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

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

Comparison of luteal phase profile in gonadotrophin stimulated cycles with or without a gonadotrophin-releasing hormone antagonist.

BACKGROUND: The aim of our study was to explore luteal phase hormone profiles in gonadotrophin-stimulated cycles with or without gonadotrophin-releasing hormone (GnRH) antagonist therapy during intrauterine insemination (IUI). Forty-one infertile couples were recruited in this randomized clinical study. METHODS: The 19 patients included in group A were treated for 21 cycles with recombinant FSH 150 IU/day starting from day 3 of the cycle and with the GnRH antagonist cetrorelix at the dose of 0.25 mg/day starting from the day in which a follicle with a mean diameter of > or =14 mm was seen at ultrasound scan. Cetrorelix was administered until human chorionic gonadotrophin (HCG) administration. The 22 patients included in group B were administered recombinant FSH alone at the same dosage for 27 cycles. RESULTS: The two treatment groups showed a similar increase in progesterone concentration during the luteal phase. In the mid-luteal phase (day 6 after HCG), oestradiol concentrations in group B were significantly higher compared with group A (P < 0.05) but the oestradiol:progesterone ratio was similar in the two groups. Serum LH was completely suppressed during the follicular phase only in group A, concomitantly with GnRH antagonist administration. A total of six pregnancies, all ongoing, were achieved (14.3% per patient and 12.2% per cycle), equally distributed in group A and in group B. CONCLUSION: GnRH antagonists can be safely administered in gonadotrophin-stimulated IUI cycles without luteal phase supplementation because no deleterious effects of GnRH antagonist administration were noted on luteal progesterone concentration or on the duration of the luteal phase.     

Human endometrial maturation is markedly improved after luteal supplementation of gonadotrophin-releasing hormone analogue/human menopausal gonadotrophin stimulated cycles

In human cycles stimulated for ovulation with gonadotrophin–releasinghormone (GnRH) agonists and human menopausal gonadotrophin (HMG),a luteal phase defect has been described. To evaluate the influenceon the endometrium, endometrial development in GnRH agonist/HMGstimulated cycles was assessed in cycles with and without lutealphase supplementation. Endometrial histological maturation,ultrastructure and oestrogen receptor (ER) and progesteronereceptor (PR) status were analysed in the mid-luteal phase.Serum concentrations of oestradiol and progesterone were measureddaily from days 1–5 of the luteal phase. Supplementationof the luteal phase was achieved with either human chorionicgonadotrophin or natural progesterone, administered intramuscularlyor intravaginally. In non-supplemented cycles all endometrialfeatures were consistent with an impaired progesterone bioavailability.After supplementation of the luteal phase, fewer signs of lutealphase deficiency were visible, especially with the intravaginalroute of progesterone administration. We concluded that theendometrial parameters confirm the need for luteal support inGnRH agonist/HMG stimulated cycles.     

The efficacy of short-term gonadotrophin-releasing hormone agonists versus human chorionic gonadotrophin to enable oocyte release in gonadotrophin stimulated cycles

One of the reasons for failure to conceive following human menopausalgonadotrophin (HMG) therapy may be due to non-release of oocytesfrom the follicles. We hypothesized that by using a gonadotrophin-releasinghormone agonist (GnRHa) for a short duration, endogenous releaseof luteinizing hormone and follicle stimulating hormone mayenable oocyte release to occur, similar or superior to the effectof human chorionic gonadotrophin (HCG). This study attemptedto compare the efficacy of HCG versus the GnRHa leuprolide acetateto release oocytes and achieve pregnancies and to compare theeffectiveness of leuprolide acetate versus a combination ofHCG with HMG to release oocytes. Unfortunately due to lack ofprior data, many patients preferred to reject leuprolide acetatein favour of HCG, resulting in three times as many patientsbeing treated with HCG in cycle 1; 78.2% of oocytes were releasedfollowing leuprolide acetate versus only 55.7% with HCG. Interestingly,87.5% of those females in whom oocyte release failed in cycle1 with HCG did indeed release with leuprolide acetate in cycle2, but none of these previous failures released with HCG incycle 2. Pregnancy rates were equal in those women releasingoocytes, whether treated with HCG or leuprolide acetate. Thesepreliminary data justify a larger randomized study.     

