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.     

Endocrinology: The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone

To evaluate the relative importance of follicle stimulatinghormone (FSH) and luteinizing hormone (LH) in follicular developmentand oocyte fertility in the human species, the use of recombinanthuman FSH, human menopausal gonadotrophin (HMG), and very highlypurified urinary human FSH (FSH-HP) plus oestradiol valeratefor ovarian stimulation and in-vitro fertilization (IVF) werecompared in three cycles in a woman with isolated congenitalgonadotrophin deficiency who had never been treated with ovarianstimulating agents. The total number of ampoules of gonadotrophinsused was lower in the HMG treatment cycle. Ovarian responseand IVF outcome in the three treatment cycles were as follows:(i) HMG cycle: normal follicular growth, normal pattern of oestradioland inhibin through the menstrual cycle, high fertilizationrate (93%); (ii) recombinant FSH cycle: normal follicular growth,low oestradiol and abnormal inhibin, finally poor rate of fertilization(28%); (iii) FSH-HP plus oestradiol valerate cycle: normal folliculargrowth, normal pattern of inhibin and poor fertilization rate(27%). Luteal plasma progesterone concentrations were much higherin the HMG treatment cycle. This case shows that FSH is theonly factor required in order to induce follicular growth inthe human, although LH or a product derived from its actionmay assist in order to achieve full follicular maturity andoocytes capable of fertilization. Though oestradiol might havea mediatory role in the process of follicular maturation, ourresults favour a direct primary role of LH in complete maturationof the follicle.     

Endocrinology: Influence of serum follicle stimulating hormone to luteinizing hormone ratio during buserelin acetate-induced pituitary desensitizafion on ovarian response to exogenous gonadotrophins in an in-vitro fertilization and embryo transfer programme

We investigated the effect of endogenous gonadotrophins duringpituitary desensitization with gonadotrophin-releasing hormoneagonist (GnRHa) on ovarian responsiveness or the outcome ofin-vitro fertilization (IVF) and embryo transfer. The resultsof 67 women who participated in the IVF programme at NagasakiUniversity Hospital, Japan, were analysed retrospectively. Allwomen received GnRHa from the third day of the menstrual cycle,and ovarian stimulation with exogenous gonadotrophins was initiatedwhen the serum oestradiol concentration decreased to <30pg/ml. The serum follicle stimulating hormone (FSH)/luteinizinghormone (LH) ratio, rather than serum FSH or LH concentrationsduring GnRHa-induced pituitary desensitization, showed a significantpositive correlation with age and the total dose of exogenousgonadotrophins. The FSH/LH ratio also showed a significant negativecorrelation with oestradiol response and the number of retrievedoocytes, and was significantly lower in pregnant women comparedwith the non-pregnant group during pituitary desensitization.Our results indicate that, even under pituitary desensitizationwith GnRHa, the serum FSH/LH ratio influences individual ovarianresponsiveness and the state of the intra-ovarlan hormonal environment.Our results suggest that the FSH/LH ratio may be a useful clinicalpredictor of the ovarian response to exogenous gonadotrophinsunder pituitary desensitization.     

Purified urinary follicle stimulating hormone induces different hormone profiles compared with menotrophins, dependent upon the route of administration and endogenous luteinizing hormone activity

