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.     

Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study

A total of 346 women with normal ovulatory function was stimulated with human menopausal gonadotrophins (HMG) to attain ovarian stimulation for IVF or intracytoplasmic sperm injection (ICSI). Stimulation with HMG started on cycle day 2 or 3. After 6 days of stimulation, Cetrorelix in its minimum effective multiple dose of 0. 25 mg/day, was administered daily until induction of ovulation. In total, 333 patients (96.2%) reached the day of HCG administration, and 324 (93.6%) underwent oocyte retrieval. A mean of 25.2 ampoules of HMG was applied for a mean of 10.4 days. Cetrorelix was administered for a mean time lapse of 5.7 days. The mean normal fertilization rate was 60% in the IVF group and 59% in the ICSI group. Seventy pregnancies were attained, reflecting an ongoing clinical pregnancy rate of 24% per transfer. The ongoing clinical implantation rate was 11.4%. Only three cases of raised luteinizing hormone (LH) (>/=10 IU/l) with increased progesterone secretion (>/=1 ng/ml) were observed after initiation of Cetrorelix administration, reflecting an incidence of premature luteinization of 0.9%. The abortion rate was 17%. The incidence of severe ovarian hyperstimulation syndrome (World Health Organization grade III) was as low as 0.6%.     

Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group

In this prospective and randomized study, 188 patients received the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix, and 85 patients the LHRH agonist buserelin to prevent endogenous luteinizing hormone (LH) surges during ovarian stimulation in in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Ultimately, 181 patients (96.3%) in the cetrorelix group, and 77 (90.6%) in the buserelin group, reached the day of the human chorionic gonadotrophin (HCG) injection. The mean number of human menopausal gonadotrophin (HMG) ampoules administered and the mean number of stimulation days with HMG were significantly less in the cetrorelix group than in the buserelin group (P < 0.01). A rise in LH and progesterone concentrations was observed in three of the 188 patients (1.6%) who received cetrorelix. On the day of the HCG administration, more follicles of a small diameter (11-14 mm) were observed in the buserelin group than in the cetrorelix group (P = 0. 02) and the mean serum oestradiol concentration was significantly higher in patients who received buserelin than in those who received cetrorelix (P < 0.01). Similar results were observed in fertilization, cleavage and pregnancy rates in the two groups. In conclusion, the use of the LHRH antagonists might be considered more advantageous because of the short-term application needed to inhibit gonadotrophin secretion, so allowing a reduction in the treatment time in a clinically significant manner.     

Subcutaneous low dose leuprolide acetate depot versus leuprolide acetate for women undergoing ovarian stimulation for in-vitro fertilization

A total of 100 women undergoing ovarian stimulation with gonadotrophin-releasinghormone agonist (GnRHa) and a human menopausal gonadotrophin(HMG) for in-vitro fertilization (IVF) participated in thisrandomized comparative study. Leuprolide acetate at a dose of0.5 mg/day s.c. (n = 52, group I), or low-dose leuprolide acetatedepot at a dose of 1.88 nig s.c. (n = 48, group II), was startedon days 21–23 of the cycle. Stimulation with 225 IU/dayHMG was started after pituitary desensitization had been achieved.The luteal phase was supported by human chorionic gonadotrophin(HCG) i.m. injection. There were nostatistical differences inbaseline oestradiol (24.5 ± 4.8 versus 21.9 ±4.5 pg/ml) and follicle stimulating hormone (FSH) concentrations(3.9 ± 1.9 versus 3.2 $ 1.8 mlU/ml), and concentrationson the day of HCG administration of oestradiol (1657 ±245 versus 1512$165 pg/ml), luteinizing hormone (LH; 6.2 ±4.8 versus 5.6 ± 4.3 mlU/ml) and FSH (10.6 ± 2.8versus 10.8 ± 3.6 mIU/ml). There were also no statisticaldifferences in the HMG dosage (26.8 ± 1.8 versus 28.5± 1.5), the number of oocytes retrieved (7.6 ±3.0 versus 8.1 ± 4.3), the number of oocytes fertilized(5.3 ± 2.1 versus 5.6 ± 3.0) and the number ofembryos transferred (3.5 ± 1.3 versus 3.4 ± 1.6).There was no evidence of a premature LH surge in either group,but two patients appeared to have a poor response in the leuprolideacetate group (group I). There were 11 pregnancies (21.2%) afterthe use of leuprolide acetate and 12 pregnancies (25.0%) inthose given leuprolide acetate depot; no statistical differenceexisted between these two groups. Thus, an s.c. low-dose leuprolideacetate depot injection may offer a useful alternative for pituitarysuppression in ovarian stimulation for IVF.     

