Endocrinology: Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study

One-hundred women undergoing ovarian stimulation with gonadotrophin-releasinghormone agonist (GnRH-a) and a human menopausal gonadotrophin(HMG) for in-vitro fertilization (IVF) participated in thisrandomized comparative study. The effectiveness of long-actings.c. goserelin (Zoladex depot; 49 patients) and intranasally(i.n.) administrated buserelin acetate (Suprefact; 51 patients)for pituitary down-regulation was compared. Treatment with s.c.goserelin (3.6 mg) or i.n. buserelin acetate (200 µg;6 times/day) was started on day 21–23 of the cycle. Stimulationwith 150 IU of HMG/day was started after at least 11 days ofGnRH-a treatment. There were no differences in the time requiredfor follicular development nor in the clinical outcome betweengroups treated with either goserelin or buserelin. The numberof oocytes recovered in the goserelin group was 6.7 ±5.0 versus 6.3 ± 4.9 in the buserelin group. There were11 pregnancies after the use of goserelin (22.4%) and 12 pregnanciesin those given buserelin (24.0%). The number of HMG ampoulesneeded for follicular maturation was higher in the goserelingroup (27.9 ± 7.8) than in the buserelin group (24.6± 7.8, P < 0.05). The patients given buserelin sufferedsignificantly more from tiredness, depression, headache andabdominal pain than those receiving goserelin, whereas therewere no differences between the groups in experiencing mentalirritability, nausea and swelling. Subcutaneous goserelin depotinjection offers a useful alternative for pituitary down-regulationin IVF stimulation.     

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.     

Ovarian stimulation with buserelin/HMG/HCG: prospective randomized study of short versus long protocol

The combined administration of the gonadotrophin-releasing hormone(GnRH) agonist buserelin and human menopausal gonadotrophin(HMG) was evaluated in 527 cycles (428 patients) of an assistedreproduction programme. All women were randomly allocated accordingto the ovulation induction protocol into two groups: group I(short protocol; 318 cycles) was given buserelin (1 mg/day)intranasally from cycle day 1 and HMG (2 ampoules/day) fromday 3 until human chorionic gonadotrophin (HCG) administration:group H (long protocol; 209 cycles) was given buserelin (1 mg/day)intranasally from cycle day 1 for at least 14 days and then2 ampoules HMG/day were added, increasing progressively accordingto the ovarian response. The number (mean ± SEM) of folliclesdeveloped was higher in group II than in group I (9.1 ±0.4 versus 7.7 ± 0.3, respectively; P < 0.05). Moreoocytes were retrieved in group II (8.4 ± 0.5) than ingroup I (6.5 ± 0.3) (P < 0.001), as well as more embryos(6.3 ± 0.5 and 4.0 ± 0.3, respectively; P <0.001). Moreover, in group II there was a better correlationbetween oestradiol and the total follicular volume (r = 0.5391)on cycle day 0 compared with group I (r = 0.458), while oestradiolvalues were similar between the two groups. No differences wereobserved in the cancellation rate, fertilization rate and maturityof the oocytes between the two groups. The pregnancy rate pertransfer was slightly better in group II (25.8%) than in groupI (19.4%), but this difference was not significant. More stimulationdays were needed in group II than in group I (11.8 ±0.2 and 10 ± 0.2, respectively) (P < 0.001) and moreHMG ampoules (37.7 ± 1.4 and 27.9 ± 0.1, respectively)(P < 0.001). In conclusion, the administration of the longprotocol is associated with a higher number of follicles developed,oocytes retrieved and embryos obtained, while it seems morepromising concerning the pregnancy rates. Nevertheless, treatmentwith this protocol increases the stimulation days and the numberof HMG ampoules administered and hence the cost.     

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.     

