Endocrinology: The combination of gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH normalizes luteinizing hormone secretion in polycystic ovarian disease but fails to induce follicular maturation

To evaluate the role of altered luteinizing hormone (LH) releasein the mechanism of polycystic ovarian disease (PCOD) anovulation,we have co-administered a gonadotrophin-releasing hormone (GnRH)antagonist and pulsatile GnRH therapy to two clomiphene citrate-resistantPCOD patients. The aim was to correct their inappropriate gonadotrophinsecretion. Nal-Glu was administered s.c. every 72 h to bothsubjects for 3 weeks. On day 7 after commencing the study, intravenouspulsatile GnRH therapy was initiated (10 ug/ pulse) every 90min for 15 days to both subjects. In one subject, Nal-Glu treatmentwas continued and the GnRH dose was increased to 20 ug/pulsefor 10 additional days. Prior to Nal-Glu, mean serum LH levelswere 10.4 ±1.6 and 9.3 ± 1.3 mlU/ml (mean ±SEM) and mean interpulse intervals were 67.1 and 60 min in patients1 and 2, respectively. Mean serum FSH levels were 4.9 ±0.4 and 4.2 ± 0.2 mIU/ml for patients 1 and 2, respectively.LH pulsatility was abolished following Nal-Glu, mean serum LHdecreased to 1.1 ± 0.1 and 1.3 ± 0.5 mIU/ml andmean FSH to 1.8 ± 0.1 and 2 ± 0.1 mIU/ml in the two subjects. On the 4th day ofthe combined therapy, mean serum LH increased to 5.4 ±1.3 and 3.9 ± 0.9 mIU/ml with a mean interpulse intervalof 72 and 80 min, respectively. Mean FSH levels increased to3 ± 0.1 and 2.8 ± 0.1 mIU/ml, respectively andto 5.5 ± 0.2 mIU/ml after the GnRH dose was increasedin patient 2. Testosterone levels decreased but remained abovethe normal range following combined therapy. Levels increasedto the pretreatment values after augmentation of the GnRH dosein subject 2. Oestradiol levels remained <50 pg/ml and nofollicular development was observed on vaginal endosonography.Failure to obtain an ovarian response in PCOD after re-establishmentof improved pituitary gonadotrophin release may reflect thepresence of an inherent ovarian defect in PCOD patients.     

Induction of multiple follicular growth by pulsatile gonadotrophin-releasing hormone (GnRH) treatment in women with normal cycles: the role of the route of administration.

In a prospective study, seven patients with normal menstrual cycles were treated with pulsatile gonadotrophin-releasing hormone. They received one cycle of intravenous (i.v.) therapy and one cycle of subcutaneous (s.c.) therapy. Another four volunteers with normal cycles were treated for one s.c. cycle only. Cycles were compared to each other and to the normal unstimulated cycles of 14 other volunteers. Multiple follicular development could be achieved using both the i.v. and the s.c. routes. However, the i.v. route showed significantly higher luteinizing hormone (LH) and luteal steroid levels. Comparing s.c. cycles to controls, significantly lower LH levels were observed, resulting in significantly lower steroid production if calculated per large follicle. We conclude that the i.v. route is superior to the s.c. route in inducing multiple follicular growth in women with normal cycles.     

Endocrinology: Follicle cyst formation after administration of different gonadotrophin-releasing hormone analogues for assisted reproduction