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: Induction of pre-ovulatory gonadotrophin surge with gonadotrophin-releasing hormone agonist compared to pre-ovulatory injection of human chorionic gonadotrophins for ovulation induction in intrauterine insemination treatment cycles

The clinical outcome of intrauterine insemination (IUI) treatmentcycles employing a gonadotrophin-releasing hormone agonist [GnRHa,triptorelin (Decapeptyl)] or human chorionic gonadotrophin (HCG)for ovulation induction was compared. A group of 48 patientspresenting with amenorrhoea, oligomenorrhoea or unexplainedinfertility were all treated with human menopausal gonadotrophins(HMG) from day 5 of the cycle, on an individualized schedule.They were then randomly divided into two groups to receive eithera single s.c. injection of 0.1 mg triptorelin or a single i.m.injection of 10 000 IU HCG after follicular maturation. IUIwas performed 24 and 48 h following the injection. A transitoryincrease in serum luteinizing hormone and follicle stimulatinghormone concentrations was achieved following injection of GnRHa.A total of 24 patients received 72 treatment cycles with GnRHa,producing 11 conceptions (15.3%) and two abortions (18.2%),resulting in a term pregnancy rate of 13.6%. There were fourcases of grade 3–4 ovarian hyperstimulation syndrome (OHSS),two of which were conception cycles. In all, 24 patients underwent68 cycles treated with HCG, producing 18 conceptions (26.5%)and six abortions (33.3%), resulting in a term pregnancy rateof 19.0%. There were eight cycles of grade 3–4 OHSS, twoof which were conception cycles. These results show that ans.c. injection of a relatively low dose of GnRHa can be as effectiveas HCG in producing pregnancy in IUI treatment cycles.     

Gonadotrophin-releasing hormone agonist compared with human chorionic gonadotrophin for ovulation induction after clomiphene citrate treatment

The objective of this study was to compare hormonal response,luteal phase adequacy and pregnancy and abortion rates in patientsrandomized to receive human chorionic gonadotrophin (HCG) orgonadotrophinreleasing hormone agonist (GnRHa) during ovulationcycles stimulated by clomiphene citrate. Anovulatory patientsreceived either one s.c. dose of tryptorelin (0.1 mg; n = 104)or one i.m. dose of HCG (10 000 IU; n = 106) after clomiphenecitrate stimulation had induced enlarged ovarian follicles (>17mm in diameter). A short-lived, transitory increase in serumluteinizing hormone (98 ± 9 IU/1) and follicle-stimulatinghormone (30 ± 5 IU/1) concentrations was measured at12 h following the injection of GnRHa, and these concentrationsreturned to baseline levels by 36 h post-injection. Midlutealprogesterone concentrations were similar in both groups (>10ng/ml), and the mean luteal phase duration was also not significantlydifferent (13 days). There were no significant differences inthe mean number of pregnancies (12.0 versus 12.6% per cycle)and the abortion rate (18.2 versus 12.5%) between the GnRHa-and HCG-treated groups respectively. There were no complicationsrelated to treatment in either group. The results show thata relatively low dose of GnRHa can be used in place of HCG toinduce ovulation in clomiphene citrate-treated patients.     

Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF

BACKGROUND: It has been reported that ceasing the administration of gonadotrophin-releasing hormone (GnRH) agonist causes a profound suppression of circulating serum gonadotrophins. A comparative prospective and randomized study was conducted to investigate the effect of continuous administration of GnRH agonist during the luteal phase in an ovarian stimulation programme for IVF. METHODS: GnRH agonist was administered intranasally from the midluteal phase of the previous cycle, and pure FSH administration started on cycle day 7. In the continuous-long protocol (cL) group (n = 161 ), GnRH agonist administration was continued until 14 days after oocyte retrieval. In the long protocol (L) group (n = 158 ), GnRH agonist was administered until the day before human chorionic gonadotrophin (HCG) administration. RESULTS: The implantation rate and live birth rate per unit of transferred embryos were significantly higher in the cL group than the L group (P < 0.05 ). Serum LH and FSH concentrations on the day of, and 1 day after, HCG administration were significantly lower in the L group than the cL group (P < 0.01 ). CONCLUSIONS: Continuation of GnRH agonist administration during the luteal phase might facilitate implantation, and prevent the profound suppression of serum gonadotrophins.     

