Endocrinology: Reduced implantation rate associated with a subtle rise in serum progesterone concentration during the follicular phase of cycles stimulated with a combination of a gonadotrophin-releasing hormone agonist and gonadotrophin

Our objective was to assess the effects of subtle increasesin serum progesterone concentration (1.0–2.0 ng/ml) onthe outcome of in-vitro fertilization (IVF), particularly onthe quality of embryos, during the follicular phase of cyclesstimulated with gonadotrophin-releasing hormone agonist (GnRHa)and human menopausal gonadotrophin (HMG). A total of 97 patientsunderwent 116 cycles of IVF and were stimulated with a combinationof HMG and GnRHa. They were divided into two groups: those witha subtle progesterone rise and those with no progesterone rise.The two groups were compared with respect to serum oestradiol,progesterone, immunoreactive luteinizing hormone (I-LH), bioactiveLH (B-LH), and results of IVF. The groups did not differ significantlyin mean age or in total dose of HMG received. On the day thathuman chorionic gonadotrophin was administered, concentrationsof oestradiol and progesterone were significantly higher inthe subtle progesterone rise cycles than in the no progesteronerise cycles. In the no progesterone rise cycles, the percentagesfor embryos beyond the 4-cell stage, grade 1 embryos, and implantationrates were significantly higher than those in subtle progesteronerise cycles. The combination of GnRHa and HMG eliminated anysignificant rise in serum I-LH or B-LH concentration duringthe follicular phase, but did not suppress the subtle rise inprogesterone. These results confirm our previous finding thata subtle progesterone rise adversely affects the outcome ofIVF. It is also suggested that a reduction in embryo qualitymay influence the lower rate of implantation in subtle progesteronerise cycles.     

Endocrinology: Daily measurements and in-vitro effects of human chorionic gonadotrophin in the early luteal phase

The purpose of the present study was to analyse daily measurementsof human chorionic gonadotrophin (HCG) in in-vitro fertilization(IVF) cycles and to reproduce the effects of HCG in vitro usinghuman granulosa—luteinized cells from the same patients.The study population consisted of nine women undergoing IVFbecause of tubal infertility in whom blood was drawn every 24h from the day of the ovulatory dose of HCG (10 000 IU) until6 days after ovum pick-up. Granulosa—luteal cells fromthe follicular aspirates were collected and cultured in vitroup to 6 days in the presence of increasing concentrations (0,0.01, 0.1, 1.0 and 100.0 IU/ml) of HCG. Serum progesterone andHCG in vivo as well as progesterone accumulation in vitro ondays 2, 4 and 6, were the main outcome measures. Maximum HCGconcentrations (0.25 IU/ml) were reached the day before ovumpick-up, and continuously decreased until day 6 after ovum retrieval.HCG did not stimulate progesterone production in vitro at anydose tested until day 6 after ovum pick-up. Then, 0.01 IU/mlresulted significantly (P < 0.05) stimulatory compared tocontrols, while 1.0 IU/ml was inhibitory (P < 0.05). It isconcluded that HCG supplementation in an IVF cycle is unnecessaryuntil day 6 after ovum pick-up. On day 6, progesterone productionis stimulated with very low concentrations of HCG.     

Endocrinology: Pharmacokinetics of two human menopausal gonadotrophin preparations after single intravenous administration during pituitary suppression

A randomized study was performed in nine healthy women, to investigatepharmacokinetic parameters and bioequivalence of two human menopausalgonadotrophin preparations after i.v. administration. Endogenousgonadotrophin activity was suppressed by triptorelin administration.Humegon and Pergonal (225 IU of each) were injected i.v. ina cross-over way with an interval of 1 week. Blood samples werecollected frequently and serum concentrations of follicle stimulatinghormone (FSH), luteinizing hormone (LH), specific LH, and humanchorionic gonadotrophin (HCG) were determined by fluoroimmunoassaysassays. Serum LH bioactivity was measured by an in-vitro bioassay.The area under curve (AUC) and half-life of FSH were respectively431.5 IU h/1 and 22.20 h for Humegon, and 402.6 IU h/1 and 21.33h for Pergonal. For both preparations, the (total) LH immunoactivityand in-vitro bioactivity of serum LH were very similar, andappeared to be a composite of specific LH and HCG activity.The AUC data of specific LH were 17.50 IU h/1 for Humegon and21.79 IU h/1 for Pergonal respectively. The AUC and half-lifeof HCG were 153.7 IU h/1 and 14.80 h for Humegon, and 134.1IU h/1 and 12.11 h for Pergonal. The two preparations were bioequivalentwith respect to FSH and HCG immunoreactivity. Bioequivalencecould not be proven for LH activity because of the small numberof subjects.     