The aim of this study was to examine the occurence of ovariancysts during the administration of three different gonadotrophin-releasinghormone analogues (GnRHa) in the long protocol as well as theircharacteristics, management and outcome compared with patientswith no cyst formation. A total of 172 in-vitro fertilization(IVF) cycles in which GnRHa was administered at menstruationwere analysed. Group B consisted of 72 cycles in which buserelinwas used. Of these, 10 (13.9%) were with cysts (group B1) and62 (86.1%) without cysts (group B2). Group T included 49 cyclesin which triptorelin was injected. Of these, seven (14.2%) werewith cysts (group T1) and 42 (85.7%) without cysts (group T2).Group L comprised 51 cycles in which leuprolide was administered.Of these, eight (15.7%) were with cysts (group L1) and 43 (84.3%)without cysts (group L2). All women with ovarian cysts had higherserum oestradiol concentrations and all except five underwentcyst aspiration with no complication. No differences were observedin the number of follicles and oocytes between groups B, T andL or between the groups with cysts and those without cysts.The pregnancy rate was similar in all groups. In conclusion,follicle cyst formation does not seem to be related to the useof a specific GnRHa, its short- or long-acting form or to themode of administration. In addition, follicle cyst aspirationis a safe and successful solution to the problem of functionallyactive ovarian cysts.     

Multiple follicular development in women with normal menstrual cycles treated with pulsatile gonadotrophin-releasing hormone.

In a prospective study, 15 patients with normal menstrual cycles were treated with pulsatile gonadotrophin-releasing hormone (GnRH) for one to four cycles. These cycles were compared to unstimulated cycles of 14 volunteers. There was a surprisingly stable number of large (greater than or equal to 14 mm diameter) follicles per patient. The number of large follicles in induction cycles was significantly greater than in controls (2.4 versus 1.07). This was due to significantly higher follicle stimulating hormone levels during the first days of treatment. Our data provide a rationale for the use of pulsatile GnRH for a safe and mild form of stimulation in assisted reproductive therapies.     

Endocrinology: Outcome of inadvertent administration of a gonadotrophin-releasing hormone agonist (buserelin) in early pregnancy

All women undergoing pituitary down-regulation before plannedin-vitro fertilization (IVF) treatment in two IVF units werestudied to assess the risks of and to pregnancies occurringinadvertently when gonadotrophin-releasing hormone agonists(GnRHa) were used to achieve pituitary desensitization duringthe luteal phase prior to planned IVF treatment. In 2670 cycles,25 women conceived (0.9% of cycles). Of these, three resultedin pre-clinical abortions (12%) but there were no clinical abortions,and 22 have ended with live births at term of apparently normalinfants. Collation of these and other published data suggestthat pregnancy outcome is not adversely affected by GnRHa administrationin the luteal phase of the conception cycle.     

Induction of ovulation with pulsatile GnRH in hypothalamic amenorrhoea

Pulsatile administration of gonadotrophin releasing hormone(GnRH) is a very effective treatment for induction of ovulationin hypothalamic amenorrhoea (HA). Thirty-seven women have beentreated for a total of 117 cycles which resulted in 42 pregnancies–fourtreatment failures occurred. If these cycles are excluded, the42 pregnancies were obtained within 2.3 cycles. One twin pregancyoccurred and no hyperstimulation was observed. The treatmentwas administered intravenously with a dosage schedule basedon the grading of HA. We concluded that pulsatile GnRH was safeand very successful in induction of pregnancy in HA. Other indications(polycystic ovary syndrome and luteal phase defect) remain muchless suitable for this treatment.     

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.     

Ovulation induction using s.c. pulsatile gonadotrophin-releasing hormone: effectiveness of different pulse frequencies