An update of luteal phase support in stimulated IVF cycles

Stimulated IVF cycles are associated with luteal phase defect. In order to overcome this, different doses, durations and types of luteal phase support (LPS) have been evaluated. There is still no agreement regarding the optimal supplementation scheme. The aim of this paper is to assess the past and the current clinical practices of luteal supplementation in IVF. The databases of Medline and PubMed were searched to identify relevant publications. LPS with human chorionic gonadotrophin (hCG) [n=262, odds ratio (OR) 2.72 (95%), confidence interval (CI) 1.56-4.90, P<0.05] or progesterone (n=260, OR 1.57 CI 1.13, 2.17, P<0.05) results in an increased pregnancy rate compared with placebo, however, hCG is associated with increased risk of ovarian hyperstimulation syndrome. Natural micronized progesterone is not efficient if taken orally. The data on oral dydrogesterone are still conflicting. Vaginal and intra muscular progesterone have comparable outcomes. The addition of estradiol (E2) seems to be beneficial in long GnRH agonist protocol (implantation rate 39.6% with E2 compared with no E2; P<0.05) but not in the short GnRH agonist and GnRH antagonist protocol. Despite the early promising results, it is too early to recommend the use of GnRH agonist in LPS. LPS should cease on the day of positive HCG. Since the cause of luteal phase defect in IVF appears to be related to the supraphysiological levels of steroids, milder stimulation protocols should be advocated in order to eventually overcome the luteal phase defect.     

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.     

Hormonal and histological evaluation of the luteal phase after combined GnRH-agonist/gonadotrophin treatment for superovulation and luteal phase support in in-vitro fertilization.

A hormonal and histological study of the luteal phase was performed in 21 stimulated in-vitro fertilization (IVF) patients not undergoing embryo transfer. Ovarian stimulation was carried out with gonadotrophins [follicle stimulating hormone (FSH) + human menopausal gonadotrophin (HMG)] under pituitary suppression with buserelin. Ovulation was induced with 5000 IU human chorionic gonadotrophin (HCG) and additional doses of 5000, 2500 and 2500 IU were given on the day of follicular aspiration, and 2 and 5 days later respectively, to support the luteal phase. Supraphysiological levels of oestradiol (E2) and progesterone in plasma were found in the midluteal phase of all women, while prolactin was in the normal range. An endometrial biopsy taken in the late luteal phase was normal in 90.5% (19/21) of patients, most of them (15/19, 79%) having E2 greater than 1500 pg/ml on the day of HCG. Conversely, both patients with defective endometrial biopsies had E2 levels less than 1500 pg/ml.     

Fractured zona oocytes in in-vitro fertilization cycles stimulated with gonadotrophin-releasing hormone analogue and human menopausal gonadotrophin

In order to assess the possible influence of gonadotrophinreleasinghormone analogue and human menopausal gonadotrophin on the occurrenceof fractured zona oocytes (FZOs) in in-vitro fertilization (IVF)treatment cycles, we analysed 267 consecutive cycles in 199patients. In 87 cycles, at least one fractured zona oocyte wasrecovered, and in 180 cycles only intact zona oocytes (IZOs)were recovered. FZOs represented 5.8% of all oocytes retrievedand 14.8% when only cycles with FZOs were considered. Serumoestradiol concentrations were significantly higher at day –3and day –2 (P < 0.02) in cycles yielding at least onefractured zona oocyte compared to IZO cycles (day 0 = retrievalday), and there was a higher incidence of G terminal patternof oestradiol curve (P < 0.01) in cycles with FZOs. The meannumbers of all oocytes retrieved and of mature oocytes weresignificantly higher in FZO than in IZO cycles (P < 0.001).The fertilization rate of mature oocytes was significantly reduced(P < 0.05) in cycles with one or more oocytes with fracturedzonae. There was no significant difference in the number ofembryos transferred, pregnancy and abortion rates in both groups.We conclude that although the occurrence of fractured zona oocytesis a frequent event, it does not affect the overall resultsof our IVF programme. Zona pellucida fragility may be the resultof over-maturation of some oocytes.     

Differential effects of gonadotrophin-releasing hormone agonists administered as desensitizing or flare protocols on hormonal function in the luteal phase of hyperstimulated cycles

