Serum relaxin and the major endometrial secretory proteins in in-vitro fertilization and down-regulated hormone-supported and natural cycle frozen embryo transfer

Relaxin has been postulated to be a modulator of the expressionof the endometrial secretory proteins, insulin-like growth factorbinding protein (IGFBP-1) and placental protein 14(PP14). Thisstudy evaluated the expression of relaxin in relation to concentrationsof these secretory proteins along with oestradiol, progesteroneand human chorionic gonadotrophin in groups of pregnant andnon-pregnant patients who underwent differing assisted conceptiontreatments. Serum samples were taken from 88 patients at 8 and12 days after embryo transfer. At 12 days after embryo transfer,relaxin concentrations in the pregnant patients who had undergonein-vitro fertilization (IVF) or natural cycle frozen embryotransfer were significantly higher than those who did not conceivein these groups (mean concentrations 8334 versus 28 and 2608versus 62 pg/ml respectively, P <0.001). However concentrationsin the pregnant patients who had hormone support and transferof frozen embryos were not significantly different from thepatients who did not conceive after the same treatment. Althoughrelaxin expression was associated with corpus luteum activity,it was not related to the number of corpora lutea in IVF patients.A wide range of relaxin concentrations was seen to be compatiblewith a healthy pregnancy. These serum relaxin concentrationswere not found to be directly related to the serum concentrationsof IGFBP-1, PP14 or the other factors assessed in this study.     

Pregnancy: Serum placental protein 14 concentrations are similar in the first trimester pregnancies of women after pituitary down-regulation with a gonadotrophin-releasing hormone agonist and normal cycles with frozen embryo transfers

Previous studies suggest that, in pregnancies after in-vitrofertilization (IVF) and embryo transfer following pituitarydown-regulation with a gonadotrophin-releasing hormone analogue(buserelin) and ovulation induction with human gonadotrophins,the serum placental protein 14 (PP14) concentration is lowerthan in normally conceived pregnancies. We studied serum PP14concentrations in two groups of women: (i) in 17 infertile womenwhose pregnancy followed IVF and embryo transfer using buserelin(long protocol) and human menopausal gonadotrophin for ovulationinduction; (ii) in 15 women whose pregnancy followed transferof frozen-thawed embryos. Similar PP14 concentrations were foundin both groups on days 9–10, 14–15 and 70–77after human chorionic gonadotrophin administration (buserelin,IVF/embryo transfer) or spontaneous luteinizing hormone surge(frozen-thawed embryo transfer). Our results show that PP14secretion is not compromised by pituitary down-regulation withbuserelin in infertile women with functional ovaries.     

Maternal plasma concentrations of insulin-like growth factor binding protein-1 and placental protein 14 in multifetal pregnancies before and after fetal reduction

The aim of this study was to investigate the changes in maternalplasma insulin-like growth factor binding protein-1 (IGFBP-1)and placental protein 14 (PP14) in multifetal pregnancies beforeand after embryo reduction. Maternal plasma IGFBP-1 and PP14were measured serially in three groups of pregnant women at8–21 weeks gestation. Groups 1 and 2 were 12 singletonand 12 twin pregnancies achieved after in-vitro fertilization(IVF). Group 3 comprised 26 women with multifetal pregnanciesundergoing embryo reduction to twins. In the IVF pregnanciesmaternal plasma IGFBP-1 and PP14 increased with gestation toreach a peak at 20 and 10 weeks respectively; the mean concentrationsin twin pregnancies were significantly higher than in singletons.In multifetal pregnancies the mean plasma concentration of bothproteins was similar to that of IVF twin pregnancies beforereduction; after reduction, the values fell to less than thoseof twins. These findings suggest that the maximum secretorycapacity of the endometrium is achieved with twin pregnancies.In multifetal pregnancies undergoing iatrogenic reduction totwins, total residual endometrial function was less than intwin conceptions.     

