Endocrinology: Different follicle stimulating hormone/luteinizing hormone ratios for ovarian stimulation

The aim of the present study was to investigate whether reducingthe amount of luteinizing hormone (LH) in gonadotrophic preparationsimpairs follicular growth in in-vitro fertilization (IVF) cyclesduring suppression of endogenous LH levels. A selected groupof 20 IVF patients was randomly divided into two groups. Onegroup was treated with Org 31338 [follicle stimulating hormone(FSH)/LH 3: 1], the other group with Metrodin® (purifiedFSH), both during pituitary down-regulation with buserelin.A fixed daily dose of 150 IU FSH i.m. was given. Serum concentrationsof FSH, LH, oestradiol and progesterone were determined frequentlyand serial ultrasound examinations were performed. Multiplefollicular growth with concomitant rise of oestradiol levelswas observed in all cycles. The duration of the stimulationphase was shorter in the group treated with Org 31338 than inthe group treated with Metrodin. The number of follicles andoocytes and the fertilization rate was larger and the mean embryoquality was higher in the Org 31338 group, but the differencesdid not reach statistical significance. No significant differenceswere found in hormonal values. In women with normal endocrineprofiles, lowering of the LH activity in gonadotrophic preparationsduring gonadotrophin-releasing hormone agonist treatment resultsin adequate ovarian stimulation. However, a preparation withsome LH needed a shorter stimulation than a purified FSH preparation.Whether the other beneficial effects of Org 31338 also occurin a larger population needs further investigation.     

Endocrinology: Pure and highly purified follicle-stimulating hormone alone or in combination with human menopausal gonadotrophin for ovarian stimulation after pituitary suppression in in-vitro fertilization

The use of pure follicle stimulating hormone (pFSH) and highlypurified FSH (FSH-HP) versus the combinations pFSH/human menopausalgonadotrophin (HMG) and FSH-HP/HMG, respectively, was comparedfor stimulating follicular development after gonadotrophin-releasinghormone agonist (GnRHa) suppression in women undergoing in-vitrofertilization (TVF)—embryo transfer. Two consecutive prospective,randomized studies were carried out at the Assisted ReproductionUnit of the Hospital Clínic i Provincial in Barcelona,a tertiary care setting. Two groups of 188 (study 1) and 252(study 2) consecutive infertile patients respectively, scheduledfor IVF-embryo transfer were included. Pretreatment with leuprolideacetate (long protocol) was followed by gonadotrophin treatmentin all patients. In study 1, 92 patients received i.m. pFSHalone (group pFSH) and 96 were treated with the combinationof i.m. pFSH and i.m. HMG (group HMG-1). In study 2, 123 patientsreceived s.c. FSH-HP alone (group FSH-HP) and 129 patients weregiven the combination of s.c FSH-HP and i.m. HMG (group HMG-2).Main outcome measures included follicular development, oocyteretrieval, fertilized oocytes, duration and dose of gonadotrophintherapy, and clinical pregnancy. There were no significant differencesbetween pFSH and pFSH/HMG nor between FSH-HP and FSH-HP/HMGcycles with regard to the number of ampoules of medication used,day of human chorionic gonadotrophin (HCG) administration, meanpeak serum oestradiol concentrations, number of follicles punctured,and number of oocytes aspirated, embryos transferred, or pregnancies.We conclude that urinary FSH (either purified of highly purified)alone is as effective as the conventional combination of urinaryFSH/HMG for ovarian stimulation under pituitary suppressionin IVF cycles. Therefore, they can be used interchangeably inFVF programmes.     

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.     

Recombinant follicle stimulating hormone is effective in poor responders to highly purified follicle stimulating hormone

Ovarian stimulation in cases of poor ovarian responsiveness is an important challenge in in-vitro fertilization (IVF) programmes. Despite improvements in oocyte number and quality, an ideal ovarian stimulation strategy has yet to be defined. Here, the results of ovarian stimulation with recombinant follicle stimulating hormone (rFSH) in 28 poor responders to highly purified FSH (FSH-HP) with high basal concentrations of FSH are reported. The protocols used on the FSH-HP and rFSH cycles were identical with the sole exception of the FSH preparation: triptorelin 0.1 mg/day (gonadotrophin-releasing hormone, GnRH-agonist short protocol) and the starting FSH dose of 300 IU/day were administered from day 2 of the menstrual cycle. Ovarian outcome was classified as 'normal', 'intermediate' and 'poor', depending on the number of mature oocytes retrieved and the peak serum oestradiol concentration. Nine of the 28 subjects had an intermediate ovarian response to re-stimulation with rFSH. In the 26 patients who received human chorionic gonadotrophin on both cycles, re-stimulation resulted in a significant increase (P < 0.05) in the mean number of mature oocytes (2.4 +/- 1.4 versus 1.7 +/- 0.8), mean peak oestradiol concentration (606 +/- 252 versus 443 +/- 32 pg/ml) and fertilization rate (73.0 versus 53.3%). Four pregnancies were achieved. It is concluded that rFSH in a GnRH-agonist short protocol improves the ovarian outcome in poor responders to FSH-HP with high basal concentrations of FSH.     

