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)     

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.     

Analysis of hormonal changes during combined buserelin/HMG treatment

Changes of serum oestradiol, LH and progesterone have been analysed in view of the effect of the GnRH analogue buserelin on the late follicular and early luteal phase of cycles stimulated with combined buserelin/HMG (n = 31) in an IVF-ET/GIFT programme. Patients undergoing cycles with HMG only (n = 57) served as the control group. With the use of the GnRH analogue buserelin, a significantly higher amount of HMG (25 versus 20 ampoules; P less than 0.001) for a significantly longer stimulation period (10 versus 8 days; P less than 0.001) was necessary to achieve the same oestradiol response as seen in HMG cycles. Serum progesterone levels during a three day period before ovulation induction tended to be lower in the combined buserelin/HMG cycles than in cycles with HMG stimulation only. We did not observe any significant difference in the luteal phase progesterone levels of the buserelin/HMG and the HMG group. On the other hand, we found that an inadequate luteal phase in buserelin/HMG cycles could be avoided by HCG administration during the luteal phase. Both the elevation of basal serum LH and a premature LH rise could also be avoided by the use of buserelin.     

A controlled study of human chorionic gonadotrophin induced ovulation versus urinary luteinizing hormone surge for timing of intrauterine insemination.

Forty-eight patients in a programme of intrauterine insemination (IUI) were randomized in a cross-over study. All were stimulated with clomiphene citrate (CC) and inseminated either after follicular rupture induced by human chorionic gonadotrophin (HCG) or after a spontaneous urinary luteinizing hormone (LH) surge. The HCG was administered when follicles of 18-22 mm in diameter were observed on ultrasound and IUI was performed 37-40 h thereafter. The monitoring of a urinary LH peak was carried out using a rapid urinary LH test. IUI took place approximately 22 h after detection of the LH surge. Overall, the pregnancy rates were 9.3% (4/43) after HCG induced ovulation and 20.5% (9/44) after spontaneous ovulation (P = 0.12). Analysis of mid-cycle events showed that following sonographic criteria, the HCG injection was performed significantly earlier in the cycle compared with the spontaneous LH surge. In addition, the mean diameter of the preovulatory follicles was significantly smaller and insemination was substantially earlier in the HCG induced cycles. These findings suggest that a beneficial effect arises from allowing the natural process of final follicular maturation to occur.     

Blunted LH surge after HCG administration in cycles superovulated for in-vitro fertilization

The preovulatory pattern of serum luteinizing hormone (LH) was investigated in cycles superovulated for in-vitro fertilization (IVF). The method used was immunoradiometric assay which shows no cross-reactivity with human chorionic gonadotrophin (HCG) at concentrations usually found after HCG administration. Of the 245 cycles stimulated by clomiphene citrate + human menopausal gonadotrophin, an endogenous LH surge was observed in 29.8% of the patients shortly prior to the HCG injection. In the post-HCG period, 49.4% of the cycles exhibited a blunted LH rise, whereas in the remaining 20.8% the LH level did not exceed twice the mean preovulatory value. According to the oestradiol-17 beta (E2) and progesterone concentrations, different hormonal patterns were found in patients with pre-HCG and post-HCG elevation of LH. However, the occurrence of a blunted LH surge following HCG administration cannot be attributed to different, HCG-induced secretory patterns of progesterone. There were no significant differences in clinical parameters, the pregnancy rate was slightly but not significantly higher (19.0%) in the post-HCG LH surge group than in the two other groups (13.7%). It is presumed that various factors may contribute to the suspension of preovulatory LH suppression. The possible beneficial influence of a post-HCG surge of LH requires further investigation.     

Is continuation of a gonadotrophin-releasing hormone agonist (GnRHa) necessary for women at risk of developing the ovarian hyperstimulation syndrome?