Implantation: Endometrial and placental protein markers and ovarian steroids in serum during in-vitro fertilization cycles

The objective of this study was to find the earliest time atwhich it was possible to detect clinical pregnancy in an in-vitrofertilization (IVF) treatment cycle supported with human chorionicgonadotrophin (HCG), and also retrospectively to diagnose abnormalovarian- or endometrium-related situations in failure cycles.Serum samples were taken in 41 IVF cycles at frequent intervalsfrom the beginning of ovarian stimulation until menstrual bleedingoccurred or a pregnancy was established. Concentrations of oestradiol,progesterone, placental protein 14 (PP14), pregnancy-specific1-glycoprotein (SP₁), and pregnancy-associated plasma proteinA (PAPP-A) were determined in the serum samples using commerciallyavailable (steroid) or purpose-developed (protein) immunoassays.The cycles were retrospectively distributed into four outcomegroups: (i) fertilization failure (FF, n = 8); (ii) implantationfailure (IF, n = 10); (iii) ‘interaction’ (embryo-endometrium)cycle (IC, n = 14), and (iv) clinical pregnancy (CP, n = 9).The embryo-endometrium interaction was detected by a rise inSP₁ in 23 cycles (70% of embryo transfers) at a time when endogenousHCG was still masked by external support. Early (‘false’)positive SP₁ concentrations were observed in two out of eightand five out of 14 cases in groups FF and IC respectively, butnever amongst the ongoing pregnancies (CP). PAPP-A did not distinguishpregnancy from the other outcomes. The PP14/progesterone ratiowas lower, later in the cycle, in CP than in the other groups.We conclude that, while it is not possible to predict the outcomeof a given IVF cycle earlier than 2 weeks after embryo transfer,the hormonal patterns can be used to detect abnormalities (e.g.endometrial asynchrony) which may be useful for subsequent treatmentcycles in the same patient.     

Placental and ovarian hormones in anembryonic pregnancy

The circulating levels of human chorionic gonadotrophin (HCG),pregnancy-associated plasma protein-A (PAPP-A), Schwangerschaftprotein 1 (SP-1), oestradiol and progesterone were measuredin 81 pregnant patients between 4 and 11 weeks gestation, followingin-vitro fertilization and embryo transfer. The patients weredivided as follows: singleton anembryonic pregnancies, n = 22;singleton pregnancies which spontaneously aborted followingthe demonstration of fetal heart activity, n = 7; and normalsingleton pregnancies, n = 52. The levels of all substancesmeasured were significantly reduced in women with anembryoniccompared to those with singleton pregnancies which proceededto term. The serum levels of SP-1, weeks 6–8 (P < 0.01);HCG, weeks 6–8 (P < 0.05); oestradiol, weeks 5–8(P < 0.05) and progesterone, weeks 6–8 (P < 0.05),were lower in anembryonic pregnancies than in those of pregnancieswhich spontaneously aborted. These differences may be a reflectionof the fact that miscarriage, after the demonstration of fetalheart activity, represents fetal demise at a later stage inpregnancy. In anembryonic pregnancies, significant associationswere found between HCG and both oestradiol and progesteronelevels from weeks 6 and 8, suggesting that in the absence ofan embryo, HCG is the prime determinant of steroid synthesisby the corpus luteum.     

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 influence of ovarian follicular activity on late proliferative phase serum IGFBP-1 in down-regulated assisted conception cycles

Serum insulin-like growth factor binding protein-1 (IGFBP-1)concentrations were measured at the end of the proliferativephase in infertility patients undergoing normal menstrual cyclefrozen embryo transfer, exogenous hormone-supported frozen embryotransfer and in-vitro fertilization (IVF) treatment cycles.These patients were divided into five groups according to theirovarian follicular activity. The exogenous hormone-supportedfrozen embryo transfer group, who had no ovarian follicles,and the IVF groups (number of follicles ranging from 4–38)showed statistically higher serum IGFBP-1 concentrations whencompared to the normal menstrual cycle group (P0.01). Therewas no significant difference in the serum IGFBP-1 concentrationsbetween the exogenous hormone support frozen embryo transfergroup and the poor or normal response IVF groups (number offollicles ranging from 4 to 16). An IVF group that displayedan excessive response to our standard human menopausal gonadotrophinstimulation (>>20 mature follicles or oestradiol >>10000 pmol/1) showed a significantly higher serum IGFBP-1 concentrationwhen compared with the other groups (P = 0.001). This subgroupwas subsequently given a modified (follicle-stimulating hormone)stimulation regime which resulted in a significant reductionin serum IGFBP-1 concentrations (P << 0.05). There wasno correlation between serum oestradiol and IGFBP-1 overallor within the patient groups. We conclude that serum IGFBP-1concentrations in our down-regulated assisted conception cyclesdid not increase in line with ovarian follicular activity, unlessan excessive response was displayed.     

