Reduction of postoperative adhesions with an auto-crosslinked hyaluronan gel in gynaecological laparoscopic surgery: a blinded, controlled, randomized, multicentre study

BACKGROUND: Following myomectomy, postoperative adhesions occur in many patients with adverse effects on fertility. This study investigated the applicability, safety and efficacy of an auto-crosslinked hyaluronan gel in preventing adhesion formation after laparoscopic myomectomy. METHODS: Fifty-two patients aged 22-42 years, undergoing surgery at four centres, were randomly allocated to receive either the gel or no adhesion prevention. The incidence and severity of postoperative adhesions were assessed laparoscopically after 12-14 weeks in a blinded, scored fashion. The primary efficacy variable was the presence/absence of postoperative adhesions at second-look. RESULTS: A nonsignificantly higher proportion of patients receiving the gel were free from adhesions (13 of 21; 62%) compared with control patients (9 of 22; 41%), with a statistically significant difference between the severity of uterine adhesions at baseline and at second-look (0.3 +/- 0.9 versus 0.8 +/- 1.0, P < 0.05). In subjects undergoing myomectomy without concomitant surgery, the proportion of adhesion-free patients was 8 of 12 (67%) and 4 of 11 (36%) (not significant) in the gel and control groups, respectively, with a significant difference in the mean severity scores (P < 0.05). In subjects without uterine adhesions before myomectomy, 12 of 18 (67%) and 8 of 20 (40%) patients in the gel and control groups, respectively were adhesion-free (not significant), with a significant difference in the severity of uterine adhesions (P = 0.05). CONCLUSIONS: Our results suggest that the auto-crosslinked hyaluronan gel may have a favourable safety profile and efficacious antiadhesive action following laparoscopic myomectomy.     

A safety and efficacy study of a resorbable hydrogel for reduction of post-operative adhesions following myomectomy

BACKGROUND: This multicenter, randomized, single-blind study assessed thesafety and efficacy of a resorbable hydrogel (‘Hydrogel’)for the reduction of post-operative adhesion formation followingmyomectomy. METHODS: Women (n = 71) who were undergoing laparoscopic (67.6%) or laparotomicmyomectomy were randomized (2:1) to Hydrogel (sprayed over surgicallytreated areas prior to wound closure, n = 48) or to control(standard care, n = 23). Patients (38 Hydrogel, 20 control)returned 8–10 weeks later for a second look. Adhesionswere graded using a modified American Fertility Society (mAFS)scoring method. The primary efficacy measure was the posterioruterus mAFS score. RESULTS: For Hydrogel and control patients, respectively, mean ±SD mAFS scores were 0.5 ± 1.4 and 0.0 ± 0.0 atbaseline, and 1.1 ± 1.9 and 2.6 ± 2.2 at the secondlook. Similarly, mean changes from baseline were 0.8 ±2.0 and 2.6 ± 2.2 (P = 0.01); 95% confidence intervalsfor these mean changes were (0.16–1.44) and (1.64–3.56).Adverse events were reported by 9.6 and 17.4% of Hydrogel andcontrol patients, respectively. No intra-abdominal infectionsor post-operative site infections were reported. CONCLUSIONS: This 71-patient study provides the first clinical evidence ofthe safety and efficacy of Hydrogel for the reduction of adhesionsfollowing myomectomy. The ClinicalTrials.gov Identifier is NCT00562471 [ClinicalTrials.gov] .     

Ultrasound evidence for variability in the size and development of normal human embryos before the tenth post-insemination week after assisted reproductive technologies

Differences in human chorionic gonadotrophin (HCG), averagechorionic sac diameter, embryo/fetus crown —rump lengthand biparietal diameter were determined in 107 singleton pregnanciesdelivered after 34 weeks, whose post-insemination age was preciselyknown as a result of in-vitro fertilization (n = 28) or gameteintra-Fallopian transfer (n = 79). Crown — rump lengthswere interpreted in relation to the developmental stage of theembryo. A 7-fold to 10-fold difference in HCG levels was observedon post-insemination days 13–16. A 2-fold to 3-fold differenceoccurred in average chorionic sac diameter on days 25–36.A 2-fold difference occurred in crown — rump length onseven of 10 days prior to day 44. Biparietal diameter differedby no more than 42% from day 57–68 and 20% after day 68.Chorionic sac diameter, crown -rump length, and biparietal diameterwere also related to newborn weight. The results suggest firstlythat marked differences occur in the rate of early human development,secondly, that the differences occur prior to day 27 when observablecardiac activity begins, and thirdly, that the differences areminimized after day 68 when the embryonic period of developmentis completed.     