Endocrinology: The effects of gonadotrophin-releasing hormone agonist on follicular development in patients with polycystic ovary syndrome in an in-vitro fertilization and embryo transfer programme

The aim of the study was to evaluate ovarian response to gonadotrophinstimulation, with and without premedication with gonadotrophin-releasinghormone (GnRH) agonist, in patients with polycystic ovary syndrome.In all, 40 women included in the in-vitro fertilization/embryotransfer programme were divided into two groups. In the firstgroup, buserelin, 500 µg/day s.c., was given until pituitarydesensitization was achieved. Ovarian stimulation was performedby the combination of GnRH agonist and human menopausal gonadotrophin(HMG). The second group was treated using a conventional HMGand human chorionic gonadotrophin(HCG) protocol. Desensitizationwas achieved in 15.2 ± 6.3 days (mean ± SD) andthe luteinizing hormone:follicle stimulating hormone ratio decreasedfrom 2.84± 1.54 to 0.60 ±0.35. Comparing the durationof stimulation, the number and size of all observed and aspiratedfollicles, oocytes recovered and fertilized and the number ofembryos replaced, no statistically significant differences werefound between the groups. The average oestradiol concentrationon the day of HCG administration was lower in the group treatedwith premedication (P< 0.05). These data suggest that shortpre-treatment with GnRH agonist can temporarily correct endocrineabnormalities of polycystic ovary syndrome but do not changethe ovarian response to gonadotrophin stimulation and multiplefollicular development.     

Human prolactin release induced by follicle stimulating hormone, luteinizing hormone and human chorionic gonadotrophin

Plasma prolactin levels rise in stimulated cycles. To clarifythe effects of gonadotrophin on the lactotrophs, three studieswere performed. First, plasma concentrations of prolactin duringclomiphene citrate (CC)-human menopausal gonadotrophin (HMG)-humanchononic gonadotrophin (HCG) treatment of women enrolled forin-vitro fertilization (IYF) were compared with those duringHMG-HCG administration while under pituitary suppression witha gonadotrophin releasing hormone (GnRH) analogue (buserelin).Women suppressed with buserelin had higher basal levels of PRLin plasma (14.4 ± 4.3 nglml versus 6.9 ± 1.4 ng/ml,P<0.001). Only buserelin-suppressed women showed a significantrise in plasma prolactin before HCG administration, while bothpatient groups had marked prolactin peaks after HCG injection.This peak was higher in the buserelin group (71.9 ± 50.7ng/ml versus 52.6 ± 29.7 ng/ml). The second study showedthat plasma levels of prolactin of 6 post- menopausal womenwere significantly increased 48 h after an injection of 5000IU HCG, i.m. (24.9 ± 17.4 ng/ml versus 12.4 ±6.2 ng/ml P<0.05). Third, plasma prolactin was studied in5 women over 30 days after surgical castration. An upward trendwas observed similar to that of endogenous gonadotrophin, withthe change in prolactin values closely correlating with thechange in concentrations of follicule stimulating hormone (P<0.005).All these findings suggest that human gonadotrophins stimulatelactotrophs.     

Comparison of HMG/HCG superovulation for AID with or without superactive GnRH agonist

New methods of ovulation induction have been discovered andperfected in recent years. Among others, gonadotrophin-releasinghormone (GnRH) agonists are being used increasingly in the treatmentof ovulatory infertility. In a prospective study, 24 women undergoingartificial insemination with donor sperm (AID) and facing failureof treatment because of ovulation disorders, were treated withhuman menopausal gonadotrophin/human chorionic gonadotrophin(HMG/HCG) superovulation with or without pituitary densensitizationusing a superactive luteinizing hormone-releasing hormone (LHRH)agonist, buserelin (BUS), Suprefact (Hoechst, Frankfurt a/Main,FRG). In 86 cycles stimulated with HMG/HCG no pregnancy occurred,whereas 12 pregnancies occurred in the same group of patientsafter a total of 43 BUS/HMG/HCG stimulation cycles. SuperactiveLHRH agonists have a definite place in the treatment of AIDpatients presenting with refractory ovulation disorders and/orluteal insufficiency.     

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.     

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.     