Fertilization and early embryology: A bridge to intracytoplasmic sperm injection--high insemination concentrations benefit patients who have a reduced chance of fertilization with standard in-vitro fertilization

This study was carried out to determine whether high inseminationconcentrations (HIC) could improve fertilization and pregnancyrates in patients who had either previously demonstrated poorfertilization rates in vitro using standard protocols (Group1) or in whom a reduced chance of fertilization was indicatedat semen assessment prior to in-vitro fertilization (IVF) (Groups2 and 3). Forty nine patients were recruited for the study.Standard IVF was carried out in 1 ml volumes using 10⁵ spermatozoa/mlHIC treatment involved co-culture of spermatozoa and oocytesin microdroplets with insemination concentrations increased10–50 fold higher than standard IVF. Fertilization andpregnancy rates were compared between standard IVF and HIC inindividual patients either in consecutive cycles (Group 1) orusing sibling oocytes in the same cycle (Group 2). Group 3 patientswere treated with HIC for their first treatment cycle. HIC significantlyimproved the fertilization rate compared with standard IVF forGroups 1 (59.7±10.7 versus 19.6±5.4% respectively)and 2 (54.9±8.5 versus 34.0±85% respectively).HIC increased the pregnancy rate from 0% with standard IVF to20% per embryo transfer in Group 1 patients. A single pregnancyderived from the transfer of HIC and IVF embryos occurred inGroup 2. The fertilization rate (47.2±7.6%) and pregnancyrate (31.3% per embryo transfer) for Group 3 patients was higherthan predicted. There was no increase in the rate of polyploidywith HIC. Provided there are sufficient numbers of motile spermatozoa,HIC may be offered as an initial form of treatment, thus permittingreferral of only the poorest responders for intracytoplasmicsperm injection (ICSI).     

Pregnancy: Reduced circulating placental protein concentrations during the first trimester are associated with preterm labour and low birth weight

Serum concentrations of human chorionic gonadotrophin (HCG),Schwangerschaftsprotein 1 (SP-1), pregnancy-associated plasmaprotein A (PAPP-A), progesterone and oestradiol were measuredat weekly intervals between the fifth (embryo transfer plus3 weeks) and 13th week of gestation during the first trimesterof pregnancies achieved following in-vitro fertilization (IVF)and embryo transfer in a group of women who delivered before(n = 8) or at term (n = 52). Those women who had a preterm deliveryhad significantly lower concentrations of PAPP-A (weeks 7–13;P = 0.0001–0.028) and SP-1 (weeks 6–8 and 10–12;P = 0.004–0.04). After correction of birth weight forsex and gestational age at delivery, preterm delivery was foundnot to be associated with growth retardation. However, comparisonof the circulating concentrations of the substances analysedin mothers who delivered babies of < 85% of the 50th centileof the normal range of birth weight for a given gestationalage and sex, with those who delivered babies of >85% revealedthat the concentrations of HCG (P = 0.012–0.04 on weeks6–9) and SP-1 (P = 0.003–0.03 on weeks 7, 9–13)were significantly lower in the former group. Weak, inconsistentassociations were found between the circulating concentrationsof HCG, SP-1 and PAPP-A and both corrected birth weight andgestational age at delivery. Thus, both the gestational ageat delivery and low birth weight may be related to impairedplacental development/function during the first trimester.     

