, admission to intensive care and specific morbidities e.g. jaundice, respiratory distress syndrome) outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: In an IPD meta-analysis of the clinical trials, a single oral dose of nolasiban 900 mg was associated with an absolute increase of 5.0% (95% CI 0.5, 9.6) in ongoing pregnancy rate and a corresponding increase of 4.4% (95% CI -0.10, 8.93) in live birth rate compared to placebo. Similar magnitude increases were observed for D3 or D5 transfers but were not significantly different from the placebo. Population pharmacokinetics (PK) demonstrated a correlation between higher exposures and pregnancy. LIMITATIONS, REASON FOR CAUTION: The meta-analysis was not a pre-specified analysis. While the individual trials did not show a consistent significant effect, they were not powered based on an absolute increase of 5% in ongoing pregnancy rate. Only a single dose of up to 900 mg nolasiban was administered in the clinical trials; higher doses or extended regimens have not been tested. Only fresh ET has been assessed in the clinical trials to date. WIDER IMPLICATIONS OF THE FINDINGS: The finding support the hypothesis that oxytocin receptor antagonism at the time of ET can increase pregnancy rates following IVF. The overall clinical and population PK data support future evaluation of higher doses and/or alternate regimens of nolasiban in women undergoing ET following IVF. STUDY FUNDING/COMPETING INTERESTS: The trials were designed, conducted and funded by ObsEva SA. A.H., O.P., E.G., E.L. are employees and stockholders of ObsEva SA. E.L. is a board member of ObsEva SA. G.G. reports honoraria and/or non-financial support from ObsEva, Merck, MSD, Ferring, Abbott, Gedeon-Richter, Theramex, Guerbet, Finox, Biosilu, Preglem and ReprodWissen GmbH. C.B. reports grants and honoraria from ObsEva, Ferring, Abbott, Gedeon Richter and MSD. P.P. reports consulting fees from ObsEva. H.T. reports grants and or fees from ObsEva, Research Fund of Flanders, Cook, MSD, Roche, Gedeon Richter, Abbott, Theramex and Ferring. H.V. reports grants from ObsEva and non-financial support from Ferring. P.T. is an employee of Cytel Inc., who provides statistical services to ObsEva. J.D. reports consulting fees and other payments from ObsEva and, Scientific Advisory Board membership of ObsEva. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02310802, NCT03081208, NCT03758885. TRIAL REGISTRATION DATES: December 2014 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885). FIRST PATIENT'S ENROLMENT: January 2015 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885).

Inhibition of steroid sulfatase decreases endometriosis in an in vivo murine model.

BACKGROUND: Steroid sulfatase (STS) is involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of disease-free and endometriosis patients. The present study was designed to investigate its role in endometriosis development. METHODS: Human endometrial explants were cultured on inserts for 24 h to assess the effectiveness of an STS inhibitor (STS-I), estradiol-3-O-sulfamate (E2MATE), on STS activity in endometrial tissue. Endometriosis was induced in mice, and E2MATE (or vehicle alone) was given orally for 21 days. Plasma estradiol levels were measured, and STS activity was assessed in murine organs (uterus, liver and leukocytes) and in lesions. Lesion number, weight and size (morphometry) were quantified. Lesion STS and progesterone receptor (PR) expression, proliferation and apoptosis rates were determined by immunohistochemistry. RESULTS: In vitro, addition of 1 µM E2MATE to the culture medium resulted in decreased STS activity in endometrial explants (P < 0.001). Treatment of mice with E2MATE (1.0 and 0.5 mg/kg) did not modify plasma estradiol levels, but inhibited STS activity in murine uterus (P < 0.05), liver (P < 0.001) and leukocytes (P < 0.001), as well as in induced lesions (P < 0.05). E2MATE reduced lesion weight (P < 0.01) and size (P < 0.05), but had no impact on proliferation or apoptosis rates, nor STS protein expression. Stromal edema was observed in the uterus of animals treated with E2MATE, but not in the stroma of lesions. Increased PR expression was detected in endometriotic lesions (P < 0.001). CONCLUSIONS: E2MATE was shown to effectively inhibit STS activity in endometrial tissue in vitro. In vivo, E2MATE decreased endometriosis development without affecting systemic estradiol levels. Use of STS-I could therefore be of potential interest in endometriosis treatment.