Recurrence of fibroids after myomectomy: a transvaginal ultrasonographic study

Frequency of recurrence of fibroids after myomectomy has beenevaluated in 145 women (median age 38 years, range 21–52)who underwent myomectomy. After surgery all women returned forfollow-up visit every 12 months after surgery. Transvaginalultrasound examination was performed routinely in every patientat 24 and 60 months and at 12, 36 and 48 months if there wereany abnormal pelvic findings or suspicious symptomatology. Atotal of 39 (27%) women gave birth after myomectomy. For thewhole series, the cumulative probability of recurrence (CPR)increased constantly during the study period reaching 51% in5 years. The 5-year CPR decreased with parity after myomectomy,being 55% for women with no childbirth after surgery and 42%(based on 13 recurrences, P < 0.01) for those who gave birth.     

Reduction of postoperative adhesion formation after laparoscopic ovarian cystectomy

The purpose of this randomized, open-label study was to assessthe efficacy of the product Interceed absorbable adhesion barrierin the prevention of adhesion formation on the ovary after laparoscopicovarian cystectomy. A total of 25 patients requiring laparoscopicbilateral ovarian cystectomy were enrolled into this study.After removal of ovarian cysts, peri-adnexal adhesions, andperitoneal irrigants, and the attainment of meticulous haemostasis,the random assignment of one ovary for wrapping with Interceedwas revealed to the surgeon. The other ovary served as the untreatedcontrol. A follow-up laparoscopy was performed 8–30 weeksafter the initial procedure in 17 patients. Significantly feweradhesions formed at the Interceed treated ovaries compared withthe control (untreated) ovaries (P < 0.05). In terms of adhesion-freeoutcome, 76% (13/17) of Interceed treated ovaries and 35% (6/17)of control ovaries were free of adhesions. A significant reductionwas observed in the area of the sutured ovaries involved withadhesions when Interceed (6%) was used, compared with controls(20%). The reduction of adhesion formation was not related tothe size of the cysts at the initial procedure. No adverse eventswere reported by any patient during the study. In conclusion,Interceed was found to be safe and effective in reducing theincidence of postoperative adhesion formation in patients undergoinglaparoscopic ovarian cystectomy.     

Long-term results of laparoscopic myomectomy: recurrence rate in comparison with abdominal myomectomy

Laparoscopic myomectomy is still a debated procedure and there are conflicting opinions regarding the recurrence rate. Laparoscopic myomectomy may present a higher risk of recurrence compared with abdominal myomectomy. The aim of this investigation was to analyse the recurrence rate of myomas after surgery. From January 1991 to June 1998, 165 myomectomies were performed for symptomatic myomas measuring at least 3 cm in diameter and numbering seven or less per patient. During the first 3 years of this survey, 81 patients were randomized for abdominal or laparoscopic myomectomy. Transvaginal ultrasound examination was performed within 15-30 days of surgery and every 6 months for a post-operative period of 40 months. The two groups had similar pre-operative clinical features and the number and volume of myomas did not differ between the two groups. At the end of the study the group of abdominal myomectomies showed nine recurrences (23%) against 11 (27%) of the laparoscopic group. In order to evaluate the recurrence rate in relation to several risk factors, laparoscopic myomectomies were performed from 1991 in 84 patients who agreed to follow-up (and were not in the randomized group). Of these, 78 patients were evaluated with transvaginal ultrasound for a mean interval of 26 months and 17 (21.78%) recurrences were found. Most recurrences (75%) were seen at ultrasound between 10 and 30 months after surgery. The patient's age, pre- and post-operative gravidity and parity had no influence on recurrence. Neither the number of myomas removed nor the depth of penetration or size were positively associated with the risk of recurrence. However, an associated risk factor was pre-operative gonadotrophin-releasing hormone agonist treatment (P < 0.02). None of the women with recurrence required additional surgery. We conclude that laparoscopic myomectomy is a reliable procedure. The recurrence rate is similar to that seen after abdominal myomectomy.     