To determine the ovarian response to a fixed dose of gonadotrophin-releasinghormone (GnRH) administered s.c. at four different pulse frequencies,20 patients with hypothalamic amenorrhoea were treated over41 cycles using a dose of 200 ng/kg/pulse. These patients wererandomly assigned to receive GnRH at pulse frequencies of 60,90, 120 or 180 min. GnRH was administered s.c using portableinfusion pumps. Subjects were paid volunteers with a diagnosisof hypothalamic amenorrhoea. All patients had low to less thandetectable serum concentrations of luteinizing hormone and folliclestimulating hormone on 8 h serial sampling, and normal serumconcentrations of prolactin and androgen, including andro-stenedione,testosterone and dihydroepiandrosterone sulphate. Six of the20 patients were enrolled in the protocol to achieve a pregnancy,while 14 were volunteers using a barrier method of contraception.Highest ovulation rates were achieved using pulse frequenciesof 90 and 120 min (60 and 88% of cycles respectively). Ovulationoccurred significantly less often with frequencies of 60 and180 min (12 and 38% respectively; P 0.05). Pregnancy was achievedin four of the six patients who desired a pregnancy at pulsefrequencies of 90 (three out of three) and 120 (one out of one)min. No pregnancies occurred at pulse frequencies of 60 (noneout of one) and 180 (none out of one) min. When ovulatory cycleswere considered, oestradiol concentrations were not differentamong pulse frequencies but varied significantly between ovulatoryand anovulatory cycles. Integrated luteal progesterone concentrationsfor 90 and 120 min frequencies (118.26 25.89 and 125.15 32.10 ng/ml/luteal phase respectively) were significantly higherthan for 60 and 180 min (80.1 48.2 and 42.75 26.48 ng/ml/lutealphase respectively). Ovulation may be induced by a broad rangeof pulse frequencies. Pulse frequencies of 90 or 120 min fors.c GnRH appear to induce more reliably the sequence of folliculardevelopment, ovulation and normal luteal function than frequenciesof either 60 or 180 min. Significantly higher ovulation ratesoccurred at 90 and 120 min by s.c administered GnRH.     

Endocrinology: Long-term evaluation of implantation of fresh and cryopreserved human embryos following ovarian stimulation with buserelin acetate-human menopausal gonadotrophin (HMG) or clomiphene citrate-HMG

This study is a long-term evaluation of the total pregnancypotential of cohorts of fresh and cryopreserved sibling embryosfrom in-vitro fertilization (TVF) cycles stimulated with eitherthe gonadotrophin-releasing hormone analogue buserelin (BUS)(long protocol) or clomiphene citrate (CC) both in combinationwith human menopausal gonadotrophin (HMG). Therefore a retrospectiveanalysis was performed on patients who entered the FVT programmebetween January 1986 and July 1987 and who had triple embryotransfer in the collection cycle. Significantly more fertilizedoocytes developed to good-quality embryos in the CC-HMG group(86.1%) than in the BUS-HMG group (80.8%). Transfer of the threemorphologically best-looking embryos was performed on day 2post-insemination in 106 CC-HMG and 80 BUS-HMG cycles. Supernumeraryembryos were cultured for a further 24 h and multicellular embryoswith up to 20% of fragments were frozen slowly with 1.5 M dimethylsulphoxideon day 3 post-insemination (162 embryos in CC-HMG cycles, 102embryos in BUS-HMG cycles). Outcome was measured by embryo survivalrate, embryo implantation rate and delivery rate in fresh andfrozen embryo transfers. Delivery rates were 31.3 and 21.7%per fresh embryo transfer in BUS-HMG and CC-HMG cycles respectively.Fresh embryo implantation rates were significantly higher incollection cycles stimulated with BUS-HMG (17.9%) than in cyclesstimulated with CC-HMG (113%). Implantation rates were significantlyenhanced in embryos transferred in excess of one in cycles leadingto pregnancy, perhaps indicative of higher embryo quality inBUS-HMG cycles. Almost all cryopreserved embryos have by nowbeen thawed, so the contribution of frozen embryos to overallpregnancy rates can be evaluated. Overall morphological survivalrates of frozen-thawed embryos were similar for 140 embryosfrom CC-HMG cycles (50%) and 100 embryos from BUS-HMG cycles(46%). The percentage of fully intact embryos was, however,significantly lower in the BUS-HMG group (19%) than in the CC-HMGgroup (39.5%). Delivery rates were significantly lower following30 transfers of frozen-thawed embryos from BUS-HMG-stimulatedcycles (3.3%) than following 42 transfers of frozen-thawed embryosfrom CC-HMG cycles (19.1%). Embryo implantation rates were lowerfor frozen-thawed embryos from BUS-HMG cycles (23%) than fromCC-HMG cycles (12.7%). Here we demonstrate that ovarian stimulationwith the long protocol BUS-HMG instead of the CC-HMG protocolled to higher embryo implantation rates in collection cyclesbut to lower intact embryo survival rates and to lower embryoimplantation rates for frozen sibling embryos. Despite the lowerimplantation rates with frozen embryos originating from theBUS-HMG protocol, there was no significant difference betweentotal delivery rate per transfer from cycles stimulated withCC-HMG (30.2%) compared with BUS-HMG (33.8%).     

