Will GnRH antagonists provide new hope for patients considered 'difficult responders' to GnRH agonist protocols?

We have assessed the use of cetrorelix, a gonadotrophin releasing hormone (GnRH) antagonist, in conjunction with clomiphene citrate and gonadotrophin in 31 in-vitro fertilization (IVF)/gamete intra-Fallopian transfer (GIFT) cycles for 25 difficult responders. Group I included 18 poor responders (24 cycles) with no live birth in 23 previous IVF cycles with GnRH agonists. Group II included seven patients (seven cycles) with polycystic ovaries. Thirteen previous IVF/GIFT cycles with GnRH agonists had resulted in one live birth and three of these patients had developed ovarian hyperstimulation syndrome (OHSS). The treatment protocol involved a daily dose of clomiphene citrate 100 mg for 5 days and gonadotrophin injections from cycle day 2. Cetrorelix 0.25 mg/day was started when the leading follicle reached 14 mm. The outcome in both groups was favourable compared to previous treatment with GnRH agonists. In group I the abandoned cycle rate was 29 versus 57% (P = 0.06). More oocytes were produced (6.4 versus 4.7 oocytes/cycle) at a lower dose of follicle-stimulating hormone (FSH) (709 versus 1163 IU/oocyte; P = 0.08) and two live births resulted (11.8%). In group II fewer oocytes were produced (10.2 versus 14.5 oocytes/cycle), using a lower dose of gonadotrophin (170 versus 189 IU/oocyte) and resulted in one ongoing pregnancy. No patients experienced OHSS. This report is preliminary and a further controlled randomized study is required.     

Addition of GnRH antagonist in cycles of poor responders undergoing IVF

Concern about the use of gonadotrophin-releasing hormone (GnRH) agonists in ovarian stimulation of poor responder IVF patients has arisen from the claim that GnRH agonists might have a direct deleterious effect through their receptors on the ovary. In this study, we compared two ovarian stimulation protocols in which no GnRH agonists were used. In all, 40 patients with a poor response in previous treatment cycles were included. They were divided into two groups: group I (n = 20) received ovarian stimulation for 20 cycles, without the addition of either GnRH agonist or antagonist; while group II (n = 20) patients received ovarian stimulation for 20 cycles, including the administration of a GnRH antagonist (Cetrorelix, 0.25 mg daily) during the late follicular phase. There was no statistically significant difference between the groups for mean age, duration of infertility, baseline FSH concentration, cancellation rate, number of ampoules of gonadotrophin used, number of mature oocytes retrieved, oestradiol concentrations on the day of injection of human chorionic gonadotrophin (HCG), fertilization rate and number of embryos transferred. The clinical pregnancy and implantation rates in group II appeared higher than in group I, but were not significantly different (20 and 13.33% compared with 6.25 and 3.44% respectively). The addition of GnRH antagonists to ovarian stimulation protocols might be a new hope for poor responder IVF patients, but this report is preliminary and further controlled randomized prospective studies with larger sample sizes are required.     

Modified natural cycle for IVF does not offer a realistic chance of parenthood in poor responders with high day 3 FSH levels, as a last resort prior to oocyte donation

BACKGROUND: The purpose of this study was to evaluate the use of the modified natural cycle (MNC) for IVF in poor responders as a last resort prior to oocyte donation. METHODS: Thirty-two patients with a regular menstrual cycle, FSH levels on day 3 of the cycle >12 IU/l and one or more failed IVF cycles with five or fewer cumulus-oocyte complexes (COCs) retrieved were included in this prospective study. Recombinant FSH 100 IU and GnRH antagonist 0.25 mg/day were started concomitantly when a follicle with a mean diameter of 14 mm was present at ultrasound. HCG 10 000 IU was administered as soon as the mean follicular diameter was > or =16 mm. RESULTS: Twenty-five out of 78 cycles performed (32.1%) did not result in oocyte retrieval. In nine out of 53 cycles (16.9%) in which oocyte retrieval was performed, no COCs were retrieved. Following fertilization, embryo transfer was performed in 19 out of 44 cycles in which COCs were retrieved (43.2%). No ongoing pregnancy was achieved in 78 MNCs (0.0%; 95% confidence interval 0.0-4.7). CONCLUSIONS: MNC does not offer a realistic chance of parenthood in patients with high levels of FSH on day 3 of the cycle and previous poor response to ovarian stimulation, when offered as a last resort prior to oocyte donation.     

GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial

BACKGROUND. This is the first published report of a prospective, randomized, controlled trial comparing a fixed, multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders undergoing IVF. METHODS. Sixty-six poor responders were randomized into two groups: the study group received 0.25 mg of cetrorelix daily starting on day 6 of stimulation; the control group received 600 microg of buserelin acetate daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a fixed dose of recombinant FSH (300 IU daily) for stimulation. RESULTS. There were no significant differences in the cycle cancellation rates, duration of stimulation, consumption of gonadotrophins, and mean numbers of mature follicles, oocytes and embryos obtained. The implantation rates were similar, but the number of embryos transferred was significantly higher for the antagonist group (2.32 +/- 0.58 versus 1.50 +/- 0.83; P = 0.01). The pregnancy rates were also higher in the antagonist group, but the difference was not statistically significant. CONCLUSION. A fixed multi-dose GnRH antagonist protocol is feasible for patients who are poor responders on a long agonist protocol; however, our study failed to demonstrate an overall improvement in ovarian responsiveness. Clinical outcomes may be improved by developing more flexible antagonist regimens, an approach that requires further evaluation.     

Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation

BACKGROUND: To compare the clinical results and the cost-effectiveness of using the aromatase inhibitor, letrozole, in conjunction with FSH and FSH alone for controlled ovarian stimulation (COS) in patients undergoing intrauterine insemination (IUI) for a variety of indications. METHODS: Four hundred and thirty-two consecutive patients who underwent 872 IUI cycles were included. The study population was composed of two groups. Group I included 308 patients who underwent 589 IUI cycles with letrozole and FSH for the following indications: anovulation (143 cycles), male factor infertility (147 cycles), unexplained infertility (250 cycles), endometriosis (18 cycles) and combined indications (31 cycles). Group II included 124 patients who underwent 283 IUI cycles who received FSH only for the following indications: ovarian factor infertility (82 cycles), male factor infertility (66 cycles), unexplained infertility (114 cycles), endometriosis (13 cycles) and other indications (8 cycles). Main outcome measures included number of mature follicles >16 mm in diameter, dose of FSH used per cycle, clinical pregnancy rate and cost-effectiveness ratio per pregnancy. RESULTS: FSH dose required for ovarian stimulation was significantly lower when letrozole was used (P < 0.0001). Although a significantly higher number of follicles >16 mm and endometrial thickness at the day of hCG administration (P < 0.0001) were observed in Group II, pregnancy rate per started (14.4 versus 15.9%) and per completed cycles (15.77 versus 18.07%) was the same in Group I and Group II, respectively. IUI cancellation rate was significantly lower with letrozole treatment (P = 0.05%). The cost per cycle was significantly lower in Group I versus Group II (468.93 Can dollars +/- 418.18 versus 1067.28 +/- 921.43; P < 0.0001). The cost-effectiveness ratio was 3249.42 dollars in the letrozole group and 6712.00 dollars in the FSH-only group. CONCLUSION: A letrozole-FSH combination could be an effective ovarian stimulation protocol in IUI cycles. Such a protocol may be more cost-effective than FSH alone because of the difference of FSH dose and cost. A randomized controlled trial is needed to further substantiate this finding.     

Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series

In patients with poor response to ovarian stimulation with gonadotrophins, growth hormone (GH) is sometimes used to increase paracrine insulin-like growth factor-1 (IGF-1) effect. We postulated that dehydroepiandrosterone (DHEA) administration to poor responders would augment gonado-trophin effect via a similar mechanism. Baseline ovarian stimulation response to a cycle with DHEA in five healthy non-smoking women <41 years old was compared with day 3 FSH <20 mIU/ml. All had documented poor response to vigorous gonadotrophin administration. After day 2 ultrasounds, DHEA-sulphate (DHEA-S), FSH, human chorionic gonadotrophin (HCG), and testosterone were measured, and the women were given 80 mg/day of oral micronized DHEA for 2 months. While still on DHEA, they underwent ovarian stimulation with FSH given i.m. twice a day, and HCG (10 000 IU) at follicular maturity, followed by intrauterine insemination. Cycle parameters assessed were peak oestradiol, and peak oestradiol/ampoule. The DHEA/ovarian stimulation cycles occurred between 4 and 24 months after the control cycles. After 2 months DHEA treatment, DHEA-S increased to 544 +/- 55 microg/dl, and testosterone increased to 67.3 +/- 6.1 ng/dl. All five subjects (six cycles; one subject had two DHEA cycles) had increased responsiveness; peak oestradiol concentrations increased from 266.3 +/- 69.4 pg/ml to 939.8 +/- 418.9 pg/ml. The oestradiol/ampoule ratio increased in all six cycles, by a mean of 2.94 +/- 0.50 fold (P = 0.012). One of the cycles resulted in a delivered twin pregnancy. In this small series, DHEA improved response to ovarian stimulation even after controlling for gonadotrophin dose. Supplemental DHEA treatment during ovarian stimulation may represent a novel way to maximize ovarian response.     