The effects of treatment of patients with gonadotrophin-releasinghormone analogue (GnRHa) combined with purified follicle stimulatinghormone (FSH) for in-vitro fertilization (IVF) were investigatedin detail to determine the influences of different administrationroutes and the degree of suppression of luteinizing hormone(LH). Responses to exogenous gonadotrophins were studied ininfertile women (n = 60) with normal menstrual rhythm whoseendogenous gonadotrophin activity was suppressed using a GnRHain a long protocol. They were randomized to receive i.m. administrationof human menopausal gonadotrophins (HMGim, Pergonal) or purifiedfollicle stimulating hormone (FSH, Metrodin High Purity) administeredeither i.m. (MHPim) or s.c (MHPsc). Responses were assessedby measuring plasma FSH, LH, oestradiol, testosterone and progesterone.After stimulation day 4, the MHPsc group showed significantlyhigher circulating concentrations of FSH than either the MHPimor HMGim group. However, the HMG group showed significantlyhigher oestradiol concentrations after stimulation day 5 thaneither MHP group. The differences in circulating oestradiolconcentrations in the MHP-treated patients appeared to be stronglyinfluenced by the mean circulating concentrations of LH in thefollicular phase. The patients who showed mean follicular phaseLH concentrations of <1 IU/1 showed longer follicular phases,lower circulating oestradiol and testosterone concentrationsand also lower follicular fluid concentrations of oestradioland testosterone, indicating a reduction in the normal follicularmetabolism of progesterone to androgens and oestrogens underthese conditions. This group of patients also showed longerfollicular phases, which may have consequences for future clinicalmanagement.     

Endocrinology: Effects of recombinant human follicle stimulating hormone on cultured human granulosa cells: comparison with urinary gonadotrophins and actions in preovulatory follicles

The effects of recombinant human follicle stimulating hormone(rFSH; Org 32489) have been examined in human granulosa cellsfrom ovaries obtained from women with spontaneous menses. Inthe first series of experiments the actions of rFSH on productionof oestradiol and progesterone were compared with those of urinary-derivedgonadotrophins. Recombinant FSH induced dose-dependent increasesin production of both oestradiol and progesterone which weresimilar to the effects of ’pure‘ FSH (Metrodin®)and the International Standard IS 71/223. In further studies,the actions of rFSH on oestradiol production by individual preovulatoryfollicles were investigated; rFSH increased oestradiol accumulationfrom cells obtained from follicles before the luteinizing hormone(LH) surge. In contrast, rFSH inhibited oestradiol productionby granulosa cells derived from a follicle after the onset ofthe LH surge, whereas the gonadotrophic action of growth hormonewas maintained. Following preliminary reports of the in-vivoeffects of rFSH in women, these findings provide further validationof the efficacy of rFSH in the human ovary. The results of studiesof the preovulatory follicle illustrate the experimental importanceof the availability of recombinant preparations of pure gonadotrophins,produced by recombinant technology, in the understanding ofhuman ovarian function.     

Pure human follicle stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction: Norfolk's total experience.

Fifty patients [79 in-vitro fertilization (IVF) cycles] with severe male factor infertility were included in an experimental clinical trial running from October 1987 to March 1991 to assess the potential of systemic follicle stimulating hormone (FSH) treatment to improve sperm fertilizing ability in IVF. Two groups were defined: a secondary group (24 patients, 33 IVF cycles) with a history of failed fertilization in previous IVF attempts and a primary group (26 patients, 46 IVF cycles) with poor sperm parameters which suggested that fertilization would not occur according to previously established criteria. Basic semen analysis and a battery of endocrine radioimmunoassays [serum FSH, luteinizing hormone (LH), oestradiol, prolactin and testosterone] were performed in these patients. Bioactive-FSH and LH were also determined in some patients. For this study, pure FSH was administered (150 IU i.m. three times per week) for at least 3 months, after which the semen analysis and endocrine tests were repeated. Although no significant changes were observed after FSH therapy, either in the endocrine profile or in the basic semen parameters, except for FSH radioimmunoassay levels, the fertilization rate of pre-ovulatory oocytes was significantly improved from 2 to 54.4% in the secondary group; the primary group showed a 52.3% fertilization rate. Eighteen clinical pregnancies were achieved, 11 in the primary group and seven in the secondary group, giving 30 and 26% term pregnancy rates per transfer respectively. These results, which are in complete agreement with our preliminary study, re-emphasized the benefits of systemic FSH administration as an adjunct to assisted reproduction in selected cases of severe male factor infertility.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of human menopausal gonadotrophin and highly purified, urine-derived follicle stimulating hormone on the outcome of in-vitro fertilization in down-regulated normogonadotrophic women