Endocrinology: Pulsatile subcutaneous versus bolus intramuscular gonadotrophin administration after pituitary suppression with a long-acting gonadotrophin-releasing hormone analogue: a controlled prospective study

The potential advantages of pulsatile s.c. administration insteadof daily bolus i.m.administration of human urinary gonadotrophinpreparations were tested after the administration of a long-actinggonadotrophin-releasing hormone (GnRH) analogue within a programmefor in-vitro fertilization (IVF) and embryo transfer. First,the pharmacokinetic properties of human urinary gonadotrophinswere analysed with immunological and biological methods, bothduring bolus i.m. injections and during pulsatile s.c. administration.Second, a prospective randomized controlled study was performedin 75 patients undergoing IVF/embryo transfer in whom the effectsof pulsatile s.c. administration were compared with the effectsof single daily bolus i.m. injections of the same gonadotrophinpreparation. The results showed that neither method of gonadotrophinadministration induced measurable changes in the serum concentrationof luteinizing hormone (LH). Both oestradiol and andro-stenedioneconcentrations were slightly lower during pulsatile s.c. gonadotrophinadministration, suggesting that this method of gonadotrophinadministration results in less LH occupying the ovarian LH receptors.Pulsatile s.c. gonadotrophin administration resembles a continuousinfusion of follicle-stimulating hormone (FSH). Significantfluctuations in the serum concentrations of FSH were observedduring single daily bolus i.m. administration of human urinarygonadotrophins, but the pregnancy rate of IVF/embryo transferper cycle after pulsatile s.c. administration was not significantlybetter than after the daily bolus i.m. injection of gonadotrophins(42.1 versus 37.2%). It is concluded that pulsatile s.c. administrationof gonadotrophins instead of single daily injections does notimprove the pregnancy rate in IVF/embryo transfer     

Endocrinology: Ovarian suppression with the gonadotrophin-releasing hormone agonist goserelin (Zoladex) in management of the premenstrual tension syndrome

The objective of this study was to determine the effectivenessof ovarian suppression by a GnRH agonist analogue in 32 womenwith prospectively confirmed severe premenstrual tension. Thedesign was a randomized, double-blind study comparing goserelin3.6 mg with placebo, both given as a monthly s.c. injectionfor 3 months. Self-assessment was by daily visual analogue scales(VAS) for anxiety and depression, daily quantitative symptomrating for breast discomfort, swelling, irritability, tension,depression and by monthly Hospital Anxiety and Depression (HAD)scales. Of the 16 women in each group, 15 completed active and12 completed placebo therapy. Median symptom scores for wholecycles showed a significant reduction of breast discomfort andswelling during active treatment, with no significant improvementin psychological symptoms. Analysis by cycle phase showed thatfor individual subjects, pre-treatment differences in VAS scoresfor anxiety and depression were abolished in a significantlygreater proportion of actively treated cycles. Within-groupcomparisons showed a marked placebo effect and, comparing thetwo groups, differences reached significance only during treatmentcycle 1 and the first post-treatment cycle for anxiety withno significant differences for depression. It was concludedthat while suppression of ovarian activity with a gonadotrophin-releasinghormone analogue dampens down cyclical mood swings, it has amore marked effect on the physical components of the premenstrualsyndrome. Results reconfirm the positive role of placebo inthe management of this condition.     

The effect of gonadotrophin-releasing hormone (GnRH) agonist in the follicular phase on in-vitro fertilization outcome in normo-ovulatory women.