Endocrinology: High incidence of embryo transfer cancellations in patients with polycystic ovarian syndrome

This study was aimed at assessing the outcome of in-vitro fertilization(IVF) and embryo transfer in patients with polycystic ovariansyndrome (PCOS). The results of IVF and embryo transfer in PCOSpatients (PCOS group, 78 cycles of 26 patients) were comparedwith those of a control group (423 cycles in 202 patients withoutmale factor; age and ovarian stimulation protocol were matched).Although the pregnancy rate per transfer was not different inthe two groups of patients (25 versus 34%, PCOS versus controlgroup), the PCOS group had a significantly lower pregnancy rateper follicle aspiration (19 versus 31%, P < 0.05). A notableresult was a significantly higher incidence of embryo transfercancellations in the PCOS group (22 versus 8%, P < 0.01),which resulted from unpredictable failure of either oocyte recoveryor fertilization. The incidence of unexplained complete failureof fertilization was significantly higher in the PCOS group(18 versus 5%, P < 0.01). These results may reflect a reducedquality of the oocytes in the PCOS group, and there was a subgroupof PCOS patients who repeatedly produced poor results of treatment.Although the ovarian stimulation regimen best suited to PCOSpatients remains to be determined, special care should be takenduring ovarian stimulation, especially when the PCOS patientshad experienced unexplained failure of oocyte recovery or fertilizationin the previous treatment cycle(s).     

Fertilization and early embryology: Effects of embryo density and co-culture of unfertilized oocytes on embryonic development of in-vitro fertilized mouse embryos

We have evaluated the effects of embryo density and the co-cultureof unfertilized (degenerating) oocytes on the development ofin-vitro fertilized (IVF) mouse embryos. In experiment 1, groupsof one, five, 10 or 20 zygotes were cultured in 20 µldrops of modified human tubal fluid (HTF) medium for 168 h at38.7°C in 5% CO₂ and 95% air. As the embryo density increased,significantly (P < 0.05) higher rates of embryos reachedhatched blastocyst stage. In addition, the time required forhatching after IVF was significantly (P < 0.05) shortenedby the increase in embryo density. In experiment 2, 10 IVF zygoteswere cultured with or without 10 unfertilized (degenerating)oocytes in 20 µl drops of HTF medium. The rates of IVFembryos that developed to morula, blastocyst, expanded blastocystand hatched blastocyst stages were decreased significantly (P< 0.01) by culturing embryos with unfertilized oocytes comparedwith culturing embryos alone. In experiment 3, groups of oneor 10 IVF zygotes or 10 IVF zygotes plus 10 unfertilized oocyteswere cultured in 20 µl drops of HTF medium and the numberof cells per blastocyst was examined at 120 h after IVF. Increasingembryo density resulted in a significant (P < 0.05) increasein the number of cells per blastocyst. In contrast, the cellnumber of IVF embryos that developed to blastocyst decreasedsignificantly (P < 0.05) when they were cultured with unfertilizedoocytes. The results suggest that in-vitro development of IVFmouse embryos is enhanced by increasing embryo density and isimpaired by co-culture with unfertilized (degenerating) oocytes.     

Ovary and Ovulation: Contralateral selection of dominant follicle favours pre-embryo development