Endocrinology: The induction of ovulation with pulsatile gonadotrophin-releasing hormone (GnRH) administration in hyperandrogenic women after down-regulation with buserelin or suppression with an oral contraceptive

The hypothalamic—pituitary axis of 22 hyperandrogenicinfertile women had suppression with either the gonadotrophin-releasinghormone (GnRH)-analogue buserelin (n = 12) or with an oestrogen—gestagencompound (Diane^®; ⁿ = 12). This was followed by pulsatileGnRH application for inducing ovulation (Zyklomat^®). Interms of ovulation and pregnancy rates the buserelin pre-treatmentwas more effective than the steroid pre-treatment, especiallyin hyperandrogenic non-polycystic ovaries (PCO).     

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

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

Physiology: Morphological characteristics of preimplantation stage endometrium in the rhesus monkey

The morphological characteristics of endometrium on day 6 afterovulation of conception (group 1) and non-fecund, menstrual(group 2) cycles have been studied in the rhesus monkey (n =30). A conception cycle was distinguished by the presence ofa developmentally normal, age—stage-synchronized embryo.Thus, 78% of the mated cycles (n = 18) yielding synchronousembryos (12 zona-encased and two zona-free blastocysts) wereused for this study. On day 6 after ovulation, no significantchanges in the serum concentrations of oestrogen and progesteronewere seen in conception cycles (n = 14) compared with the non-mated,normal ovulatory cycles (n = 12). Morphometric analyses revealedthat on day 6 of gestation (n = 8), endometrium differed fromthe corresponding non-mated luteal phase (n = 7) with significantincreases in epithelial mitosis (P < 0.01), height of glandularepithelium (P < 0.05), volume ratio of gland cell to gland(P < 0.03), degree of pseudostratification (P < 0.02),and higher frequency of supranuclear, adluminal accumulationof vacuoles in gland cells (P < 0.05). The degree of stromaloedema was higher (P < 0.02) in fecund cycles but there wasno change in venular diameter. In a separate set of experiments,estimates of tissue vascular response revealed a higher (P <0.02) endometrial extravascular albumin space on the same dayof gestation; there were no differences, however, in endometrialblood volume, or in the number of von Willebrand antigen-positivecapillaries and small vessels between the two groups (group1, n = 6; group 2, n = 5). The overall results of the presentstudy together with our earlier reports support the hypothesisthat differential changes occur in luteal phase endometriumfunctionalis in the presence of preimplantation stage blastocystin the rhesus monkey.     

Endocrinology: Pre-ovulatory oxytocin administration promotes the onset of the luteinizing hormone surge in human females

Luteinizing hormone (LH) secretion during the ovulatory cycleis believed to be predominantly regulated by gonadotrophin-releasinghormone. Investigations in animals have strongly suggested thatoxytocin also participates in LH control and the physiologicalevents controlling LH surge initiation. In the human female,however, there has been no evidence supporting oxytocin's involvementin the processes leading to ovulation. In this study the effectof a preovulatory infusion of oxytocin on the onset of the LHsurge was investigated in women aged 20–35 years who hadnatural ovulatory menstrual cycles of lengths between 25–35days. Vaginal ultrasound scanning monitored follicular growthduring the late follicular phase. When a follicle >>14mm in diameter was observed each woman was randomized into oneof two groups. One group (n = 8) received an oxytocin infusionof 256 mlU/min for 2 h, the other group (n = 8) received normalsaline. The women who were administered oxytocin at this latefollicular stage had an earlier onset of the LH surge than thosewho had received saline (P < 0.01). The results indicatethat oxytocin promotes the onset of the LH surge in humans.     