Sixty-three normo-ovulatory infertile women were randomly divided into two groups. All women were first desensitized with the gonadotrophin-releasing hormone agonist (GnRHa), buserelin. Thereafter, ovarian stimulation with human menopausal gonadotrophins (HMG) was started in both groups but in group A the GnRHa was stopped on the same day. In group B, the GnRHa was continued during HMG treatment until the ovulatory human chorionic gonadotrophin stimulus was given. Premature luteinization was not observed in either group, although the preovulatory basal luteinizing hormone (LH) secretion was significantly higher in group A. An equal number of embryos of comparable quality was transferred in both groups and the pregnancy outcome was similar. However, the supernumerary embryos of group A were of a lower morphological quality and survived the cryopreservation process less well. We concluded that the continuous administration of a GnRH agonist during HMG treatment resulted in better quality of supernumerary embryos.     

GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study

BACKGROUND: We aimed to determine the efficacy of ovarian hyperstimulation protocols employing a GnRH antagonist to prevent a premature LH rise allowing final oocyte maturation and ovulation to be induced by a single bolus of either a GnRH agonist or hCG. METHODS: A total of 122 normogonadotrophic patients following a flexible antagonist protocol was stimulated with recombinant human FSH and prospectively randomized (sealed envelopes) to ovulation induction with a single bolus of either 0.5 mg buserelin s.c. (n = 55) or 10,000 IU of hCG (n = 67). A maximum of two embryos was transferred. Luteal support consisted of micronized progesterone vaginally, 90 mg a day, and estradiol, 4 mg a day per os. RESULTS: Ovulation was induced with GnRH agonist in 55 patients and hCG in 67 patients. Significantly more metaphase II (MII) oocytes were retrieved in the GnRH agonist group (P < 0.02). Significantly higher levels of LH and FSH (P < 0.001) and significantly lower levels of progesterone and estradiol (P < 0.001) were seen in the GnRH agonist group during the luteal phase. The implantation rate, 33/97 versus 3/89 (P < 0.001), clinical pregnancy rate, 36 versus 6% (P = 0.002), and rate of early pregnancy loss, 4% versus 79% (P = 0.005), were significantly in favour of hCG. CONCLUSIONS: Ovulation induction with a GnRH agonist resulted in significantly more MII oocytes. However, a significantly lower implantation rate and clinical pregnancy rate in addition to a significantly higher rate of early pregnancy loss was seen in the GnRH agonist group, most probably due to a luteal phase deficiency.     

Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group

A multicentre, open-label, randomized study of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix (Orgalutran((R))/Antagon((TM))) was performed in women undergoing ovarian stimulation with recombinant FSH (rFSH: Puregon((R))). The study was designed as a non-inferiority study using a long protocol of buserelin (intranasal) and rFSH as a reference treatment. A total of 730 subjects was randomized in a treatment ratio of 2:1 (ganirelix:buserelin) using an interactive voice response system which stratified for age, type of infertility and planned fertilization procedure [IVF or intracytoplasmic sperm injection (ICSI)]. The median duration of GnRH analogue treatment was 5 days in the ganirelix group and 26 days in the buserelin group, whereas the median total rFSH dose was 1500 IU and 1800 IU respectively. In addition, in the ganirelix group the mean duration of stimulation was 1 day shorter. During ganirelix treatment the incidence of LH rises (LH >/=10 IU/l) was 2.8% versus 1.3% during rFSH stimulation in the buserelin group. On the day of triggering ovulation by human chorionic gonadotrophin (HCG), the mean number of follicles >/=11 mm diameter was 10.7 and 11.8, and the median serum oestradiol concentrations were 1190 pg/ml and 1700 pg/ml in the ganirelix and buserelin groups respectively. The mean number of oocytes per retrieval was 9.1 and 10.4 respectively, whereas the mean number of good quality embryos was 3.3 and 3.5 respectively. The fertilization rate was equal in both groups (62.1%), and the same mean number of embryos (2.2) was replaced. The mean implantation rates were 15.7% and 21.8%, and the ongoing pregnancy rates per attempt were 20.3% and 25.7% in the ganirelix and buserelin groups respectively. Evaluation of all safety data indicated that the ganirelix regimen was safe and well tolerated. The overall incidence of ovarian hyperstimulation syndrome was 2.4% in the ganirelix group and 5.9% in the reference group. The results of this study support a safe, short and convenient treatment regimen of ganirelix, resulting in a good clinical outcome for patients undergoing ovarian stimulation for IVF or ICSI.     