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.     

Endocrinology: Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study

One-hundred women undergoing ovarian stimulation with gonadotrophin-releasinghormone agonist (GnRH-a) and a human menopausal gonadotrophin(HMG) for in-vitro fertilization (IVF) participated in thisrandomized comparative study. The effectiveness of long-actings.c. goserelin (Zoladex depot; 49 patients) and intranasally(i.n.) administrated buserelin acetate (Suprefact; 51 patients)for pituitary down-regulation was compared. Treatment with s.c.goserelin (3.6 mg) or i.n. buserelin acetate (200 µg;6 times/day) was started on day 21–23 of the cycle. Stimulationwith 150 IU of HMG/day was started after at least 11 days ofGnRH-a treatment. There were no differences in the time requiredfor follicular development nor in the clinical outcome betweengroups treated with either goserelin or buserelin. The numberof oocytes recovered in the goserelin group was 6.7 ±5.0 versus 6.3 ± 4.9 in the buserelin group. There were11 pregnancies after the use of goserelin (22.4%) and 12 pregnanciesin those given buserelin (24.0%). The number of HMG ampoulesneeded for follicular maturation was higher in the goserelingroup (27.9 ± 7.8) than in the buserelin group (24.6± 7.8, P < 0.05). The patients given buserelin sufferedsignificantly more from tiredness, depression, headache andabdominal pain than those receiving goserelin, whereas therewere no differences between the groups in experiencing mentalirritability, nausea and swelling. Subcutaneous goserelin depotinjection offers a useful alternative for pituitary down-regulationin IVF stimulation.     

Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix

Luteinizing hormone (LH) is mandatory for the maintenance of the corpus luteum. Ovarian stimulation for IVF has been associated with a defective luteal phase. The luteal phases of two groups of patients with normal menstrual cycles and no endocrinological cause of infertility were retrospectively analysed in IVF cycles. Thirty-one infertile patients stimulated with human menopausal gonadotrophins (HMG) for IVF to whom the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix 0.25 mg was also administered to prevent the LH surge (group I) were compared with 31 infertile patients stimulated with HMG alone (group II). Despite differences in the stimulation outcome, luteal LH serum concentrations were similar in the two groups. LH values dropped from 2.3 +/- 1 IU/l on the day of human chorionic gonadotrophin (HCG) administration to 1.1 +/- 0.7 IU/l on day HCG +2 in group I (P < 0.0001) and from 5.1 +/- 3 to 1.2 +/- 1.7 IU/l (P < 0.0001) in group II. In the mid-luteal phase, LH concentrations were low in both groups. Our results suggest that suppressed LH concentrations in the early and mid-luteal phase may not be attributed solely to the GnRH-antagonist administration. Pituitary LH secretion may be inhibited by supraphysiological steroid serum concentrations via long-loop feedback and/or by the central action of the exogenously administered HCG via a short-loop mechanism.     

Differential effects of gonadotrophin-releasing hormone agonists administered as desensitizing or flare protocols on hormonal function in the luteal phase of hyperstimulated cycles