Circulating placental protein 14: in the first trimester of spontaneous and IVF pregnancies

Circulating placental protein 14 (PP14) levels were measuredduring the first trimester in three groups of pregnant women:(i) natural conception (n = 15); (ii) pituitary desensitizationwith buserelin and ovarian stimulation with human menopausalgonadotrophin (HMG) followed by in-vitro fertilization and embryotransfer (IVF—ET) (n = 15); and (iii) ovarian stimulationwith clomiphene citrate and HMG, followed by IVF—ET (n= 16). A 7- to 8-fold increase in serum PP14 levels was observedin normal pregnancies between weeks 4 and 10. This increasewas earlier and less marked in group (ii) and absent in group(iii). These findings support the concept that endometrial functionis altered in pregnancies achieved following ovarian stimulation.Alternatively, if the ovary is an important source of PP14,then these data suggest that in contrast to ovarian synthesisof steroids and the peptide relaxin, ovarian stimulation resultsin an impairment of PP14 synthesis, and that this is most markedwhen clomiphene citrate has been used.     

Endocrinology: Follicle stimulating hormone-granulosa cell axis involvement in the antifolliculotrophic effect of low dose mifepristone (RU486)

This study was designed to assess the involvement of folliclestimulating hormone (FSH)—granulosa and luteinizing hormone(LH)—theca axes in the antifolliculotrophic effect ofmifepristone. Plasma gonadotrophins, including plasma LH bioactivityand pulsatility, oestradiol, testosterone and inhibin concentrations,and follicular growth were monitored in volunteer women treatedwith placebo or mifepristone in two consecutive cycles. Mifepristonewas given either as a single dose of 5 mg (n = 7) when the leadingfollicle had reached a diameter between 12 and 14 mm, or asa multiple dose of 5 mg/day for 3 days, beginning when the leadingfollicle had reached a diameter between 14 and 16 mm (n = 5)or between 6 and 11 mm (n = 5). Following the single dose ofmifepristone, follicular growth and the accompanying increasein plasma oestradiol were arrested at 12 and 36 h respectivelywithout changes in gonadotrophin or testosterone serum concentrations.The 3 day regimen arrested follicular growth and oestradiolrise and decreased plasma inhibin concentrations when follicleswere larger than 12 mm at the onset of treatment. These resultsindicate that the antifolliculotrophic action of mifepristoneis associated with a selective compromise of the FSH—granulosaaxis of dominant follicles that have passed a critical stageof growth.     

In-vitro synthesis of total protein and placental protein PP14 by the Fallopian tube mucosa: variation in relation to anatomical site, the ovarian cycle and the menopause

De-novo synthesis and secretion of protein by short term explantsof mucosa from each anatomical section of the Fallopian tubeand endometrium of pre-menopausal (n = 25) and tubal mucosaof post-menopausal (n = 5) women were studied by demonstrationof incorporation of radiolabelled L-[³⁵S]methionine and one-dimensionalSDS — polyacrylamide gel electrophoresis. A consistentfinding in 25 pre-menopausal women was the presence of a 25kDa protein band synthesized by tissue obtained throughout theovarian cycle. Western blotting demonstrated that this proteinband contained placental protein 14 (PP14)-like immunoreactivityin the proliferative (n = 2) and luteal phase (n = 2) of theovarian cycle. To determine if there is quantitative variationin total protein and PP14 synthesis and secretion during theovarian cycle, the total quantities of protein and PP14 synthesizedwere determined by Coomassie Brilliant Blue staining and radioimmunoassayrespectively. Analysis of the results of total protein assayrevealed statistically significant differences in relation tothe anatomical origin of the study tissue (P < 0.01), thestage of the ovarian cycle (P < 0.04) and the manner in whicheach anatomical site varied during the ovarian cycle (P <0.01), the endometrium being significantly different from theFallopian tube. When the data for PP14 synthesized by the Fallopiantube mucosa were analysed, these effects were not seen. PP14was not detected in the culture media of Fallopian tube mucosaobtained from post-menopausal women.     