Absence of aromatase protein and mRNA expression in endometriosis.

BACKGROUND: Aromatase has been reported to be involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of endometriosis patients. The objective of the present study was to investigate its expression and localization in three distinct types of endometriosis. METHODS: Human peritoneal, ovarian and rectovaginal endometriotic lesions and matched eutopic endometrium were collected from patients during laparoscopy. Aromatase protein localization (immunohistochemistry, n = 63) and mRNA expression [quantitative polymerase chain reaction (Q-PCR), n = 64] were assessed. RESULTS: No aromatase protein was detected by immunohistochemistry in either the glandular or stromal compartment of endometriotic lesions or eutopic endometrium, while it was strong in placental syncytiotrophoblasts, granulosa and internal theca cells from pre-ovulatory follicles, and luteal cells from corpus luteum. By Q-PCR, low but discernible levels of aromatase expression were found in endometriomas, probably due to follicular expression. Transcripts for aromatase were barely detectable in only a few peritoneal and rectovaginal endometriotic lesions, and a few eutopic endometrium samples, probably due to contaminating surrounding tissues (adipose tissue, intact peritoneum). CONCLUSIONS: Unlike previous studies, we observed no aromatase protein in any of the endometriosis types, and barely detectable aromatase mRNA expression, suggesting that locally produced aromatase (within endometriotic lesions) may be less implicated in endometriosis development than previously postulated. Potential factors responsible for these discrepancies are discussed.

GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study.

BACKGROUND: The aim of the study was to investigate whether intranasal (IN) administration of a GnRH agonist could provide luteal support in IVF/ICSI patients. METHODS: Controlled ovarian hyperstimulation (COH) was performed using hMG/FSH and a GnRH antagonist. Patients were then randomly allocated to either 10,000 IU hCG, followed by vaginal administration of micronized progesterone (3x 200 mg/day) (group A), or 200 microg IN buserelin followed by either 100 microg every 2 days (group B), or 100 microg every day (group C), or 100 microg twice a day (group D), or 100 microg three times a day (group E). Luteal support was continued for 15 days. RESULTS: Twenty-three patients were randomized. Groups B and C were discontinued prematurely in view of the short luteal phase. The luteal phase was significantly shorter in groups B, C and D, whereas group E was comparable with group A, 13.5 and 13.0 days, respectively. In the mid-luteal phase, median progesterone levels were significantly lower in groups B, C and D, whereas group E was comparable with group A, 68.9 and 98.0 ng/ml, respectively. Estradiol (E2) was significantly reduced in groups B and D but sustained in group E. In the hCG group, LH levels were undetectable (<0.1 IU/l), whereas LH was detectable and significantly higher in groups C, D and E. Two pregnancies were obtained in the hCG group (two of five), one ectopic and one ongoing. Three pregnancies were obtained in group E, one miscarriage and two ongoing twin pregnancies (three of five). CONCLUSION: IN administration of buserelin may be effective in triggering follicular maturation and providing luteal phase support in patients undergoing assisted reproduction techniques (ART).

GnRH agonist as novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin.

BACKGROUND: The study objective was to investigate whether repeated intranasal administration of a GnRH agonist could provide convenient and safe luteal support. METHODS: Twenty-four patients with unexplained infertility were enrolled. All patients were treated with an aromatase inhibitor. When ovulation trigger criteria were met, patients were randomly allocated to either 5000 IU hCG (group A), or 200 microg intranasal buserelin followed by 100 microg every 3 days (group B), 100 microg every 2 days (group C), or 100 microg every day (group D), up to day 14 of the luteal phase. All patients underwent intrauterine insemination. RESULTS: Follicular development was similar in all groups with 1.1 +/- 0.3 follicles > or = 16 mm, 229.4 +/- 95.2 pg/ml estradiol (E2) and 0.8 +/- 0.5 ng/ml progesterone (mean+/-SD). The luteal phase duration (median; 95% confidence interval) was 15 (14.1, 15.0), 14 (12.5, 15.5), 15 (11.8, 18.2) and 15 (14.4, 15.6) days in groups A, B, C and D respectively. From luteal phase day 7 onwards, progesterone levels tended to be higher in group D compared with A. On day 14 of the luteal phase, progesterone levels were 3.0 (0.8, 5.2), 1.7 (-0.5, 3.9), 3.9 (-0.7, 8.5) and 7.7 (3.4, 11.9) ng/ml in groups A, B, C and D respectively (P = 0.045). No pregnancy was recorded in group A, but there was one biochemical pregnancy in group B, one biochemical and one singleton clinical pregnancy in group C, and two singleton clinical pregnancies in group D. CONCLUSION: Intranasal administration of buserelin could be effective to provide luteal support. This treatment was associated with a good pregnancy rate (5/18, 28%).

