A controlled study comparing patients with and without polycystic ovaries undergoing in-vitro fertilization

The outcome of in-vitro fertilization and embryo transfer (IVF—ET)was compared in 76 patients with polycystic ovaries (PCO) diagnosedon pre-treatment ultrasound scan, and 76 control patients whohad normal ovaries and were matched for age, cause of infertilityand stimulation regimen. Despite receiving significantly lesshuman menopausal gonadotrophin (HMG), patients with PCO, ascompared with controls, had significantly higher serum oestradiollevels on the day of human chronic gonadotrophin administration(5940 ± 255 versus 4370 ± 240 pmol/1, P < 0.001),developed more follicles (14.9 ± 0.7 versus 9.8 ±0.6, P < 0.001) and produced more oocytes (9.3 ± 0.6versus 6.8 ± 0.5, P = 0.003). However, fertilizationrates were reduced in the PCO patients (52.8 ± 3.4% versus66.1 ± 3.4%, P = 0.007). There was no significant differencein cleavage rates. The pregnancy rate/embryo transfer was 25.4%in the PCO group and 23.0% in the group with normal ovaries.There were three high order multiple pregnancies in the PCOgroup compared with none in the group with normal ovaries. Ofthe PCO patients, 10.5% developed moderate/severe ovarian hyperstimulationsyndrome (OHSS) compared with none of the controls (P = 0.006).Patients with and without PCO undergoing IVF have comparablepregnancy and livebirth rates. However, it is important to diagnosePCO before ovarian stimulation is initiated as these patientsare more likely to develop moderate or severe OHSS following1VF—ET.     

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.     

Ovarian stimulation for in-vitro fertilization combining administration of gonadotrophins and blockade of the pituitary with D-Trp6-LHRH microcapsules: pilot studies with two protocols

In women undergoing in-vitro fertilization and embryo transfer(TVF-ET), a total of 408IVF cycles were stimulated using humanmenopausal gonadotrophin (HMG) or pure follicle stimulatinghormone (FSH) plus HMG in combination with a single injectionof D-Trp⁶-LHRH microcapsules in order to enhance the ovarianresponse to gonadotrophins and to avoid spontaneous LH surges.Sixty-seven pregnancies were achieved. Two protocols were employed.In protocol 1 (‘blocking protocol’, n = 268), thepituitary was first inhibited with a full dose (3.75 mg) ofD-Trp⁶-LHRH in microcapsules and ovarian stimulation was startedafter the hypogonadotrophic hypogonadal state was ascertained(Ej >50 pg/ml). In protocol 2 (‘flareup protocol’,n = 140), the treatment with D–Trp⁶LHRH microcapsules(half-dose = 1.80 mg) and the ovarian stimulation with gonadotrophinswere started at the same time. Higher doses of gonadotrophinswere needed (39.5 11.2 ampoules FSH and/or HMG) in protocol1, in which the pituitary was blocked prior to and during thestimulation, than in protocol 2 (209 ampoules) where the exogenousgonadotrophin stimulation appeared to be augmented by the initialagonistic effect of the injection of D-Trp⁶LHRH microcapsules.In patients with purely tubal infertility, under 38 years oldand no male factor, the results obtained with protocols 1 and2 were similar in terms of pregnancy rate per cycle or per embryotransfer: 22.6 versus 20.5% and 28.3 versus 27.4%, respectively.However, considering the cost benefit, ‘flare-up’protocols appeared to be a better choice and could be recommended.     

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’.     

Pharmaco-dynamics of human menopausal gonadotrophin (HMG) and follicle-stimulating hormone (FSH). The importance of the FSH concentration in initiating follicular growth in polycystic ovary-like disease