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.     

Endocrinology: Pituitary responsiveness to gonadotrophin-releasing hormone agonist stimulation: a dose--response comparison of luteinizing hormone/follicle-stimulating hormone secretion in women with polycystic ovary syndrome and normal women

In polycystic ovary syndrome (PCOS), the mechanism responsiblefor abnormal gonadotrophin secretion, elevated serum luteinizinghormone (LH) and normal or low follicle-stimulating hormone(FSH) concentrations has not been elucidated. One proposed mechanism,as suggested by previous studies, is an augmented sensitivityof pituitary LH release and a corresponding insensitivity ofpituitary FSH release to gonadotrophin-releasing hormone (GnRH)agonist stimulation. This study was designed to further comparegonadotrophin responses to GnRH agonist stimulation within andbetween individual patients in a dose—response manner.Each of six PCOS and six normal ovulatory women was administereda single s.c. injection of the GnRH agonist [(imBzl)D-His⁶,Pro⁹-NEt]-GnRH (D-His) at a dose of 0.01, 0.1, 1 and 10 µg/kgon four separate occasions. Blood samples were obtained overa 72 h period following D-His administration. Gonadotrophinresponses were measured by (i) the maximal rise from pretreatmentbaseline values (Amax); (ii) the maximal percentage change frombaseline (%Amax); and (iii) the integrated response (mean ofthe cumulative sum of deviations from baseline). Within-groupand between-group dose—responses were compared by two-factoranalysis of variance and further characterized using the ‘Flexifit’computer program. Our results showed that in both groups, progressiveincreases of LH and FSH occurred following D-His at doses of0.01 and 0.1 µg/kg. Further increases beyond the 0.1 µg/kgdose were not observed. In PCOS women, Amax and integrated responsefor LH were significantly greater than those of normal subjectsat each dose tested. %max of LH was significantly lower in PCOS,reflecting higher pretreatment baseline LH concentrations inthis group. FSH responses to D-His were not significantly differentbetween PCOS and normal women. In PCOS, within-group comparisonsfailed to reveal a uniform pattern of LH dose—response.In contrast, LH integrated response curves were homogeneousamong individual normal women, as were the corresponding curvesfor FSH among both PCOS and normal women. These findings indicatethat PCOS patients exhibit greater LH responsiveness to GnRHagonist on a per-dose basis than that of normal women. Amongindividual PCOS patients, inconsistent dose—response patternsof LH release underscore the subtle variability of LH secretionamongst women with this disorder.     

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.     

Endocrinology: On the dynamics between gonadotrophin surge-inhibiting factor and gonadotrophin releasing hormone (GnRH): role of self-priming and desensitization in the luteinizing hormone response to GnRH after follicle stimulating hormone treatment

The effects were studied of follicle stimulating hormone (FSH)-inducedproduction of gonadotrophin surge-inhibiting factor (GnSIF)on three phases of the pituitary responsiveness to gonadotrophinreleasing hormone (GnRH): the unprimed, primed and desensitizedphases. Rats were injected with FSH on two occasions duringthe oestrous cycle. Spontaneous luteinizing hormone (LH) surgeswere measured as well as GnRH-induced LH surges on the day ofpro-oestrus during infusions with 100–4000 pmol GnRH/rat/10h, in phenobarbital blocked rats. The spontaneous LH surgeswere attenuated or completely inhibited by the FSH treatment.FSH suppresses and prolongs the unprimed LH response and delaysGnRH self-priming, especially during infusions with low concentrationsof GnRH. This treatment does not affect the total LH response(area under curve) to the highest concentrations of GnRH andafter ovariectomy. On the other hand, this response is suppressedduring infusions with the lower concentrations of GnRH. Hence,FSH, via GnSIF, delays maximal priming of the LH response toGnRH, whereas the suppression of LH release is a consequenceof the GnRH-induced progressed state of desensitization. Theinconsistent effects of FSH on the mid-cycle LH surges are explainedas a result of the interaction between the relative strengthsof GnRH and GnSIF.     