The incorporation of gonadotrophin-releasing hormone agonist (GnRHa) in in-vitro fertilization (IVF) stimulation protocols has led to doubt about the quality of the subsequent luteal phase. The effects of two GnRHa stimulation protocols on luteal phase concentrations of oestradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were compared with the standard clomiphene stimulation regimen. Subjects receiving clomiphene with human menopausal gonadotrophin (HMG, n = 377) showed essentially similar luteal phase P concentrations to those receiving leuprolide acetate/HMG as a desensitization protocol. Subjects receiving concomitant leuprolide and HMG from day 2 to utilize the flare effect of the GnRHa exhibited significantly lower P levels in the luteal phase compared to clomiphene/HMG and leuprolide desensitization protocols despite the addition of HCG support. This occurred despite equivalent E2 concentrations at the time of ovulation and identical numbers of oocytes recovered. LH concentrations in non-conception cycles were suppressed for at least 14 days in the luteal phase in both GnRHa protocols compared to clomiphene stimulation. Differences were less obvious in cycles where conception occurred suggesting that implantation may proceed more favourably when the luteal endocrinology was optimal. It is concluded that flare methods of GnRHa hyperstimulation are associated with significantly different luteal phases compared with clomiphene or desensitization protocols. It is proposed that the use of the flare type of stimulation may significantly influence the response of the granulosa cells to LH or HCG via gonadotrophin receptors or through altered post-receptor function.     

Effect of disruption versus continuation of gonadotrophin-releasing agonist after human chorionic gonadotrophin administration on corpus luteum function in patients undergoing ovulation induction for in-vitro fertilization

Previous studies have described the luteolytic effect of gonadotrophin- releasing hormone agonist (GnRHa) administered in the early luteal phase. The present work was undertaken to compare in a prospective and randomized design the effect of disruption versus continuation of daily GnRHa after human chorionic gonadotrophin (HCG) administration on corpus luteum function in patients undergoing ovulation induction for in-vitro fertilization (IVF). Two different studies were designed and a total of 38 ovum donors, aged 23-30 years, were included. In the first study, the effect of GnRHa on the early luteal phase of IVF-stimulated cycles was investigated (n = 27); the patients were divided into two groups, according to whether they stopped (n = 13) or continued with daily GnRHa injections (n = 14) for an additional period of 15 days after HCG administration. Blood was drawn from luteal phase days 2 to 6 (day 0 = day of HCG administration) and oestradiol and progesterone concentrations were analysed. The second study focused on the effects of continuation versus disruption of GnRHa administration in the mid- late luteal phase. A similar design was employed including six patients who stopped GnRH on day 0 and five other women who continued GnRHa for 15 days after HCG administration. In this second study, blood was drawn from days 5 to 11 and oestradiol, progesterone and luteinizing hormone (LH) concentrations were analysed. IVF parameters were similar in both groups. The results indicate that continuous GnRHa administration, after HCG injection, does not produce changes in oestradiol, progesterone and LH concentrations in the early, mid- and late luteal phases compared to those patients in whom GnRHa is discontinued at the day of HCG administration. The present work demonstrates that, when ovulation induction is performed, the corpus luteum is driven primarily by the HCG, regardless of the administration or disruption of GnRHa in the luteal phase. This suggests that the lack of differences between continuation versus disruption of GnRHa may be due to the accumulation of the product over the previous 2-3 weeks of treatment.      

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.     

Endocrinology: Daily measurements and in-vitro effects of human chorionic gonadotrophin in the early luteal phase

The purpose of the present study was to analyse daily measurementsof human chorionic gonadotrophin (HCG) in in-vitro fertilization(IVF) cycles and to reproduce the effects of HCG in vitro usinghuman granulosa—luteinized cells from the same patients.The study population consisted of nine women undergoing IVFbecause of tubal infertility in whom blood was drawn every 24h from the day of the ovulatory dose of HCG (10 000 IU) until6 days after ovum pick-up. Granulosa—luteal cells fromthe follicular aspirates were collected and cultured in vitroup to 6 days in the presence of increasing concentrations (0,0.01, 0.1, 1.0 and 100.0 IU/ml) of HCG. Serum progesterone andHCG in vivo as well as progesterone accumulation in vitro ondays 2, 4 and 6, were the main outcome measures. Maximum HCGconcentrations (0.25 IU/ml) were reached the day before ovumpick-up, and continuously decreased until day 6 after ovum retrieval.HCG did not stimulate progesterone production in vitro at anydose tested until day 6 after ovum pick-up. Then, 0.01 IU/mlresulted significantly (P < 0.05) stimulatory compared tocontrols, while 1.0 IU/ml was inhibitory (P < 0.05). It isconcluded that HCG supplementation in an IVF cycle is unnecessaryuntil day 6 after ovum pick-up. On day 6, progesterone productionis stimulated with very low concentrations of HCG.     

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.     