Using a randomized double-blind cross-over design, the pharmaco-dynamicand pharmaco-kinetic properties of ‘pure’ follicle-stimulatinghormone (FSH) (Metrodin) and human menopausal gonadotrophin(HMG) (Pergonal) were studied in 24 women with polycystic ovary-likedisease (PCOD) during induction of ovulation. Fifty-six cycleswere stimulated with FSH and 60 cycles with HMG, according toa standard protocol. Gonadotrophins were administered i.v. ina pulsatile fashion using pulse frequencies of either 30 or120 min. The cycles stimulated with either 30 or 120 min pulseintervals showed no differences among themselves. During thestimulation phase, the FSH and HMG stimulated cycles showedequal and dose dependent FSH concentrations (mean ± SD).The luteinizing hormone (LH) concentrations (mean ± SD)were also equal but unchanged compared to the mean basal concentration.The LH, FSH, total urinary oestrogen excretion, and testosteroneprofiles (mean ± SD) obtained from cycle days –10to 0 as well as the pregnanediol profiles obtained from cycledays 0 to +14 showed no differences either. The occurrence ofan endogenous preovulatory LH surge was significantly more frequentin the cycles stimulated with a pulse interval of 30 min comparedto the cycles stimulated with a pulse interval of 120 min. Theaddition of LH as provided in HMG did not influence the FSHthreshold concentration above which initiation of folliculargrowth occurred, since no differences were found in the FSH‘stable’ concentrations between FSH and HMG stimulatedcycles. However, intra- and inter-individual variation in theFSH ‘stable’ concentration at which follicular growthwas initiated became obvious. It has been hypothesized thateither diminished circulating bioactive FSH or intrafollicularparacrine factors may influence the FSH threshold concentrationabove which the ovary responds with follicular growth.     

Pregnancy: The influence of the number of embryos transferred in 1060 in-vitro fertilization pregnancies on miscarriage rates and pregnancy outcome

To assess the incidence of miscarriage, multiple pregnancy andoutcome of pregnancy in relation to the number of embryos transferredduring in-vitro fertilization (IVF), an analysis was performedof 1060 pregnancies conceived in a tertiary-referral IVF clinic.There was no difference in the miscarriage rate after transferof one or two embryos (37.7% and 34.6%), or after three or fourembryos (22.5% and 25.2%). The miscarriage rate was, however,higher when one or two embryos were transferred compared withthree (P < 0.01) or four embryos (P < 0.02). Of the 724ongoing pregnancies, 524 (72.3%) were singleton, 164 (22.7%)twin, 33 (4.6%) triplet and three (0.4%) quadruplet. The mean(±SD) ages of women with singleton, twin, triplet andquadruplet pregnancies were 32.5 (±3.8), 32.0 (±3.5),29.76 (±4.3) and 29.67 (±2.5) years respectively.The mean age of women with singleton and twin pregnancies wassimilar and both were greater than that of triplet pregnancies(P < 0.007). The overall perinatal mortality rate (PNMR)was 39.7/1000. The PNMR for singletons was 17.2/1000, for twins80.0/1000 and for triplets 30.6/1000. All of the babies fromthe three quadruplet pregnancies survived. There were more babieslost in the twin pregnancies than any other group, althoughthis only reached significance for singletons versus twins (P< 0.00005). We conclude that the incidence of miscarriageis increased in women in whom one or two embryos are transferred.Multiple pregnancies are more likely to occur in younger womenand are associated with a significantly higher rate of perinatalmortality.     

Pregnancy: Endometrial ultrasonography as a predictor of pregnancy in an in-vitro fertilization programme

The endometrial pattern and thickness were analysed by ultrasonographyin 139 cycles stimulated for in-vitro fertilization (IVF) onthe day of administration of human chorionic gonadotrophin (HCG).A semi-programmed schedule based on the pill + clomiphene citrate+ human menopausal gonadotrophin (HMG) was used in all cycles.On the day of HCG administration, endometrial pattern and thicknesswere assessed with an Ultramark 4 (ATL) ultrasound equippedwith a 5 MHz vaginal probe. Endometrial pattern I (a ‘tripleline’multilayer) was observed in a total of 105 cycles (76%), andpattern II (fully homogeneous and hyperechogenic in relationto myometrial tissue) in 34 (24%). The incidence of clinicalpregnancy did not differ (P = 0.52) between the groups withendometrial patterns I (23.8%) and II (29.4%). Endometrial thicknesson the day of HCG administration in the group with pattern I(8.4 ± 1.9 mm) was similar (P = 0.96) to that observedin the group with pattern II (8.4 ± 2.0 mm). In addition,the endometrial thickness of the patients who became pregnant(8.0 ± 1.7 mm) did not differ (P = 0.15) from that ofwomen who did not achieve pregnancy (8.6 ± 2.0 mm). Theconclusion from the present data is that ultrasonographic analysisof endometrial thickness and refringency on the day of HCG administrationhad no predictive value for conception in IVF cycles.     

