Endocrine responses to gonadotrophins after LHRH agonist administration on cycle days 1-4: prevention of premature luteinization

A treatment regime comprising an intranasally administered luteinizinghormone-releasing hormone (LHRH) agonist analogue (buserelin)on cycle days 1–4, followed by gonadotrophin administration[follicle stimulating hormone (FSH)/human menopausal gonadotrophin(HMG)] resulted in identical oestradiol (E₂) responses comparedwith the reference method using clomiphene citrate (CC) andgonadotrophins. Immediately after analogue administration (day4), buserelin-treated women showed short-lived elevations inserum LH and progesterone concentrations, but in the later follicularphase, the serum LH concentration was lowered compared withthe controls. None of the women treated with analogue displayedelevated serum LH or progesterone concentrations at the timeof injection of human chorionic gonadotrophin. In the earlyluteal phase, these women had higher serum levels of progesteroneand higher progesterone to E2 ratios than the controls, butthe length of the luteal phase was slightly shortened. Hence,in hyperstimulated cycles, 4-day treatment with buserelin causedprofound endocrinological changes: namely, short-term rescueof the corpus luteum, prevention of an endogenous LH rise andpremature luteinization and increased progesterone productionin the early luteal phase     

IVF pregnancy after induction of an ovulatory endogenous gonadotrophin surge using an LHRH agonist nasal spray

A successful human twin IVF pregnancy is reported after using a single 50 micrograms dose of LHRH agonist nasal spray (Buserelin) to induce an ovulatory endogenous gonadotrophin surge 34 h prior to oocyte collection. The couple had 10 years of primary male factor infertility, associated with significant anti-sperm antibodies. The clinical features and endocrine profile are presented.     

Effect of an intranasal LHRH agonist on gonadotrophins and hot flushes in post-menopausal women

Alterations in circulating gonadotrophins have been reported at the time of onset of menopausal flushes. In order to study this association D-SER(TBU)6-EA10-LHRH, a luteinizing hormone releasing hormone (LHRH) agonist was given intranasally at a dose of 200 micrograms twice daily to 12 post-menopausal women to study its effect on gonadotrophin secretion and hot flushes. Following an initial period of 3-5 days of increased gonadotrophin secretion, pituitary desensitization occurred, with a significant suppression of circulating LH and follicle-stimulating hormone (FSH) levels (P less than 0.001) and a reduction in gonadotrophin pulse amplitude (P less than 0.05). This was accompanied by a significant diminution of the pituitary's response to exogenous LHRH (P less than 0.05). However, no significant alteration in the incidence of hot flushes was observed on such therapy.     

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.     

Comparison between long and short protocols of LHRH agonist in the treatment of polycystic ovary disease by in-vitro fertilization

Two groups of patients with polycystic ovary disease were treatedwith analogues of LHRH to compare long and short protocols ofpituitary desensitization. In group 1 (n = 15), decapeptyl wasadministered for 30 days associated with stimulation by pureFSH. In group 2 (n = 12) Buserelin was given for 15 days withthe same ovarian stimulation. Patients were randomly assignedto the two groups. Six patients in each group had received treatment,for at least 4 months, to induce ovulation with clomiphene citrateor HMG and failed to conceive, despite the absence of a tubalfactor. The best results were obtained using the long protocol.Androgen concentrations, particularly ⁴-androstenedione, weresignificantly lower on the day of oocyte retrieval in group1 than in group 2 (2.52 ? 0.73 ng/ml versus 4.44 ? 2.62, respectively(P < 0.02). Polycystic follicular formation was less pronouncedin group 1 and no clinical hyperstimulations occurred in thisgroup. The pregnancy rate was comparable in the two groups (sixongoing pregnancies in 21 cycles in the 15 patients in group1 versus three pregnancies in 12 cycles in the 12 patients ingroup 2).     

Pregnancy outcome following early exposure to maternal luteinizing-hormone-releasing hormone agonist (buserelin)

A human pregnancy exposed to a luteinizing-hormone-releasing hormone agonist (buserelin) in its early stages is reported. The possible mechanisms leading to conception under this mode of treatment and its consequences are discussed.     

