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.     

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 of in-vitro fertilization pregnancies during the first trimester

The endocrine function of the corpus luteum and placenta andthe inter-relationships between ovarian steroids and the placentalproteins in pregnancies achieved following ovarian stimulation,in-vitro fertilization and embryo transfer (IVF-ET) have beeninvestigated. The serum concentrations of human chorionic gonadotrophin(HCG), Schwangerschaft protein-1 (SP-1), pregnancy-associatedplasma protein A (PAPP-A), progesterone and oestradiol weremeasured at weekly intervals between the 4th (ET plus 2 weeks)and 14th week of gestation in 86 pregnancies. The mean concentrationsof the placental proteins and oestradiol were significantlyhigher in twin than in singleton pregnancies from as early as5 weeks gestation, but the mean concentrations of progesteronewere significantly higher only at the end of the first trimester.Ranking, as demonstrated by the presence of statistically significantcorrelations between serum levels of each substance analysedin week 13 with those of preceding weeks, was established forprogesterone and SP-1 from the 5th week, for oestradiol andPAPP-A from the 7th week and for HCG from the 8th week of gestation.The presence of statistically significant correlations betweeneach substance analysed suggests that the placenta becomes thedominant source of oestradiol from 8 weeks gestation and ofprogesterone not until 12 weeks gestation, and that the placentalsynthesis of HCG, SP-1, PAPP-A, oestradiol and progesteroneappear to be linked. There were no statistically significantcorrelations between the serum concentrations of HCG and eitherprogesterone or oestradiol until the production of each hadbecome predominantly placental.     

Is luteal function maintained by factors other than chorionic gonadotrophin in early pregnancy?

Women with ectopic pregnancy (n = 14) and early embryonic arrest(‘blighted ovum’) (n = 9) were studied 16 days afterconception, at a time when they were asymptomatic and serumconcentrations of -human chorionic gonadotrophin (HCG) werein the normal range and increasing at an apparently normal rate.Serum progesterone and oestradiol concentrations were comparedwith those from normal women matched for gestational age andserum -HCG concentration whose singleton intra-uterine pregnanciesproceeded normally beyond 20 weeks. Mean serum progesteroneconcentrations were significantly lower in the women with ectopicpregnancies than in matched controls (P < 0.002); however,there was no difference in the serum progesterone concentrationsbetween women with blighted ova and matched controls. Statisticallysignificant differences were not seen in serum oestradiol concentrationsbetween either group and matched controls. Similarly there wasno difference in serum progesterone or oestradiol concentrationsin 20 women who conceived ectopic pregnancies and 20 women conceivingblighted ovum pregnancies and their matched intra-uterine controlswhen conception followed ovarian stimulation. The low serumprogesterone concentrations seen in ectopic pregnancy suggestthat there is a specific and selective deficiency in progesteronesynthesis, which implies that factors other than HCG may influenceluteal function.     

Maternal serum concentrations of pregnancy associated placental protein A and pregnancy specific {beta}-1-glycoprotein in multifetal pregnancies before and after fetal reduction

Placental function in multifetal pregnancies before and afterembryo reduction was investigated by measuring maternal serumconcentrations of pregnancy associated placental protein-A (PAPP-A)and pregnancy specific -1-glycoprotein (SP-1). Three groupsof pregnant women were studied following assisted reproduction;groups 1 and 2, were 12 singleton and 12 twin pregnancies respectively,and group 3 comprised 12 women with multifetal pregnancies undergoingembryo reduction. PAPP-A and SP-1 were measured serially at8–21 weeks gestation. In all pregnancies, maternal serumPAPP-A and SP-1 increased with gestation. In twin pregnanciesthe mean concentrations of SP-1 were significantly higher thanin singletons at all gestations, whereas for PAPP-A, concentrationswere similar between these groups. In multifetal pregnanciesbefore embryo reduction, the serum concentrations of both proteinswere significantly higher than in twin pregnancies. Followingreduction, the concentrations of PAPP-A remained significantlyhigher than for twins throughout, whereas the concentrationsof SP-1 gradually converged towards those of twins; by 19 weeksthere was no difference between the means of the two groups.These findings suggest that circulating concentrations of SP-1reflect total placenta mass, which is proportional to the numberof live fetuses, whereas the pattern of PAPP-A changes suggeststhat this protein is produced by the placenta, decidua and othertissues.     