Fertilization and early embryology: Embryo quality and pregnancy potential of fresh compared with frozen embryos--is freezing detrimental to high quality embryos?

To determine the effect of cryopreservation on embryo qualityand the pregnancy potential of embryos, donated oocytes fromthe same donor (n = 24) were randomly allocated, with subsequenttransfer to two or more different ovum recipients resultingin at least one fresh and one frozen embryo transfer cycle fromthe same cohort of oocytes. Endometrial receptivity was controlledin all ovum recipients, and male factor patients were excluded.The number of embryos transferred, mean embryo grade transferred,number of high quality embryos (grade 2.5, grade 1 being best)transferred and embryo implantation and live birth rates arereported. Significantly more embryos (4.4 ± 1.2 versus3.3 ± 1.2, P < 0.00003) of higher quality (1.9 ±0.5 versus 2.1 ± 0.5, P < 0.013) and of a more advancedcell stage (3.0 ± 0.6 versus 2.6 ± 0.7, P <0.019) were transferred fresh than after cryopreservation respectively.Implantation rates/embryo [19/151 (12.6%) and 9/111 (8.1%)]and live birth rates/transfer [11/42 (26.2%) and 6/45 (13.3%)],from fresh and frozen transfers respectively, were not significantlydifferent despite the larger number of high quality embryostransferred fresh. Embryo cryopreservation adversely affectsembryo quality, but does not have detrimental effects on theimplantation or pregnancy potential of high quality embryos.Because of the loss of embryos during freeze — thawingduring frozen embryo cycles, every effort should be made toattempt a fresh transfer.     

The effect of smoking and varicocele on human sperm acrosin activity and acrosome reaction

Smoking and varicocele are frequent findings in the medicalhistory and physical examination of patients attending and rologicaloutpatient departments. However, data about their influenceon human semen parameters, such as sperm concentration and motility,are contradictory. Therefore, the purpose of this study wasto examine sperm function (acrosin activity and induction ofthe acrosome reaction) in smokers (n = 130) and varicocele patients(n = 30)compared with normal fertile donors (n = 20). The acrosomereaction was detected by triple staining after 3 h ofincubationat 37°C, followed by treatment with 0.1%dimethyl sulphoxide(spontaneous acrosome reaction) and 10 µM calcium ionophoreA23187 (induced acrosome reaction) for 1 h at 37°C. Acrosinactivity was measured by gelatinolysis. The diameters aroundthe sperm heads after gelatinolysis and the percentages of spermatozoashowinghalo formations were evaluated. The inducibility of theacrosome reaction was significantly lower in semen samples fromsmokers than in those from the fertile group (7.1 ±3.2versus 11.2 ± 4.0%, P < 0.01), whereas no statisticallysignificant difference was demonstrated in spermatozoa frompatients with varicocele (9.3 ± 4.3%). Both the percentagesof spermatozoa with halo formation (53.3 ±20.0 versus76.6 ± 13.6%, P < 0.05) and the halo diameters (16.1± 6.6 versus 31.0 ± 14.5 urn, P < 0.001) weresignificantly lower in the varicocele group than in thesamplesfrom fertile men. These data suggest that smoking and varicoceleaffect sperm function, and that the standard semen parametersalone are insufficient to evaluate the influence of both factorson human male fertility.     

Evaluation of the spindle apparatus of in-vitro matured human oocytes following cryopreservation

