Subcutaneous low dose leuprolide acetate depot versus leuprolide acetate for women undergoing ovarian stimulation for in-vitro fertilization

A total of 100 women undergoing ovarian stimulation with gonadotrophin-releasinghormone agonist (GnRHa) and a human menopausal gonadotrophin(HMG) for in-vitro fertilization (IVF) participated in thisrandomized comparative study. Leuprolide acetate at a dose of0.5 mg/day s.c. (n = 52, group I), or low-dose leuprolide acetatedepot at a dose of 1.88 nig s.c. (n = 48, group II), was startedon days 21–23 of the cycle. Stimulation with 225 IU/dayHMG was started after pituitary desensitization had been achieved.The luteal phase was supported by human chorionic gonadotrophin(HCG) i.m. injection. There were nostatistical differences inbaseline oestradiol (24.5 ± 4.8 versus 21.9 ±4.5 pg/ml) and follicle stimulating hormone (FSH) concentrations(3.9 ± 1.9 versus 3.2 $ 1.8 mlU/ml), and concentrationson the day of HCG administration of oestradiol (1657 ±245 versus 1512$165 pg/ml), luteinizing hormone (LH; 6.2 ±4.8 versus 5.6 ± 4.3 mlU/ml) and FSH (10.6 ± 2.8versus 10.8 ± 3.6 mIU/ml). There were also no statisticaldifferences in the HMG dosage (26.8 ± 1.8 versus 28.5± 1.5), the number of oocytes retrieved (7.6 ±3.0 versus 8.1 ± 4.3), the number of oocytes fertilized(5.3 ± 2.1 versus 5.6 ± 3.0) and the number ofembryos transferred (3.5 ± 1.3 versus 3.4 ± 1.6).There was no evidence of a premature LH surge in either group,but two patients appeared to have a poor response in the leuprolideacetate group (group I). There were 11 pregnancies (21.2%) afterthe use of leuprolide acetate and 12 pregnancies (25.0%) inthose given leuprolide acetate depot; no statistical differenceexisted between these two groups. Thus, an s.c. low-dose leuprolideacetate depot injection may offer a useful alternative for pituitarysuppression in ovarian stimulation for IVF.     

Endocrinology: A randomized prospective study of gonadotrophin with or without gonadotrophin-releasing hormone agonist for treatment of unexplained infertility

The use of gonadotrophin-releasing hormone agonist (GnRHa) incombination with human menopausal gonadotrophin (HMG) for ovulationinduction has been advocated for the treatment, particularlyby in-vitro fertilization (IVF) of various types of infertility.The present study was designed to compare the clinical efficacyof HMG alone with a short protocol of GnRHa/HMG for treatmentof unexplained infertility. A total of 91 couples with unexplainedinfertility were randomly assigned to one of two treatments;either HMG with intra-uterine insemination (IUI) (45 patients,62 cycles) or GnRHa/HMG with IUI (46 patients, 69 cycles) treatments.Progesterone concentrations on the day of human chorionic gonadotrophin(HCG) administration were significantly higher in HMG (1.5 ±0.9 ng/ml) versus GnRHa/HMG (0.8 ± 0.6 ng/ml; P <0.05)cycles. Furthermore, GnRHa suppressed the occurrences ofpremature luteinization (GnRHa/HMG 5.8% and HMG 24.2% respectively).However, there were no significant differences in HMG dose requirements,plasma oestradiol concentrations or follicular development onthe day of HCG administration between the two groups. Nor wereany significant differences found in the pregnancy rates betweenthe two treatment protocols (GnRHa/HMG 13.0% and HMG 11.3% respectively).Our results suggest no beneficial effect of GnRHa/HMG comparedto HMG alone for the treatment of unexplained infertility, basedon pregnancy rates.     