Rapid diagnosis of early ectopic pregnancy in an emergency gynaecology service--are measurements of progesterone, intact and free {beta} human chorionic gonadotrophin helpful?

The clinical usefulness of measuring serum concentrations ofprogesterone, human chorionic gonadotrophin (HCG) and the free-subunit of HCG in distinguishing between early viable and non-viablepregnancy, before an accurate ultrasound diagnosis is possible,was evaluated in a prospective study of patients presentingto our emergency gynaecology service with a clinical suspicionof ectopic pregnancy. Patients were selected on the basis ofinitial HCG concentrations; samples with HCG 25–10 000IU/I were later analysed for progesterone and free HCG. Of the181 patients studied, 38 (21%) had an ectopic pregnancy, 108(60%) had a spontaneous abortion and 35 (19%) had a viable intra-uterinepregnancy. Concentrations of HCG and free HCG in the group withviable pregnancies were significantly higher than in the groupwith ectopic pregnancy (P < 0.001) and than those destinedto miscarry (P < 0.01). Progesterone concentrations werealso significantly higher in the viable versus the ectopic andthe spontaneous abortion groups (P < 0.001 in each case).Despite these highly significant differences there was a degreeof overlap such that it was impossible to devise a cut-off levelfor any hormone analysed, either singly or in combination, whichwould offer a clinically useful predictor of outcome.     

Relationship of biochemical pregnancy to pre-ovulatory endometrial thickness and pattern in patients undergoing ovulation induction

In order to assess the relationship between pre-ovulatory endometrialthickness and pattern and biochemical pregnancy, the pregnancyoutcome was retrospectively analysed in 81 patients undergoingovulation induction evaluated by vaginal ultrasound on the dayof human chorionic gonadotrophin (HCG) administration or luteinizinghormone (LH) surge. Biochemical pregnancies occurred in 7/32(21.9%) pregnancies when endometrial thickness was <9 mm,compared to 0/49 when endometrial thickness was 9 mm on theday of HCG administration or LH surge (P < 0.0025). Clinicalabortions occurred in 5/32 (15.6%) pregnancies when endometrialthickness was 6–8 mm, compared to 6/49 (12.2%) when endometrialthickness was 6–8 mm (NS). Endometrial thickness was relatedto the cycle day of HCG or LH surge (r = 0.37, P < 0.001)but was unrelated to oestradiol level on the day of HCG administrationor LH surge (r = 0.12). Biochemical pregnancies were relatedto endometrial pattern (r = – 0.22, P = 0.02) but wereunrelated to maternal age or previous abortions. Clinical abortionswere related to age (r = 0.26, P = 0.01) and to previous abortion(r = 0.25, P = 0.013) but were unrelated to endometrial pattern.Neither biochemical pregnancy nor clinical abortion was relatedto oestradiol or LH levels on the day of HCG administrationor LH surge. These findings suggest that the majority of biochemicalpregnancies do not result from karyotypically abnormal embryos,as do clinical abortions.     

Preliminary results on the role of embryonic human chorionic gonadotrophin in corpus luteum rescue during early pregnancy and the relationship to abortion and ectopic pregnancy.

The precise mechanisms by which corpus luteum (CL) function is modulated during early pregnancy are not known. Evidence in failed pregnancies (ectopic, abortions), shows that factors other than human chorionic gonadotrophin (HCG) could be involved in its regulation. The objective of this study was to investigate the dynamics of beta-HCG, progesterone and oestradiol production in early pregnancy and its relation to embryonic quality and topographic localization. Plasma concentrations of progesterone, oestradiol and beta-HCG were studied between days +12 and +21 after an in-vitro fertilization (IVF) embryo transfer in 11 intrauterine pregnancies, 10 intrauterine abortions and seven tubal pregnancies. Tubal pregnancies and abortions were grouped according to doubling time (DT) of HCG. Results showed that oestradiol concentrations were apparently reduced in both ectopic pregnancies and abortions compared with normal pregnancies. The fall in oestradiol concentrations was seen in ectopic pregnancies with an abnormal DT for HCG and in all abortions. When the ectopic pregnancy had a normal DT, oestradiol and progesterone concentrations were normal. In abortions, the fall in oestradiol and progesterone concentrations was less influenced by the DT of HCG. These findings suggest that corpus luteum function depends on an adequate DT of HCG more than an absolute value, and with normal trophoblastic tissue the site of implantation does not affect CL function.     