A total of 28 women scheduled for in-vitro fertilization used buserelin and human menopausal gonadotrophin (HMG) for ovarian stimulation. One group (I) of 17 women was given human chorionic gonadotrophin (HCG 10,000 IU) to trigger ovulation, but the resulting embryos were electively cryopreserved because of the risk (serum oestradiol greater than or equal to 3500 pg/ml) of developing the ovarian hyperstimulation syndrome (OHSS). Six women continued the buserelin therapy in the luteal phase and eleven did not. In group II (n = 11), the HMG injections were discontinued because of an exaggerated ovarian response and the HCG was omitted. Six of these women continued the buserelin injections until the onset of menses and five did not. In both groups, the ovarian response to induction of ovulation (serum oestradiol concentrations and number of follicles) was similar for those who did or did not continue buserelin therapy. There was no difference in the rate of ovarian quiescence (weekly fall in serum oestradiol concentration following the stimulation) between those women who did or did not continue the buserelin therapy in either group. The serum luteinizing hormone concentrations remained low in all women in both groups. We conclude that the omission of buserelin therapy after discontinuing the HMG in women at risk of developing OHSS does not affect subsequent ovarian quiescence.     

Studies on the influence of gonadotrophin levels in the early follicular phase on the ovarian response to stimulation

The gonadotrophic regulation of folliculogenesis has been extensively investigated but little attention has been paid to the influence of early follicular phase levels of endogenous FSH and the FSH/LH ratio when planning ovulation stimulation therapy for IVF. The influence of these factors was investigated in the three studies reported in this paper. A fixed schedule of ovulation stimulation therapy which employed standard treatment regimens, irrespective of the ovarian response, was used to eliminate variation due to treatment factors. Cycles were pretreated with an oestrogen-progestogen contraceptive pill or a progestogen (norethisterone). It was found that both oestrogen-progestogen and progestogen alone decreased the plasma FSH level, although the FSH/LH ratio was significantly reduced only by oestrogen-progestogens. In clinical IVF studies, oestrogen-progestogen pretreatment was associated with a significant reduction in the preovulatory concentration of oestradiol in plasma and the number of aspirated follicles, compared to norethisterone. The administration of FSH for 2 days following oestrogen-progestogen pretreatment and prior to the fixed schedule of ovulation stimulation normalized ovarian steroidogenesis and follicular development. Early follicular phase supplementation with FSH had no influence on progestogen pretreated cycles. The final experiment investigated the influence of FSH/LH levels in the early follicular phase on the outcome of ovarian stimulation. The preovulatory oestradiol concentration was reduced when baseline FSH/LH levels were low compared with when these values were high. Administration of FSH for 2 days in the early follicular phase improved the preovulatory level of oestradiol when baseline FSH/LH was low but had no effect when baseline FSH/LH levels were high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Outcome of treatment subsequent to the elective cryopreservation of all embryos from women at risk of the ovarian hyperstimulation syndrome.

From 1st June 1989 to 31st May 1991, 78 women with a serum oestradiol level greater than 3500 pg/ml on the day of the ovulatory trigger, following pituitary suppression with buserelin and ovarian stimulation with human menopausal gonadotrophins (HMG), had all their embryos electively cryopreserved at the pronucleate stage to minimize the risk of developing ovarian hyperstimulation syndrome (OHS). Treatment with buserelin was continued in the luteal phase. A median of 19 oocytes (range 7-43) was obtained and 12 embryos (range 1-37) frozen per cycle. Twenty-one (27%) women developed OHS (six severe). Women developing OHS had higher (P less than 0.05) serum oestradiol concentrations on the 7th day after oocyte retrieval, compared to those who did not. No differences were found for any of the following criteria: aetiology of infertility, age, total dose of HMG, number of oocytes, fertilization rate or freeze-thaw survival of embryos. Subsequently, 125 frozen-thawed embryo replacements have been undertaken, using buserelin and hormone replacement therapy (HRT) (n = 93) or natural cycles (n = 32). The overall freeze-thaw survival and implantation rates per embryo were 71.8 and 11.7%, respectively. The pregnancy rates in natural cycles (19%) and buserelin/HRT cycles (29%) were not significantly different.     