Ovulation was studied using vaginosonography in a total of 410natural cycles of 123 women undergoing infertility treatment[267 intrauterine insemination (IUI) cycles of 103 women and143 in-vitro fertilization (IVF) cycles of 50 women]. None ofthe women received ovarian stimulation. Each follicle was measureddaily from 14 mm in diameter until formation of corpus luteumor oocyte retrieval. Contralateral ovulation as compared withthe preceding cycle occurred in 57% of the 410 cycles. Contralateralovulations occurred in 72% of cycles with a follicular phase<13 days. In cycles with a follicular phase of >14 days,ovulations occurred at random. The length of follicular phasein contralateral ovulation cycles (15.2 ± 3.2 days) wassignificantly (P < 0.05) shorter than that of ipsilateralovulation cycles (15.8 ± 2.8). During the 57% contralateralovulations in 143 IVF cycles, the rates of oocyte retrieval(89%), fertilization (69%), cleavage (90%) and embryo transfer(56%) were significantly higher than those of ipsilateral ovulations(69, 51, 64 and 23% respectively). The pregnancy rate of contralateralovulations (9%) was also higher, though not significantly, thanthat of ipsilateral ovulations (3%), although the pregnancyrates per transfer were similar (16 and 14% respectively). Thetotal pregnancy rate of both IUI and IVF was higher in contralateralthan in ipsilateral ovulation cycles (8.1 and 4.0% respectively).The dominant follicles in contralateral ovulation cycles showedsignificantly higher oestradiol/androstenedlone ratio (P <0.025) and oestradlol/testosterone + androstenedione ratio (P< 0.025), and lower androstenedione (P < 0.05) than thoseof ipsilateral ovulation cycles. There was no significant differencein oestradiol, progesterone and testosterone. These resultsindicate that the dominant follicles in contralateral ovulationcycles are healthier than those of ipsilateral ones. Local intra-ovarianfactors, e.g. from the corpus luteum, may negatively affectthe health of the dominant follicle and the enclosed oocyte.Therefore contralateral selection of the dominant follicle inthe succeeding cycle may favour pre-embryo development. Thechance of conceiving during a natural cycle may be affectedby the site of ovulation in the preceding cycle.     

Conversion of cycles involving ovarian hyperstimulation with intra-uterine insemination to in-vitro fertilization

Conversion to in-vitro fertilization (IVF) and embryo transferas an alternative to cancellation was offered in 27 consecutivecycles of controlled ovarian hyperstimulation and intra-uterineinsemination (IUI) cycles with excessive follicular developmentin patients with idiopathic infertility. IVF and embryo transferwas performed in 25 cycles, resulting in 13 pregnancies (52%),with 22% of couples having at least two embryos cryopreserved.The pregnancies have resulted in one singleton and two twinbirths, one spontaneous abortion, and nine ongoing pregnancies(including one triplet gestation). Four patients developed severeovarian hyperstimulation syndrome (OHSS) after IVF and embryotransfer, including two cases requiring paracentesis. Threeof four OHSS patients were pregnant, resulting in live birthsof healthy twins, one spontaneous abortion and one ongoing singletongestation. In two cycles a spontaneous luteinizing hormone (LH)surge occured, preventing oocyte retrieval. For these two women,drainage of all follicles except the five most likely to fertilize(18–22 mm diameter) was performed, followed by IUI, withno pregnancies or OHSS observed. Conversion of patients fromIUI cycles to IVF/embryo transfer cycles avoids cancellationof the very cycles with the best chance of achieving pregnancy.OHSS remains a problem, necessitating extensive pre-IVF counsellingand post-transfer vigilance.     

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.     

A self-migration method for preparation of sperm for in-vitro fertilization

Human sperm samples (n = 211) were prepared for in-vitro fertilization(IVF) and embryo transfer by a self-migration procedure in Earle'smedium containing highly purified hyaluronic acid (Hya) (MW3 000 000) included to increase the viscosity of the medium.The method resulted in the recovery of a significantly higherpercentage of motile spermatozoa compared with the traditionalcentrifugation method, 87.5 ± 0.9% versus 76.1 ±1.3% (P < 0.001). When comparing media with and without Hyain the selfmigration method for preparation of normal spermsamples, the media containing Hya resulted in the recovery ofa significantly higher percentage of motile spermatozoa, 89.0± 0.8% versus 73.8 ± 2.0% (P < 0.001). In agroup of 80 consecutive couples entering our IVF programme,sperm samples from 44 of the men were allocated at random forthe self migration method in medium containing Hya and spermsamples from 36 men for preparation by centrifugation and swim-up.Significantly more pregnancies were achieved in the group preparedin medium containing Hya. It is concluded that self-migrationof sperm in a medium containing Hya is simple and rapid, andresults in a high recovery of motile spermatozoa which can beused for in-vitro insemination of human oocytes with favourableresults.     

