Why do couples refuse or discontinue ART?

The first child born after in-vitro fertilisation, (IVF)-treatment, just passed its 26th birthday in July 2004. Since that birth-assisted reproduction techniques (ART) became a practicable technology, they had been used all over the world, and more than 2 million children were born after IVF-treatment. Despite all success in this field, ART is neither accepted nor used for all infertile couples, although this might be the only possibility of becoming pregnant. Two different kinds of ART refusal are distinguishable: the primary refusal being for financial, psychosocial, moral, ethical and medical reasons including the risk of severe ovarian hyperstimulation syndrome, the risk of multiple pregnancies and the risk of malformations. The secondary refusal includes dropouts after one or more unsuccessful IVF-treatments mainly influenced by the outcome of previous cycles (prognostic factors: oocyte and embryo count, embryo quality, females age) associated with psychological and emotional aspects. However, financial factors seem to be the most potent reasons for ART-refusal.

Previous miscarriages influence IVF and intracytoplasmatic sperm injection pregnancy outcome.

Previous conceptions are one predictor for the outcome of assisted reproductive technology procedures. Approximately 18-34% of clinical pregnancies following assisted reproduction procedures result in spontaneous abortion. The risk of such pregnancy loss is believed to increase with women's age, previous miscarriages and use of frozen-thawed embryos. This study analyses German IVF Registry data to examine the impact of previous miscarriages on the outcome of assisted reproduction procedures. The data set consists of a total of 174,909 assisted reproduction procedures performed between January 1998 and December 2000. Multiple logistic regression is used to assess the correlation between women's age, spousal/partner change, and infertility diagnosis. It is demonstrated that any previous miscarriage will increase the treatment-dependent miscarriage rate in assisted reproduction procedures. A significantly higher impact is shown for one previous miscarriage achieved by assisted reproduction procedures compared with spontaneous conception. Partner change is shown to have no specific impact on the treatment dependent miscarriage rate, whereas a statistically significant increase in miscarriages in all assisted reproduction procedures was found among women older than 34 years of age. Overall, the highest rate of treatment-dependent miscarriages was seen in assisted reproduction procedures with cryopreserved embryo transfer.

Safety and efficacy of a 3 mg dose of the GnRH antagonist cetrorelix in preventing premature LH surges: report of two large multicentre, multinational, phase IIIb clinical experiences.

Gonadotrophin-releasing hormone antagonists are effective and safe in preventing premature LH surges, a leading cause of cycle cancellation or failure during assisted conception. Two studies assessed two administration regimens for cetrorelix (as Cetrotide): the multiple-dose (MD, 0.25 mg/day, n = 1066) and single-dose (SD, 3 mg, n = 541) protocols. Patient outcomes were very similar: >90% reached criteria for human chorionic gonadotrophin (HCG) administration and underwent oocyte retrieval; embryo transfer was performed in 83-84%; failure to retrieve oocytes was rare (0.8%); on average, 11 follicles > or =10 mm in diameter were seen on the day of HCG administration. The SD protocol was associated with higher numbers of oocytes retrieved and available for insemination, although the numbers of embryos obtained or transferred were comparable. A total of 251 and 121 pregnancies were reported in the MD and SD groups respectively. Pregnancy rates per embryo transfer were 27 and 28% respectively. Severe ovarian hyperstimulation syndrome (OHSS) occurred in <1% of cycles. Twelve per cent of patients reported local reactions to injections in the MD group, compared with 8% in the SD group; none was serious or led to discontinuation. Seventy-three per cent of patients in the SD group received only one injection. These two studies therefore show that the single-dose cetrorelix protocol offers equal efficacy and safety to the MD regimen, while having the advantage of requiring only one injection in most patients.

Use of GnRH antagonists in the treatment of endometriosis.