A randomized comparative study of highly purified follicle stimulating hormone and human menopausal gonadotrophin for ovarian hyperstimulation in an oocyte donation programme

A randomized comparative study of highly purified human follicle-stimulatinghormone (FSH-HP), administered s.c, and human menopausal gonadotrophin(HMG), administered i.m., was carried out in 41 volunteer oocytedonors. The response to ovarian hyperstimulation was similarin both groups. One cycle in both groups was cancelled. Thenumber of oocytes recovered was 16.0 ± 7.9 (mean ±SD) following stimulation with 32.8 ± 103 ampoules ofFSH-HP (n = 19) over 12.3 ± 1.7 days. Following stimulationwith 29.8 ± 10.6 ampoules of HMG over 11.5 ± 1.6days, the number of oocytes collected was 18.4 ± 12.7(n = 20). The oocyte recipients were allocated 9.2 ±3.6 oocytes in the FSH-HP group (n = 33) and 9.6 ± 4.6oocytes in the HMG group (n = 37). The fertilization rate (2PN/cell)was significantly higher in the HMG group (48%, 170/355) thanin the FSH-HP group (36%, 109/304) (P < 0.01). The numberof embryos transferred per recipient was 2.0 ± 0.4 inthe FSH-HP and 2.0 ± 03 in the HMG group. The pregnancyrate per embryo transfer was 25% in the FSH-HP (5/20) and 26%(8/31) in the HMG group. Fertile donors with body mass index£25 made up a poor responder group to s.c FSH-HP, possiblyindicating reduced absorption of the drug.     

Multiple follicular development and ovarian steroidogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study

A multicentre, multinational study was carried out between November1990 and February 1992 to assess the safety and efficacy ofa new highly purified urinary human follicle stimulating hormone(FSH; Metrodin HP®) which is practically devoid of luteinizinghormone (LH) activity. Metrodin HP was administered s.c. tostimulate multiple follicular development in women undergoingin-vitro fertilization (IVF) and embryo transfer. A total of139 women were recruited from 10 participatin centres. Of these,135 underwent pituitary desensitization with a long gonadotrophin-releasinghormone (GnRH) agonist protocol and following deter-minationof ovarlan inactivity (mean± SD of 12.9 ± 3.2days), Metrodin Hp s.c. stimulation was started; 122 patientswere fully eligible for efficacy analysios and 118 of these(97%) received up to 10 000 IU human chrionic gonadotrophin(HCG) to induce final folicular maturation and timed oocyterecovey. Mean plasma LH concentrations at the beginning of Metro-dinHP treaement were 1.6 ± 0.8 mIU/ml and by the day ofHCG administration were significantly (p<0.001) reduced (1.2±0.8mIU/ml). The mean plasma oestradiol and inhibin concentrationson the day of HCG were 6173±3567 pmol/l and 8.2 ±4.4IU/ml respectively. There was a positive correlation (r= 0.49,p<0.001) between individual oestradiol and inhibin concentrationson the day of HCG. In the 118 patients who received HCG, themean number of oocytes recovered was 8.4 ± 4.7 followingstimulation with 36 ± 10, 75 IU ampoules of MetrodinHP over 12.2±2.1 days. One-hundred-and-eight patients(89% of 122 eligible) ahd 5.3±3.3 oocyted fertilized,and 105 (86%) had 2.8±1.0 embryos transferred; 28 patients(23% perinitiated cycle) had a clinical pregnancy and subsequently18 of these (15% per initiated cycle) had a live birth. A totalof 135 patients who reveiced Metrodin HP were eligible for safetyanalysis. One patient did not receive HCG because of the riskof developing ovarian hyperstimulation syndrome (OHSS). Sevenpatients (5% of those who received HCG) developed OHSS, onesevere, five moderate and one mild case. Three OHSS patientswere pregnant and hospitalized. The patient with severe OHSSwas found to have an ectopic pregnancy. Local side effects werereported by 24 (18%) patients at the site of s.c injection.The most common compliant was brusing (48.5%). There was nodevelopment of antobodies to FSH. In conclusion Metrodln HP,a urinary gonadotrophin preparation in which>95% of the proteincontent is FSH, was effective in stimulating multiple folliculardevelopment and oestradol synthesis to a similar degree reportedfor other gonadotrophin preparations, even when endogenous LHsecretion was significantly reduced by a GnRH agonist. Thesedata support the concept that only very low concentrations ofLH are required in conjunction with FSH for the stimulationof follicular development and ovarian steroidogenesis. MetrodinHp was well tolerated locvally thus enabling convenient self-adminstrationwithout compromising safety or efficacy     

Women with one ovary have decreased response to GnRHa/HMG ovulation protocol in IVF but the same pregnancy rate as women with two ovaries