Comparison of recombinant human luteinising hormone (r-hLH) and human menopausal gonadotropin (hMG) in assisted reproductive technology.

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) act in concert in the stimulation of folliculogenesis and ovulation. However, high levels of LH promote follicular atresia and early miscarriage, and this has led to the concept of a 'therapeutic window' of LH for successful conception in assisted reproductive technology (ART) and ovulation induction. Until now, urinary-derived human menopausal gonadotropin (hMG) has been the only available source of exogenous LH activity. hMG preparations contain highly variable levels of LH, and are often augmented with human chorionic gonadotropin (hCG), which mimics LH activity. Accumulation of hCG bioactivity, however, may have detrimental effects on follicular development and oocyte quality. Recombinant human LH (r-hLH) (Luveris) is the only pure source of LH activity. r-hLH is well characterised and production is tightly controlled, resulting in a highly consistent product. Clinical studies in hypogonadotropic hypogonadal women have demonstrated the efficacy of r-hLH, 75 IU/day, together with r-hFSH, 150 IU/day, in promoting optimal follicular development, oestrogen secretion and endometrial thickness. r-hLH therefore provides the clinician with the opportunity for precise and consistent dosing within the therapeutic window for patients requiring exogenous LH, without the risk of LH overexposure that is associated with hCG.

[Ovarian stimulation: is exogenous LH necessary in all patients?]. / Stimulation ovarienne: la LH exogène est-elle nécessaire chez toutes les patientes?

FSH and LH play an essential but different role in the growth of ovarian follicles during the cycle. In stimulation protocols, good follicular development is obtained in most patients treated with FSH alone whereas the role of LH is more complex and controversial. Clinical and pre-clinical studies have shown that optimal follicular development is obtain if (i) exposure to endogenous and/or exogenous LH is sufficient ("threshold" concept) and (ii) exposure to LH is not excessive ("ceiling" concept). The recombinant luteinizing hormone (r-hLH, Luveris) is the only available stand-alone preparation of LH. Its characteristics are a high specific activity, the absence of undesirable proteins and an excellent batch to batch consistency. Luveris is indicated in association with FSH for stimulating follicular development in LH and FSH deficient women (defined by an endogenous LH level < 1.2 UI/l). In this subgroup of patients, the therapeutic benefit of exogenous LH at a daily dose of 75 IU is only observed when endogenous serum LH is below than 1.2 IU/l: LH threshold concept. In ART, the combination of exogenous LH at a daily dose from 75 to 150 IU and recombinant FSH improved the ovarian stimulation results only in a minority of patients (5 to 17%). On the opposite, studies conducted in OMS I and II patients showed that high doses of exogenous LH lead to atresia of secondary follicles. So, a daily dose of exogenous LH greater than 225 IU had a deleterious effect on follicular growth: LH ceiling concept.

Leukemia inhibitory factor in human reproduction.

OBJECTIVE: To describe the clinical findings, expressions, interactions, and clinical implications of leukemia inhibitory factor (LIF) in human reproduction. DESIGN: Review of published articles. SETTING: Clinical development unit of biotechnology company. INTERVENTION(S): None. RESULT(S): In the endometrium, LIF is expressed in a menstrual cycle-dependent manner, with the highest level occurring at the time of implantation. LIF is also detected in uterine flushing, and its level is significantly lower in women with unexplained infertility. Likewise, endometrial explants derived from women with unexplained infertility showed reduced levels of LIF secretion. Binding of LIF to LIF receptor and gp130 activates signal transduction pathways. LIF receptor is expressed in endometrium, oocytes, and blastocysts. Cytotrophoblasts cultured in the presence of LIF differentiate toward an anchoring extravillous phenotype. CONCLUSION(S): On the basis of reports gathered from animal and human studies, LIF appears to play an important role in implantation and in the establishment of pregnancy.

A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins.