Clinical and endocrinological changes in women following ovulation induction using buserelin acetate/human menopausal gonadotrophin augmented with biosynthetic human growth hormone.

Biosynthetic human growth hormone added to an ovarian stimulation regime of human menopausal gonadotrophin (HMG) for IVF treatment improves the response of women who were previously resistant. This study investigated the efficacy of growth hormone (GH)/buserelin/HMG treatment in women with a previous normal response to buserelin/HMG stimulation. Ten patients (28-36 years, mean 32.5 years) were treated with GH (6 IU/day) plus buserelin/HMG. A control group of 10 women (28-37 years mean 31.0 years) received buserelin/HMG alone. All were given buserelin 500 micrograms and 2 ampoules (150 IU) HMG daily once pituitary suppression had been confirmed. There was no improvement in the GH group as assessed by follicular growth rate or number, oocyte number per woman and pregnancy rate. There was no effect of GH upon the serum oestradiol level and the follicular fluid levels of oestradiol, GH and inhibin. Serum IGF-1 increased significantly during GH administration, returning to pre-treatment levels 2 days after the last dose of GH. Follicular IGF-1 was much higher in the GH-treated group than the controls. Significant correlations were found in the GH-treated group between follicular fluid GH and follicular fluid oestradiol concentrations and between follicular GH and follicular size. Follicular IGF-1 was correlated with the serum IGF-1 concentration on day 8 of the GH/HMG treatment. In conclusion GH/buserelin/HMG treatment in women with a previous normal response to buserelin/HMG stimulation increased their serum and follicular IGF-1 concentrations. However, it does not improve the clinical ovarian response or the follicular secretion of oestradiol or inhibin.     

Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation

Natural cycles were abandoned in in-vitro fertilization (IVF) embryo transfer, due to premature luteinizing hormone (LH) surges--and subsequent high cancellation rates. In this study, we investigated the administration of a new gonadotrophin-releasing hormone antagonist (Cetrorelix) in the late follicular phase of natural cycles in patients undergoing IVF and intracytoplasmic sperm injection (ICSI). A total of 44 cycles from 33 healthy women [mean age 34.1 +/- 1.4 (range 26-36) years] were monitored, starting on day 8 by daily ultrasound and measurement of serum concentrations of oestradiol, LH, follicle stimulating hormone (FSH) and progesterone. When plasma oestradiol concentrations reached 100-150 pg/ml, with a lead follicle between 12-14 mm diameter, a single injection (s.c.) of 0.5 mg (19 cycles) or 1 mg (25 cycles) Cetrorelix was administered. Human menopausal gonadotrophin (HMG; 150 IU) was administered daily at the time of the first injection of Cetrorelix, and repeated thereafter until human chorionic gonadotrophin (HCG) administration. Four out of 44 cycles were cancelled (9.0%). No decline in follicular growth or oestradiol secretion was observed after Cetrorelix administration. A total of 40 oocyte retrievals leading to 22 transfers (55%) was performed. In 10 cycles (25%), no oocyte was obtained. Fertilization failure despite ICSI occurred in six cycles (15%). In two patients the embryo was arrested at the 2 pronuclear (PN) stage. The stimulation was minimal (4.7 +/- 1.4 HMG ampoules). A total of seven clinical pregnancies was obtained (32.0% per transfer, 17.5% per retrieval), of which five are ongoing. Thus, a spontaneous cycle and the GnRH antagonist Cetrorelix in single dose administration could represent a first-choice IVF treatment with none of the complications and risks of current controlled ovarian hyperstimulation protocols, and an acceptable success rate.     

Controlled ovarian stimulation using highly purified FSH results in a lower serum oestradiol profile in the follicular phase as compared with HMG

We have examined the efficacy of highly purified follicle stimulatinghormone (FSH-HP) for controlled ovarian stimulation in our in-vitrofertilization (IVF) programme, and compared the results obtainedwith this preparation with those using human menopausal gonadotrophin(HMG) in 15 patients who had received treatment with both FSH-HPand HMG in consecutive cycles (n = 39). No differences werefound in the duration of stimulation, which was 13.9 days (HMG)as compared with 143 days (FSH-HP). However, in the FSH-HP-treatedcycles we found a striking difference in the rise of serum oestradiol,which was significantly lower than in HMG-treated cydes (2953± 938 pmol/1 as compared with 6349 ± 3683 pmol/1on the day before ovum retrieval). Number and size of follicleswere similar in the two groups, as were oocyte characteristics.Increase in endometrial thickness at two days prior to ovumretrieval was slightly higher after HMG. The results indicatethat in combination with a long gonadotro-phin-releasing hormoneagonist (GnRHa) protocol, pure FSH is sufficient for adequatefollicle recruitment and growth. However, since FSH-HP resultedin markedly reduced concentrations of serum oestradiol as comparedto HMG cycles, IVF programmes using repeated oestradiol measurementsto decide the day of ovum retrieval must take this into considerationin order not to prolong the stimulation unnecessarily.     