Short term use of an LHRH agonist to treat poor responders entering an in-vitro fertilization programme

Seven patients who had previously responded poorly to stimulationwith clomiphene citrate (CC) and human menopausal gonadotrophin(HMG) and also exhibited high tonic urinary LH output (>0.25 IU/h) were given an LHRH agonist (500 µg/daily) ondays 1 to 3 of the menstrual cycle followed by exogenous gonadotrophinstimulation. During the latter stages of follicular developmentplasma and urinary LH output were significantly lower (P <0.01) than in the previous CC/MMG stimulated cycle. All sevenpatients had oocytes recovered, and embryos replaced. Threeout of these seven became pregnant. To conclude, the efficacyof short term LHRH agonist treatment is equivalent to presentlonger term modes of administration in reducing gonadotrophinsecretion and inhibiting the LH surge. The more widespread adoptionof this abbreviated protocol could improve the prognosis forpatients undergoing IVF in centres where facilities for intensiveendocrine monitoring are not available.     

Comparison of the effects of HMG or pure FSH stimulation during suppression with an LHRH agonist analogue.

Infertile patients who responded poorly in an in-vitro fertilization programme were treated with human menopausal gonadotrophin (HMG) or with pure follicle stimulating hormone (FSH) during continuous administration of a luteinizing hormone-releasing hormone (LHRH) agonist, to determine whether a low level of LH is required for follicle maturation. No statistically significant differences were detected in the dose of gonadotrophins, duration of treatment, oestradiol and LH levels, numbers of recovered oocytes, transferred embryos or fertilization rates. It is concluded that an absence of low levels of LH does not disturb follicular development in the follicular phase. Based on the low fertilization rates in the present study (0.32 with HMG versus 0.45 with FSH) the authors suggest that, as well as hormonal deficiency, other factors may also influence follicular and early embryonic development.     

Rapid inhibitory effects of an LHRH agonist implant on the oestrogen-induced LH surge and the induction of a defective luteal phase after an agonist-induced ovulation in the macaque

Three experiments were performed to evaluate in detail pituitary--ovarian function during the first 21 days after treatment with a luteinizing hormone releasing hormone (LHRH) agonist implant. First, six adult macaques with normal menstrual cycles received an LHRH agonist implant during the late luteal or early follicular phase. To investigate the rapidly of effects on pituitary responsiveness the macaques were treated with 50 micrograms LHRH at the time of implant (day 0) and at days 4, 10 and 21. Effects on serum LH and FSH were determined on basal samples and at 30 and 60 min. At 4 days, LH and FSH were elevated as a result of the implant and no further response to LHRH challenge was observed. By 10 days, LH had returned to the pretreatment range but was unresponsive to the LHRH challenge; by 21 days, LH was lower than the pretreatment range and again LHRH failed to induce a significant response. Serum FSH concentrations also declined during treatment, but in contrast to LH, a significant response to LHRH was observed on day 10. Secondly, the ability to respond to an oestrogen provocation test was examined in six macaques with normal menstrual cycles treated with the LHRH agonist implant during the late luteal or early follicular phase and 7 days later with 50 micrograms/kg oestradiol benzoate in oil s.c. to induce an LH/FSH surge. In control animals, oestrogen treatment resulted in a positive feedback surge, reaching a maximum at 48 h post-injection. In contrast, agonist-treated animals showed complete abolition of the expected increase in LH and FSH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytogenetic analysis of unfertilized oocytes retrieved after treatment with the LHRH analogue, buserelin

Chromosome analysis is reported on 155 oocytes from an in-vitro fertilization (IVF) programme in which the LHRH analogue, buserelin, was used in the superovulation regime. Seventy-one oocytes had the normal number of metaphase II chromosomes. Hyperhaploidy was apparent in four cases only; doubling this figure to include the reciprocally formed hypohaploid oocytes gave an aneuploidy rate due to non-disjunction of 10%. This is close to the figure for naturally occurring aneuploidy which may be calculated from data on recognized conceptions at a comparable maternal age. Taken together with the suggestion of a maternal age effect in our series these data suggest that follicular stimulation regimes which precede IVF do not necessarily add to the naturally high aneuploidy rate of the human species. Thirteen oocytes had failed to form the first polar body and the presence of diploid mitotic or sperm chromosomes provided evidence of fertilization and arrested development in 15. These figures for chromosomal anomalies following buserelin treatment are not significantly different from those obtained from comparable surveys following clomiphene citrate stimulation, providing no evidence that the improved pregnancy rate with buserelin is due to chromosomal factors.     

GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study

BACKGROUND: The aim of the study was to investigate whether intranasal (IN) administration of a GnRH agonist could provide luteal support in IVF/ICSI patients. METHODS: Controlled ovarian hyperstimulation (COH) was performed using hMG/FSH and a GnRH antagonist. Patients were then randomly allocated to either 10,000 IU hCG, followed by vaginal administration of micronized progesterone (3x 200 mg/day) (group A), or 200 microg IN buserelin followed by either 100 microg every 2 days (group B), or 100 microg every day (group C), or 100 microg twice a day (group D), or 100 microg three times a day (group E). Luteal support was continued for 15 days. RESULTS: Twenty-three patients were randomized. Groups B and C were discontinued prematurely in view of the short luteal phase. The luteal phase was significantly shorter in groups B, C and D, whereas group E was comparable with group A, 13.5 and 13.0 days, respectively. In the mid-luteal phase, median progesterone levels were significantly lower in groups B, C and D, whereas group E was comparable with group A, 68.9 and 98.0 ng/ml, respectively. Estradiol (E2) was significantly reduced in groups B and D but sustained in group E. In the hCG group, LH levels were undetectable (<0.1 IU/l), whereas LH was detectable and significantly higher in groups C, D and E. Two pregnancies were obtained in the hCG group (two of five), one ectopic and one ongoing. Three pregnancies were obtained in group E, one miscarriage and two ongoing twin pregnancies (three of five). CONCLUSION: IN administration of buserelin may be effective in triggering follicular maturation and providing luteal phase support in patients undergoing assisted reproduction techniques (ART).     

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.     

Exposure to LHRH agonists in early pregnancy following the commencement of mid-luteal buserelin for IVF stimulation.

Exposure to buserelin in early pregnancy has been reported following its use in in-vitro fertilization treatment cycles. The number of reported cases is small. There are still no answers regarding embryotoxicity, and the need for luteal support is still unclear. A further six cases are reported here, five receiving luteal support and resulting in the delivery of healthy children, and one, without luteal support ending in a first trimester miscarriage. We propose that further data should be collected to allow adequate monitoring and follow-up of these pregnancies.     

The effect of HCG supplementation after combined GnRH agonist/HMG treatment in an IVF programme

The necessity of luteal-phase supplementation in an IVF programme is of continuing interest. After ovarian stimulation with clomiphene and human menopausal gonadotrophin (HMG), the beneficial effect of supporting the luteal phase has never been scientifically demonstrated. After ovarian stimulation with GnRH agonist/HMG, the luteal phase seems to be inadequate, but in a previous study we did not find evidence to support the need for oral progesterone supplementation. To evaluate the beneficial effect of human chorionic gonadotrophin (HCG) supplementation, we performed a multicentre, double-blind, randomized study with HCG (193 transfers) against placebo (194 transfers). The ongoing pregnancy rate per transfer cycle was significantly better with HCG (18.7 versus 9.3). This is the first truly objective (randomized) study demonstrating the beneficial effect of supporting the luteal phase in an IVF programme.     

The development of an oocyte-containing follicle during gonadotrophin-releasing hormone agonist administration

Administration of gonadotrophin-releasing hormone (GnRH) agonist in a 29 year old woman with infertility due to ovulatory dysfunction resulted in the development of several ovarian cysts. After human chorionic gonadotrophin (HCG) was injected, the cysts were aspirated and one mature oocyte was retrieved. Intracytoplasmic sperm injection (ICSI) was performed and the resulting embryo was transferred. A singleton pregnancy was obtained and a healthy baby was born at 36 weeks of gestation. Because GnRH agonist-derived cysts may contain oocytes, we suggest that when the growth of cysts is accompanied by high concentrations of oestradiol, the administration of HCG may be useful to achieve oocyte maturation and advance IVF treatment.     

A comparison of treatments with exogenous FSH to promote folliculogenesis in patients with quiescent ovaries due to the continued administration of an LHRH agonist

The circulating levels of plasma follicle-stimulating hormone(FSH), luteinizing hormone (LH) and oestradlol (E₂) have beendetermined in three groups of three subjects during the continuous,subcutaneous administration of an LH-RH agonist (250 µg/day)and after the intramuscular injection of urinary FSH (groupI, 150 IU daily for 8 days, total 1200 IU; group II, 300 IUon alternate days for four injections, total 1200 IU; and groupIII, 150 IU on alternate days for four injections, total 600IU). The level of circulating FSH in group I rose steadily froma geometric mean of 1.11 (preinjection) to 8.76 U/I (at day8), while the corresponding levels in groups II and III fluctuatedaccording to the time and dose of the injected material. Twenty-fourhours after the injection the mean level of FSH in group IIwas significantly higher (7.31 U/I) than the corresponding valuefor group I (2.79 U/I) or group III (3.48 U/I). Only those subjectsin group II showed a resumption of folliculogenesis (leading,mean maximum follicular diameters of 16, 13 and 14 mm, respectively)and a corresponding Increase in the concentration of plasmaE₂ (from 22, 43 and 103 to 906, 1477 and 2362 pmol/l, respectively).     