Endometriosis is an oestrogen-dependent disease that is treatable by oestrogen withdrawal, a therapy that has been effectively provided by the use of a gonadotrophin-releasing hormone (GnRH) agonist. Complete oestrogen withdrawal results in unacceptable side-effects, in particular in accelerated bone density loss. This problem has been effectively overcome with 'add-back therapy' using low-dose oestrogens and progestins in combination with a GnRH agonist to limit these side-effects, while still allowing regression of endometriotic lesions. The aim of this study was to determine the feasibility of using a subcutaneous injection of GnRH antagonist in the treatment of endometriosis. All patients (15/15; 100%) reported a symptom-free period during GnRH antagonist treatment, including mood changes, hot flushes, loss of libido, vaginal dryness and other symptoms. Serum oestradiol oscillated around a mean concentration of 50 pg/ml during therapy. Diagnostic laparoscopy before GnRH antagonist administration showed a mean stage III of disease. Regression occurred in 60% of cases (9/15) and the degree of endometriosis declined to stage II. Sequential administration of the GnRH antagonist cetrorelix (Cetrotide) in a 3 mg dosage once weekly over 8 weeks creates a new opportunity for medical treatment of symptomatic endometriosis. Preserving basic oestrogen production during the course of treatment apparently does not influence regression of disease, and has no major side-effects.

Plasma and follicular fluid concentrations of LHRH antagonist cetrorelix (Cetrotide) in controlled ovarian stimulation for IVF.

Cetrorelix was administered in differing daily dosages for controlled ovarian stimulation. The dosage levels were 3 mg (9 cycles), 1 mg (19 cycles), 0.5 mg (43 cycles), 0.25 mg (46 cycles) and 0.1 mg (7 cycles). In the 3 mg, 1 mg and 0.5 mg group the respective median plasma concentrations of cetrorelix on the day of oocyte pick-up (OPU) were 2.10 ng/ml, 1.42 ng/ml and 0.88 ng/ml and 1.03 ng/ml, 0.46 ng/ml and 0.49 ng/ml on the day of embryo transfer (ET). In the 0.25 mg and 0.1 mg groups plasma cetrorelix levels were below the limit of quantification. The cetrorelix concentrations in follicular fluid (FF) in the 0.25 mg group were detectable in only 14 out of 44 samples, while in the 0.1 mg group no detectable concentrations could be obtained. We also examined 80 cycles after single doses of 5 mg (7 cycles), 3 mg (42 cycles), and 2 mg (31 cycles) cetrorelix. On the day of OPU the respective median plasma concentrations of cetrorelix were 0.57 ng/ml, 0.62 ng/ml, and 0.56 ng/ml, and 0.61 ng/ml and 0.28 ng/ml on the day of ET in the 5 mg and 3 mg groups. In the 2 mg group, the plasma concentrations fell to below limits of quantification in 8/9 samples on the day of ET. In 26 out of 27 FF samples cetrorelix was detectable in the 3 mg single dose group (median level: 0.69 ng/ml).

Safety aspects of gonadotrophin-releasing hormone antagonists in ovarian stimulation procedures: ovarian hyperstimulation syndrome and health of children born.

The safety of ovarian stimulation procedures or the procedure of assisted reproduction in general can be estimated by various parameters. Two of the most important are the health of children born after the procedure and the incidence of ovarian hyperstimulation syndrome (OHSS). The latter is important because it is the most severe, potentially life-threatening complication of any stimulation procedure. The use of gonadotrophin-releasing hormone (GnRH) antagonists in ovarian stimulation protocols has had no impact on the health of children born. This was proven in 227 children born after the use of cetrorelix and in 73 children born after the use of ganirelix. To analyse the incidence of OHSS and the impact of GnRH antagonists on clinical pregnancy rates compared with the long protocol, a meta-analysis was done. This showed a reduction of OHSS with the use of cetrorelix. Furthermore, when compared with the long protocol, clinical and ongoing pregnancy rates were not significantly reduced with the use of cetrorelix. Taken together, the use of GnRH antagonists are safe with regard to children's health. The incidence of OHSS does not increase with ganirelix, and a reduction can be expected with cetrorelix.

The role of gonadotropin-releasing hormone antagonists in in vitro fertilization.