OBJECTIVE: To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation. DESIGN: Cohort study. SETTING: Fertility center in a university hospital. PATIENT(S): Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996. INTERVENTION(S): The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999. MAIN OUTCOME MEASURE(S): Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS). RESULT(S): The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS. CONCLUSION(S): The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.

Effects of human recombinant luteinizing hormone and follicle-stimulating hormone in patients with acquired hypogonadotropic hypogonadism: study of Sertoli and Leydig cell secretions and interactions.

UNLABELLED: Experimental data suggest that FSH-stimulated Sertoli cells can enhance LH-induced Leydig cell testosterone (T) production. The function of Leydig and Sertoli cells can be selectively studied by using recombinant human LH (rhLH) and recombinant human FSH (rhFSH) in patients with complete gonadotropin deficiency. The aim of the present study was to assess the secretion of testicular T, estradiol (E2), and inhibin B and the physiological relevance of the Sertoli-Leydig cell interaction in man. For that purpose, six patients with acquired complete hypogonadotropic hypogonadism received the following treatments for three periods of 1 month in a random order: 1) rhLH, 900 IU/day sc; 2) rhFSH, 150 IU/day sc; and 3) combined rhLH/rhFSH treatments. Each treatment period was separated by a washout period of 15 days. Plasma LH, FSH, T, E2, and inhibin B were measured before and every 10 days during each treatment. During rhLH administration, mean plasma LH levels rose significantly from 0.4 +/- 0.2 IU/L to 11.7 +/- 1.2 IU/L (P < 0.01) and plasma FSH levels did not change. rhFSH administration induced a significant increase in plasma FSH levels (from 0.5 +/- 0.4 to 12.1 +/- 1.4 IU/L; P < 0.01), whereas mean plasma LH levels remained low. Mean plasma E2 levels were unchanged during rhFSH treatment, but they increased significantly during rhLH from 22 +/- 4 to 54 +/- 8 pmol/L (P < 0.01) and during rhLH plus rhFSH administration. rhFSH treatment induced a sustained elevation of mean plasma inhibin B levels from 58 +/- 13 to 175 +/- 25 pg/mL (P < 0.01), similar to the increase occurring during rhFSH plus rhLH administration. In contrast, mean plasma inhibin B levels did not increase during rhLH administration. Finally, a similar and significant increase in mean plasma T levels occurred during both rhLH and rhLH plus rhFSH treatment from 0.9 +/- 0.3 to 5.4 +/- 0.7 nmol/L (P < 0.01) and from 1.0 +/- 0.4 to 6.0 +/- 0.9 nmol/L (P < 0.01), respectively. In contrast, during rhFSH treatment mean plasma T levels remained unchanged when compared with baseline. IN CONCLUSION: 1) the increase of plasma E2 induced by rhLH and the absence of effect of rhFSH confirm that Leydig cells are the major site of testicular E2 production in man; 2) the secretion of inhibin B is increased by rhFSH and not by rhLH, and, thus, Sertoli cells seem to be the main source of inhibin B production; and 3) the increase of plasma T induced by rhLH is not enhanced by rhFSH. These results suggest that the stimulatory effect of FSH on Leydig cell steroidogenesis by a Sertoli cell paracrine factor does not seem to play a major physiologic role in man.

A comparison of the efficacy and tolerability of two recombinant human follicle-stimulating hormone preparations in patients undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the efficacy and tolerability of two recombinant human FSH (r-hFSH) preparations, follitropin-alpha (Gonal-F; Ares Serono, Geneva, Switzerland) and follitropin-beta (Puregon; Organon, Oss, the Netherlands), for superovulation in patients undergoing IVF-ET. DESIGN: Randomized, parallel-group, assessor-blind, single-center trial. SETTING: Outpatient tertiary referral center for assisted reproductive techniques. PATIENT(S): Forty-four infertile women undergoing IVF-ET. INTERVENTION(S): After down-regulation with buserelin acetate, patients were randomized to receive follitropin-alpha or follitropin-beta, 150 IU/d for 6 days; after that, dosages were adjusted according to the ovarian response. MAIN OUTCOME MEASURE(S): Cumulative dose of r-hFSH; duration of r-hFSH treatment; number of follicles of > or =11 mm and of 14 mm on day 7 of r-hFSH treatment and on the day of hCG administration; number of oocytes retrieved; number of viable embryos; and number of pregnancies (biochemical, ectopic, miscarried) and clinical pregnancies. RESULT(S): There were no statistically significant differences in any efficacy measures between the two preparations. The incidence of systemic adverse events was comparable in the two groups. Local reactions at the injection site were significantly more common and more severe with follitropin-beta than with follitropin-alpha CONCLUSION(S): Follitropin-alpha and follitropin-beta have comparable efficacy in patients undergoing IVF-ET.