Endocrinology: The induction of ovulation with pulsatile gonadotrophin-releasing hormone (GnRH) administration in hyperandrogenic women after down-regulation with buserelin or suppression with an oral contraceptive

The hypothalamic—pituitary axis of 22 hyperandrogenicinfertile women had suppression with either the gonadotrophin-releasinghormone (GnRH)-analogue buserelin (n = 12) or with an oestrogen—gestagencompound (Diane^®; ⁿ = 12). This was followed by pulsatileGnRH application for inducing ovulation (Zyklomat^®). Interms of ovulation and pregnancy rates the buserelin pre-treatmentwas more effective than the steroid pre-treatment, especiallyin hyperandrogenic non-polycystic ovaries (PCO).     

Use of microdose GnRH agonist protocol in women with low ovarian volumes undergoing IVF

Ovarian volume measurements have been recently shown to be predictive of response to ovarian stimulation. Women with small ovarian volumes, i.e. <3 cm(3), have a higher incidence of cycle cancellation, together with a lower peak oestradiol concentration, lower number of retrieved oocytes, and lower pregnancy rates, compared with women with larger ovarian volumes. We prospectively investigated whether a higher dose, microdose flare gonadotrophin-releasing hormone (GnRH) agonist protocol, can improve IVF outcome in women with a small ovarian volume. Only the first IVF cycle was reviewed. In total, 109 women aged <40 years undergoing 109 cycles were prospectively evaluated. Women with an ovarian volume of < or =3 cm(3) noted on the day of luteal GnRH agonist administration had their stimulation regimen changed to a more aggressive microdose flare GnRH agonist protocol. In all, 30 women (27.5%) with an ovarian volume of <3 cm(3), and 79 women (72.5%) with an ovarian volume of >3 cm(3) were compared. Women with an ovarian volume of <3 cm(3) had a significantly higher incidence of unexplained infertility as their presenting aetiology, compared with women with a larger ovarian volume (33 and 8.6%, P = 0.0036). There was a significant negative correlation between age and ovarian volume, and between day 3 FSH concentration and ovarian volume. We also report a significant positive correlation between body mass index and ovarian volume. There was also a significant positive correlation between ovarian volume and the number of oocytes retrieved. Despite a trend towards higher day 3 FSH concentrations, a significantly longer duration of stimulation, higher gonadotrophin requirements, and lower oocyte yield, the implantation and pregnancy rates were comparable between the two groups. Women with a small ovarian volume noted at baseline ultrasound can have comparable implantation and pregnancy rates to those with larger ovarian volumes with the use of a higher dose gonadotrophin, microdose GnRH agonist stimulation.     

Pre-operative gonadotrophin-releasing hormone agonist treatment in surgery for uterine leiomyomata

To determine whether pre-operative treatment with gonadotrophin-releasinghormone (GnRH) analogue may have a beneficial effect on surgeryoutcome, 53 patients with symptomatic fibroid uteri awaitingmyomectomy or transabdominal hysterectomy (TAH), were randomlydivided into a study group (n = 29) and a control group (n =24). The study group of patients were treated by an i.m. injectionof D-Trp⁶ LHRH microcapsules at 2 months and 1 month prior tosurgery. The control group had no pre-operative treatment. Haemoglobinconcentration and oestradiol, follicle-stimulating hormone andluteinizing hormone concentrations were measured at 2 monthsand 1 month prior to surgery, and at surgery. The duration ofsurgery was shorter in the study group (49 versus 70 min inthe hysterectomy group) and intraoperative blood loss was less(208 versus 309 ml in the hysterectomies and 320 versus 476ml in the myomectomies). Pre-operative treatment with GnRH-agonistswhich induces shrinkage of the uterus and fibroids is thereforeefficient in shortening the duration of surgery, and diminishingthe intraoperative blood loss in surgery for fibroid uteri.Such preoperative treatment is therefore a useful addition tosurgery in cases with symptomatic fibroid uteri.     

GnRH agonist protocol administration in the luteal phase in ICSI-ET cycles stimulated with the long GnRH agonist protocol: a randomized, controlled double blind study

BACKGROUND: GnRH agonist administration in the luteal phase was reported to beneficially affect the clinical outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This double blind, randomized, placebo controlled trial evaluates whether a single dose GnRH agonist administered 6 days after ICSI increases ongoing pregnancy rates following ET in cycles stimulated with the long GnRH agonist protocol. METHODS: Five hundred and seventy women undergoing ET following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of ET according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. RESULTS: There were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval -5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. CONCLUSIONS: Single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase >or=12% in ongoing pregnancy rates.