Endocrinology: Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women

Seven women suffering from hypogonadism due to previous hypophysectomy,isolated gonadotrophin deficiency, or Kallman's syndrome [medianage 39 years (range 24–45)] volunteered to participatein a study to assess ovarian response following multiple-doseadministration of recombinant human follicle-stimulating hormone(rhFSH; Org 32489). Baseline serum FSH and luteinizing hormone(LH) concentrations were 0.25 (<0.05–1.15) IU/l and0.06 (<0.05–0.37) IU/l, respectively. Subjects receiveddaily i.m. injections of rhFSH for 3 weeks (week 1: 75 IU/day,week 2: 150 IU/day, week 3: 225 IU/day). Blood sampling andsonographic investigations were performed on alternate days.Steady-state FSH concentrations were reached 3–5 daysafter alterations of the doses administered. Maximum FSH concentrationswere between 7.1 and 11.8 IU/l, whereas serum LH concentrationsremained unchanged. Due to absent follicle development and lackof a rise in immunoreactive inhibin (INH) (response failurepossibly due to early ovarian failure or resistant ovary syndrome)in two subjects, analysis of ovarian response was restrictedto five volunteers. Serum androstenedione levels showed no significantchanges during rhFSH administration. Although serum immunoreactiveINH concentrations reached normal late follicular values [659(388–993) IU/l], serum oestradiol revealed only a minorincrease [77 (18–210) pmol/I]. Moreover, growth of (multiple)ovarian follicles was observed up to pre-ovulatory sizes (>15mm) in these patients. It may be concluded from the presentstudy that (i) rhFSH exhibits no intrinsic LH activity; (ii)rhFSH stimulation in hypogondotrophic women resulted in an immunoreactiveINH rise which was similar to that in normal women, whereasin contrast only a minor increase in oestradiol concentrationswas observed (suggesting normal granulosa cell function andlow availability of androgens as a substrate for aromatization);(iii) despite the minimal oestrogen increase, ovarian folliclesdeveloped normally to the pre-ovulatory stage.     

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.     

A sporadic case of delayed implantation after in-vitro fertilization in the human?

A possible case of delayed implantation after in-vitro fertilization(IVF) is described. The patient was sterilized in 1981, andmade fertile again by tubal anastomosis in 1988. In 1990 and1992 the patient had two right-sided tubal pregnancies, thefirst was treated with prostaglandin instillation, the secondwith salpingectomy. In connection with the salpingectomy in1992, the left tube was observed to be constricted in the middlepart and with phimosis of the ostium. In 1994 three IVF embryoswere transferred, but 15 days after the transfer, serum humanchorionic gonadotrophin (HCG) was negative (<10 IU/ml). Sevenweeks after the embryo transfer, menstruation was still missing,and the serum HCG was now positive (329 IU/ ml). Subsequentultrasound scans were compatible with an intrauterine pregnancy,progressing normally, but 5 weeks delayed compared with theoocyte aspiration. The pregnancy was successfully carried toterm. Such a long delay in detection of HCG, in associationwith a normal pregnancy, has not been described in the literaturebefore.     