It has been suggested that the luteinizing hormone (LH) activityof human menopausal gonadotrophin (HMG) preparations used forovarian stimulation in in-vitro fertilization (IVF) may haveadverse effects on reproductive outcome. In the present prospective,randomized trial of 218 infertile couples this notion was investigated.A total of 114 women were treated with Pergonal (HMG group)and 104 with Fertinorm HP (HP-FSH group). The two groups werecomparable with regard to duration of infertility, cause ofinfertility, age and number of previous IVF attempts and allhad normal basal gonadotrophin concentrations before treatmentwas started. A standard hormonal treatment consisting of pituitarydown-regulation with gonadotrophin-releasing hormone analogue(GnRHa) for 14 days starting on cycle day 21, followed by eitherHMG or highly purified follicle stimulating hormone (HP-FSH),three ampoules (225 IU) per day for 7 days, was used in allcases. The daily hormone dose was thereafter individualizedaccording to the ovarian response. A maximum of two pre-embryoswere transferred after 3 days of culture. Luteal support withprogesterone (300 mg per day intravaginally) was used in allcases. Serum concentrations of oestradiol, FSH and LH were measuredon days 1 and 8 of stimulation and on the day of oocyte retrieval.The mean number of days of stimulation, mean number of ampoulesof HMG or HP-FSH used, mean total motile sperm count on theday of oocyte retrieval and mean numbers of oocytes retrieved(13.4 versus 13.7) or pre-embryos transferred (1.8 versus 1.8)were similar for both groups. Significantly (P < 0.05) morecycles in the HP-FSH group (17 = 16%) were cancelled due tocomplete failure of fertilization than in the HMG group (7 =6%). The mean fertilization rate was significantly (P < 0.05)higher in the HMG group (56%) than in the HP-FSH group (50%),and significantly more transferable pre-embryos were obtainedin the HMG than in the HP-FSH group (mean: 4.0 versus 3.2; P< 0.01). Serum hormone concentrations were similar in thetwo groups on stimulation day 1, but differed significantlywith regard to FSH, LH and oestradiol on stimulation day 8.The clinical outcome was similar in the two groups, with anongoing pregnancy rate (>12 weeks of gestation) per startedcycle of 33% in the HMG group and 29% in the HP-FSH group. Theclinical abortion rates were similar(10 and 14%), and the implantationrate was 30% in each group. In conclusion, no detrimental effectof the LH activity of HMG on the clinical outcome of IVF inGnRHa down-regulated normogonadotrophic women was found. Tothe contrary, some beneficial effects of HMG on fertilizationrates and pre-embryo development as compared with HP-FSH weredemonstrated. These effects, as well as the differences in serumhormone concentrations during ovarian stimulation, may be causedby differences in LH content and/or in the composition of FSHisoforms of the HMG and HP-FSH preparations.     

Endocrinology: Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonist-treated monkeys

Both follicle stimulating hormone (FSH) and luteinizing hormone(LH) are proposed requirements for follicular growth and steroidogenesis;however, the role of LH in primate folliculogenesis is unclear.Follicular stimulation by recombinant human FSH (n = 5) withand without recombinant LH (1: 1; n = 6) following 90 days ofgonadotrophin-releasing hormone (GnRH) antagonist (Antide) treatmentin macaques was evaluated. Human chorionic gonadotrophin (HCG)was administered when six follicles >4 mm were observed.Oocytes were aspirated 27 h later and inseminated in vitro.Chronic Antide reduced serum oestradiol and bioactive LH toconcentrations observed in hypophysectomized rhesus monkeys.Multiple follicular growth required a longer interval followingrecombinant FSH (12 ± 1 days) than recombinant FSH +recombinant LH (9 ± 0.2 days), but the total number offollicles/animal did not differ between groups. The day priorto HCG, oestradiol concentrations were 4-fold less followingrecombinant FSH compared to recombinant FSH + recombinant LH.With recombinant FSH, more oocytes completed meiosis to metaphaseII(51%) and fertilized (89 ± 5%) relative to recombinantFSH + recombinant LH (12 and 52 ± 11% respectively).Follicular growth and maturation in LH-deficient macaques occurredwith FSH alone. Thus, LH is not required for folliculogenesisin primates. Higher fertilization rates following follicularstimulation with FSH alone suggest that the presence of LH withFSH (1: 1) during the pre-ovulatory interval impairs gametogenicevents in the periovulatory period.     

Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction

The impact of suppressed concentrations of circulating luteinizing hormone (LH) during ovarian stimulation on the outcome of in-vitro fertilization or intracytoplasmic sperm injection treatment in 200 consecutive, normogonadotrophic women (couples) was analysed retrospectively. A standard stimulation protocol with mid-luteal gonadotrophin-releasing hormone (GnRH) agonist down-regulation and ovarian stimulation with recombinant follicle stimulating hormone (FSH) was used in all cases. Blood was sampled from each woman on stimulation days 1 and 8 for analysis of oestradiol and LH in serum. A threshold value of serum LH of 0.5 IU/l on stimulation day 8 (S8) was chosen to discriminate between women with low or 'normal' LH concentrations. Low concentrations of LH on S8 (<0.5 IU/l) were found in 49% (98/200) of the women. This group of women was comparable with the normal LH group with regard to pre-treatment clinical parameters, and to the parameters characterizing the stimulation protocol with the exception of serum oestradiol concentration, which on S8 was significantly lower than in the normal LH group (P < 0.001). The proportion of positive pregnancy tests was similar in the two groups (30% versus 34% per started cycle), but the final clinical treatment outcome was significantly different, with a five-fold higher risk of early pregnancy loss (45% versus 9%; P < 0.005) in the low LH group and consequently a significantly poorer chance of delivery than in the normal LH group. It is concluded that a substantial proportion of normogonadotrophic women treated with GnRH agonist down-regulation in combination with FSH, devoid of LH activity, experience LH suppression, which compromises the treatment outcome. Whether these women would benefit from supplementation with recombinant LH or human menopausal gonadotrophin during ovarian stimulation, remains to be proven in the future by prospective randomized trials.     

Studies on the influence of gonadotrophin levels in the early follicular phase on the ovarian response to stimulation

The gonadotrophic regulation of folliculogenesis has been extensively investigated but little attention has been paid to the influence of early follicular phase levels of endogenous FSH and the FSH/LH ratio when planning ovulation stimulation therapy for IVF. The influence of these factors was investigated in the three studies reported in this paper. A fixed schedule of ovulation stimulation therapy which employed standard treatment regimens, irrespective of the ovarian response, was used to eliminate variation due to treatment factors. Cycles were pretreated with an oestrogen-progestogen contraceptive pill or a progestogen (norethisterone). It was found that both oestrogen-progestogen and progestogen alone decreased the plasma FSH level, although the FSH/LH ratio was significantly reduced only by oestrogen-progestogens. In clinical IVF studies, oestrogen-progestogen pretreatment was associated with a significant reduction in the preovulatory concentration of oestradiol in plasma and the number of aspirated follicles, compared to norethisterone. The administration of FSH for 2 days following oestrogen-progestogen pretreatment and prior to the fixed schedule of ovulation stimulation normalized ovarian steroidogenesis and follicular development. Early follicular phase supplementation with FSH had no influence on progestogen pretreated cycles. The final experiment investigated the influence of FSH/LH levels in the early follicular phase on the outcome of ovarian stimulation. The preovulatory oestradiol concentration was reduced when baseline FSH/LH levels were low compared with when these values were high. Administration of FSH for 2 days in the early follicular phase improved the preovulatory level of oestradiol when baseline FSH/LH was low but had no effect when baseline FSH/LH levels were high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of LH during ovarian stimulation: effects differ in cycles stimulated with purified urinary FSH and recombinant FSH