Gonadotropin-releasing hormone (GnRH)-antagonists can suppress the pituitary hormone secretion completely within a few hours, allowing the avoidance of premature luteinization within controlled ovarian hyperstimulation (COH) for assisted reproductive technologies (ART) by midcycle administration. Two different protocols were described, which were widely used in COH in several phase II and III studies as well as in clinical practice since the GnRH-antagonists Cetrorelix (Cetrotidesound recording copyright sign; Serono International S.A., Geneva, Switzerland) and Ganirelix (Orgalutansound recording copyright sign, Antagonsound recording copyright sign; Organon, Oss, The Netherlands) are available on the market. Cetrorelix was applied in single- and multiple-dose protocols; Ganirelix was used until now only according to the multiple-dose protocol. Fertilization rates of >60% as well as clinical pregnancy rates of about 30% per transfer sound most promising. Estradiol secretion is not compromised by the GnRH-antagonists using recombinant follicle-stimulating hormone (FSH) for COH. The incidence of a premature leutinizing hormone (LH) surge is far below 2% while the pituitary response remains preserved, allowing the induction of ovulation by GnRH or GnRH-agonists. However, luteal phase support remains mandatory. The incidence of severe ovarian hyperstimulation syndrome (OHSS) seems to be lower under antagonist treatment than in the long agonistic protocol. Treatment time is significantly shortened. Without any doubt GnRH-antagonists have the potential to become the new standard for controlled ovarian hyperstimulation.

Health of 227 children born after controlled ovarian stimulation for in vitro fertilization using the luteinizing hormone-releasing hormone antagonist cetrorelix.

OBJECTIVE: To summarize data from completed phase II and III clinical trials on children born after controlled ovarian stimulation using the luteinizing hormone-releasing hormone antagonist cetrorelix. DESIGN: All children born after ovarian stimulation in patients treated for infertility who were in prospective studies until March 23, 1999. SETTING: Academic research center. PATIENT(S): Children born after IVF or IVF plus ICSI. INTERVENTION(S): Controlled ovarian stimulation with cetrorelix in a multiple-dose or single/dual-dose protocol. MAIN OUTCOME MEASURE(S): Outcome of pregnancy and, in deliveries, the date of birth, number and sex of children born, birth weight, body length, and abnormalities were recorded. At approximately 1 year of age and 2 years of age, body weight and length and abnormalities in physical and mental development were recorded. RESULT(S): Two hundred nine and 18 children were born after fresh and frozen embryo transfers, respectively. Of the pregnancies, 76.2% (179 of 234) resulted in live birth and ectopic pregnancy occurred in 3.4% (8 of 231); one heterotopic pregnancy and four induced abortions were recorded. The malformation rate among all live births, stillbirths, and aborted fetuses was 3.1%. CONCLUSION(S): Use of cetrorelix in controlled ovarian stimulation does not harm the subsequently born children.

Preoperative reduction of uterine fibroids in only 16 days by administration of a gonadotrophin-releasing hormone antagonist (Cetrotide).

Ten premenopausal women with symptomatic uterine fibroids confirmed by magnetic resonance imaging (MRI) were treated with four injections (s.c.) of 3 mg of the gonadotrophin-releasing hormone (GnRH) antagonist cetrorelix every 4 days, starting on the first day of cycle. On every fourth day, blood samples were drawn for the measurement of gonadotrophins and sex steroids. On the 17th day of treatment after a final MRI control, myomectomy was performed laparotomically, laparoscopically or hysteroscopically. All patients showed a deep and sustained suppression of gonadotrophins and sex steroids over the treatment time. In three patients, no change or even an increase in uterine fibroids volume was observed according to MRI, and in one patient MRI did not allow a reliable interpretation. However, six patients showed a mean reduction of 31% in fibroid size after only 16 days of hormonal treatment. In nine patients laparoscopic or hysteroscopic myomectomy could be performed, while laparotomy was necessary only in one non-responder. Preparation of the cleavage plane during surgery was easy and blood loss was minimal. Patient compliance was excellent. No side-effects occurred. The GnRH antagonist Cetrotide(R), acting as an intermediate depot preparation at a dose of 3 mg, opens up a new avenue for preoperative short term treatment in a subgroup of patients with uterine fibroids, minimizing treatment time and patient discomfort.

Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist Cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction.

A prospective, randomized study was performed to compare the efficiency of hormonal stimulation for IVF (in vitro fertilization) in either the long luteal protocol, using the LHRH agonist Buserelin, or the multiple dose LHRH antagonist protocol, using the LHRH antagonist Cetrorelix. Here we present the data on the incidence of ovarian hyperstimulation syndromes (OHSS). 85 and 188 patients were recruited for the stimulation in the LHRH agonist and in the LHRH antagonist protocol, respectively. The groups were comparable regarding anamnestic data. The incidence of WHO degrees II and degrees III OHSS was significantly lower in the Cetrorelix than in the Buserelin group (1.1% vs. 6.5%, p=0.03). Additionally 3 patients in the Cetrorelix group (1.6%) and 5 patients in the Buserelin group (5.9%) did not receive hCG because of a threatening OHSS. The follicle maturation was more homogeneous in the Cetrorelix protocol, with less small follicles on the day of hCG administration but a similar number of oocyte cumulus complexes retrieved. The pregnancy rates per cycle were not significantly different in the Cetrorelix and Buserelin protocol (22% vs. 26%). The Cetrorelix multiple dose protocol is advantageous compared to the long protocol regarding the incidence of OHSS, a potentially life threatening complication of controlled ovarian stimulation.