The study compares the response after gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG) stimulation for in-vitro fertilization (IVF) in patients with either one or two ovaries. The study group (group A) included 73 cycles in women who had unilateral oophorectomy before their IVF treatment and the control group (group B) included 988 cycles in women with two ovaries. Tubal disease was the sole cause for infertility in all cases. The two groups were similar in age and parity. The patients with one ovary required more ampoules of HMG (62.9 versus 48.9, P < 0.001), a longer induction period (13.5 versus 12.7, P < 0.01) and had significantly lower oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration (5840 versus 6473 pmol/l, P = 0.035). They yielded fewer follicles (11.2 versus 13.1, P = 0.005), fewer oocytes (7.3 versus 9.1, P = 0.006) and produced fewer embryos (4.4 versus 5.1, P < 0.05). There was no difference in fertilization rate (60 compared with 58%), or pregnancy rate (25.8 compared with 27.1% per oocyte retrieval). Women with only one ovary responded less well to GnRH agonist/HMG stimulation than women who had both ovaries but pregnancy outcome was the same in both groups.      

EndocrinologyHormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix)

A third-generation gonadotrophin-releasing hormone antagonist(Cetrorelix) was used during ovarian stimulation in 32 patientsundergoing assisted reproduction, in order to prevent the prematureluteinizing hormone (LH) surge. In all patients, ovarian stimulationwas carried out with two or three ampoules of human menopausalgonadotrophin (HMG), starting on day 2 of the menstrual cycle.In addition, 0.5 mg of Cetrorelix was administered daily fromday 6 of HMG treatment until the day of ovulation inductionby human chorionic gonadotrophin (HCG). A significant drop inplasma LH concentration was observed within a few hours of thefirst administration of Cetrorelix (P<0.005). Moreover, noLH surge was detected at any point in the treatment period inany of the 32 patients. A mean oestradiol concentration of 2122±935ng/1 was observed on the day of the HCG administration, indicatingnormal folliculogenesis. Like LH, progesterone concentrationalso dropped within a few hours of the first administrationof Cetrorelix (P< 0.005). A 0.5 mg daily dose of Cetrorelixprevented a premature LH surge in all the 32 patients treated.     

Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group

In this prospective and randomized study, 188 patients received the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix, and 85 patients the LHRH agonist buserelin to prevent endogenous luteinizing hormone (LH) surges during ovarian stimulation in in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Ultimately, 181 patients (96.3%) in the cetrorelix group, and 77 (90.6%) in the buserelin group, reached the day of the human chorionic gonadotrophin (HCG) injection. The mean number of human menopausal gonadotrophin (HMG) ampoules administered and the mean number of stimulation days with HMG were significantly less in the cetrorelix group than in the buserelin group (P < 0.01). A rise in LH and progesterone concentrations was observed in three of the 188 patients (1.6%) who received cetrorelix. On the day of the HCG administration, more follicles of a small diameter (11-14 mm) were observed in the buserelin group than in the cetrorelix group (P = 0. 02) and the mean serum oestradiol concentration was significantly higher in patients who received buserelin than in those who received cetrorelix (P < 0.01). Similar results were observed in fertilization, cleavage and pregnancy rates in the two groups. In conclusion, the use of the LHRH antagonists might be considered more advantageous because of the short-term application needed to inhibit gonadotrophin secretion, so allowing a reduction in the treatment time in a clinically significant manner.     

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.     

Ovarian stimulation for in-vitro fertilization combining administration of gonadotrophins and blockade of the pituitary with D-Trp6-LHRH microcapsules: pilot studies with two protocols