Endocrinology: Human chorionic gonadotrophin is a better luteal support than progesterone in ultrashort gonadotrophin-releasing hormone agonist/menotrophin in-vitro fertilization cycles

In an attempt to determine the best luteal support in in-vitrofertilization (IVF) cycles treated with gonadotrophin-releasinghormone agonist (GnRHa) and human menopausal gonadotrophin (HMG)by the ultrashort protocol, 60 patients were prospectively randomizedfor either i.m. progesterone or human chorionic gonadotrophin(HCG) luteal support. The two groups did not differ in the meannumber of oocytes retrieved and embryos replaced, nor in themean age of the patients and the amount of HMG used. HCG maintainedhigher levels of oestradiol and progesterone during the lutealphase. Conception rate was significantly higher in the HCG group.We conclude that HCG is superior to i.m. progesterone as lutealsupport in IVF cycles in which GnRHa is used in the ultrashortprotocol.     

Early unilateral follicular aspiration compared with coasting for the prevention of severe ovarian hyperstimulation syndrome: a prospective randomized study.

Thirty women undergoing in-vitro fertilization or intracytoplasmic sperm injection considered to be at high risk of ovarian hyperstimulation syndrome (OHSS) were randomly allocated to have early unilateral follicular aspiration (EUFA) (group 1) or coasting (group 2) when the serum oestradiol concentration was >6000 pg/ml and there were more than 15 follicles each of >/=18 mm diameter in each ovary. EUFA was performed in group 1 at 10-12 h after the human chorionic gonadotrophin (HCG) trigger injection and human menopausal gonadotrophin (HMG) were withheld for 4.9 +/- 1.6 days until serum oestradiol concentrations fell below 3000 pg/ml when HCG was administered. The mean total dose and duration of administration of HMG were similar in groups 1 and 2 (48.3 +/- 17.4 and 50.2 +/- 16.5 ampoules; 13.7 +/- 2.2 and 14.1 +/- 3.2 days respectively). The mean serum oestradiol concentrations (9911 pg/ml versus 10 055 pg/ml) and number of follicles (43.3 versus 41.4) seen in both ovaries on the day of HCG administration in group 1 and on the day coasting was commenced in group 2 were also similar. After coasting, the mean serum oestradiol concentration on the day of HCG administration in group 2 was lower than in group 1 (1410 pg/ml versus 9911 pg/ml; P < 0.001). The mean serum progesterone concentrations on the day of HCG administration in both groups were similar, and fell in all women in group 2. The mean number of oocytes retrieved and percentage of oocytes retrieved per follicle punctured was significantly higher in group 1 (15.4 +/- 2.1 versus 9.6 +/- 3.2, P < 0.001; 91.4 +/- 4.4% versus 28.3 +/- 3.7%, P < 0.001 respectively). The fertilization and embryo cleavage rates were similar in both groups. Clinical pregnancy was diagnosed in 6/15 (40%) patients in group 1 and in 5/15 (33%) patients in group 2, while four women in group 1 and three in group 2 developed severe OHSS.     

Endocrinology: Growth hormone, oestradiol, progesterone and testosterone concentrations in follicular fluid after ovarian stimulation with various regimes for assisted reproduction

Follicular fluid samples and oocytes were obtained from 75 women(87 cycles), who participated in an assisted conception programme.Determinations of the concentration of oestradiol, progesterone,testosterone and growth hormone were performed in all follicularfluid samples. Patients were stimulated with the following regimes:group A (24 cycles, 94 samples), human menopausal gonadotrophin(HMG) (three ampoules/day) and human chorionic gonadotrophin(HCG); group B (23 cycles, 53 samples), HMG/HCG with prednisolone(7.5 mg/day) after cycle programming with oral contraceptives;group C (40 cycles, 60 samples), buserelin with HMG/HCG. Oestradiolconcentrations (mean ± SEM) were significantly higher(P < 0.05) in group A (320.1 ± 27.3 ng/ ml) and thoseof growth hormone in both groups A and C (3.8 ± 0.2 and3.2 ± 0.15 ng/ml, respectively), as compared to the othergroups, whereas progesterone and testosterone concentrationswere similar in all groups. The mean concentrations of oestradiol,progesterone, testosterone and growth hormone were significantlyhigher (P < 0.01) in follicular fluid with oocytes of intermediatematurity than with mature oocytes (382.5 ng/ml, 7847.5 ng/ml,1704.5 ng/dl and 3.7 ng/ml versus 217.8 ng/ml, 5488.4 ng/ml,1313.6 ng/dl and 2.7 ng/ml, respectively). On the other hand,only oestradiol concentrations were significantly higher infollicular fluid of fertilized compared to non-fertilized oocytes.Concentrations of the other hormones analysed, except growthhormone, were similar in follicular fluid from pregnant andnon-pregnant women after assisted reproduction. Growth hormone,on the other hand, was significantly lower (P < 0.05) infollicular fluid from pregnant compared to non-pregnant women(2.8 versus 3.5 ng/ml). It is concluded that intermediate maturityoocytes and oocytes which will be subsequently fertilized arefound in follicles with higher follicular fluid concentrationsof growth hormone and steroids. Moreover, oocytes leading topregnancy after in-vitro fertilization and embryo transfer arederived from follicles with lower growth hormone concentrationsin follicular fluid.     

Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures.

Ovarian hyperstimulation syndrome (OHSS) is the most serious iatrogenic complication of ovarian stimulation. In severe cases, haemoconcentration, hypovolaemia, thromboembolism and death may result. It is reassuring that its incidence is not increased after ovarian stimulation for in-vitro fertilization despite very high serum oestradiol levels and large numbers of follicles and oocytes. This may be related to follicular aspiration, expert monitoring or low implantation rates. However, complete prevention has not been achieved despite the wide availability of ultrasound and oestradiol assays, thus presenting the clinician with a continuous challenge. Our aim is to analyse critically the most recent published series of OHSS in in-vitro fertilization and other assisted reproduction techniques using stimulation with gonadotrophin releasing hormone agonists (GnRHa) and human menopausal gonadotrophin (HMG). The main determining factor in the development of OHSS appears to be ovarian predisposition. Patients with polycystic ovarian disease are at a high risk of OHSS and therefore a small dose and slow start of HMG is recommended, tailoring the dosage according to the ovarian response. Accurate prediction by ultrasound and oestradiol assays and strict prevention by withholding human chorionic gonadotrophin (HCG) or cryopreservation of all the embryos have a major impact on the occurrence of OHSS. It is interesting that fixed-schedule IVF cycles, without detailed monitoring, are not associated with an increased incidence of OHSS. The use of GnRHa, despite expectations, is associated with a higher prevalence of OHSS. Luteal phase supplementation with progesterone rather than HCG should be used in cycles where oestradiol is greater than 2500 ng/l or where the number of oocytes exceeded 10.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrinology: Comparison of gonadotrophin-releasing hormone analogues and human chorionic gonadotrophin for the induction of ovulation and prevention of ovarian hyperstimulation syndrome: a case-control study

Gonadotrophin-releasing hormone analogue (GnRHa) has been suggestedas an alternative to human chorionic gonadotrophin (HCG) fortriggering ovulation, while preventing ovarian hyperstimulationsyndrome (OHSS). Since a prospective, controlled study wouldbe unethical at this point, we used a retrospective, case-selfcontrol approach to compare GnRHa with HCG in that context.A group of 16 in-vitro fertilization (IVF) patients who hadsevere OHSS in previous cycles, in which HCG was given to triggerovulation, were studied in subsequent cycles in which GnRHawas used. Each GnRHa cycle (case) was compared to a previousHCG cycle that resulted in OHSS (self control). None of thesesubsequent cydes resulted in severe OHSS. The use of GnRHa didnot affect the number of oocytes retrieved or their quality.Serum oestradiol concentrations on the day of ovulation triggeringwere signilicantly (P<0.01) higher in the GnRHa cycles comparedto HCG cycles. Exogenous progesterone and oestra diol were effectivein maintaining relatively constant serum oestradiol and progesteroneserum concentrations during the luteal phase. Pregnancy rateper cycle was similar in the two groups. In conclusion, theuse of GnRHa to induce ovulation in IVF patients, who are athigh risk for developing OHSS, effectively eliminates this riskwithout affecting other parameters of the stimulation cycle.     