Pregnancy: The expectant management of early pregnancies of uncertain site

The role of expectant management was evaluated in 80 women inwhom clinical examination, including vaginal ultrasound, hadfailed to identify the location of an early pregnancy. In 45cases, spontaneous resolution of the pregnancy products occurred.A normal intra-uterine pregnancy was diagnosed in 12 patients.A total of 23 patients underwent active therapeutic measuresdue to an ectopic pregnancy (n = 16) or a spontaneous abortion(n = 7). The effectiveness of different diagnostic measuresto identify patients suitable for expectant management was analysed.In 33/34 patients (97%) with a relative daily human chorionicgonadotrophin (HCG) change of <–5%, and a serum progesteroneconcentration of <20 nmol/l, spontaneous resolution of thepregnancy products occurred. Among 46 cases, with a relativedaily HCG change of >–5% and/or serum progesterone>20 nmol/l, active therapeutic measures were carried outin 22 cases (48%), a normal intra-uterine pregnancy was diagnosedin 12 cases (26%) and spontaneous resolution of the pregnancyproducts occurred in 12 cases (26%). In conclusion, the combinationof a single progesterone assay and serial HCG determinationsretrospectively identified early pregnancies of uncertain locationin whom expectant management was a safe management option.     

Protein and steroid levels in embryonic cavities in early human pregnancy

Biochemical analysis including concentrations of urea, creatinine,human chorionic gonadotrophin (HCG), oestradiol, progesterone,and -fetoprotein (AFP), twodimensional gel electrophoresis,and the affinity of AFP for Concanavalin A (Con A)—Sepharosewere performed on samples of exocoelomic and amniotic fluidsretrieved by transvaginal puncture and maternal serum from 25normal pregnancies between 5 and 12 weeks of gestation. Biochemicalassays showed that during this period of gestation no differencesin urea concentration were found between fluids from the threecompartments, whereas creatinine concentration decreased significantly(P < 0.001) from maternal serum to amniotic fluid. The exocoelomicfluid contained significantly (P < 0.001) higher concentrationsof oestradiol, progesterone and HCG than both maternal serumand amniotic fluid. AFP concentration was similar in amnioticand exocoelomic fluids and significantly (P < 0.001) lowerin maternal serum. Between the second and the third months ofgestation, urea concentration decreased significantly (P <0.05) and oestradiol, HCG and AFP increased significantly inmaternal serum (P < 0.05, P < 0.05, P < 0.001, respectively).During the same period of gestation, exocoelomic fluid concentrationsof urea and HCG decreased significantly (P < 0.005, P <0.001, respectively). Comparison of the two-dimensional gelpatterns obtained from maternal serum with those from exocoelomicamniotic fluids revealed no significant qualitative differences,except for several small proteins. These results suggest thatprotein pathways across materno-embryonic membranes are notsimply passive transfers. Con A affinity molecular variantsof AFP demonstrated that both exocoelomic and amniotic fluidAFP were mainly of yolk sac origin and that maternal serum AFPwas mainly of fetal liver origin, suggesting that the humansecondary yolk sac has both absorptive and excretory functions.     

Analysis of the incidence and risk factors associated with ectopic pregnancy following in-vitro fertilization and embryo transfer

Ectopic pregnancy is a well known complication of in-vitro fertilization(IVF) and embryo transfer. From March 1983 to December 1993,3000 clinical pregnancies were achieved at Bourn Hall Clinic,including 135 ectopic pregnancies (4.5%). Of these ectopics20 were heterotopic, eight ovarian, six bilateral tubal andthe remainder were singleton tubal pregnancies. The main riskfactor identified in the series was a history of pelvic inflammatorydisease (P < 0.001). The data also showed that ectopic pregnancyis at present more prevalent among patients in whom tubal damageis the reason for treatment. There was slight statistical evidence(P = 0.05) that patients having ectopic pregnancies receiveda higher volume of culture medium than those having normal deliveries.There was also an apparent trend (P = 0.07, not significant)that high progesterone/oestradiol ratio on the day of embryotransfer was associated with ectopic pregnancy. There was nostatistical evidence of association between ectopic pregnancyand a history of ectopic pregnancy, abortion, still birth, terminationof pregnancy, neonatal death, tubal surgery, ovarian stimulationprotocol, plasma concentration of oestradiol, luteinizing hormoneand progesterone, number of oocytes retrieved, number or qualityof embryos transferred, administration of general anaesthesiafor embryo transfer, and the number of patent Fallopian tubes.Awareness of the risk factors associated with ectopic pregnancyplays an important part in the early diagnosis of this potentiallyfatal condition.     