Endocrine composition of follicular fluid comparing human chorionic gonadotrophin to a gonadotrophin-releasing hormone agonist for ovulation induction

Concentrations of inhibin, oestradiol and progesterone weredetermined in pre-ovulatory follicular fluid from 16 women undergoingin-vitro fertilization and embryo transfer treatment. A prospectiverandomized design was used such that ovulation was induced ineight women with human chorionic gonadotrophin (HCG) (9000 IU),and in eight women with an endogenous surge of luteinizing hormone(LH) and follicle stimulating hormone (FSH) caused by a singleinjection of gonadotrophin-releasing hormone agonist (GnRHa).Inhibin was measured by an enzyme-linked immunosorbent assay,and oestradiol and progesterone were measured by radioimmunoassay.Concentrations of inhibin and progesterone are significantlyhigher in follicular fluids collected after ovulation inductionwith HCG compared with ovulation induction with GnRHa (P <0.001, P < 0.02, respectively). Concentrations of oestradiolwere similar in the two groups. This study shows that the methodby which ovulation is triggered significantly affects the micro-environmentof the oocyte just prior to ovulation. The results indicatethat HCG causes a prolonged luteotrophic effect well beforeovulation, compared to an endogenous surge of gonadotrophinscaused by GnRHa, and suggest that follicular maturation withan endogenous surge of gonadotrophins may be closer to the naturalcycle than those cycles in which HCG is administered for ovulationinduction. In addition, this study shows that the concentrationsof inhibin and progesterone in follicular fluid may be valuableparameters in assessing the midcycle LH surge requirements forinduction of ovulation.     

Endocrinology: A prospective randomized single-blind comparative trial of nafarelin acetate with buserelin in long-protocol gonadotrophin-releasing hormone analogue controlled in-vitro fertilization cycles

The use of gonadotrophin-releasing hormone (GnRH) agonists tocontrol ovulation induction cycles for in-vitro fertilization(IVF) has been shown to increase the pregnancy rate and livebirth rate compared with non-analogue cycles. Different formulationsof GnRH agonist are available with different routes and frequenciesof administration. In this prospective study, the efficacy andsafety of intranasal nafarelin and buserelin as adjunctive therapyduring IVF were assessed. A total of 240 female patients wererecruited to the study and in the first phase patients wererandomized to receive either intranasal nafarelin 200 µgtwice daily or buserelin 200 µg five times daily. In thesecond phase, patients received either nafarelin 400 µgtwice daily or buserelin 200 µg five times daily. Nafarelin400 µg and buserelin 200 µg both produced clinicalpregnancy rates of 31% per recruit and 39% per embryo transfer.The rates for nafarelin 200 ug were 23 and 37% respectively.There was no statistically significant difference in pregnancyrates, by either drug or dosage. The time taken for pituitarydown-regulation to be achieved was significantly longer on nafarelin200 µg than on either nafarelin 400 µg or buserelin.The total number of days stimulation with human menopausal gonadotrophinrequired to reach criteria for human chorionic gonadotrophin(HCG) administration was significantly longer on buserelin thanon either dose of nafarelin. Median serum oestradiol concentrationson the day of HCG administration were significantly higher oneither dose of nafarelin than on buserelin.     

Induction of ovulation in rabbits with pure urinary luteinizing hormone and human chorionic gonadotrophin: comparison of oocyte and embryo quality.

Thirty-six 18-week-old nulliparous does were stimulated with a single dose of 25 IU pregnant mare serum gonadotrophin (PMSG). Ovulation was induced 48 h later with 50 IU luteinizing hormone (LH) (18 does) or 50 IU human chorionic gonadotrophin (HCG) (18 does) in order to determine the effects of pure urinary LH and HCG on the quality of oocytes and embryos. Nine does were mated in each group. The does were slaughtered 24 h after induction of ovulation to recover oocytes and 48 h after mating to recover embryos. The number of haemorrhagic, preovulatory and luteinizing follicles per ovary were recorded. The quality of oocytes and embryos recovered were evaluated. No significant differences in the number of haemorrhagic follicles (blood follicles without stigma), preovulatory and luteinizing follicles were observed between LH and HCG groups. LH has a selective action, which could permit the acquisition of better quality oocytes. Although the fertilization rate was similar in both groups (LH versus HCG), the percentage of degenerate embryos (grade 5) was lower for the LH (3%) than the HCG (13%) groups.     

Hormone and ultrasound parameters in ovarian stimulation cycles for direct intraperitoneal insemination.