Doubling the human menopausal gonadotrophin dose in the course of an in-vitro fertilization treatment cycle in low responders: a randomized study

The effect of doubling the human menopausal gonadotrophin (HMG)dose in the same treatment cycle in which the ovarian responseafter 5 days of ovarian stimulation with 225 IU/day is ‘low’,has been evaluated in a prospective randomized study. Forty-sixpatients met the ultrasound and oestradiol criteria for enrolmentin the study, one patient participated twice. In 22 patientstreatment was continued with 225 IU HMG/day and in 25 patientsthe HMG dose was increased to 450 IU/day. No effect of doublingthe HMG dose was found on the length of the ovarian stimulation,peak oestradiol values, number of follicles 11 and 14 mm indiameter respectively on ultrasound on the day of HCG administration,number of cancelled cycles, number of oocytes at follicularpuncture and the number of patients with 3 oocytes at retrieval.It is concluded that doubling the HMG dose in the course ofan IVF treatment cycle is not effective in enhancing ovarianresponse in low responders. This is in accordance with currenttheories on follicular growth, which state that follicular recruitmentoccurs only in the late luteal and early follicular phase ofthe menstrual cycle.     

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.     

Luteal phase support in in-vitro fertilization using gonadotrophin releasing hormone analogue before ovarian stimulation: a prospective randomized study of human chorionic gonadotrophin versus intramuscular progesterone.

This study was conducted to compare the endocrine milieu and pregnancy rates in an in-vitro fertilization and embryo transfer (IVF-ET) programme employing a gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG) when either human chorionic gonadotrophin (HCG) or progesterone were used for luteal phase support. A total of 121 IVF-ET treatment cycles were prospectively studied. All patients started leuprolide acetate in the midluteal phase and it was continued for at least 10 days. When oestradiol levels were less than 150 pmol/l, HMG was started. When at least three follicles were greater than or equal to 17 mm in diameter, HCG 5000 IU i.m. was given. Oocytes were retrieved using transvaginal ultrasound and embryos were transferred 48 h later. The patients' cycles were prospectively randomized to receive HCG (72 cycles) or progesterone (49 cycles) luteal support. The HCG group received 1500 IU i.m. on days 3, 6 and 9 after the initial trigger. The progesterone group received 12.5 mg i.m. q.d. starting from the day after the HCG trigger. The dose of progesterone was increased to 25 mg i.m. q.d. starting on the day of embryo transfer and continued for 17-21 days. If the patient became pregnant, this dose of progesterone was continued until fetal heart activity was visualized by ultrasound. Mean ages, number of eggs retrieved, embryos transferred, oestradiol levels on the day of the HCG trigger, oestradiol and progesterone at the time of embryo transfer were the same in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

The synergistic effects of clomiphene citrate and human menopausal gonadotrophin in the folliculogenesis of stimulated cycles as assessed by the gonadotrophin-releasing hormone antagonist Nal-Glu.

Clomiphene citrate (CC), alone or in combination with exogenous gonadotrophins, has been widely used in ovulation induction. CC promotes endogenous release of gonadotrophins, yet when used in combination with exogenous gonadotrophins, its contribution to folliculogenesis is difficult to assess. In order to determine the contribution of CC-induced endogenous gonadotrophin production to the overall ovarian stimulation in cycles treated with CC/human menopausal gonadotrophin (HMG), Nal-Glu, a gonadotrophin-releasing hormone (GnRH) antagonist was administered. Fertile women (n = 10) undergoing ovarian stimulation and oocyte aspiration for the sole purpose of gamete donation were studied. Five women received CC (100 mg daily for 5 days) in conjunction with pure follicle stimulating hormone (FSH) 150 IU daily. Five women received HMG alone. Nal-Glu (50 micrograms/kg/day) was administered intramuscularly to both groups when the leading follicles reached a mean diameter of 16 mm. Human chorionic gonadotrophin (HCG) 10,000 IU was given when the largest follicles reached a mean diameter of 20-22 mm. A significant fall in serum oestradiol levels was observed in women given CC/FSH (37.9 +/- 7.3%) within the first 24 h of Nal-Glu administration. Serum luteinizing hormone (LH) decreased greater than 20% within 24 h of Nal-Glu administration and remained low throughout the rest of the treatment. No decrease in oestradiol levels was noted in cycles receiving HMG alone. With supplemental FSH, falling oestradiol levels in CC/FSH cycles rebounded and continued to rise until the day after HCG administration. Despite a drop in oestradiol in CC/FSH cycles, the aspirated oocytes exhibited no untoward effects. The fertilization and cleavage rates were similar, and pregnancies occurred in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrinology: Pure and highly purified follicle-stimulating hormone alone or in combination with human menopausal gonadotrophin for ovarian stimulation after pituitary suppression in in-vitro fertilization