The benefits of mid-luteal addition of human chorionic gonadotrophin in in-vitro fertilization using a down-regulation protocol and luteal support with progesterone

Luteal support is essential in in-vitro fertilization (IVF)when long-acting gonadotrophin-releasing hormone agonist (GnRHa)is used. Because progesterone lacks luteotrophic stimulation,it seems to be the drug of choice in cases with an increasedrisk of ovarian hyperstimulation syndrome (OHSS). The aim ofthis study was to assess the beneficial effect of the mid-lutealaddition of human choriomc gonadotrophin (HCG) in IVF, usinga down-regulation protocol and luteal support with progesterone,in a prospective randomized study. The study included 170 IVFcycles down-regulated with long-acting GnRHa which were supportedwith 50 mg/day progesterone i.m. during the luteal phase. Patientswere evaluated in the mid-luteal period. Those without clinicalsigns of OHSS, oestradiol concentrations <1000 pg/ml andprogesterone concentrations <50 mg/ml were randomly allocatedto either the addition of 2500 IU HCG (HCG+ group) or no HCG(HCG– group). End luteal phase progesterone concentrationsamong non-pregnant patients were used to assess the contributionof exogenous progesterone and to categorize pregnancies accordingto their corpus luteum function. Similar low OHSS (2.7 and 1.8%)and pregnancy (30 and 29%) rates were observed in the HCG+ andHCG– groups respectively. Of the 26 pregnancies in theHCG+ cases, there was only one case with reduced corpus luteumfunction, compared with 12 of the 25 pregnancies among HCG–patients. Cases with reduced corpus luteum function requiredcontinuous progesterone support and presented lower HCG concentrationsand a higher rate of adverse pregnancy outcome. We concludethat mid-luteal HCG addition does not affect pregnancy rate,but in fact helps to preserve corpus luteum function and avoidsthe need for further supplementation during early pregnancy.     

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.     

Endocrinology: Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial

Two different regimens of luteal support in gonadotrophin hormone-releasinghormone (GnRH) analoguefhuman menopausal gonadotrophin (GnRHa/HMG)-inducedin-vitro fertilization cycles (IVF) were compared in a randomizedclinical trial. After embryo transfer, either vaginal progesteronealone was administered (n=89, P group), or a combination ofvaginal progesterone and human chorionic gonadotrophin (n=87,P/HCG group). The primary aim of this study was to assess theeffect of the different regimens of luteal support on the pregnancyrate. The secondary aim was to compare oestradiol and progesteroneconcentrations in the luteal phase between the two groups, andassess their effect on the pregnancy rate. A clinical pregnancyrate of 15% was found in the P/HCG group in comparison with26% in the P group (odds ratio 0.49; 99% confidence interval:0.18–1.3). The luteal serum oestradiol and progesteronevalues in the P/HCG group were significantly higher when comparedwith the P group on the 6th, 9th and 12th day after oocyte retrieval(Wilcoxon P<0.001). In accordance with the high oestradiolconcentrations, more cases of ovarian hyperstimulation syndrome(OHSS) were found in the P/HCG group. Oestradiol values on the9th day after oocyte retrieval, presumably the day of implantation,appeared to be higher in women who did not become clinicallypregnant. We conclude that vaginal progesterone alone providessufficient luteal support in GnRHa/HMG induced IVF cycles. Thecombination of vaginal progesterone and HCG as luteal supportleads to significant high luteal oestradiol and progesteroneconcentrations. But a high concentration of oestradiol seemsto have a deleterious effect on the implantation process, resultingin a low pregnancy rate.     