Endocrinology: Luteal function following ovulation induction in polycystic ovary syndrome patients using exogenous gonadotrophins in combination with a gonadotrophin-releasing hormone agonist

The luteal phase was studied in 12 polycystic ovary syndrome(PCOS) patients following ovulation induction using exogenousgonadotrophins combined with a gonadotrophin-releasing hormoneagonist (GnRH-a). Human menopausal gonadotrophin (HMG) was precededby 3 weeks of treatment with GnRH-a (buserelin; 1200 µg/dayintra-nasally) and administered in a step-down dose regimenstarting with 225 IU/day i.m. GnRH-a was withheld the day beforeadministration of human chorionic gonadotrophin (HCG; 10 000IU i.m.). Blood sampling and ultrasound monitoring was performedevery 2–3 days until menses. The luteal phase was significantlyshorter in PCOS patients as compared to eight regularly cyclingcontrols: 8.8 (3.3–11.4) days [median(range)] versus 12.8(8.9–15.9) days (P = 0.01). Median peak values for progesteronedid not show significant differences comparing both groups:52.3 (17.1–510.3) nmol/l versus 43.0 (31.2–71.1)nmol/l, respectively (P = 0.8). The interval between the dayof the progesterone peak and return to baseline was significantlyshorter in the PCOS patients than in controls: 2.5 (0.3–4.9)days versus 4.2 (3.9–10.5) days (P < 0.005). Luteinizinghormone (LH) concentrations during the luteal phase as reflectedby area under the curve were significantly lower in PCOS ascompared to controls: 4.4 (1.6–21.0) IU/l x days and 49.0(27.8–79.6) IU/l x days, respectively (P < 0.001).In conclusion, patients with PCOS may suffer from insufficientluteal phases after ovulation induction using HMG/HCG in combinationwith a GnRH-a. The corpus luteum apparently lacks the supportof endogenous LH and may be stimulated only by the pre-ovulatoryinjection of HCG. Potential involvement of adjuvant GnRH-a medicationor HCG itself in luteal suppression of endogenous gonadotrophinsecretion, and the importance of luteal function for pregnancyrates following treatment, warrant further studies.     

Endocrinology: The empty follicle syndrome: a pharmaceutical industry syndrome

The purpose of this study is to provide evidence that emptyfollicle syndrome (EFS) is a result of an abnormality in thein-vivo biological activity of some batches of commerciallyavailable human chorionic gonadotrophin (HCG). This is a comparativestudy between six consecutive in-vitro fertilization (IVF) caseswith EFS (study group) and 10 IVF pregnancy cycles (controlgroup). Both groups received the same ovarian stimulation protocolconsisting of leuprolide acetate and human menopausal gonadotrophin(HMG). An i.m. injection of 10 000 IU of HCG was administeredonce follicles had reached 18–20 mm and oestradiol/follicle16 mm was at least 900 pmol/l. Transvaginal aspiration was performed36 h later. Plasma HCG prior to and 12 h after i.m. injectionas well as the follicular fluid (FF) concentrations of oestradiol,progesterone, luteinizing hormone (LH) and HCG were determinedin the study group and controls. The in-vitro biological activityof the batch of HCG used by the EFS cases and the control groupwas determined using a Leydig cell preparation from adult rats.Furthermore, the plasma clearance rate after i.v. injectionof 5000 IU of HCG, from the same batches, was studied in threemale volunteers. In the IVF cycles, no HCG was detected in plasmaprior to the injection of commercial HCG. After 12 h, no HCGwas detected in the study group compared to a mean of 207.5IU/l (110–360) in controls. Mean FF concentration of LH,HCG, progesterone and oestradiol was 0.9 IU/1, 0 IU/l, 3.1 nmol/mland 4.4 nmol/ml in EFS compared to 1.0, 98.3, 32.0 and 3.7 inpregnancy cycles. The in-vitro biological activity in both HCGbatches was not significantly different; however, immunoreactiveHCG used in EFS cases was undetectable in plasma of male volunteersas soon as 10 min after i.v injection of 5000 IU of HCG. Theendocrine abnormalities found in follicular fluids of EFS arenot a consequence of an ovarian problem but the result of alack of exposure to biologically active HCG. The rapid clearanceof the drug after i.v. injection and the high affinity of desialylatedHCG to liver cells suggest this to be a possible explanationfor this infrequent but unfortunate event.     

Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors

This study was designed to identify clinical predictors forearly and late ovarian hyperstimulation syndrome (OHSS). A retrospectiveanalysis of all 592 in-vitro fertilization (IVF) cycles fromthe programme's inception in 1988 up to March 1993 was performed.Six patients (1.0° of cycles) had moderate or severe OHSSpresenting 3–7 days post-human chorionic gonadotrophin(HCG), and four patients (0.7° of cycles) had severe OHSSpresenting 12–17 days post-HCG. No patient with earlyOHSS went on to develop late OHSS, and no patient with lateOHSS had demonstrated early OHSS. Stepwise logistic regressionshowed that early OHSS was predicted by the number of oocytesretrieved (range 18–46) (P= 0.0001) and the oestradiolconcentration on the day HCG was given (range 12 122–24454 pmol/1) (P = 0.0003). Late OHSS was predicted by the numberof gestational sacs (range 2–3) on ultrasound 4 weeksafter embryo transfer (P = 0.0001) but not by the number ofoocytes or oestradiol. Early OHSS was an acute effect of theHCG administered prior to egg retrieval in women with high oestradioland larger numbers of follicles (range 22–51). Late OHSSwas induced by the rising serum concentration of HCG producedby the early pregnancy, and in this series of cases it was associatedonly with multiple gestation.     

Paired human chorionic gonadotrophin determinations for the prediction of pregnancy outcome in assisted reproduction

The aim of this study was to determine the prognostic value of single and paired measurements of serum concentrations of human chorionic gonadotrophin (HCG) for successful pregnancy following in-vitro fertilization (IVF) and tubal embryo transfer (TET). We analysed serum HCG concentrations 15 and 22 days after IVF or TET in 198 conception cycles. Cut-off values of serum HCG were determined by a receiver operating characteristic (ROC) curve. On the basis of single HCG samples on day 15 (HCG15) after transfer, using a cut-off value of HCG15 = 150 mIU/ml, the sensitivity was 71% and the specificity was 77%. The positive predictive value (HCG15 > or = 150 mIU/ml indicating a normal pregnancy) was 89%, while the negative predictive rate (HCG15 < 150 mIU/ml indicating an abnormal pregnancy) was 51%. Patients with HCG15 < 150 mIU/ml but HCG22/HCG15 ratio > or = 15, still had a 90% chance of normal pregnancy. However, in patients with HCG15 < 150 mIU/ml and an HCG22/HCG15 ratio < 15, there was an 84% chance of an abnormal pregnancy. We conclude that a single HCG15 determination combined with the ratio of HCG22 to HCG15 has a higher diagnostic accuracy for prediction of pregnancy outcome than either analysis alone.      

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: Variability in the immunoreactive and bioactive follicle stimulating hormone content of human urinary menopausal gonadotrophin preparations

The within- and between-batch variation in the immuno-reactiveand in-vitro bioactive FSH content of Pergonal, Metrodin andMetrodin-HP was investigated. Three batches of Pergonal andMetrodin, consisting of three ampoules in each batch, and threebatches of Metrodin-HP, consisting of between one and threeampoules per batch, were selected at random. The follicle stimulatinghormone (FSH) content of Pergonal, Metrodin and Metrodin-HPwas determined by radioimmunoassay (R-FSH) and the in-vitrorat Sertoli cell bioassay (B-FSH) using the international urinarystandard 70/45. The variability in the FSH content of the preparationswas evaluated within and between batches by analysis of variance.Within-batch variability of B-FSH was not observed in Pergonalor Metrodin-HP but was seen in two batches of Metrodin in whichthe potency varied by up to 2.4 fold (P = 0.03). The between-batchR-FSH potencies of Pergonal (P1–P3) varied, with P2 (59.8± 0.6) and P3 (61.7 ± 0.9) being higher than P1(47.1 ± 1.5 mean ± SEM IU/ampoule, P < 0.01).A similar pattern of variability was observed for B-FSH. ForMetrodin, each of the batch R-FSH potencies was dissimilar (P< 0.02), with estimates ranging from 34.9 ± 1.2 to64.3 ± 1.8 IU/ampoule. Furthermore, the extensive within-batchB-FSH variation from two batches confounded any meaningful comparisonof between-batch variability. For Metrodin-HP, there was nobetween-batch B-FSH variation (29.0 ± 6.1 to 33.0 ±0.3 IU/ampoule) and the R-FSH content was also well controlled(41.2 ± 0.5 to 46.9 ± 1.1 IU/ampoule). The B:I(bioassay: immunoassay) FSH ratios of Pergonal (0.9 ±0.1, n = 9), Metrodin (2.2 ± 0.3, n = 9) and Metrodin-HP(0.7 ± 0.04, n = 5) were all dissimilar (P < 0.03).Within- and between-batch variations were observed to varyingdegrees in three human urinary gonadotrophin preparations. Thevariations in B-FSH content between the preparations appearedmore extensive than for R-FSH. Of the preparations studied,Metrodin-HP exhibited the least variability.     