To determine hormonal and ultrasound parameters associated with pregnancies, 115 women with unexplained infertility (n = 82), endometriosis (n = 22) or cervical factor (n = 11) were treated with direct intraperitoneal insemination (DIPI) after ovarian stimulation with clomiphene citrate and human menopausal gonadotrophins (HMG). Twenty women conceived and were compared with the remaining 95 non-pregnant women during one treatment cycle. Women with basal FSH levels less than or equal to 1.25 micrograms/l responded with higher oestradiol levels (P less than 0.0001), with the development of more follicles (P less than 0.05) and higher progesterone levels (P less than 0.05) than women with basal FSH levels greater than 1.25 micrograms/l, but the conception rates were similar. Women with miscarriages or biochemical pregnancies had a higher basal FSH value than both the women with term pregnancies and the non-pregnant women. Women with at least 3 preovulatory follicles greater than or equal to 15 mm had a higher pregnancy rate than those with fewer follicles, but a further increase was not observed above that number. The endometrium was thicker on the day of ovulation induction in cycles leading to a term pregnancy than in cycles without conception or with a biochemical pregnancy. No term pregnancy was observed when the endometrium was thinner than 8 mm. Women with a short luteal phase (less than 12 days) had a higher ratio of oestradiol/progesterone in the midluteal phase than women with a luteal phase of greater than or equal to 12 days and pregnant women.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Delayed occurrence of an LH surge after HCG administration during ovarian stimulation with gonadotrophins: effect of LHRH treatment

Previous studies have shown the appearance of a spontaneous luteinizing hormone (LH) surge after human chorionic gonadotrophin (HCG) administration in human menopausal gonadotrophin (HMG)/HCG-stimulated menstrual cycles. In this report we investigated the effect of leuprolide acetate, a long-acting luteinizing hormone releasing hormone (LHRH) agonist, on the occurrence of these post-HCG rises in serum LH. Two groups of patients were included. Group 1: 10 patients receiving HCG as a part of an HMG/HCG protocol for induction of follicular development in an IVF/GIFT program and Group II: 10 patients treated as Group I, but receiving the LHRH agonist leuprolide acetate to inhibit gonadotrophin secretion prior to and during ovarian stimulation. In Group I, none of the patients showed a surge prior to HCG administration. However, an LH surge following HCG treatment was apparent in four patients (40%). Pregnant patients (2/10) had low mean levels (less than or equal to 2.5 mIU/ml LH) in the follicular phase and showed no LH surge after HCG. In Group II, baseline levels of serum LH were reduced significantly (mean, 1.4 +/- 0.1 mIU/ml; P less than 0.001) compared to Group I. No patient showed an LH surge either before or after HCG administration and the occurrence of pregnancy was higher (6/9 transfers) than in Group I. In spite of the differences in pregnancy rates, the combined therapy versus HMG therapy showed no significant difference in number of oocytes collected or serum oestradiol levels. This suggests that high levels of serum LH, whether prior to or after HCG administration, may have a detrimental effect on the establishment of pregnancy despite adequate follicular growth.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of corpus luteum function

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

Complete and partial luteinized unruptured follicle syndrome after ovarian stimulation with clomiphene citrate/human menopausal gonadotrophin/human chorionic gonadotrophin

A total of 31 clomiphene citrate/human menopausal gonadotrophin(HMG)/human chorionic gonadotrophin (HCG)-stimulated cyclesin 28 patients were investigated to determine the fate of eachof the matured follicles. A standard stimulation regimen wasadhered to, and ultrasound as well as hormonal monitoring wasperformed. All follicles were measured by vaginal ultrasoundat –12, +35 and +45 h relative to HCG administration andat 7 days after HCG administration. Of the 220 follicles, 107(48.6%) ruptured. The number of ruptured follicles per cyclewas correlated with the mid-luteal progesterone concentration(r = 0.63, P = 0.0005). The probability of follicular rupturewas related to follicular diameter at 12 h before HCG administration;6% of follicles <12 mm in diameter ruptured compared with87% of follicles 18–19 mm. A complete luteinized unrupturedfollicle (LUF) syndrome was observed in six cycles (20%). Inthese cycles, follicular growth and oestradiol, progesterone,luteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations at 12 h before HCG administration were similarto those in cycles with follicular rupture. However, mid-lutealprogesterone concentrations were lower in complete LUF cycles(46.97 ± 8.95 nmol/1 versus 108.74 ± 12.27 nmol/1;P = 0.02). These data demonstrate that in stimulated cyclesmany follicles, usually the smaller ones, fail to rupture, evenafter HCG administration. Complete LUF syndrome, despite a strongexogenous ovulatory signal, and the absence of any differencein peri-ovulatory hormonal parameters, indicates that the defectcausing LUF resides in the follicle itself and/or hormonal changesduring the follicular phase.     