Clinical application of GnRH-antagonists.

Due to the different pharmacological mode of action, GnRH-antagonists seem to open up new avenues to hormonal treatment in several indications. Although it may be still too early to speculate about the possible end of the era of GnRH-agonists, from what is known today, the advantages of GnRH-antagonists are most evident in our opinion. When the development of sustained delivery systems may continue and be completed, the antagonists will have a major potential within benign gynecological conditions and also in the treatment of malignancies such as prostatic, mammary, endometrial or ovarian cancer. Suitable sustained delivery systems and the development of GnRH-antagonists with sufficient oral bioavailability, represent the present and future challenge for these efforts.

Deep vein thrombosis during administration of HMG for ovarian stimulation.

We report a case of activated protein C (APC) resistance and deep calf vein thrombosis under controlled ovarian stimulation for in vitro fertilization. The thrombosis occurred before administration of human chorionic gonadotrophin for ovulation induction on the 8th day of hMG (human menopausal gonadotrophin). The patient was stimulated according to the long luteal protocol. Cases of arterial and venous thrombosis as a result of ovarian stimulations are reviewed.

Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study.

A total of 346 women with normal ovulatory function was stimulated with human menopausal gonadotrophins (HMG) to attain ovarian stimulation for IVF or intracytoplasmic sperm injection (ICSI). Stimulation with HMG started on cycle day 2 or 3. After 6 days of stimulation, Cetrorelix in its minimum effective multiple dose of 0. 25 mg/day, was administered daily until induction of ovulation. In total, 333 patients (96.2%) reached the day of HCG administration, and 324 (93.6%) underwent oocyte retrieval. A mean of 25.2 ampoules of HMG was applied for a mean of 10.4 days. Cetrorelix was administered for a mean time lapse of 5.7 days. The mean normal fertilization rate was 60% in the IVF group and 59% in the ICSI group. Seventy pregnancies were attained, reflecting an ongoing clinical pregnancy rate of 24% per transfer. The ongoing clinical implantation rate was 11.4%. Only three cases of raised luteinizing hormone (LH) (>/=10 IU/l) with increased progesterone secretion (>/=1 ng/ml) were observed after initiation of Cetrorelix administration, reflecting an incidence of premature luteinization of 0.9%. The abortion rate was 17%. The incidence of severe ovarian hyperstimulation syndrome (World Health Organization grade III) was as low as 0.6%.

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.

[Medical treatment of uterine fibroids with the LHRH antagonist: Cetrorelix]. / Traitement médical des fibromes utérins avec un antagoniste de la LHRH: Cetrorelix.

A depot preparation of the LHRH-antagonist Cetrorelix was used for the preoperative treatment of 20 premenopausal women with symptomatic uterine fibroids to undergo surgery. In an open, prospective and randomised study, 60 mg of this depot preparation were administered i.m. at the second day of cycle. Patients were randomised for a second dosage of 60 mg or 30 mg to be injected on day 21 or day 28 of treatment according to the degree of estradiols' suppression (< 50 pg/mL). The operation was carried out after six or eight weeks of treatment according to the timing of second dosages administration. Weekly transvaginal sonography as well as MRI before and after Cetrorelix treatment were performed for fibroids volume assessment; 16 patients showed satisfactory suppression of gonadotrophins and sexual steroids. No flare up effect was to be observed. In this group of patients the maximum reduction in fibroids size was of 33.5% at the end of treatment. After 14 days of treatment the reduction was of 31.3%. Within the group of good responders (reduction of fibroids size > 20%) the volume of the biggest fibroid after 14 days of treatment was of 56.7% of the initial assessment. Although MRI showed minor mean shrinkage rates of only 25.4% of the initial volume, these differences in comparison to transvaginal sonography were not statistically significant. The avoidance of any flare up phenomenon by the LHRH-antagonist may explain this fast reduction in size. The basic advantages of this treatment modality are the reduction of treatment time with a fast restoration of the ovarian function. The rate of poor responders may be reduced by improving the galenic preparation.