Pulsatile gonadotrophin secretion in women with polycystic ovary syndrome after gonadotrophin-releasing hormone agonist treatment

In polycystic ovary syndrome (PCOS), increased luteinizing hormone (LH) pulse frequency has been attributed to either the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator or ovarian oestrogen feedback. To address this issue, a detailed examination of pulsatile LH secretion was undertaken during recovery from GnRH agonist (GnRHa) suppression. Each of six women with PCOS and six normal ovulatory women received daily GnRHa treatment for 14 weeks. Frequent blood samples were collected and assayed for gonadotrophins, androgens and oestrogens before, during and up to 4 weeks after treatment. Women with PCOS had higher basal LH pulse frequency and amplitude and increased serum concentrations of LH, androstenedione, testosterone and oestrone than controls. After 3 months of GnRHa treatment, all these parameters were suppressed with no differences observed between the two groups. One week after cessation of GnRHa, LH pulse frequency promptly returned to pre-treatment range with no between-group differences noted, whereas LH pulse amplitude, serum gonadotrophins and ovarian steroids remained maximally suppressed and equivalent in the two groups. Subsequent LH pulse frequency remained constant while LH pulse amplitude and circulating concentrations gradually increased in parallel with a return of serum oestrogen to pre-treatment values. Despite comparable resumption of LH secretion in the two groups, corresponding androgen concentrations in women with PCOS were greater than those of normal ovulatory women. Thus, the immediate restoration of LH pulse frequency after discontinuing GnRHa treatment is largely independent of ovarian oestrogen production and reflects primacy of the GnRH pulse generator in determining basal LH pulse frequency. Equivalent LH pulse frequency rates in the two groups during the recovery period do not suggest an intrinsic hypothalamic-pituitary hyperactivity in PCOS.      

Initiation of periovulatory events in gonadotrophin-stimulated macaques with varying doses of recombinant human chorionic gonadotrophin

During in-vitro fertilization (IVF) cycles, a large bolus of human chorionic gonadotrophin (HCG) is used to induce periovulatory events, but the efficacy of lower doses is undefined. Following follicular stimulation in rhesus monkeys, oocyte nuclear maturation, IVF, granulosa cell luteinization and corpus luteum function were compared after injection of 100, 300 or 1000 IU recombinant HCG or 1000 IU urinary HCG. Bioactive HCG rose to peak concentrations within 2 h that were proportional to the dose administered (100 < 300 < 1000 IU, recombinant HCG = urinary HCG). The duration of surge values (>100 ng/ml) was also dose-dependent (0 h, 100 IU; 24 h, 300 IU; >48 h, 1000 IU, recombinant and urinary HCG). While the proportions of oocytes resuming meiosis and undergoing IVF were similar among groups, fewer animals yielded fertilizable oocytes following 100 and 300 IU (five of nine) compared to 1000 IU recombinant and urinary HCG (nine of 10). Peak values of serum progesterone in the luteal phase were similar, but declined 2 days earlier after 100 and 300 IU relative to 1000 IU recombinant and urinary HCG. Thus, 3-10 fold lower doses of HCG elicit low amplitude surges of short duration that induce periovulatory events such as re-initiation of oocyte meiosis and granulosa cell luteinization. However, oocyte fertilization and luteal function may optimally require surges of higher amplitude and longer duration similar to those produced by standard doses of 1000 IU recombinant or urinary HCG.      

Human chorionic gonadotrophin concentrations in early pregnancy after in-vitro fertilization.

There is increased risk of early pregnancy loss after assisted reproduction. In this study the use of serum human chorionic gonadotrophin (HCG) concentrations on day 12 after in-vitro fertilization (IVF) and embryo transfer was evaluated to predict pregnancy outcome. A total of 417 IVF pregnancies were included. Early pregnancy loss was defined as biochemical pregnancies, ectopic pregnancies and first trimester abortions. Vital pregnancies were defined as delivered singletons, multiple pregnancies and second trimester abortions. On the post embryo transfer day 12, the mean HCG concentration of the vital pregnancy group was significantly higher than in early pregnancy loss outcomes (P < 0.00001). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the cut-off value of HCG giving maximal sensitivity and specificity in order to discriminate early pregnancy losses from vital pregnancies. A patient with a HCG value higher than the calculated cut-off value (55 IU/l) had a 90% chance of having a vital pregnancy after IVF and embryo transfer. It can be concluded that a discriminatory HCG value on day 12 after IVF and embryo transfer cycles may be useful in predicting pregnancy outcome and may guide clinicians in identifying those pregnancies at risk for adverse outcomes and instituting more intensive surveillance in this population.