A prospective randomized study on oestradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation

A prospective randomized study was conducted to evaluate theuse of adding oestradiol valerate 6 mg per os daily to intravaginalmicronized progesterone (600 mg daily) as luteal supplements.The study comprised 378 infertile women superovulated with agonadotrophin releasing-hormone agonist (GnRHa) and human menopausalgonadotrophins (HMG) for in-vitro fertilization (IVF) or zygoteintra-Fallopian transfer (ZIFT). The clinical pregnancy ratewas similar (29%) whether or not oestradiol valerate was addedto intravaginal progesterone. Eighteen out of twenty-two endometrialbiopsies were in phase, and morphological evaluations of thetwo luteal supplementation groups were not different. Serumhormone profiles in singleton pregnancies showed a similar dayof appearance of human chorionic gonadotrophin (HCG) in bothprotocols but significantly lower oestradiol concentrationsarose in the group without oestradiol valerate. In 32% of thesingleton pregnancies, the first appearance of HCG occurredlater than day 12 after HCG injection; in those ongoing pregnancies,corpus luteum rescue—as measured by significantly lowerserum oestradiol and progesterone concentrations—was compromised.This study provided no evidence of any benefit of routinelysupplementing GnRHa/HMG cycles with oestradiol valerate in additionto intravaginal micronized progesterone.     

Pregnancy: Temporal relationship between the human chorionic gonadotrophin peak and the establishment of intervillous blood flow in early pregnancy

The purpose of this study was to investigate the temporal relationshipbetween the early pregnancy peak of circulating human chorionicgonadotrophin (HCG) concentration and the establishment of maternalblood flow in the placental intervillous space. The presenceof blood flow echoes within intervillous space was determinedby colour Doppler imaging from 44 women with clinically uncomplicatedpregnancy between 6 and 18 weeks gestation. Circulating HCG,free - and HCG subunits, oestradiol and progesterone concentrationswere immunoassayed in blood samples collected at the time ofDoppler examination. A continuous intervillous blood flow wasdetected in all cases with a gestational age 11.7 weeks (n =18) but never before this time. Circulating concentrations offree HCG, oestradiol and progesterone were linearly or exponentiallycorrelated with gestational age (r = 0.860, 0.903 and 0.538respectively, all with P < 0.001), indicating steady increaseof these hormones with advancing gestation. However, the bestfitted lines were found to be parabolic for HCG (r = 0.771,P < 0.001) and HCG (r = 0.695, P < 0.001), their highestpoints corresponding to 11.24 and 10.74 weeks gestational agerespectively. The close temporal relationship between the Doppleradvent of intervillous maternal blood flow and the HCG peaksuggests that the establishment of the intervillous blood flowis associated with the decline in circulating HCG concentrations.     

Single progesterone assay for early recognition of abnormal pregnancy

Serum progesterone and human chorionic gonadotrophin (HCG) were analysed using a time-resolved fluoroimmunoassay in an unselected group made up of 158 women with clinical suspicions of abnormal early gestation. Only cases in which endovaginal sonography had failed to localize the pregnancy were included. A single HCG determination had no diagnostic value. On the other hand, a critical progesterone level of 30 nM was determined below which no viable intrauterine pregnancies were found. Eighty-eight per cent of the ectopic pregnancies (n = 97) and 83% of the spontaneous abortions had progesterone levels below this limit. The discriminatory efficacy of one single progesterone determination was independent of the actual HCG level and serial determinations of progesterone did not increase the discriminatory power.     

Regulation of corpus luteum function

The effects have been studied of different ovulation inductionregimens [either domiphene citrate or buserelin in combinationwith human menopausal gonadotrophin (HMG)] on the circulatingconcentrations of progesterone, oestradiol, relaxin and humanchorionic gonadotrophin (HCG) during the first trimester ofpregnancy. Ovulation induction with clomiphene resulted in elevatedconcentrations of gonadotrophins in both phases of the cycle,while during ovulation induction with buserelin, gonadotrophinconcentrations were elevated in the follicular phase only. Theconcentrations of all corpus luteum products were greater inclomiphene pregnancies compared with spontaneous pregnancies,but only oestradiol and relaxin concentrations were greaterin clomiphene pregnancies compared with buserelin pregnancies.The concentrations of HCG were significantly reduced in clomiphenepregnancies compared to natural pregnancies. Relaxin concentrationswere significantly higher from 7 weeks gestation in buserelincompared with spontaneous pregnancies, while progesterone, oestradioland HCG concentrations were not consistently different. Consistentassociations were found between relaxin and HCG concentrationsin spontaneous pregnancies and between the concentrations ofrelaxin and both progesterone and oestradiol in pregnanciesachieved after ovulation induction. These data suggest that(i) given the similarity in the circulating concentrations ofHCG, the relatively lower circulating gonadotrophin concentrationsduring the luteal phase of the cycle of conception result inreduced circulating concentrations of oestradiol and relaxin;while in the case of relaxin this effect is partially reversible,there is no evidence that this is so for oestradiol; (ii) synthesisof progesterone in the corpus luteum is less affected by lowerconcentrations of gonadotrophins during the luteal phase; (iii)ovulation induction with clomiphene results in pregnancies withlower concentrations of HCG, suggesting that trophoblast functionmay be impaired; and (iv) corpus luteum function is linked withplacental steroidogenesis.     