There has been much debate about the role of luteinizing hormone (LH) during follicle stimulating hormone (FSH)-treated ovarian stimulation for assisted reproduction, where the endogenous LH is suppressed using a gonadotrophin-releasing hormone analogue. The requirement for LH in oestradiol biosynthesis is established, but other effects of 'insufficiency' are less clear, and little attention has been paid to the specific origin of the FSH used. The aim of this study was to examine the roles of profoundly suppressed circulating LH concentrations in cycles of ovarian stimulation for IVF, which were affected in two large separate cohorts of patients undergoing assisted reproduction. They were stimulated by either purified urinary FSH (MHP) or recombinant human FSH (rFSH). Within each dataset, outcomes were examined with respect to the circulating concentrations of LH in the mid-follicular phase, as plasma samples were stored prospectively, and assayed retrospectively. Patients with profoundly suppressed LH showed much reduced oestradiol concentrations at mid-follicular phase and at human chorionic gonadotrophin administration in cycles treated with either MHP or rFSH. However, gross ovarian response, as became evident by FSH dose demands, duration of stimulation, and also oocyte and embryo yields and embryo cryopreservation were influenced only in cycles treated with MHP. Furthermore, no effect upon pregnancy survival was observed. Thus, it is concluded that there is a demand for additional exogenous LH treatment only in cycles treated with purified urinary FSH where the LH is profoundly suppressed.     

Comparison of plasma and follicular fluid hormone profiles following stimulation with HMG, with or without LHRH agonists, for in-vitro fertilization.

Plasma and follicular fluid (FF) hormone assays for follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestradiol (E2), progesterone (P), delta-4-androstenedione (A4) and testosterone (T) were performed on the day of oocyte retrieval in two groups of normo-ovulatory women enrolled in an in-vitro fertilization (IVF) programme: 24 were treated using the decapeptyl agonists DTRP6, of luteinizing hormone-releasing hormone (LHRH) in the long protocol associated with human menopausal gonadotrophin (HMG) (49 FF) and 14 were stimulated with HMG alone (33 FF). In both FF and plasma the mean concentration of P was greater, and the E2/P ratios as well as the LH levels were lower in the agonist-treated group. In this group the follicular concentration of P was greater and the E2/P ratio lower when pregnancy occurred following IVF. The hormonal modifications may be due to greater functional maturity of the granulosa cells.     

Follicle-stimulating hormone as a prognostic indicator in clomiphene citrate/human menopausal gonadotrophin-stimulated cycles for in-vitro fertilization

Follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and prolactin levels were studied in a sequential clomiphene citrate/human menopausal gonadotrophin (CC/HMG) regimen for in-vitro fertilization. At completion of CC administration, the median FSH level in 44 cancelled cycles was elevated compared to a control group of 65 completed cycles, 29 IU/l versus 15 IU/l, P less than 0.01. Also the median FSH/LH ratio was higher in the cancelled cycles than in the control group, 1.08 versus 0.71, P less than 0.05. Conversely, the median oestradiol level was lower in the cancelled cycles than in the completed cycles, 0.27 nmol/l versus 0.59 nmol/l, P less than 0.01. No difference was seen in the median LH and prolactin levels. An FSH value above the 95% confidence limit was found in 24 of the cancelled cycles, but in only two of the completed cycles. Based on this study, an elevated FSH value following CC administration predicts a poor response to further stimulation with an accuracy of 92.3% and should result in cancellation of the cycle.     

Single monthly administration of the anti-progestagen Org 31710 in users of the 75 microg desogestrel progestagen-only pill: effects on pituitary-ovarian activity

Endocrine and ultrasound effects were studied of an intermittent (every 28 days) oral administration of 150 mg of the anti-progestagen Org 31710 during the continued daily use of 75 microg desogestrel (DSG) for progestagen-only contraception. A randomized, double-blind, placebo-controlled two-centre study was conducted in 50 healthy volunteers. Serum luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol and progesterone concentrations, and follicle number and size were studied, as well as endometrial thickness, which was assessed by transvaginal sonography at least twice weekly during a single medication cycle (cycle 3-5). Forty-eight women were evaluated (Org 31710, n = 25; placebo, n = 23). Seven ovulations were observed in the treated group versus none in the placebo group. LH concentrations were higher on days 9 and 11 and oestradiol concentrations lower on day 3 in the treated group, irrespective of whether ovulation occurred. No parameter could predict ovulation. Endometrial thickness was greater on cycle days 7-13 and 19 in the treated group. However, within the Org 31710 group, no significant differences were found in volunteers who did or did not ovulate. Observed differences may be attributed to a competitive effect of Org 31710 with progestagen-induced suppression of the pituitary-ovarian axis, altered oestradiol feedback mechanisms, and/or altered receptor availability.     