In women undergoing in-vitro fertilization and embryo transfer(TVF-ET), a total of 408IVF cycles were stimulated using humanmenopausal gonadotrophin (HMG) or pure follicle stimulatinghormone (FSH) plus HMG in combination with a single injectionof D-Trp⁶-LHRH microcapsules in order to enhance the ovarianresponse to gonadotrophins and to avoid spontaneous LH surges.Sixty-seven pregnancies were achieved. Two protocols were employed.In protocol 1 (‘blocking protocol’, n = 268), thepituitary was first inhibited with a full dose (3.75 mg) ofD-Trp⁶-LHRH in microcapsules and ovarian stimulation was startedafter the hypogonadotrophic hypogonadal state was ascertained(Ej >50 pg/ml). In protocol 2 (‘flareup protocol’,n = 140), the treatment with D–Trp⁶LHRH microcapsules(half-dose = 1.80 mg) and the ovarian stimulation with gonadotrophinswere started at the same time. Higher doses of gonadotrophinswere needed (39.5 11.2 ampoules FSH and/or HMG) in protocol1, in which the pituitary was blocked prior to and during thestimulation, than in protocol 2 (209 ampoules) where the exogenousgonadotrophin stimulation appeared to be augmented by the initialagonistic effect of the injection of D-Trp⁶LHRH microcapsules.In patients with purely tubal infertility, under 38 years oldand no male factor, the results obtained with protocols 1 and2 were similar in terms of pregnancy rate per cycle or per embryotransfer: 22.6 versus 20.5% and 28.3 versus 27.4%, respectively.However, considering the cost benefit, ‘flare-up’protocols appeared to be a better choice and could be recommended.     

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.     

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.     

Randomized controlled trial of follicle stimulating hormone versus human menopausal gonadotrophin in in-vitro fertilization*

The adverse effect of raised luteinizing hormone (LH) concentrationson reproductive outcome suggests that exogenous LH administrationfor ovarian stimulation may not be desirable. The aim of thisstudy was to compare the clinical pregnancy rates between folliclestimulating hormone (FSH) and human menopausal gonadotrophin(HMG) used in in-vitro fertilization (IVF) cycles. A total of232 infertile patients, with a mean duration of infertilityof 67.1 ± 32.9 months, were selected for IVF (femaleage <38 years, FSH <15 IU/1, and total motile sperm count>5x10⁶). A short (flare-up) protocol with daily leuprolideacetate was followed randomly from day 3 with FSH (n = 115)or human menopausal gonadotrophin (HMG; n = 117), at an initialdose of two ampoules per day. A maximum of three embryos wastransferred, and the luteal phase was supported with four dosesof HCG (2500 IU). No differences were observed between the twogroups in any of the cycle response variables except fertilizationrates per oocyte and per patient, both of which were significantlyhigher with FSH. Clinical pregnancy rates per cycle initiated,per oocyte retrieval and per embryo transfer were 19.1, 21.0and 22.7% respectively for FSH, and 12.0, 12.8 and 15.4% respectivelyfor HMG. Whilst these differences were not statistically significant,the results of this interim analysis suggest that HMG may beassociated with a lower clinical pregnancy rate than FSH.     

Relationship between the threshold of ovarian sensitivity to human menopausal gonadotrophin stimulation and in-vitro fertilization treatment outcome

In a retrospective study of 813 oocyte retrieval–embryotransfer cycles in women with normal follicle stimulating hormoneand luteinizing hormone concentrations, we sought to investigatethe relationship between the amount of human menopausal gonadotrophin(HMG) used for ovarian stimulation and treatment outcome. Patientswere divided into three groups: group A patients (495 cycles)required <40 ampoules of HMG and had a predicted probabilityfor pregnancy of 25% per embryo transfer; group B patients (165cycles) required 41–77 ampoules per cycle, with a predictedprobability rate for pregnancy of 5–25% per embryo transfer;and group C patients (153 cycles) required >77 ampoules ofHMG and the predicted probability for pregnancy was <5% perembryo transfer. Groups C and A differed significantly (P <0.005). The mean oestradiol concentration on the day of HCGadministration in group C was 6412 pmol/l, and the mean numberof eggs retrieved was seven. The highest success rates werefound when up to 2.5 ampoules of HMG were required for eachegg or 4.4 ampoules for each embryo. The lowest rates were obtainedwhen >4.8 ampoules of HMG were necessary for each oocyteor >9.6 ampoules for each embryo (P < 0.005). We identifieda group of infertile patients who required excessive amountsof HMG to achieve a fair degree of steroidogenesis, number ofeggs and number of embryos but who had very low pregnancy rates.Although all other relevant parameters were normal, this mayhighlight the beginning of ovarian–gamete insufficiencybefore the basic hormonal status is affected. In cases of repeatedfailure, oocyte donation should be considered.