Initiation of periovulatory events in gonadotrophin-stimulated macaques with varying doses of recombinant human chorionic gonadotrophin

During in-vitro fertilization (IVF) cycles, a large bolus of human chorionic gonadotrophin (HCG) is used to induce periovulatory events, but the efficacy of lower doses is undefined. Following follicular stimulation in rhesus monkeys, oocyte nuclear maturation, IVF, granulosa cell luteinization and corpus luteum function were compared after injection of 100, 300 or 1000 IU recombinant HCG or 1000 IU urinary HCG. Bioactive HCG rose to peak concentrations within 2 h that were proportional to the dose administered (100 < 300 < 1000 IU, recombinant HCG = urinary HCG). The duration of surge values (>100 ng/ml) was also dose-dependent (0 h, 100 IU; 24 h, 300 IU; >48 h, 1000 IU, recombinant and urinary HCG). While the proportions of oocytes resuming meiosis and undergoing IVF were similar among groups, fewer animals yielded fertilizable oocytes following 100 and 300 IU (five of nine) compared to 1000 IU recombinant and urinary HCG (nine of 10). Peak values of serum progesterone in the luteal phase were similar, but declined 2 days earlier after 100 and 300 IU relative to 1000 IU recombinant and urinary HCG. Thus, 3-10 fold lower doses of HCG elicit low amplitude surges of short duration that induce periovulatory events such as re-initiation of oocyte meiosis and granulosa cell luteinization. However, oocyte fertilization and luteal function may optimally require surges of higher amplitude and longer duration similar to those produced by standard doses of 1000 IU recombinant or urinary HCG.      

Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol

BACKGROUND: Suppression of endogenous LH production by mid-follicular phase GnRH-antagonist administration in controlled ovarian hyperstimulation protocol using recombinant (rec) FSH preparations void of LH activity may potentially affect ovarian response and the outcome of IVF treatment. The present study prospectively assessed the effect of using a combination of recFSH and recLH on ovarian stimulation parameters and treatment outcome in a fixed GnRH-antagonist multiple dose protocol. METHODS: 127 infertile patients with an indication for IVF or ICSI were recruited and randomized (using sealed envelopes) to receive a starting dose of either 150 IU recFSH (follitropin alpha) or 150 IU recFSH plus 75 IU recLH (lutropin alpha) for ovarian hyperstimulation. GnRH-antagonist (Cetrorelix) 0.25 mg was administered daily from stimulation day 6 onwards up to and including the day of the administration of recombinant HCG (chorion gonadotropin alpha). Gonadotropin dose adjustments were allowed from stimulation day 6 onwards, HCG was administered as soon as three follicles > or =18 mm were present. The primary outcome parameter was treatment duration until administration of HCG. RESULTS: Exogenous LH did not shorten the time necessary to reach ovulation induction criteria. Serum estradiol (E(2)) and LH levels were significantly higher on the day of HCG administration in the recLH-supplemented group (1924.7 +/- 1256.4 vs 1488.3 +/- 824.0 pg/ml, P < 0.03), and 2.1 +/- 1.4 vs 1.4 +/- 1.5 IU/l, P < 0.01, respectively). CONCLUSIONS: Except for higher E(2) and LH levels on the day of HCG administration, no positive trend in favour of additional LH was found as defined by treatment outcome parameters.     