Recombinant follicle stimulating hormone in in-vitro fertilization treatment-clinical experience with follitropin alpha and follitropin beta

The objective of this prospective study was to compare the outcome of ovarian hyperstimulation for in-vitro fertilization (IVF) using two different preparations of recombinant follicle stimulating hormone (FSH). The study was based on 296 consecutive IVF cycles in 1997, 199 performed using follitropin alpha (Gonal-F) and 97 performed using follitropin beta (Puregon). Outcome was compared regarding pregnancy rate, oestradiol and progesterone response, endometrial thickness, follicle number, number of retrieved oocytes, fertilized oocytes, sperm count and sperm motility. There was no significant difference in outcome of stimulation. Clinical pregnancy rate was similar, 29.1% for Gonal-F and 28.1% for Puregon. There was no difference in endometrial response, oestradiol response, number of smaller (12-15 mm) or larger (>15 mm) follicles, number of oocytes retrieved, fertilized, divided and replaced, in sperm counts or in sperm progressive motility. There was a lower follicle number in the Puregon group, but not statistically significant. The serum progesterone concentrations on the day of oocyte retrieval, however, were significantly lower in the Puregon group. In conclusion, it was not possible to find significant differences in the IVF programme with regard to stimulation outcome between Gonal-F and Puregon. The results of this study indicate that Gonal-F and Puregon may be equally suitable for use in ovarian stimulation for IVF.     

Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis

Around 400 follicles sequentially mature and ovulate duringan average women‘s reproductive lifetime. From birth tothe menopause, the other 99.98% of her follicles begin developmentbut never complete it. Instead they default to atresia due toinadequate stimulation by follicle stimulating hormone (FSH).Follicular growth to the stage of antrum formation (0.25 mmdiameter) is independent of gonadotrophic stimulation. Antrumformation and further growth to the stage at which folliclesbecome potentially able to begin pre-ovulatory development (2–5mm diameter) require tonic stimulation by FSH. Before onsetof puberty, blood concentrations of FSH do not rise sufficientlyto sustain development beyond this stage, therefore all antralfollicles become atretic. After puberty, as each menstrual cyclebegins, FSH concentrations rise beyond a critical ‘threshold’and multiple follicles are recruited to begin pre-ovulatorydevelopment. Due to increases in its responsiveness to FSH andluteinizing hormone (LH), one of these follicles becomes selectedto ovulate while the remainder become atretic. At mid-follicularphase, the dominant follicle reaches 10 mm in diameter and increasinglysynthesizes oestradiol. Tonic stimulation by FSH and LH, underpinnedby local paracrine signalling, maintains oestrogen secretionby the dominant follicle, which grows to 20 mm in diameter beforeit ovulates in response to the mid-cycle LH surge. The development-relatedresponse to LH shown by the pre-ovulatory follicle raises thepossibility that exogenous LH might be used as an adjunct totherapy with exogenous FSH in clinical ovulation induction regimenswhere the aim is to induce monovulation.     