Effect of profound suppression of luteinizing hormone during treatment with gonadotrophin-releasing hormone analogue and purified follicle stimulating hormone upon development of cryopreserved embryos

In response to previously published evidence from monkeys, this study examined the influence of the degree of luteinizing hormone (LH) suppression during the follicular phase of the stimulation cycle, upon cryopreserved embryo survival and development. The LH concentration of the mid-follicular phase was assessed in 250 in-vitro fertilization (IVF) cycles treated with gonadotrophin-releasing hormone analogue (GnRHa) and either purified follicle stimulating hormone (FSH) or human menopausal gonadotrophin (HMG), and was related to the performance of cryopreserved embryos in 351 subsequent embryo transfer cycles. Rates of embryo survival, embryo development rates, implantation rates, and pregnancy rates were examined with respect to the LH concentration recorded in the mid-follicular phase. In contrast to experimental evidence from other primates, there was no significant influence of the follicular phase LH concentration upon any of the parameters examined.      

Induction of follicular growth and production of a normal hormonal milieu in spite of using a constant low dose of luteinizing hormone in women with hypogonadotrophic hypogonadism

This study was designed to examine ovarian performance, i.e.follicular growth, normal steroidogenesis and luteal phase function,following the administration of multiple increasing doses ofhuman follicle stimulating hormone (FSH) with a constant lowdose of luteinizing hormone (LH) in women with isolated hypogonadotrophichypogonadism. Human meno–pausal gonadotrophin (HMG) wasused in the first treatment cycle, starting with 150 IU of LHand 150 IU of FSH per day, for 7 days. The dose was increaseddaily with 75 IU of LH and 75 IU of FSH for another 7 days ifno response was detected by serial ultrasound measurements andserumoestradiol determinations. In the second treatment cycle,a constant dose of 75 IU of LH (using HMG) was administeredper day and up to 150 IU of FSH (using urofollitrophin) wassupplemented. If no response was detected after 7 days of treatment,the dose of FSH was increased. For the final stage of ovulationinduction, human chorionic gonadotrophin (HCG) was administeredin the presence of at least one follicle >17 mm in diameterbut with no more than three follicles >16mm in diameter.To verify the adequacy of the luteal phase, a pharmacokinetic/pharmacodynamicstudy of -HCG, oestradiol and progesterone was performed followingthe second treatment cycle only. Ovarian stimulation using aconstant dose of 75 IU of LH and increasing doses of FSH upto 225 IU, resulted in normal follicular growth and hormonalmilieu. Both women showed normal luteal phase oestradiol andprogesterone production and both women conceived following thesecond treatment cycle     

Inhibin

Inhibin is a glycoprotem which specifically inhibits FSH secretion.In follicular fluid, several forms of inhibin have been identifiedwith mol. wts between 120 and 32 kd. The smallest active formis a glycosylated 32-kd protein with an 18-kd A chain and a13-kd B chain. The secretion of inhibin by granulosa cells ofthe follicle is stimulated by FSH and testosterone, but notLH, and treatment of women with clomiphene and HMG/FSH resultsin an increase In the plasma concentration of inhibin. However,during the follicular phase of the normal menstrual cycle, FSHis inhibited mainly by oestradiol and inhibin levels remainconstant or decline In parallel with those of FSH. It is probablethat inhibin and oestradiol act together to cause the suppressionof FSH. During the luteal phase, the human corpus luteum underthe influence of LH secretes Inhibin as well as oestradiol andprogesterone. This combined negative feedback signal from thecorpus luteum accounts for the suppression of FSH release andthus the failure of follicular growth during the luteal phase.     

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.     

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.     

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.     

The significance of elevated basal follicle stimulating hormone in regularly menstruating infertile women

Elevated plasma follicle stimulating hormone (FSH) during thereproductive life is an early manifestation of ovarian ageing.The presence of elevated basal FSH in young, regularly menstruatingwomen may represent a stage of menopausal transition consequenton premature ovarian failure. A total of 48 regularly menstruating,infertile women aged <40 years, with high FSH and aged-matchedcontrols with normal FSH underwent detailed monitoring of endocrineand follicle growth during one complete menstrual cycle. Duringthe same cycle, detailed immunological screening was performedand the epidemiological features of all subjects were also reviewed.Subjects in the high FSH group had significantly higher basalFSH, luteinizing hormone (LH) and follicular phase LH concentrations.Despite their normal preovulatory oestradiol production, thehigh FSH group showed significantly slower follicular growth,smaller follicle diameter and lower luteal phase salivary progesterone.All these features have been described in older women duringtheir menopausal transition. In addition, the prevalence ofautoimmune antibodies was significantly higher in the high FSHgroup. This study suggests that infertile women with elevatedFSH are in their perimenopause despite having regular ovulatoryand apparently normal cycles. An autoimmune basis is suggestedas a factor underlying their premature ovarian failure. Furtherendocrinological and auto-immunological follow-up is recommended.     