Endocrinology: Pre-ovulatory progesterone growth rate in patients treated with gonadotrophin-releasing hormone agonist and outcome of in-vitro fertilization

The present study was undertaken to assess whether the increasein serum progesterone concentration following the administrationof human chorionic gonadotrophin (HCG) may have predictive valueon the in-vitro fertilization (IVF) success rate. Progesteroneconcentration on the day of HCG administration and the increasein progesterone concentration on the following day were evaluatedin 140 consecutive patients undergoing IVF with embryo transfer.Stimulation protocol in all study patients entailed intranasaladministration of short-acting gonadotrophin-releasing hormoneagonist (GnRHa) buserelin and human menopausal gonadotrophin.A pregnancy rate of 37.2% was achieved when at least three embryoswere transferred. The only significant difference between conceptionand non-conception cycles was found in serum progesterone concentrationsafter HCG administration (P < 0.01), whereas the mean progesteroneconcentration on the day of HCG did not differ. No differencein other hormonal or cycle parameters was observed. The increasein progesterone concentration was significantly greater in thegroup of patients who achieved pregnancy than in the group whodid not (2.2 ± 0.2 versus 1.6 ± 0.1 ng/ml, respectively;P < 0.01). A critical breakpoint in serum progesterone wasarbitrarily determined at 1 ng/ml. An increase in progesteroneconcentration 1 ng/ml when three or more embryos were transferredwas associated with a positive predictive value for pregnancyof 40.4% (sensitivity of 94.7%), whereas a negative predictivevalue of 86.7% was obtained when this value was <1 ng/ml.These findings indicate that an adequate rise in serum progesteronefollowing HCG administration provides useful information aboutthe possible outcome of the treated cycle.     

Supplementary growth hormone treatment of women with poor ovarian response to exogenous gonadotrophins: changes in serum and follicular fluid insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3)

The effects of supplementary growth hormone (GH) treatment uponinsulin-like growth factor-1 (IGF-1), IGF binding protein-3(IGFBP-3) concentrations in serum and ovarian follicular fluidwere investigated in women undergoing buserelin human menopausalgonadotrophin (HMG) ovulation induction for in-vitro fertilization.Women (n = 40), aged 24–39 (mean 35 years), who showedpoor ovarian responses to HMG, were recruited and randomly dividedinto two groups. Each patient received two cycles of ovulationinduction, one with GH (12 IU/day x 12 days/HMG/buserelin) andanother with placebo/HMG. Serum IGF-1 increased substantiallyduring the GH treatment and remained significantly higher thanthe control 2 days after the last GH injection. Serum IGFBP-3fell steadily during the placebo/HMG treatment and to a nadiron the day of oocyte retrieval (P <0.05 compared to serumbefore any treatment). In contrast, IGFBP-3 was increased (P<0.01) during the GH administration and returned to the controllevel 2 days after GH injection. Serum oestradiol concentrationson the eighth day of HMG and the day of human chorionic gonadotrophin(HCG) were not significantly different between the two groups.Serum IGF-1 was highly correlated with IGFBP-3 before any treatment(r = 0.433, P < 0.001). This correlation disappeared afterbuserelin, placebo/HMG treatment in the control group, but itwas maintained during GH/HMG treatment (r = 0.343, P = 0.04).Follicular fluid concentrations of GH and IGF-1, not IGFBP-3or oestradiol, were significantly elevated in the GH-treatedwomen. Serum IGF-1 on the day of oocyte retrieval was highlycorrelated to the follicular fluid IGF-1 in both groups. Therelationships between the follicular fluid GH and IGF-1 werecompletely opposite in the two groups, being positive in thecontrol group and negative in the GH-treated group. In the controlgroup, significant correlations were found between follicularfluid concentrations of IGF-1 and IGFBP-3, and GH and IGFBP-3which were not found in the GH-treated group. There were nocorrelations found between follicular fluid concentrations ofGH or IGF-1 or IGFBP-3 and oestradiol. The results clearly demonstratethat the normal GH, IGF-1, IGFBP-3 relationships can be alteredby treatments which influence the ovarian—pituitary axis;the significance of such changes to ovulation remains to bediscovered.     