Implantation: Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients

This study was undertaken to investigate an empirical observationthat ‘high responder patients have poorer in-vitro fertilization(IVF) outcome than normal responder patients’. The aimof our study was to analyse the effect of high serum oestradioland progesterone concentrations at the day of human chorionicgonadotrophin (HCG) administration on endometrial receptivityand oocyte—embryo quality in high and normal responderpatients. The IVF patients were divided into two groups: 59high responder patients who voluntarily donated some of theiroocytes, and a control group consisting of 105 normal responderpatients. Both groups were compared in terms of the number andquality of oocytes retrieved, embryos transferred, fertilization,implantation and gestation rates, serum oestradiol and progesteroneconcentrations and the oestradiol: progesterone ratio on theday of HCG injection. To ascertain oocyte—embryo quality,a second control group of 96 women undergoing oocyte donation(receiving oocytes from high responder patients) was considered.To assess the impact of steroid concentrations on endometrialreceptivity, high responder patients were divided into two subgroupsaccording to oestradiol concentration, above or below the minimaloestradiol and progesterone concentrations (mean – SD)in this group. The normal responder patients were divided intotwo subgroups according to oestradiol concentration, above orbelow the maximal oestradiol and progesterone concentrations(mean + SD) in this group. To assess further the relevance ofoestradiol concentration on endometrial receptivity, patientswere divided into different subgroups according to increasingoestradiol concentration, regardless of whether they were highor normal responders. High responder patients had significantlydecreased implantation and pregnancy rates per cycle comparedwith normal responder patients (33.3 versus 16.3 and 11.1 versus5.4% respectively; P < 0.05). The results of 108 embryo transfersin 91 recipients who received oocytes from the high respondergroup showed normal embryo quality. Implantation rates and pregnanciesper cycle were significantly lower in high responder patientswith serum oestradiol concentrations > 1700 pg/ml comparedwith those having oestradiol concentrations 1700 pg/ml, as wellas in normal responder patients with serum oestradiol concentrations2200 pg/ml compared with those having oestradiol concentrations<2200 pg/ml. Considering all the patients together, significantdecreases in pregnancy and implantation rates were observedwhen oestradiol concentrations were >2500 pg/ml comparedwith patients having lower oestradiol concentrations. Our clinicalresults demonstrate that high serum oestradiol concentrationson the day of HCG injection in high and normal responder patients,regardless of the number of oocytes retrieved and the serumprogesterone concentration, are detrimental to uterine receptivitywithout affecting embryo quality.     

Implantation: Stimulation of human endometrial epithelial cell interleukin 6 production by interleukin 1 and placental protein 14

The effect of interleukin 1 (ILI) and placental protein 14 (PP14)on the production of interleukin 6 (IL6) by cultured human endometrialepithelial cells prepared from endometrial biopsy material obtainedat different stages in the menstrual cycle was investigated.Basal IL6 production by cells prepared from proliferative endometriumwas greater than that produced by cells prepared from secretoryendometrium (7.3 ± 0.3 and 1.1 ± 0.2ng/well/24h respectively, P < 0.001). IL1 (0.025–2.5 ng/ml) causeda dose-dependent increase in IL6 production by cells preparedfrom both proliferative and secretory endometrium, but cellsprepared from secretory endometrium responded to a lower concentrationof ILI than those prepared from proliferative endometrium. ILI-stimulatedIL6 production by epithelial cells prepared from secretory endometriumtypically reached 10 times basal values, while in cells preparedfrom proliferative endometrium stimulated levels were approximatelytwice the basal values. PP14 (1–50 µg/ml) also causeda dose-dependent increase in IL6 production by epithelial cellsprepared from secretory endometrium, but had no effect on IL6production by cells prepared from proliferative endometrium.Even in secretory cells PP14 was less effective than IL1 atstimulating IL6 production, with stimulated levels only reachingtwice the basal values. This suggests that PP14 and IL1 actvia different mechanisms in the stimulation of IL6 production.The results show that IL6 production by human endometrial epithelialcells is stimulated by other immunomodulatory peptides and thismay be part of the network of such peptides in the endometriumwhich may influence embryo implantation.     