Efficacy and safety of recombinant follicle stimulating hormone (Puregon(R)) in infertile women pituitary-suppressed with triptorelin undergoing in-vitro fertilization: a prospective, randomized, assessor-blind, multicentre trial

The objective of this study was to compare the efficacy andsafety of a recombinant follicle stimulating hormone (FSH) preparation(Org 32489, Puregon^®) with a urinary FSH preparation (Metrodin^®)in infertile women undergoing in-vitro fertilization (IVF andembryo transfer and who were pituitary-suppressed with triptorelin.In an assessor-blind, group-comparative, multicentre study,60 women were randomized to Org 32489 and 39 to urinary FSH.An evaluation of the main parameter, the mean total number ofoocytes recovered, indicated a similar efficacy for the twopreparations: 9.7 with Org 32489 versus 8.9 with urinary FSH.In addition, there were no significant between-group differenceswith respect to other efficacy variables such as the total doseused, the duration of the treatment, the number of follicles17 mm in diameter and embryo quality. The ongoing pregnancyrates per attempt (30.2 versus 17.4%) and per transfer (34.0versus 18.8%) were higher with Org 32489, but this differencewas not statistically significant. No clinically relevant differencesbetween Org 32489 and urinary FSH were seen with respect tosafety variables. Serum antibodies were not detected in anyof the subjects. It is concluded that Org 32489 compares favourablywith urinary FSH in the treatment of infertile pituitary-suppressedwomen undergoing IVF and embryo transfer.     

Endocrinology: Development of a human granulosa cell culture model with follicle stimulating hormone responsiveness

In order to study the effects of follicle-stimulating hormone(FSH) on differentiation of granulosa cells, a well-definedand validated in-vitro culture system is indispensable. In thisstudy, pooled follicular aspirates were stimulated in vitrowith FSH and luteinizing hormone (LH) for 2, 4 and 6 days, eitherimmediately after plating or after 7 days of preincubation.Cultures were assayed for progesterone and oestradiol production.Fresh cells displayed very high basal progesterone productionwhich could be stimulated with LH but not FSH. After preincubation,addition of LH and FSH resulted in dose-dependent increasesof progesterone and oestradiol. When cultured on human fibronectin-coatedwells, similar basal but higher progesterone concentrationsafter stimulation were observed. In comparison with serum-freemedia, addition of Serum-Plus^TM resulted in higher basal andstimulated progesterone concentration, possibly due to the presenceof serum factors. This study demonstrates firstly that after7 days preincubation, cultures gained responsiveness to FSHbut remained responsive to LH during 4 days of stimulation.This suggests a persisting differentiated cell population invitro. Secondly, the use of human fibronectin extracellularmatrix and serum promotes steroid production, either due tofactors promoting cell growth and function or to availabilityof steroid precursors. Therefore one has to be cautious withinterpretation of data obtained from this widely used culturesystem, employing highly differentiated cells obtained afterovarian stimulation for in-vitro fertilization for study oflocal regulation of granulosa cell function.     

Day 5 inhibin B serum concentrations as predictors of assisted reproductive technology outcome in cycles stimulated with gonadotrophin-releasing hormone agonist-gonadotrophin treatment

The present study investigates the usefulness of inhibin A, inhibin B and serum oestradiol concentrations obtained in the fifth day of gonadotrophin therapy in predicting ovarian response and assisted reproductive treatment outcome in women undergoing ovarian stimulation under pituitary desensitization. A total of 80 women undergoing their first cycle of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment were studied. Twenty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, 60 women were randomly selected from our assisted reproductive treatment programme matching by race, age, body mass index, and indication for IVF/ICSI to those in the cancelled group. For each cancelled cycle, three IVF/ICSI women who met the matching criteria were included. Basal follicle stimulating hormone (FSH) concentrations were significantly higher in the cancelled than in the control group, whereas basal inhibin B was significantly higher in the latter. Basal oestradiol concentrations were similar in both groups of patients. On day 5 of gonadotrophin therapy serum concentrations of oestradiol, inhibin A and inhibin B were significantly lower in the cancelled group as compared with controls. Logistic regression analysis showed that the association for day 5 inhibin B (with a predictive value of ovarian response of 91.03%) with cancellation rate was significant, independent of, and stronger than, the effects of any other hormone variable investigated. In addition, day 5 inhibin B concentrations were correlated directly with parameters of ovarian response, ovum retrieval and oocyte and fertilization outcome. However, day 5 inhibin B was not a better predictor of pregnancy than the other hormone variables studied on this day. It is concluded that inhibin B concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproductive treatment are highly predictive of ovarian response.     

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.