Endocrinology: Ultrasonographic appearance of polycystic ovaries is associated with exaggerated ovarian androgen and oestradiol responses to gonadotrophin-releasing hormone agonist in women undergoing assisted reproduction treatment

While no single biochemical test is diagnostic of polycysticovary syndrome (PCOS), most patients show a characteristic ovarianultrasonographic appearance. It has been proposed that a dysfunctionof cytochrome P-450c17 in PCOS leads to an increased 17-hydroxyprogesterone(17-OHP) response to a gonadotrophin-releasing hormone (GnRH)agonist-induced gonadotrophin rise. We postulated that thisabnormality of steroid metabolism might influence the ovarianresponse during assisted reproduction treatment. We investigated106 patients undergoing a short ’boost‘ stimulationregimen for assisted reproduction treatment, including in-vitrofertilization and gamete intra-Fallopian transfers. The ovarianultrasound pattern was correlated with serum testosterone, 17-OHP,androstenedione and oestradiol responses, and with the clinicaloutcome. Polycystic ovaries, defined ultrasonographically asthe presence of 10 follicles between 2 and 10 mm diameter ineither ovary, were found in 48% of the whole study population.Dexamethasone was given to suppress adrenal androgen secretion.Functional ovarian hyperandrogenism (FOH) was defined as serumtestosterone >0.5 nmol/l after dexamethasone. There was asignificantly (P < 0.001) higher prevalence of FOH in patientswith polycystic ovaries (23%) compared with normal ovaries (7%).Patients with polycystic ovaries had approximately double the17-OHP, androstenedione and oestradiol responses to a GnRH agonistas patients with non-polycystic ovaries. Exaggerated 17-OHPand oestradiol responses to GnRH agonist were found in 89% ofpatients with clinically diagnosed PCOS. The number of oocytesretrieved was positively correlated (r = 0.51, P < 0.001)with the oestradiol responses in all patients. Although therewas no difference in the total amount of follicle stimulatinghormone (FSH) used between the patients with polycystic andnormal ovaries, the median peak oestradiol concentration was1.6 times and the oocyte yield 2.3 times greater in patientswith polycystic ovaries. The overall pregnancy rate per transferwas 32% and did not differ between patients with or withoutpolycystic ovaries and FOH. No pregnancies occurred when thebaseline FSH concentration was >10 IU/l. We conclude thatthe ultrasonographic changes characteristic of polycystic ovariesshould be sought in all women undergoing assisted reproductiontreatment.     

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.     

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.     

Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebo-controlled double-blind study

The objective of the study was to assess the effect of growthhormone (GH) supplementation to a combined gonado-trophin-releasinghormone agonist/human menopausal gonadotrophin (GnRHa/HMG) treatmentprotocol on ovarian response in ‘poor responders’undergoing in-vitro fertilization (IVF). GH or a placebo wereadministered in a prospective randomized double-blind manner.A total of 14 poor-responder patients (oestradiol < 500 pg/ml,less than three oocytes retrieved in two previous IVF cycles)were randomly allocated to a combined treatment of either GnRHa/HMG/GH (18 IU on alternate days, total dose 72 IU) or GnRHa/ HMGplacebo. No difference was found between the study and controlgroups in the number of HMG ampoules used, the number of follicles(>14 mm) and serum oestradiol concentrations on the day ofadministration of human chorionic gonadotrophin (HCG), the numberof oocytes retrieved and fertilized, and the number of embryostransferred. The GH group (n = 7) did not show a better ovulatoryresponse in the study cycles; mean ± SD serum oestradiolon day of HCG 411 ± 124 versus 493 ± 291 pg/ml,aspirated oocytes 2.2 ± 1.5 versus 1.9 ± 2.0.Interestingly, when the above results for the placebo groupwere compared with their previous cycles (serum oestradiol 403± 231 pg/ml; 0.4 ± 0.5 aspirated oocytes), a non-specificeffect was found. Follicular recruitment, oestradiol secretionby mature follicles and the number of oocytes retrieved in poorresponders were not improved by GH supplementation.     

Endocrinology: The choice of treatment for anovulation associated with polycystic ovary syndrome following failure to conceive with clomiphene

The choice of treatment for clomiphene-resistant anovulationassociated with polycystic ovary syndrome (PCOS) is presentlyarbitrary and selection criteria are not available. A totalof 144 women with anovulatory infertility associated with PCOSwho failed to conceive on clomiphene were treated with eitherpure follicle stimulating hormone (FSH) (n = 29), or human menopausalgonadotrophin (HMG) (n = 60), or gonadotrophin-releasing hormoneanalogue (GnRHa) and HMG (n = 55). Analysis of 306 treatmentcycles and 53 pregnancies revealed a cumulative conception rateat 4 months of 23% with FSH, 47% with HMG and 69% with GnRHa+ HMG. The miscarriage rate was highest in the HMG group (44%)and consequently the cumulative live birth rate was superiorwhen GnRHa was used in combination with HMG. There were no significantdifferences in the basal clinical and endocrinological featuresof those who conceived compared with those who did not, eitherin the whole group, or in the individual treatment groups. Thus,the choice of treatment for clomiphene-resistant women withPCOS cannot be guided by the basal clinical or endocrinologicalfeatures of this heterogeneous syndrome with the present stateor knowledge.     