The incorporation of gonadotrophin-releasing hormone agonist (GnRHa) in in-vitro fertilization (IVF) stimulation protocols has led to doubt about the quality of the subsequent luteal phase. The effects of two GnRHa stimulation protocols on luteal phase concentrations of oestradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were compared with the standard clomiphene stimulation regimen. Subjects receiving clomiphene with human menopausal gonadotrophin (HMG, n = 377) showed essentially similar luteal phase P concentrations to those receiving leuprolide acetate/HMG as a desensitization protocol. Subjects receiving concomitant leuprolide and HMG from day 2 to utilize the flare effect of the GnRHa exhibited significantly lower P levels in the luteal phase compared to clomiphene/HMG and leuprolide desensitization protocols despite the addition of HCG support. This occurred despite equivalent E2 concentrations at the time of ovulation and identical numbers of oocytes recovered. LH concentrations in non-conception cycles were suppressed for at least 14 days in the luteal phase in both GnRHa protocols compared to clomiphene stimulation. Differences were less obvious in cycles where conception occurred suggesting that implantation may proceed more favourably when the luteal endocrinology was optimal. It is concluded that flare methods of GnRHa hyperstimulation are associated with significantly different luteal phases compared with clomiphene or desensitization protocols. It is proposed that the use of the flare type of stimulation may significantly influence the response of the granulosa cells to LH or HCG via gonadotrophin receptors or through altered post-receptor function.     

Gonadotrophic control of human granulosa cell glycolysis

Follicular fluid lactate levels were measured in women undergoinginfertility surgery during the follicular phase or oocyte recoveryfor in-vitro fertilization (IVF). In the largest ovulatory folliclelactate levels were low in the mid-follicular phase (group 1),1.6-fold higher just prior to the onset of the luteinizing hormone(LH) surge (group 2) and a further 2.5-fold higher after theonset of the LH surge (group 3). In IVF patients mean lactatelevels in all aspirated follicles were similar to those in group3 subjects, but the levels within ertch patient were variableand were positively correlated with follicular volume. Basalgranulosa cell lactate accumulation in vitro was 3-fold higherin group 3 compared with group 2 subjects, but stimulation byFSH or HCG was higher in group 2 (2- to 3-fold) compared withgroup 3 (1.4- to 2-fold). These results demonstrate that humanfollicular fluid lactate levels increase as a function of thematurity and size of the developfng follicle. Granulosa celllactate accumulation in vitro is under gonadotrophic control,which suggests that the effects observed in vivo reflect changesin granulosa cell glycolysis in response to gonadotrophic stimulation.Our findings support the concept that low molecular weight energymetabolites transduce gonadotrophin signals that regulate oocytematuration.     

Impact of gonadotrophin dose on pre-embryo recovery and development in superovulated mice

A dose—response analysis was performed by stimulatingmice with Humegon, which contains approximately equal amountsof follicle stimulating hormone (FSH) and luteinizing hormone(LH). The effect of increasing stimulation was assessed by monitoringthe number and developmental stages of preembryos flushed fromthe tubes, and the developmental potency of these pre-embryosafter culturing for 72 h. Increasing the stimulation doses resultedin an increased recovery of 2-cell pre-embryos. A maximal plateauof 40–50 2-cell pre-embryos was reached after stimulationwith 15–30 IU FSH/LH. Higher stimulation doses up to 50IU FSH/LH showed no further increase in pre-embryo recovery.Increased stimulation doses did not affect the number of 1-cellpre-embryos or the number of pre-embryos which developed furtherthan the 2-cell stage. An average of 88 ± 1.7% of theflushed pre-embryos were 2-cell pre-embryos. The fraction offlushed pre-embryos which developed into blastocysts after 72h of culturing was constant at all stimulation doses, with anaverage of 81 ± 1.9%. A maximal plateau of 35–40blastocysts was reached after stimulating with 15–30 IUFSH/LH. The group of pre-embryos at less advanced developmentalstages and the group of degenerated pre-embryos showed a smallbut dose dependent increase in number. In conclusion, we foundthat increasing doses of Humegon resulted in an increased recoveryof pre-embryos capable of preimplantation development. Thisincreased recovery occurred despite the high level of LH containedin this FSH/LH stimulation.     

EndocrinologyHormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix)

A third-generation gonadotrophin-releasing hormone antagonist(Cetrorelix) was used during ovarian stimulation in 32 patientsundergoing assisted reproduction, in order to prevent the prematureluteinizing hormone (LH) surge. In all patients, ovarian stimulationwas carried out with two or three ampoules of human menopausalgonadotrophin (HMG), starting on day 2 of the menstrual cycle.In addition, 0.5 mg of Cetrorelix was administered daily fromday 6 of HMG treatment until the day of ovulation inductionby human chorionic gonadotrophin (HCG). A significant drop inplasma LH concentration was observed within a few hours of thefirst administration of Cetrorelix (P<0.005). Moreover, noLH surge was detected at any point in the treatment period inany of the 32 patients. A mean oestradiol concentration of 2122±935ng/1 was observed on the day of the HCG administration, indicatingnormal folliculogenesis. Like LH, progesterone concentrationalso dropped within a few hours of the first administrationof Cetrorelix (P< 0.005). A 0.5 mg daily dose of Cetrorelixprevented a premature LH surge in all the 32 patients treated.     

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: The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. II. Multiple discriminant analysis for risk prediction

The considerable overlap of distributions of values for differentparameters between control and ovarian hyperstimulation syndrome(OHSS) populations makes any single variable inefficient forrisk prediction. Combinations of variables were studied in adiscriminant function in order to increase predictivity anddecrease the false negative rate. Such analyses were performedon two groups of in-vitro fertilization (IVF) patients: allOHSS cases (n = 128) (group A) and only severe OHSS cases (n= 92) (group B). Progressive introduction and automated stepwiseselection of variables were applied to both groups. The bestprediction (78.5%) was obtained in group A under post-oocyteretrieval conditions using log oestradiol, slope of log oestradiolincrement, human menopausal gonadotrophin (HMG) dosage, numberof oocytes retrieved and ratio of luteinizing hormone/folliclestimulating hormone (LH/FSH), in the formula. The correspondingfalse negative rate was 18.1%. However, effective preventionof OHSS implies the ability to withhold human chorionic gonadotrophininjection. Therefore a formula for pre-oocyte retrieval conditionswas established yielding a prediction rate of 76.1% with a falsenegative rate of 18.1%. To be validated, such formulae haveto be applied to another population of IVF cases used as a ‘testing-set’.     

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: Prospective randomized study of clomiphene citrate and gonadotrophins versus goserelin and gonadotrophins for follicular stimulation in assisted reproduction

We performed a prospective randomized study of goserelin, along-acting gonadotrophin-releasing hormone agonist (GnRHa)and human menopausal gonadotrophin (HMG) versus clomiphene citrateand HMG for follicular stimulation in assisted reproductionto investigate whether the use of this GnRHa provides a clearadvantage in terms of pregnancy per treatment cycle in unselectedpatients, who entered a first trial of assisted reproduction.From a retrospective analysis comparing the two stimulationprotocols, a relative increase of the pregnancy rate per cycleof 50% was anticipated. To detect this difference with a powerof 90%, 300 patients had to be included. The main prognosticfactors affecting the outcome of assisted reproduction wereequally divided among the two groups by a minimization procedure.The pregnancy rates per cycle were significantly better in thegoserelin/HMG group than in the clomiphene citrate/HMG group,both for all procedures of assisted reproduction combined (36.8versus 24.5%; P < 0.02) and for the main procedure of in-vitrofertilization (IVF) (37.0 versus 23.5%; P < 0.02). Differencesin pregnancy rates per oocyte retrieval and per embryo transferwere less pronounced (37.8 versus 30.8%; P = 0.40 and 44.4 versus36.8%; not significant). On the other hand, stimulation withgoserelin/HMG was associated with a higher number of ampoulesof HMG (44.9 versus 9.9; P < 0.0001), a longer duration ofstimulation (11.2 versus 8.7 days; P < 0.0001) and an incidenceof ovarian stimulation of 4.5% (7/154) versus 0% in the clomiphenecitrate/HMG group. Goserelin was well tolerated and proved tobe very reliable as an adjunct of follicular stimulation inassisted reproduction. The main determinants of the higher efficacyof goserelin/HMG in assisted reproduction were the virtual absenceof cancellation of the cycle and the increased number of oocytes.     

Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist Cetrorelix during ovarian stimulation

Surges of luteinizing hormone (LH) that result In luteinizationbut occur prematurely with respect to the diameter of the leadingfolilde, prevent attempts to induce multiple follicular maturationfor in-vitro fertilization (IVF) in a significant number ofwomen. We examined the possibility of blocking premature LIIsurges by the administration of Cetrorelix, a potent antagonistof gonadotrophin-releasing hormone (GnRH), in a study Including20 patients, some of whom had previously shown premature LHsurges. All patients were treated with human menopausal gonadotrophins(HMG) starting on day 2. From day 7 until the induction of ovulationby human chorionic gonadotrophin (HCG) the GnRII antagon Cetrorelixwas given daily. HCG was injected when the dominant fofficlehad reached a diameter of >18 mm and oestradlol concentrationwas >300 pg/ml for each follicle having a diameter of >15mm. Oocyte collection was performed 36 h later by transvaginalultrasound puncture, followed by IVF and embryo transfer. Thehormone profiles of these patients and the results of IVF andembryo transfer are comparable to those treated with GnRH agonistsand HMG. However, less time and especially less HMG Is neededin comparison to patients stimulated with a long agonist protocol.Hence, treatment with Cetrorelix proved to be much more comfortablefor the patient. In this study we showed that combined treatmentwith gonadotrophins and the GnRH antagonist Cetrorelix is apromising method for ovarian stimulation in patients who frequentlyexhibit premature LH surges and therefore fall to complete treatment.     

Endocrinology: Nuclear maturity and oocyte morphology after stimulation with highly purified follicle stimulating hormone compared to human menopausal gonadotrophin

Several studies have shown that high concentrations of luteinizinghormone (LH) in the follicular phase of stimulation can havea negative effect on oocyte quality, pregnancy rate and incidenceof miscarriage. The aim of the present study was to examinethe effects of highly purified follicle stimulating hormone(FSH HP) on ovarian stimulation and particularly on nuclearmaturity and morphological appearance of the oocyte in intracytoplasmicsperm injection (ICSI) therapy and to compare the results withhuman menopausal gonadotrophin (HMG) stimulation. For this purpose,50 patients for ICSI (HMG: 30; FSH HP: 20) and 26 patients forin-vitro fertilization (TVF; HMG: 14, FSH HP: 12) were stimulatedwith either HMG of FSH HP using a short-term protocol. Patientswere divided into the two groups according to the first letterof their family name. No differences were observed among thegroups in relation to patient age, duration of stimulation,number of aspirated oocytes or maturity of the oocyte-cumuluscomplex. After removal of the cumulus-corona cells in the ICSIoocytes, a significantly higher proportion of oocytes in theFSH HP group were nuclear mature (metaphase II) than in theHMG group (FSH HP: 88.8%, HMG: 80.6%; P = 0.009). Furthermore,in the FSH HP group, significantly fewer oocytes with dark cytoplasmwere observed (FSH HP: 14.4%, HMG: 22.4%; P = 0.02). Fertilization,cleavage and pregnancy rates (FSH HP 38%, HMG: 34% per retrieval)were comparable in both groups. Based on the results obtained,it can be concluded that the short-term FSH HP treatment protocolsynchronizes oocyte maturation better than comparable stimulationwith HMG.     

The effects of the somatostatin analogue octreotide on ovulatory performance in women with polycystic ovaries

The elevated luteinizing hormone (LH) and androgen concentrationscharacteristic of women with polycystic ovaries (PCO) are consideredcrucial factors in their infertility. The somatostatin analogueoctreotide lowers LH and androgen concentrations in women withPCO. The effects of octreotide given concurrently with humanmenopausal gonadotrophin (HMG) were therefore compared withthat of HMG alone in 28 infertile women with PCO resistant toclomiphene. In 56 cycles of combined HMG and octreotide therapythere was more orderly follicular growth compared with the multiplefollicular development observed in 29 cycles in which HMG wasgiven alone (mean number of follicles > 15 mm diameter onthe day of human chorionic gonadotrophin (HCG) administration:2.5 ± 0.2 and 3.6 ± 0.4 respectively; P = 0.026).There was a significantly reduced number of cycles abandoned(>4 follicles > 15 mm diameter on day of HCG) in patientstreated with octreotide + HMG, so that HCG had to be withheldin only 5.4% of cycles compared to 24.1% with HMG alone (P <0.05). The incidence of hyperstimulation was also lower on combinedtreatment. Octreotide therapy resulted in a more ‘appropriate’hormonal milieu at the time of HCG injection, with lower LH,oestradiol, androstenedione and insulin concentrations. Althoughgrowth hormone concentration was similar on both regimens, significantlyhigher insulin growth factor-I concentrations were observedon the day of HCG in women on combined therapy than on HMG alone.     