The present study was conducted to determine if the cryopreservationof immature human oocytes has a deleterious effect on the meioticspindle following maturation in vitro. Oocytes were obtainedin excess from in-vitro fertilization patients and divided intofour groups. Groups 1 (n = 98) and 2 (n = 80) consisted of immatureoocytes cryopreserved before or after maturation in vitro respectively.Groups 3 (n = 37) and 4 (n = 9) served as non-frozen controlsand included oocytes matured in vitro and in vivo respectively.The meiotic spindle was identified after incubation in anti-tubulinmonoclonal antibody (1 h, 37°C) and fluorescein-conjugatedgoat anti-mouse immunoglobulin G (IgG) (1 h, RT). Chromosomeswere counterstained with 4‘, 6’-diamidino-2-phenylindole.Following cryopreservation, group 1 oocytes demonstrated a 63%survival rate and 68% maturation rate in vitro. In all, 58%of the oocytes in group 2 survived the thaw. The number of oocyteswith normal spindles in group 1 (81.0%) was not significantlydifferent from control groups 3 (83.8%) and 4 (88.9%), whilethe number of group 2 oocytes with normal structures (43.5%)was significantly lower than groups 1 (P = 0.0004), 3 (P = 0.0002),and 4 (P = 0.025). These results suggest that cryopreservationof the prophase I human oocyte does not significantly increaseabnormalities in the resulting meiotic spindle.     

Endocrinology: Randomized trial of misoprostol and cervagem in combination with a reduced dose of mifepristone for induction of abortion

Mifepristone (600 mg) in combination with a prostaglandin hasbeen demonstrated to be a safe, acceptable alternative to vacuumaspiration for induction of abortion in the first 9 weeks ofpregnancy. However, the efficacy and side-effects of differentprostaglandins used in combination with mifepristone have notbeen assessed in a randomized trial. In this study, 800 womenseeking an abortion at gestational age 63 days amenorrhoea wererandomized to receive either 0.5 mg gemeprost by vaginal pessary(group I) or 600 µg misoprostol (group II) by mouth –48h after taking 200 mg mifepristone by mouth. The side-effectsand number of complete abortions were used as measures of efficacy.There was no significant difference in the rate of completeabortion between group I [96.7%; 95% confidence interval (CI)94.9–98.5%, n = 391] and group II (94.6%; 95% CI 92.3–96.9,n = 386). It was not possible to assess the outcome with certaintyin the remaining 23 women. However, there were significantlymore ongoing pregnancies in the women who received misoprostolthan in those who received gemeprost (nine versus one, P <0.01) and in eight of these 10 women the gestation was >49days. Fewer women in group II required analgesia than in groupI (48 versus 60%, P < 0.001) although the number requestingopiate was similar in each group (6.9 versus 5.2%, P > 0.4).The incidence of nausea and vomiting after misoprostol (47.8and 21.9% respectively) was higher (P < 0.001) than aftergemeprost (33.9 and 12% respectively). The incidence of infectionand heavy bleeding was low in both groups (<2%) and onlyone woman required blood transfusion. We conclude that the recommendeddose of mifepristone and gemeprost can be reduced without impairingclinical efficacy in pregnancies up to 63 days amenorrhoea.Misoprostol is a safe alternative prostaglandin but has a higherincidence of ongoing pregnancies especially at gestation after49 days amenorrhoea.     

Routine use of hysterosalpingography prior to laparoscopy in the fertility workup: a multicentre randomized controlled trial

BACKGROUND: A multicentre randomized controlled trial with orwithout hysterosalpingography (HSG) was conducted to assessthe usefulness of HSG as a routine investigation in the fertilityworkup prior to laparoscopy and dye. METHODS: From 1 April 1997to 1 April 2002, subfertile women were allocated by a computer–based1 : 1 ratio randomization procedure, either for an HSG followedby laparoscopy and dye (the intervention group) of for laparoscopyand dye only (the control group) as a part of their fertilityworkup. Cumulative pregnancy rate (CPR) within 18 months afterrandomization was the primary outcome of interest. RESULTS:344 women were randomized to the intervention group (n = 169)and the control group (n = 175). There was no significant differencein CPR at 18 months in the intervention group (49.1%) [95% confidenceinterval (CI) 41.6 to 56.6] and the control group (50.3%) (95%CI 42.8 to 57.8), a difference of –1.2% (95% CI –11.8%to 9.5%). CONCLUSION: The routine use of HSG at an early stagein the fertility workup prior to laparoscopy and dye does notinfluence CPR, compared with the routine use of laparoscopyand dye without HSG.     