The use of pure follicle stimulating hormone (pFSH) and highlypurified FSH (FSH-HP) versus the combinations pFSH/human menopausalgonadotrophin (HMG) and FSH-HP/HMG, respectively, was comparedfor stimulating follicular development after gonadotrophin-releasinghormone agonist (GnRHa) suppression in women undergoing in-vitrofertilization (TVF)—embryo transfer. Two consecutive prospective,randomized studies were carried out at the Assisted ReproductionUnit of the Hospital Clínic i Provincial in Barcelona,a tertiary care setting. Two groups of 188 (study 1) and 252(study 2) consecutive infertile patients respectively, scheduledfor IVF-embryo transfer were included. Pretreatment with leuprolideacetate (long protocol) was followed by gonadotrophin treatmentin all patients. In study 1, 92 patients received i.m. pFSHalone (group pFSH) and 96 were treated with the combinationof i.m. pFSH and i.m. HMG (group HMG-1). In study 2, 123 patientsreceived s.c. FSH-HP alone (group FSH-HP) and 129 patients weregiven the combination of s.c FSH-HP and i.m. HMG (group HMG-2).Main outcome measures included follicular development, oocyteretrieval, fertilized oocytes, duration and dose of gonadotrophintherapy, and clinical pregnancy. There were no significant differencesbetween pFSH and pFSH/HMG nor between FSH-HP and FSH-HP/HMGcycles with regard to the number of ampoules of medication used,day of human chorionic gonadotrophin (HCG) administration, meanpeak serum oestradiol concentrations, number of follicles punctured,and number of oocytes aspirated, embryos transferred, or pregnancies.We conclude that urinary FSH (either purified of highly purified)alone is as effective as the conventional combination of urinaryFSH/HMG for ovarian stimulation under pituitary suppressionin IVF cycles. Therefore, they can be used interchangeably inFVF programmes.     

Oocyte and embryo quality as well as pregnancy rate in intracytoplasmic sperm injection are not affected by high follicular phase serum progesterone

The effect of elevated serum progesterone concentrations (>1ng/1) on or before the day of human chorionic gonadotrophin(HCG) injection on the outcome of women receiving gonadotrophin-releasinghormone analogue (GnRHa)/ human menopausal gonadotrophin (HMG)for ovarian stimulation prior to intracytoplasmic sperm injection(ICSI) was evaluated. A total of 1275 ICSI cycles were analysedretrospectively. In 53 cycles (4.5%), serum progesterone concentrationswere > 1 ng/ml. Patients in the high progesterone group hadsignificantly higher oestradiol and luteinizing hormone concentrationson the day of HCG injection. The characteristics of the cumulus-coronacell complexes and the nuclear maturity of the oocytes weresimilar in the groups of patients with high and low serum progesteronelevels. Fertilization and cleavage rates as well as embryo qualitywere not different in the two groups. No difference in implantationor clinical pregnancy rates was observed between the high progesteroneand low progesterone groups. Moreover, the cumulative exposureto progesterone during the follicular phase, as expressed bythe area under the curve (AUC), and the duration of exposureto high serum progesterone levels (>1 ng/ml) were not significantlydifferent between pregnant and non-pregnant women in the highprogesterone group. We conclude that in ICSI cycles pretreatedwith GnRHa, increased serum progesterone concentrations on orbefore the day of HCG injection do not affect ICSI outcome.     

Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups.