A double-blind cross-over controlled study to evaluate the effect of human biosynthetic growth hormone on ovarian stimulation in previous poor responders to in-vitro fertilization

The effect of exogenous human biosynthetic growth hormone (HGH;12 IU/day; Norditropin, Novo-Nordisk) on the response to ovarianstimulation using a buserelin/human menopausal gonadotrophin(HMG) regimen was assessed in women who had previously showna ‘poor response’ in spite of increasing doses ofHMG. Forty patients were recruited into a prospective double-blindplacebo-controlled study. The serum follicle stimulating hormone(FSH) on day 2–5 of a menstrual cycle (< 10 IU/I) wasused to exclude any peri-menopausal candidates. The urinary24 h GH secretion was normal in all patients. Thirty-three patientscompleted the study with 21 patients having human chorionicgonadotrophin (HCG) in both arms, thus providing a completeset of placebo control data. Of these 21 patients, the administrationof HGH compared to the placebo cycle resulted in increased serumconcentrations of fasting insulin on the 8th (median 3.9 versus5.8 mU/I; P < 0.0005) and13th (median 4.4 versus 5.8 mU/I;P < 0.05) day of HMG in those cycles receiving HGH. After8 days of co-treatment with HGH the number of cohort follicles(14–16.9 mm) was significantly increased, but this changewas not sustained on the day of HCG administration. No statisticaldifference in the serum oestradiol on the 8th day of HMG orday of HCG, length of the follicular phase, total dose of HMGused, or the number of oocytes collected was seen between theplacebo or HGH cycles. This study demonstrates that HGH doesnot improve the ovarian response to ovulation induction in previouspoor responders.     

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.     

Pregnancy: Adverse effect of a homogeneous hyperechogenic endometrial sonographic pattern, despite adequate endometrial thickness on pregnancy rates following in-vitro fertilization

We have previously presented data to show that in patients whohad in-vitro fertilization (IVF)—embryo transfer usingovarian stimulation involving the luteal phase leuprolide acetate—humanmenopausal gonadotrophin (HMG) regimen, poor pregnancy resultsensued if either the endometrial thickness was < 10 mm ora homogeneous hyperechogenic sonograpic pattern was presentimmediately prior to taking a human chorionic gonadotrophin(HCG) injection. There were only 15 cases with this hyperechogenictype endometrium (and no pregnancies). The purpose of the presentstudy was to evaluate the influence of a hyperechogenic endometriumwhen the endometrial thickess was 10 mm, in a more extensiveseries, in women having IVF—embryo transfer using thesame ovarian stimulation regimen. A total of 273 consecutivecycles, where endometrial thickness was 10 mm, were evaluated(not including the 85 cycles previously reported). Of 22 patientswith the hyperechogenic pattern, one achieved a chemical pregnancy(-HCG >500 mIU/ml) and none achieved clinical pregnancies(ultrasound confirmation). In contrast, 67 of 251 (26.7%) patientsconceived with other echo patterns (x² analysis = 5.9, df =1, P = 0.01). These data thus confirm, in a larger series, thenegative influence of this type of echo pattern on subsequentpregnancy rates following the luteal phase leuprolide acetate—HMGovarian stimulation regimen.     

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.     

Endocrinology: Follicular fluid insulin-like growth factor-I and insulin-like growth factor-II concentrations vary as a function of day 3 serum follicle stimulating hormone

We determined follicular fluid concentrations of insulin-likegrowth factor (IGF)-I, IGF-II and inhibin as a function of day3 serum follicle stimulating hormone (FSH) in 16 women undergoingfollicular fluid aspiration in preparation for in-vitro fertilizationand embryo transfer. Follicular fluid concentrations of IGF-Iand IGF-II were significantly less in the ‘low’FSH group as compared to the ‘high’ FSH group. Themean IGF-I concentration was 67.6 ng/ml [confidence intervals(CI) 51.6–92.5] in the ‘low’ FSH group comparedto 87.1 ng/ml (CI 72.8–104.2; P < 0.025) in the ‘high’FSH group. Mean IGF-II concentrations were 354.8 ng/ml (CI 297.8–422.9)in the ‘low’ FSH group compared to 489.8 ng/ml (CI384.6–624.5; P < 0.05) in the ‘high’ FSHgroup. Follicular fluid inhibin concentrations did not differbetween groups. These differences in follicular fluid IGF asa function of day 3 FSH may raise questions regarding the rolegrowth factors play in the physiological processes of the ageingfollicle.     