Endocrinology: The effect of pre-treatment with a gonadotrophin-releasing hormone agonist on reproductive functions in mature cycling rats

In order to investigate the performance of follicles in a ratmodel in which gonadotrophin-releasing hormone agonist (GnRHa)was used for hypothalamic—pituitary—ovarian axissuppression, three groups of mature cycling rats were studied.One group was treated with buserelin followed by pregnant mare'sserum gonadotrophin (PMSG), and the second group was treatedwith PMSG alone. Both these hormonally treated groups receivedhuman chorionic gonadotrophin for induction of ovulation. Thethird group received no hormonal treatment. The average numberof ovulated oocytes recovered from rat oviducts pre-treatedwith GnRHa was significantly higher than that in rats treatedwith the gonadotrophin alone, in spite of the larger numberof pre-ovulatory follicles present in the gonadotrophin-treatedgroup. The morphology of both the pre-ovulatory and the post-ovulatorycumulus—oocyte complexes in the three groups appearedsimilar. No difference in the capacity of follicles of the threegroups to synthesize progesterone in vitro in response to luteinizinghormone could be observed. We conclude that ovarian morphologyand function are not impaired by pre-treatment with buserelin.     

Endocrinology: Ultrasonographic appearance of polycystic ovaries is associated with exaggerated ovarian androgen and oestradiol responses to gonadotrophin-releasing hormone agonist in women undergoing assisted reproduction treatment

While no single biochemical test is diagnostic of polycysticovary syndrome (PCOS), most patients show a characteristic ovarianultrasonographic appearance. It has been proposed that a dysfunctionof cytochrome P-450c17 in PCOS leads to an increased 17-hydroxyprogesterone(17-OHP) response to a gonadotrophin-releasing hormone (GnRH)agonist-induced gonadotrophin rise. We postulated that thisabnormality of steroid metabolism might influence the ovarianresponse during assisted reproduction treatment. We investigated106 patients undergoing a short ’boost‘ stimulationregimen for assisted reproduction treatment, including in-vitrofertilization and gamete intra-Fallopian transfers. The ovarianultrasound pattern was correlated with serum testosterone, 17-OHP,androstenedione and oestradiol responses, and with the clinicaloutcome. Polycystic ovaries, defined ultrasonographically asthe presence of 10 follicles between 2 and 10 mm diameter ineither ovary, were found in 48% of the whole study population.Dexamethasone was given to suppress adrenal androgen secretion.Functional ovarian hyperandrogenism (FOH) was defined as serumtestosterone >0.5 nmol/l after dexamethasone. There was asignificantly (P < 0.001) higher prevalence of FOH in patientswith polycystic ovaries (23%) compared with normal ovaries (7%).Patients with polycystic ovaries had approximately double the17-OHP, androstenedione and oestradiol responses to a GnRH agonistas patients with non-polycystic ovaries. Exaggerated 17-OHPand oestradiol responses to GnRH agonist were found in 89% ofpatients with clinically diagnosed PCOS. The number of oocytesretrieved was positively correlated (r = 0.51, P < 0.001)with the oestradiol responses in all patients. Although therewas no difference in the total amount of follicle stimulatinghormone (FSH) used between the patients with polycystic andnormal ovaries, the median peak oestradiol concentration was1.6 times and the oocyte yield 2.3 times greater in patientswith polycystic ovaries. The overall pregnancy rate per transferwas 32% and did not differ between patients with or withoutpolycystic ovaries and FOH. No pregnancies occurred when thebaseline FSH concentration was >10 IU/l. We conclude thatthe ultrasonographic changes characteristic of polycystic ovariesshould be sought in all women undergoing assisted reproductiontreatment.