Ovarian abscess and heterotopic triplet pregnancy: two complications after IVF in one patient.

A patient is reported, who suffered from ovarian abscess after ovarian puncture of a functional ovarian cyst. The cyst has developed after administration of a GnRH agonist depot preparation in the preceeding luteal phase. She was planned to be stimulated for IVF according to the long luteal protocol. The abscess was removed by laparoscopy. and stimulation started two months later after administration of two further GnRH against depot preparations. The patient got pregnant after embryo transfer of three embryos. and a heterotopic triplet pregnancy, with intrauterine twins and a tubal singleton was established. Bilateral salpingectomy was performed, because of bilateral haematosalpinx and previously described bilateral tubal occlusion. The further pregnancy was uncomplicated.

Treatment of uterine fibroids with a slow-release formulation of the gonadotrophin releasing hormone antagonist Cetrorelix.

A depot preparation of the third-generation gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix (SB-75) was used for preoperative treatment in twenty premenopausal patients with symptomatic uterine fibroids who were to undergo surgery. In a prospective, open, randomized setting 60 mg of Cetrorelix pamoate salt was administered i.m. on cycle day 2. Patients were randomized for a second dose of 30 or 60 mg of Cetrorelix depot, which was administered according to the degree of oestradiol suppression (<50 pg/ml) on treatment day 21 or 28. Surgery was done after 6 or 8 weeks of treatment, depending on second dosage administration. Weekly transvaginal sonography (TVS) and magnetic resonance imaging (MRI) before and after treatment was performed, for fibroid volume assessment. Sixteen patients showed satisfactory suppression of gonadotrophins and sex steroid secretion, avoiding any initial flare-up effect. In these patients a mean shrinkage rate of largest fibroid volume of 33.5% at the end of treatment could be observed according to TVS, while the mean shrinkage rate obtained after 14 days of treatment was 31.3%. In good responders (shrinkage >20%) largest fibroid volume at day 14 was approximately 56.7% of basic assessment. Although MRI showed minor mean shrinkage rates of only 25.4% of the initial volume, these differences in comparison to TVS assessment were not statistically significant. The avoidance of any initial flare-up in gonadotrophin secretion may explain this extremely fast reduction in fibroid size. The advantages of GnRH antagonist treatment in this indication consist in the short treatment time with a fast restoration of the ovarian function. The rate of poor responders may be reduced by using an improved slow release preparation.

Preserved pituitary response under ovarian stimulation with HMG and GnRH antagonists (Cetrorelix) in women with tubal infertility.

OBJECTIVE: To examine the pituitary response in patients undergoing short-term application of the GnRH antagonist Cetrorelix in the mid-cycle phase for hypophysial suppression of premature LH surges within an IVF-program. DESIGN: Twenty patients suffering from primary or secondary tubal infertility were stimulated with hMG from cycle day 2. From day 7 till ovulation induction Cetrorelix was administered in two different dose regimens (15 patients 3 mg s.c. daily; 5 patients 1 mg s.c. daily). Three hours before ovulation induction a GnRH test was performed using 25 micrograms of native GnRH and the pituitary response examined by measurement of the serum LH concentration after 30 min. RESULTS: Premature LH surges could be avoided in the 3-mg group and in the 1-mg group, respectively. Due to this, none of the cycles had to be cancelled. Oestradiol profiles and ultrasound demonstrated a satisfactory follicular maturation. All patients showed pronounced suppression of the serum LH levels before ovulation induction. The mean increase of serum LH due to the performed GnRH test was 10 mIU/ml for the 3-mg group, while the average maximum in the 1-mg group was about 32.5 mIU/ml. CONCLUSIONS: The pituitary response is preserved by the treatment with the GnRH antagonist Cetrorelix. The extent of suppression of the adenohypophysis, as expressed by the different reactions on GnRH test, can be modulated by the dosage administered. This should allow ovulation induction by GnRH or one of its agonists instead of hCG, which could be beneficial in patients at high risk of Ovarian Hyperstimulation Syndrome (OHSS) and those suffering from Polycystic Ovary Disease (PCOD).