Dexamethasone during ovulation induction for in-vitro fertilization: a pilot study

The purpose of the present study was to determine whether adrenalandrogen suppression with dexamethasone (DEX) during ovulationinduction improves the outcome of in-vitro fertilization (IVF)cycles. A total of 25 patients with serum dehydroepiandrosteronesulphate (DHEAS) concentrations>2.5 µg/ml were randomizedto receive either 0.5 mg DEX daily or placebo during ovulationinduction with leuprolide acetate down-regulation plus humanmenopausal gonadotrophins (HMG). Nine patients undergoing asubsequent IVF cycle were crossed over to the other treatmentgroup. Ovarian responsiveness and IVF outcome variables analysedincluded number of follicles>12 mm in diameter, serum oestradiolconcentrations on the day of human chorionic gonadotrophin (HCG)administration, number of ampoules of HMG administered, numberof oocytes retrieved, percentage of oocytes fertilized, numberof embryos transferred, implantation rate and numbers of clinicalpregnancies and live birth pregnancies. The 31 randomized IVFcycles revealed a trend towards a higher implantation rate forthe placebo-treated group compared to the DEX-treated group(24 versus 10%P=0.07). The remainder of the IVF cycle variablesrevealed no statistically significant differences. In conclusion,the suppression of adrenal androgens with DEX in women withDHEAS concentrations >2.5 µg/ml appears to have nobeneficial effects on ovarian responsiveness or clinical orlive birth pregnancy rates.     

The post-menopausal uterus: the effect of hormone replacement therapy on the serum levels of secretory endometrial protein PP14/{beta}-lactoglobulin homologue

The effect of cyclical oestrogen-progestogen replacement onthe levels of endometrial secretory protein PP14 (placentalprotein 14) was studied in 39 post-menopausal women, l3 of whomhad had a hysterectomy. In those women with an intact uterus,the average rise of the late hteal phase serum PP14 concentrationwas from 29 to 45 µg/l, a 55% rise (P < 0.001). Onlya slight rise (from 27 to 30 µg/l) was observed in hysterectomizedwomen. Cyclical replacement with oestrogen and levonorgestrelcaused a greater rise in serum PP14 level than did replacementwith the same dose of oestrogen plus medroxyprogesterone acetate(P < 0.05). Because PP14 is found also in the serum of hysterectomizedpost-menopausal women, the uterus cannot be the only sourceof circulating PP14. But, the difference between hysterectomizedand non-hysterectomized women indicates that the quiescent post-menopausaluterus responds to oestrogen—progestogen replacement byincreased PP14 secretion, which can be detected and quantifiedby a blood test. The measurement of PP14 in serum may also becomeuseful for kdng the effect of various progestogens.     

In-vitro fertilization treatment for unexplained recurrent abortion: a pilot study

To determine the effectiveness of in-vitro fertilization (IVF)and embryo transfer for patients with unexplained habitual abortion,we carried out a prospective observational study using a historicalcomparison group. A total of 12 couples with three or more (mean4.91, range 3–10 miscarriages) first trimester spontaneousabortions of unknown aetiology were treated with IVF and embryotransfer (group 1). Patients underwent IVF after combined gonadotrophin-releasinghormone agonist/gonadotrophin treatment for ovarian stimulation,and three to four embryos were replaced into the uterus in allwomen. Eight of the 12 women (66.6%) in group 1 became pregnant(one patient after a frozen-thawed embryo transfer), and allof them had viable pregnancies. A patient with 10 previous abortionsbecame pregnant and carried to term after IVF and embryo transfer,and subsequently miscarried two new spontaneous gestations.A historical comparison group (group 2) included the last eightwomen with unexplained recurrent abortion (mean 4, range 3–8miscarriages) who underwent the same investigations for thecondition and received identical early supportive care in theirnext spontaneous pregnancy as patients in group 1. Three ofthe eight pregnancies in group 2 ended in an abortion. Our resultssuggest that IVF and embryo transfer may be a new therapeuticapproach for unexplained recurrent miscarriage.