Polycystic ovary syndrome: low-dose follicle stimulating hormone administration is a safe stimulation regimen even in previous hyper-responsive patients.

We studied 23 women with polycystic ovarian syndrome (PCOS), resistant to clomiphene citrate, who had a previous history of multifollicular ovarian development on gonadotrophin stimulation. Each woman had one cycle of gonadotrophin-stimulating hormone agonist/human menopausal gonadotrophin (GnRHa/HMG) stimulation and then one cycle of low-dose follicle stimulating hormone (FSH) stimulation. All GnRHa/HMG cycles were multifollicular. On the low-dose FSH protocol, 10 cycles were unifollicular, while two to three follicles were observed in nine cycles, and four cycles were multifollicular. The ovarian hyperstimulation syndrome ensued in one of the FSH cycles versus 13 of the GnRHa/HMG cycles. Despite decreasing luteinizing hormone (LH) levels and increasing FSH levels, androgen levels increased during stimulation on both protocols. There was one pregnancy in the GnRHa/HMG cycles versus six pregnancies following the FSH cycles. In conclusion, low-dose FSH administration seems a safe stimulation regimen with a satisfactory conception rate even in PCOS women with a previous record of multifollicular ovarian development.     

A family history of twinning in relation to multiple implantation

BACKGROUND: A familial basis for dizygotic twinning is known for multipleovulation. However, for multiple implantation this remains unclear.In IVF/intracytoplasmic sperm injection (ICSI) ‘multipleovulation’ is artificially induced. If multiple implantationis not hereditary, the incidences of twins in families of patientswith single and multiple implantation after IVF/ICSI with doubleembryo transfer (DET) should be comparable. METHODS: A questionnaire study was conducted among patients with intrauterine pregnancy at 6 weeks of gestation, after IVF/ICSI treatmentwith DET 3 days after oocyte retrieval. RESULTS: There were 940 patients who gave their informed consent. Forwomen with single implantation (Group A), the incidence of oneand of multiple twins among the family was 27.2 and 15.5%, respectively.For women with multiple implantation (Group B), this incidencewas 29.5 and 17.8%, respectively, P = 0.424. The incidence ofone and of multiple twins among first degree relatives was 10.6and 1.1% in Group A; for Group B this was 8.7 and 1.9%, P =0.469. Multivariate regression analysis also did not reveal‘twins in family’ or ‘twins in first degree’as an associated variable for multiple implantation at 6 weeks. CONCLUSIONS: Incidences of twins in families of patients with single implantationand patients with multiple implantation after IVF/ICSI are comparable.Our data do not support the concept that multiple implantationis hereditary.     

Cellular aspects of pre-ovulatory folliculogenesis in primate ovaries

According to current concepts of pre-ovulatory folliculogenesisin primate ovaries, each growing follicle has a ‘threshold’requirement for stimulation by FSH which must be met if it isto enter the oestrogen-secretory phase of pre-ovulatory development.Until recently, our understanding of the intra-follicular mechanismsunderlying FSH action on granulosa cells was based largely oninformation from non-primate laboratory animals, mainly polyovulatorssuch as rats. The present paper describes studies on FSH-regulatedgranulosa cell function in relation to pre-ovulatory developmentin vivo and in vitro using a laboratory primate, the commonmarmoset (Callithrix jacchus). Measurement of aromatase activityis used as an index of granulosa cell cytodifferentiation toverify three major tenets of the ‘threshold’ hypothesis:(i) that granulosa cells acquire increased responsiveness toFSH and LH during pre-ovulatory growth; (ii) that these development-allyrelated changes are directly induced by FSH; and (iii) thatintrafollicular steroids modify FSH action and thereby contributeto the establishment of follicular FSH thresholds. The resultsobtained highlight the value of this experimental animal modelfor studies of cellular and molecular aspects of pre-ovulatoryfolliculogenesis which are relevant to human ovaries.