In a retrospective analysis of 637 cycles of ovarian stimulation and transvaginal follicular aspiration for various assisted reproductive technologies, severe ovarian hyperstimulation syndrome (SOH) occurred in six (0.94%) cycles. The patients at a high risk of developing SOH in cycles of assisted reproduction were those who had excessive serum oestradiol levels on the day of human chorionic gonadotrophin (HCG) administration (oestradiol greater than 6000 pg/ml; 38% SOH) and a high number of oocytes obtained (greater than 30 oocytes; 23% SOH). In those patients with both oestradiol greater than 6000 pg/ml on the day of HCG administration and greater than 30 eggs retrieved, the chance of developing SOH was 80%. The higher the serum oestradiol levels and the more eggs retrieved, the higher the pregnancy rates observed. High oestradiol level did not appear to have a detrimental effect on pregnancy rates and outcome. Furthermore, our results are not consistent with suggestions that the addition of gonadotrophin-releasing hormone agonist to ovarian stimulation protocols, follicular aspiration and/or luteal support with progesterone may reduce the incidence of ovarian hyperstimulation syndrome.     

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

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

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.     

The effects of the somatostatin analogue octreotide on ovulatory performance in women with polycystic ovaries

The elevated luteinizing hormone (LH) and androgen concentrationscharacteristic of women with polycystic ovaries (PCO) are consideredcrucial factors in their infertility. The somatostatin analogueoctreotide lowers LH and androgen concentrations in women withPCO. The effects of octreotide given concurrently with humanmenopausal gonadotrophin (HMG) were therefore compared withthat of HMG alone in 28 infertile women with PCO resistant toclomiphene. In 56 cycles of combined HMG and octreotide therapythere was more orderly follicular growth compared with the multiplefollicular development observed in 29 cycles in which HMG wasgiven alone (mean number of follicles > 15 mm diameter onthe day of human chorionic gonadotrophin (HCG) administration:2.5 ± 0.2 and 3.6 ± 0.4 respectively; P = 0.026).There was a significantly reduced number of cycles abandoned(>4 follicles > 15 mm diameter on day of HCG) in patientstreated with octreotide + HMG, so that HCG had to be withheldin only 5.4% of cycles compared to 24.1% with HMG alone (P <0.05). The incidence of hyperstimulation was also lower on combinedtreatment. Octreotide therapy resulted in a more ‘appropriate’hormonal milieu at the time of HCG injection, with lower LH,oestradiol, androstenedione and insulin concentrations. Althoughgrowth hormone concentration was similar on both regimens, significantlyhigher insulin growth factor-I concentrations were observedon the day of HCG in women on combined therapy than on HMG alone.     

Controlled ovarian stimulation using highly purified FSH results in a lower serum oestradiol profile in the follicular phase as compared with HMG

We have examined the efficacy of highly purified follicle stimulatinghormone (FSH-HP) for controlled ovarian stimulation in our in-vitrofertilization (IVF) programme, and compared the results obtainedwith this preparation with those using human menopausal gonadotrophin(HMG) in 15 patients who had received treatment with both FSH-HPand HMG in consecutive cycles (n = 39). No differences werefound in the duration of stimulation, which was 13.9 days (HMG)as compared with 143 days (FSH-HP). However, in the FSH-HP-treatedcycles we found a striking difference in the rise of serum oestradiol,which was significantly lower than in HMG-treated cydes (2953± 938 pmol/1 as compared with 6349 ± 3683 pmol/1on the day before ovum retrieval). Number and size of follicleswere similar in the two groups, as were oocyte characteristics.Increase in endometrial thickness at two days prior to ovumretrieval was slightly higher after HMG. The results indicatethat in combination with a long gonadotro-phin-releasing hormoneagonist (GnRHa) protocol, pure FSH is sufficient for adequatefollicle recruitment and growth. However, since FSH-HP resultedin markedly reduced concentrations of serum oestradiol as comparedto HMG cycles, IVF programmes using repeated oestradiol measurementsto decide the day of ovum retrieval must take this into considerationin order not to prolong the stimulation unnecessarily.     

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.