Does growth hormone-releasing factor assist follicular development in poor responder patients undergoing ovarian stimulation for in-vitro fertilization?

Treatment with growth hormone-releasing factor (GRF) has been reported to improve the ovarian response to gonadotrophins in women who respond poorly to ovarian stimulation during in-vitro fertilization (IVF). The efficacy and tolerability of GRF were studied in a randomized, double-blind, placebo-controlled trial involving 196 patients. Following down-regulation with a gonadotrophin-releasing hormone agonist (GnRHa), patients were randomized to receive GRF (500 microg twice daily; n = 96) or placebo (n = 100) in addition to follicle stimulating hormone (FSH); treatment was continued until human chorionic gonadotrophin was given, or for a maximum of 14 days. GRF had no significant effect on the mean number of follicles with a diameter of >/=16 mm (GRF: 3.26 +/- 2.29; placebo: 3.27 +/- 2.30; P = 0.95), the number of FSH ampoules required to achieve ovarian stimulation (GRF: 55.2 +/- 16. 4; placebo: 54.9 +/- 17.2; P = 0.50), or on secondary measures of ovarian response and treatment outcome. There were, however, significant increases in circulating growth hormone (GH) and insulin-like growth factor (IGF)-1 concentrations. GRF was well tolerated. It is concluded that, despite producing significant increases in GH and IGF-1, concomitant treatment with GRF does not improve the ovarian response to FSH in poorly responsive women undergoing IVF.

The population pharmacokinetics of recombinant- and urinary-human follicle stimulating hormone in women.

AIMS: To characterize the pharmacokinetics of recombinant-human follicle stimulating hormone (r-hFSH) and urinary-human follicle stimulating hormone (u-hFSH) using population pharmacokinetic analysis and deconvolution techniques. METHODS: Sparse data were available from 62 female patients who received u-hFSH intramuscularly (i.m.) and 60 female patients who received r-hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF-ET) procedure. The dose of u-hFSH and r-hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u-hFSH/r-hFSH on subsequent days depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r-hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash-out. The volunteers then received multiple r-hFSH doses by the s.c. route: 150 IU once daily for 7 days. Intensively sampled data were available from a further 12 female volunteers who received u-hFSH, 150 IU, given by the i.v. and i.m. routes. RESULTS: Analysis of the intensively sampled r-hFSH and u-hFSH data sets found that disposition could be described using a two-compartment model and that absorption was rate limiting and essentially a first order process, for both compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h(-1) for r-hFSH and u-hFSH respectively. The calculated mean residence times (MRT) for r-hFSH and u-hFSH were 16 and 18 h, respectively. The different bioavailabilities (F) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r-hFSH and u-hFSH data. The population estimates of apparent clearance (CL/F) were 0.71 and 0.33 l h(-1) for r-hFSH and u-hFSH respectively. Urinary-hFSH CL/F increased linearly with weight and was 0.33 l h(-1) at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in CL/F for r-hFSH and u-hFSH were essentially the same, 26% and 25%, respectively. CONCLUSIONS: The population analysis indicates that the variability in CL/F is moderate, consequently, so would be the variability in exposure, given a fixed dosage regimen.

Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone.

OBJECTIVE: To assess the pharmacokinetics of a recombinant human LH preparation and its pharmacokinetic and pharmacodynamic interactions with recombinant human follicle-stimulating hormone (FSH). DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received 150 IU of s.c. recombinant human LH and FSH, either alone or in combination, followed by recombinant human LH and FSH once daily for 7 days. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters, ovarian follicle development. RESULT(S): No pharmacokinetic interaction between recombinant human LH and FSH was observed, with no significant difference in baseline-corrected maximal observed concentration over baseline, area under the concentration-time curve from t = 0 to t = 24 hours, or time to maximal concentration after single doses alone or in combination. After daily administration, the mean accumulation ratio was 1.6 for LH and 2.9 for FSH, with absorption and terminal phase half-life estimates of 4 and 11 hours for LH and 8 and 16 hours for FSH, respectively. Combined administration of FSH and LH for 7 days was effective in stimulating ovarian follicular development and steroidogenesis, with large interindividual variability related to ovarian sensitivity. CONCLUSION(S): A new recombinant human LH preparation has a low accumulation ratio at steady-state and no pharmacokinetic or pharmacodynamic interactions with recombinant human FSH.