Recombinant hormones: In-vitro biopotency and glycoform distribution of recombinant human follicle stimulating hormone (Org 32489), Metrodin and Metrodin--HP

In this study the in-vitro biopotency and glycoform distributionof human recombinant follicle stimulating hormone (FSH, Org32489) has been assessed. The biopotency of recombinant FSHwas studied using animal (rat Sertoli) and human (granulosa—lutein)cell models. Recombinant FSH, as measured in the rat Sertolicell assay, was more potent than the urinary preparations Metrodin,Metrodin—HP and IS 70/45 with half maximal stimulation(ED₅₀; mean ± SEM, n > 3) occurring at 2.2 ±0.5 IU/I (recombinant FSH), 4.7 ± 1.1 IU/I (Metrodin),13.2 ± 0.7 IU/I (Metrodin—HP) and 6.4 ±0.3 IU/I (IS 70/45); the pituitary preparation IRP 83/575 hadan ED₅₀ of 10.4 ± 0.1 IU/I. Using human granulosa—luteincells, cultured for up to 4 days in the absence of exogenoussteroid precursors, recombinant FSH was either without effect(three out of five patients) or inhibited both oestradiol andprogesterone secretion. FSH (83/575) was without effect on oestradiolwith preparations from any of the patients but slightly stimulated(134 ± 8%; mean ± SEM, P < 0.05) progesteroneproduction at the highest dose (80 IU/I). The distribution ofFSH isoforms, assessed by polyclonal radioimmunoassay, followingchromatofocusing over the ranges pH < 3.5 and pH 3.5–7.0respectively was recombinant FSH, 12.4 and 87.6%; Metrodin,19.8 and 80.2%; Metrodin—HP, 50.2 and 49.8%; IS 70/45,15.0 and 85.0%; IS 83/575, 70.9 and 29.1%. All glycoforms werepl <7.0 for the five preparations. In conclusion: (i) thepotency of FSH as measured in the rat Sertoli cell assay increasesin the order Metrodin—HP < pituitary IRP 83/575 <<Metrodin < IS 70/45 < recombinant FSH; (ii) in contrastto 83/575, recombinant FSH inhibits steroidogenesis in humangranulosa—lutein cells isolated from some patients; (iii)the glycoform distribution of recombinant FSH resembles Metrodinmore closely than Metrodin—HP which is far more acidicin nature.     

An aggressive philosophy in controlled ovarian stimulation cycles increases pregnancy rates

To assess the effect of timing of human chorionic gonadotrophin(HCG) administration in ovarian stimulation cycles, the serumoestradiol concentration and follicle profile were comparedwith the clinical pregnancy rate in 582 ovarian stimulation— intra-uterine insemination (OS—IUI) cycles and3917 in-vitro fertilization—embryo transfer (IVF—ET)cycles. The pregnancy rates increased exponentially with increasingoestradiol in both OS—IUI and IVF—ET cycles (R²= 0.720, P < 0.001) but then decreased in OS-IUI cycles whenthe oestradiol concentration exceeded 5000 pmol/l (R² = 0.936,P < 0.004) at HCG administration. In OS—IUI cyclesthe percentage of cycles with three or more mature follicles( 18 mm diameter) increased up to an oestradiol concentrationof 5000 pmol/l then declined, mirroring the pregnancy rate (R²= 0.900, P = 0.01). The exponential increase in pregnancy ratewith increasing oestradiol concentration in IVF—ET cyclessuggests that high oestradiol concentration does not have adeleterious effect on endometrial receptivity. The decreasein pregnancy rate in OS-IUI cycles when oestradiol concentrationexceeded 5000 pmol/l reflected fewer mature follicles, resultingfrom premature administration of HCG to avoid severe ovarianhyperstimulation syndrome (OHSS). We recommend that HCG administrationbe delayed until multiple follicles have reached maturity, andreducing the risk of severe OHSS by converting high risk OS—IUIcycles to IVF—ET, or if funds or facilities are unavailable,transvaginally draining all but four or five mature follicles.