Effects of varying doses of HCG on the evolution of preovulatory rabbit follicles and oocytes

To determine the effects of insufficient or excessive dosesof human chorionic gonadotrophin (HCG) on ovulation, varyingsingle doses from 5 to 100 IU were administered to 40 does inoestrus. A total of 371 preovulatory follicles and oocytes wereobserved. Low doses of HCG (5–10) started resumption ofmeiosis, but no ovulation occurred. Higher doses progressivelyinduced nuclear maturation (prometaphase, metaphase I, metaphaseII). Simultaneously increasing doses initiated ovulation ofsome of the follicles, then of most of the follicles. Unrupturedfollicles, mostly with oocytes in metaphase II were frequentand depending on the dose, these were preovulatory, haemorrhagicor luteinized. The administration of different doses demonstratedthe possible dissociation of several mechanisms leading to ovulation.The induction of nuclear maturation requires lower doses ofHCG than luteinization. Follicular rupture requires even higherdoses. Premature luteinization induces intrafollicular ovumretention without (LUF syndrome) or with follicular rupture.These mechanisms of ovulation explain the effects of bluntedlutein–izing hormone surges or inadequate HCG administration.     

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.     

Triggering of ovulation in human menopausal gonadotrophin-stimulated cycles: comparison between intravenously administered gonadotrophin-releasing hormone (100 and 500 {micro}g), GnRH agonist (buserelin, 500 {micro}g) and human chorionic gonadotrophin (10 000 IU)

We studied the peri-ovulatory and luteal phases in 38 humanmenopausal gonadotrophin (HMG)-stimulated cycles, in which ovulationwas triggered with four different i.v. bolus ovulation triggers:100 µg gonadotrophin-releasing hormone (GnRH; group A,n = 9), 500 µg GnRH agonist (GnRHa; group B, n = 10),10 000IU human chorionic gonadotrophin (HCG; group C, n = 10)and 500 µg GnRH (group D, n = 9). Endogenous luteinizinghormone (LH) surges occurred in all cycles of groups A, B andD. The rise was slowest but highest in group B (P < 0.0001)and lowest in group A. Although the t₀ serum oestradiol valueswere similar in all groups, day +8 oestradiol and day +4 and+8 progesterone concentrations were higher in group C (P <0.05). At day +4 and +8, serum LH concentrations were lowest(P < 0.01) but follicle stimulating hormone (FSH) concentrationswere higher. Clinically, day +8 luteal scores showed a moreconspicuous degree of ovarian hyperstimulation in the HCG group(P = 0.0292). Luteal insufficiency, defined as cycles with progesteroneconcentrations of <8 ng/ml, occurred much more frequentlyin groups A, B and D than in group C (day +4: P < 0.0003;day +8: P < 0.0001), despite progesterone supplementation.Three pregnancies (one in group C and two in group D) and onemoderate case of ovarian hyperstimulation syndrome (OHSS) (ina non-conceptional group D cycle) occurred. These findings showthat (i) ovulation occurs and pregnancy can be achieved followingan endogenous LH surge induced by GnRH and its agonists, (ii)a high frequency of luteal insufficiency occurs in such cycleseven with luteal supplementation and (iii) OHSS cannot be totallyprevented by this approach, although cycles with an endogenousLH surge in general result in fewer subclinical signs of ovarianhyperstimulation.     

Beneficial effects of a 24 h delay in human chorionic gonadotrophin administration during in-vitro fertilization treatment cycles

We used a gonadotrophin-releasing hormone agonist (buserelin)and human menopausal gonadotrophin (HMG) for superovulationfor in-vitro fertilization (IVF) in 143 patients. The patientswere prospectively allocated to two balanced groups. In onegroup (47 patients) human chononic gonadotrophin (HCG) was givenwhen the three largest follicles were 17 mm ni diameter, withconsistent levels of plasma oestradiol (standard group). Inthe second group (96 patients), HCG injection was delayed by24 h (delayed group). In the delayed group of patients, proportionatelymore had clinical pregnancies (52.1% versus 34.0%). These resultssuggest that IVF patients will benefit from delayed administrationof HCG. The traditional criteria for HCG administration shouldbe changed when buserelin is used.