Assessment of the role of serum luteinizing hormone and estradiol response to follicle-stimulating hormone on in vitro fertilization treatment outcome.

OBJECTIVE: To analyze the role of serum LH and of E2 secretion on IVF-ET outcome in patients stimulated with FSH. DESIGN: Using data from three studies, we analyzed ovarian response to FSH and IVF-ET outcome from two standpoints: [1] serum LH and [2] serum E2 on the day of hCG administration divided by the number of retrieved oocytes. SETTING: Twenty-six academic and private clinical centers. PATIENT(S): Three hundred twenty-three ovulatory patients eligible for IVF-ET. INTERVENTION(S): Patients were treated with a GnRH agonist and FSH and underwent IVF-ET. MAIN OUTCOME MEASURE(S): Follicular development, embryos, and pregnancy rate (PR). RESULT(S): Serum LH levels did not correlate significantly with number of oocytes retrieved, E2-oocyte ratio, fertilization rate, or PR. Five patient subpopulations were identified on the basis of E2-oocyte ratios: 0 to 70 (A), 70 to 140 (B), 140 to 210 (C), 210 to 280 (D), and > 280 (E) pg/mL per oocyte (conversion factor to SI unit, 3.671). Pregnancy rates were significantly different, i.e., 5.3%, 31.3%, 18.1%, 23.9%, and 20.4% for groups A, B, C, D, and E, respectively. Groups were not different in terms of baseline characteristics, number of follicles, fertilization rates, and number of embryos transferred. CONCLUSION: Patients with very low levels of LH respond to FSH alone as well as those with higher LH. The E2-oocyte ratio is a strong index of success rate.

[Clinical use of recombinant gonadotropins (FSH, LH, hCG)]. / L'utilisation en clinique des hormones gonadotropes recombinantes (FSH, LH, hCG).

The production of recombinant gonadotropins is independent of urine collection. They have a high specific activity and a better batch to batch consistency than urinary gonadotropins. In our IVF programme 62 normo-ovulatory patients less than 38 years old, with tubal or idiopathic infertility and normal sperm, were treated by r-FSH and randomized into four groups : with or without LHRH agonist, step-up or step-down stimulation. The overall results were higher in the agonist groups, but did not reveal any significant difference between step-up and step-down stimulation.

A population model for the follicular growth in women treated with follicle stimulating hormone.

PURPOSE: To develop a pharmacodynamic model that can describe the time course of follicular growth and to investigate the influence, if any, of covariates on the parameters of the model. METHODS: A population pharmacodynamic analysis was performed on total follicular volume data obtained after in vitro fertilisation and embryo transfer with urinary or recombinant human follicle stimulating hormone (FSH) treatment. A growth model in which the increase in total follicular volume with time is a function of several possible components was chosen. RESULTS: In the final population pharmacodynamic model, increase in total follicular volume (TFV) was described by the equation: dTFV/dt = Emax.TFV/(TFV + TFV50) + constant, in which Emax, TFV50, and constant were 508 mm3/hr (interindividual variability 72%), 12,900 mm3 (66%), and 1.43 mm3/hr (91%), respectively. Growth was positively correlated to baseline estradiol levels, so that Emax and TFV50 changed 0.52% for every picomolar change from the median baseline estradiol value of 100 pmol/L. Growth was negatively correlated to pretreatment FSH levels, so that individuals with a median FSH (6.7 IU/L) were expected to have a fivefold higher total follicular volume at day 10 after the start of treatment, compared to individuals at the high end of the pretreatment FSH range (12 IU/L). No relationship between FSH concentration and follicular growth was found. The urinary versus recombinant origin of the drug did not influence the ovarian response. CONCLUSION: Women with high endogenous levels of FSH respond less to standard doses of exogenous FSH. Women with higher baseline levels of estradiol have larger expected follicular growth rates.