Endocrinology: A comparison between a standard and reduced dose of D-Trp-6-luteinizing hormone-releasing hormone administered after pituitary suppression for in-vitro fertilization

A randomized prospective study was undertaken to compare lowand standard luteinizing hormone-releasing hormone agonist (LHRHa)dosage used in combination with gonadotrophins in ovarian stimulationfor in-vitro fertilization (IVF). A total of 42 ovulatory patientswith mechanical infertility were administered 0.5 mg/day LHRHa(Decapeptyl) from day 21 of their cycles for 14 days. Followingdown-regulation, patients were randomly allocated to continuewith the same dose of LHRHa (22 patients, group A) or to receivea lower dose of 0.1 mg/day LHRHa (20 patients, group B) duringfolliculogenesis. Luteal phase was supported by daily i.m. progesterone(50 mg) injections and human chorionic gonadotrophin (HCG; 1500IU) every 4 days. Ovarian response, human menopausal gonadotrophin(HMG) dosage used for induction of ovulation, evidence of prematureluteinization, and clinical and laboratory IVF outcome, werecompared between groups A and B. The two groups were comparablein respect of: age (32.6 ± 0.7 and 33.0 ± 0.9years), HMG dosage (33.0 ± 1.6 and 36.0 ± 2.5ampoules), day of HCG (11.2 ± 0.3 and 12.2 ± 0.4),oocytes/patient (13.3 ± 1.0 and 12.9± 1.3), fertilizationrate (68.5 and 65.2%), cleavage rate (95% for both), pregnancy/embryotransfer (32 and 35%) and implantation rate (10.8 and 10.5%),for groups A and B respectively. There was no evidence of prematureluteinization or luteolysis in either group. It was concludedthat lowering the dose of LHRHa to 0.1 mg/day during folliculogenesishad no adverse effect on ovarian response or clinical results.However, it had no advantage in reducing the HMG dose used forovulation induction.     

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.     

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.     

A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction

BACKGROUND: Studies with the GnRH antagonist ganirelix in assistedreproduction have indicated that compared with traditional GnRHagonist downregulation protocols, slightly fewer oocytes areretrieved. In this study it was investigated whether an increasein the starting dose of recombinant FSH (rFSH) could compensatefor this loss. METHODS: A randomized, double-blind, multicentreclinical trial comparing a starting dose of 150 and 200 IUof rFSH (follitropin ), in women undergoing treatment with theGnRH antagonist ganirelix. RESULTS: In total, 257 women weretreated with rFSH, of whom 131 received 150 IU and 126women 200 IU. Overall, 10.3 oocytes were retrieved in the150 IU group and 11.9 in the 200 IU group (P = 0.051).This difference became significant when women with cycle cancellationbefore HCG administration were excluded. Nearly 500 IUof additional rFSH was given in the high-dose group (2014 versus1541 IU). In the low-dose group, 4.6 high-quality embryoswere obtained compared with 4.5 in the high-dose group. Vitalpregnancy rates were similar (31 and 25% in the 150 and 200 IU-treatedwomen, respectively). Serum concentrations of FSH, estradioland progesterone were significantly higher in the high-dosegroup at day 6 of rFSH treatment and on the day of HCG administration.In the high-dose group, serum LH concentrations were higherat day 6 of rFSH treatment but lower at the day of HCG administration.CONCLUSION: By increasing the starting dose from 150 to 200 IUof rFSH, slightly more oocytes can be retrieved in GnRH antagonistprotocols for assisted reproduction. However, because this didnot translate into a higher number of high quality embryos,the clinical relevance of such a dose increase may be questioned.