Pregnancy: Oocyte donation to women of advanced reproductive age: pregnancy results and obstetrical outcomes in patients 45 years and older

We analysed the results of oocyte donation to women of advancedreproductive age (45 years old) and followed their pregnanciesthrough to delivery in order to assess obstetrical outcomes.Patients (n = 162) aged 45–59 years (mean ± SD;47.3 ± 3.4 years) underwent 218 consecutive attemptsto achieve pregnancy. Oocytes (16.2 ± 7.2 per retrieval)were provided by donors 35 years old. Cleaving embryos (8.2± 4.8 zygotes/couple) were transferred trans-cervically(4.5 ± 1.1 per embryo transfer) to recipients prescribedoral micronized oestradiol and intramuscular progesterone. Followingoocyte aspiration there were six instances of non-fertilization(2.8%) and 212 embryo transfers. A total of 103 pregnancieswas established for an overall pregnancy rate (PR) of 48.6%,which included 17 preclinical pregnancies, 12 spontaneous abortions,and 74 delivered pregnancies (clinical PR 40.6%; delivered PR34.9%). Multiple gestations were frequent (n = 29; 39.2% ofpregnancies) and included 20 twins, seven triplets, and twoquadruplets. Two of the triplet and both of the quadruplet pregnanciesunderwent selective reduction to twins. Antenatal complicationsoccurred in 28 women (37.8% of deliveries) and included pretermlabour (n = 9), gestational hypertension (n = 8), gestationaldiabetes (n = 6), carpel tunnel syndrome (n = 2), pre-eclampsia(n = 2), HELLP syndrome (n = 2), and fetal growth retardation(n = 2). 48 (64.8%) deliveries were by Caesa-rean section. Thegestational age at delivery for singletons was 383 ±1.3 weeks (range 35–41 weeks), with birth weight 3218± 513 g (range 1870–4775 g); twins 35.9 ±2.0 weeks (range 32–39 weeks), birth weight 2558 ±497 g (range 1700-3450 g); and triplets 33.5 ± 0.7 weeks(range 32-34 weeks), birth weight 1775 ± 190 g (range1550-2100 g). Neonatal complications (4.6% of babies born) includedgrowth retardation (n = 2), trisomy 21 (n = 1), ventricularseptal defect (n = 1), and small bowel obstruction (n = 1).There were no maternal or neonatal deaths. We conclude thatoocyte donation to women of advanced reproductive age is highlysuccessful in establishing pregnancy. However, despite carefulantenatal screening, obstetrical complications are common, oftensecondary to multiple gestation.     

Early diagnosis of ectopic pregnancy using receiver -- operator characteristic curves of serum progesterone concentrations

The objective was to assess the usefulness of serum progesteroneconcentrations in the differentiation of intrauterine (viableand non-viable) and extra-uterine pregnancies. Progesteroneconcentrations were prospectively measured at 4, 5 and 6 weeksgestation in 338 pregnancies which resulted in 242 viable births,81 abortions and 15 ectopic pregnancies. Progesterone thresholdanalysis was performed using receiver—operator characteristiccurves. The progesterone threshold value for ectopic pregnancyat 4 weeks was 5 ng/ml, at 5 weeks 10 ng/ml and at 6 weeks 20ng/ml. A significant difference was observed between all intra-uterineversus ectopic pregnancies (P = 0.0005), but not between viableversus non-viable intra-uterine pregnancies (P = 0.37). Thedifferences were most clearly defined at 4 weeks and decreasedwith increasing gestation. We conclude that serum progesteroneand gestational age taken together can differentiate intra-uterinefrom extra-uterine pregnancies with a very high sensitivityand specificity at 4 weeks gestation, a time when ectopic pregnanciesare not evident on ultrasound examination.