Endocrinology: The effect of growth hormone on granulosa cell function during in-vitro fertilization

The effect of growth hormone addition to human menopausal gonadotrophin(HMG), after pituitary down-regulation, on granulosa cell function,in in-vitro fertilization (IVF) was evaluated. Growth hormoneor placebo were added in a prospective, randomized and double-blindmanner to an existing IVF stimulation protocol. Forty-two normalovulatory women (38 years old) with mechanical factor infertilityand normal male factor were included in the study. Gonadotrophin-releasinghormone agonist (GnRHa) was given from day 21 of the previouscycle until human chorionic gonadotrophin (HCG) administration.Follicular stimulation with HMG was started after pituitarydown-regulation. Growth hormone 12 IU/day or placebo were administeredon alternate days, beginning day 1 until day 7 of HMG treatment.Granulosa cell function was evaluated, in all patients, by follicularfluid levels of ovarian steroids and insulin-like growth factor-I(IGF-I). In 14 patients, chosen arbitrarily granulosa luteincells were cultured in the presence and absence of additionalHCG. Follicular fluid levels of oestradiol, progesterone, testosteroneand IGF-I were similar in both growth hormone and placebo groups.Basal and post-HCG levels of oestradiol and progesterone didnot differ significantly between the two groups of granulosalutein cell cultures. We conclude that after pituitary down-regulation,in-vivo administration of growth hormone with HMG in young ovulatorywomen does not seem to affect granulosa cell function when comparedto the administration of HMG alone.     

Endocrinology: Insulin-like growth factor-I stimulated growth and progesterone production by granulosa--lutein cells. Lack of interaction with physiological concentrations of luteinizing hormone and follicle stimulating hormone

This study examined the effect of physiological concentrationsof insulin-like growth factor-I (IGF-I), follicle stimulatinghormone (FSH) and luteinizing hormone (LH) alone and in combinationon growth and progesterone production by human granulosa —lutein cells. Granulosa—lutein cells were obtained frompatients (n > 5) undergoing in-vitro fertilization (IVF)or gamete intra-Fallopian transfer (GIFT) treatment. Cells werecultured for 2 and 4 days in the presence of physiological concentrationsof human LH (code 68/40, 5IU/1), FSH (code 83/575, 20IU/1),or IGF-I (30 ng/ml) alone and in combination. Medium was changedevery 2 days. No change in cell number (relative to each patient'sown control) was observed after treatment with FSH or LH aloneor in combination at any time. IGF-I alone produced a 117 ±8% and 176 ± 15% (mean ± SEM, n = 5) increasein cell number after 2 and 4 days respectively. This increasewas unaffected by the addition of LH or FSH at any time. Basalprogesterone secretion was variable (1633, 975–2409 nmol/l,median and interquartile range, day 2) and decreased with timein culture (564, 375–1089 nmol/l, day 4). After 2 daysculture progesterone output increased by 116 ± 5% ofcontrol in response to LH and 153 ± 13% (mean ±SEM, n = 5) of control in response to IGF-I. After 4 days, LHand IGF-I stimulated progesterone levels by 279 ± 52%and 264 ± 37% (mean ± SEM, n = 5) respectively.IGF-I stimulated progesterone output was unaffected by the additionof LH or FSH at any time. FSH alone had no effect on progesteroneoutput and did not enhance the stimulation by LH. We concludefirstly that IGF-I stimulates the growth of granulosa—luteincells but this growth is unaffected by LH or FSH; secondly thatprogesterone secretion is stimulated by LH but that seen withIGF-I is secondary to an increase in cell number; thirdly thatFSH and LH do not synergize with IGF-I with regard to progesteronesecretion, and lastly that FSH does not stimulate progesteronesecretion or growth.