A prospective, randomized comparison of ovulation induction using highly purified follicle-stimulating hormone alone and with recombinant human luteinizing hormone in in-vitro fertilization.

The commercial availability of highly purified, s.c. administered urinary follicle stimulating hormone (FSH) preparations for ovarian stimulation marked the beginning of a new era in the treatment of infertility. As these new formulations contain essentially no luteinizing hormone (LH), supplemental LH may be needed for optimal folliculogenesis. It was the aim of this pilot study to compare fertilization rates, embryo morphology, implantation rates and pregnancy outcomes prospectively in two age-matched patient groups: women who received highly purified FSH (FSH-HP) (n = 17), and women who received FSH-HP plus recombinant human LH (rhLH, n = 14) throughout ovarian stimulation. All patients received mid-luteal pituitary down-regulation with s.c. gonadotrophin-releasing hormone agonist (GnRHa) (leuprolide). Mean implantation rates were 26.9 and 11.9% in the FSH-HP only and FSH-HP + rhLH groups respectively. The mean clinical pregnancy/initiated cycle rate was 64.7 and 35.7% for the FSH-HP only and FSH-HP + rhLH patients respectively. FSH-HP patients and FSH-HP + rhLH patients achieved clinical pregnancy/transfer rates of 68.8 and 45.5% respectively. One patient in the FSH-HP + rhLH group had a spontaneous abortion; no pregnancy losses occurred in the FSH-HP only group. There were more cancellations for poor ovarian response among FSH-HP + rhLH patients (n = 3) than among FSH-HP patients (n = 1). The trend toward better pregnancy outcomes among patients who received FSH-HP without supplemental rhLH did not reach statistical significance. It is postulated that appropriate endogenous LH concentrations exist despite luteal GnRHa pituitary suppression, thereby obviating the need for supplemental LH administration.     

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)     

Comparison of the effects of HMG or pure FSH stimulation during suppression with an LHRH agonist analogue.

Infertile patients who responded poorly in an in-vitro fertilization programme were treated with human menopausal gonadotrophin (HMG) or with pure follicle stimulating hormone (FSH) during continuous administration of a luteinizing hormone-releasing hormone (LHRH) agonist, to determine whether a low level of LH is required for follicle maturation. No statistically significant differences were detected in the dose of gonadotrophins, duration of treatment, oestradiol and LH levels, numbers of recovered oocytes, transferred embryos or fertilization rates. It is concluded that an absence of low levels of LH does not disturb follicular development in the follicular phase. Based on the low fertilization rates in the present study (0.32 with HMG versus 0.45 with FSH) the authors suggest that, as well as hormonal deficiency, other factors may also influence follicular and early embryonic development.     

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.     

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.     

Randomized controlled trial of follicle stimulating hormone versus human menopausal gonadotrophin in in-vitro fertilization*

The adverse effect of raised luteinizing hormone (LH) concentrationson reproductive outcome suggests that exogenous LH administrationfor ovarian stimulation may not be desirable. The aim of thisstudy was to compare the clinical pregnancy rates between folliclestimulating hormone (FSH) and human menopausal gonadotrophin(HMG) used in in-vitro fertilization (IVF) cycles. A total of232 infertile patients, with a mean duration of infertilityof 67.1 ± 32.9 months, were selected for IVF (femaleage <38 years, FSH <15 IU/1, and total motile sperm count>5x10⁶). A short (flare-up) protocol with daily leuprolideacetate was followed randomly from day 3 with FSH (n = 115)or human menopausal gonadotrophin (HMG; n = 117), at an initialdose of two ampoules per day. A maximum of three embryos wastransferred, and the luteal phase was supported with four dosesof HCG (2500 IU). No differences were observed between the twogroups in any of the cycle response variables except fertilizationrates per oocyte and per patient, both of which were significantlyhigher with FSH. Clinical pregnancy rates per cycle initiated,per oocyte retrieval and per embryo transfer were 19.1, 21.0and 22.7% respectively for FSH, and 12.0, 12.8 and 15.4% respectivelyfor HMG. Whilst these differences were not statistically significant,the results of this interim analysis suggest that HMG may beassociated with a lower clinical pregnancy rate than FSH.