Outcome of in-vitro fertilization through natural cycles in poor responders.

This prospective study examines the benefits of using natural cycles instead of stimulated cycles in poor responders to in-vitro fertilization (IVF) treatment. Eleven patients in whom puncture was cancelled or who failed to conceive because of a poor response were included in the analysis. The data for natural cycles (n = 16) were compared with data obtained during previous stimulated cycles (n = 25) in the same women. Out of 16 natural cycles, 13 (81.3%) were scheduled for oocyte retrieval compared to 13 out of 25 stimulated cycles (52%). Eighteen metaphase II oocytes were obtained during stimulated cycles, giving a 66% fertilization rate. In natural cycles, 11 metaphase II oocytes were available giving a fertilization rate of 78.6%. A mean number of 51.5 +/- 25 ampoules of gonadotrophins per cycle were used during ovarian stimulation. Three clinical pregnancies were obtained after embryo transfer in natural cycles (18.8%/started cycle) compared to none in stimulated cycles. Our findings demonstrate that an encouraging number of pregnancies can be achieved by IVF during natural cycles in poor responders to ovarian stimulation. This may not be the first approach to consider in IVF but it should be offered as an alternative after two ovarian response failures using classical protocols of stimulation.     

Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication

A new treatment option for patients undergoing ovarian stimulation is the gonadotrophin-releasing hormone (GnRH) antagonist protocol, with the possibility to trigger a mid-cycle LH surge using a single bolus of GnRH agonist, reducing the risk of developing ovarian hyperstimulation syndrome (OHSS) in high responders and the chance of cycle cancellation. This report describes the use of 0.2 mg triptorelin (Decapeptyl) to trigger ovulation in eight patients who underwent controlled ovarian hyperstimulation with recombinant FSH (rFSH, Puregon) and concomitant treatment with the GnRH antagonist ganirelix (Orgalutran) for the prevention of premature LH surges. All patients were considered to have an increased risk for developing OHSS (at least 20 follicles > or =11 mm and/or serum oestradiol at least 3000 pg/ml). On the day of triggering the LH surge, the mean number of follicles > or =11 mm was 25.1 +/- 4.5 and the median serum oestradiol concentration was 3675 (range 2980-7670) pg/ml. After GnRH agonist injection, endogenous serum LH and FSH surges were observed with median peak values of 219 and 19 IU/l respectively, measured 4 h after injection. The mean number of oocytes obtained was 23.4 +/- 15.4, of which 83% were mature (metaphase II). None of the patients developed any signs or symptoms of OHSS. So far, four clinical pregnancies have been achieved from the embryos obtained during these cycles, including the first birth following this approach. It is concluded that GnRH agonist effectively triggers an endogenous LH surge for final oocyte maturation after ganirelix treatment in stimulated cycles. Our preliminary results suggest that this regimen may prove effective in triggering ovulation and could be said to prevent OHSS in high responders. The efficacy and safety of such new treatment regimen needs to be established in comparative randomized studies.     

Long-term GnRH analogue treatment is equivalent to laparoscopic laser diathermy in polycystic ovarian syndrome patients with severe ovarian dysfunction

This prospective, randomized study included 18 polycystic ovarian syndrome (PCOS) patients with severe ovarian dysfunction, who were evaluated by standard clomiphene and FSH stimulation. In this group of patients, a 6 month down-regulation with gonadotrophin-releasing hormone (GnRH) analogues gave outcomes similar to laparoscopic ovarian laser diathermy with respect to stimulatory outcome and pregnancy rate. Clomiphene stimulation with 50 mg of clomiphene/day and FSH stimulation in a low-dose, step-up protocol with purified FSH did not result in oligofollicular development; thus patients were divided into two subgroups: one subgroup received laparoscopic laser drilling and the other received 6 months of therapy with GnRH analogues plus add-back therapy after diagnostic laparoscopy. Subsequently, three cycles of low-dose, step-up stimulation with recombinant FSH were started. In both groups, approximately 30% of cycles still remained anovulatory. In the down-regulated subgroup, this mainly happened in the first cycle. In each group, ovulation was achieved in 14 cycles, intrauterine insemination was performed, and five pregnancies were obtained. This resulted in a pregnancy rate of 36% per ovulatory cycle in both groups. Overall, 50% of the formerly unreactive patients in both groups overcame childlessness. In achieving this, long-term treatment with GnRH analogues was as successful as laparoscopic laser diathermy.     

GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study

BACKGROUND: The specific role of LH in folliculogenesis and oocyte maturation is unclear. GnRH antagonists, when administered in the late follicular phase, induce a sharp decrease in serum LH which may be detrimental for IVF outcome. This study was performed to evaluate whether the replacement of GnRH agonist (triptorelin) by a GnRH antagonist (ganirelix; NV Organon) in oocyte donation cycles has any impact on pregnancy and implantation rates. METHODS: A total of 148 donor IVF cycles was randomly assigned to use either a GnRH antagonist daily administered from the 8th day of stimulation (group I) or a GnRH agonist long protocol (group II) for the ovarian stimulation of their donors. The primary endpoints were the pregnancy and the implantation rates. RESULTS: The clinical pregnancy rate per transfer (39.72%, 29/73 versus 41.33%, 31/75) based on transvaginal scan findings at 7 weeks of gestation, the implantation rate (23.9 versus 25.4%) and the first trimester abortion rate (10.34 versus 12.90%) were similar in the two groups. CONCLUSION: In oocyte donation cycles the replacement of GnRH agonist by a GnRH antagonist appears to have no impact on the pregnancy and implantation rates when its administration starts on day 8 of stimulation.     

Prediction of over-response to ovarian stimulation in an intrauterine insemination programme.

Prediction of poor-response is of equal importance to prediction of over-response in intrauterine insemination programmes. The gonadotrophin-releasing hormone agonist (GnRHa) stimulation test (GAST) was assessed as a predictor of over-response to ovarian stimulation in 81 patients. Blood samples were taken on cycle day 2 (before and 24 h after starting the GnRHa). Day 2 and 3 samples were assayed for oestradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Linear and logistic regression analyses were used to assess age, day 2 FSH, day 2 FSH/LH, oestradiol ratio (oestradiol on day 3/oestradiol on day 2) and FSH ratio (FSH on day 3/FSH on day 2) as predictors of the number of follicles (total and > or = 14 mm), oestradiol on HCG day, and clinical pregnancy rate as appropriate. Several parameters were also compared between the patients who produced < or = 3 (> or = 14 mm) follicles (group A) and those who produced >3 (> or = 14 mm) follicles (group B). The mean +/- SEM age of the patients in the study was 32 +/- 0.4 years. The mean total dose of recombinant FSH was 800 +/- 20 IU and the mean duration of stimulation was 7.6 +/- 0.2 days. Nine (11%) and 12 (15%) patients were cancelled for poor and over-response respectively. The oestradiol ratio was significantly positively correlated with oestradiol on HCG day (P < 0.001), and with the number of mature follicles (> or = 14 mm) (P = 0.01). Age, day 2 FSH and FSH ratio were not significantly correlated with oestradiol on HCG day, total follicles and follicles > or = 14 mm. None of the above-mentioned variables was correlated with clinical pregnancy rate. Group A had significantly lower oestradiol ratio (P = 0.007), longer duration of stimulation (P = 0.002), higher total FSH dose (P = 0.001), and lower oestradiol on HCG day (P = 0.001). GAST is therefore useful in predicting the high responders to gonadotrophin stimulation.     

Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles.

The luteal phase hormonal profile and the clinical outcome of 69 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) after ovarian stimulation with human menopausal gonadotrophin (HMG) and the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix were analysed. Twenty-four patients received Cetrorelix 0.5 mg (group I) while in 45 patients Cetrorelix 0.25 mg was administered (group II). Human chorionic gonadotrophin (HCG) was used as luteal support. Nine clinical pregnancies were obtained in group I (37.5%) and 12 in group II (26. 6%). These results were not significantly different. Serum progesterone and oestradiol concentrations did not differ between the two groups either in pregnant or non-pregnant patients. An expected decrease of the same hormones was observed 8 days after the pre-ovulatory HCG injection in non-pregnant women. With regard to serum luteinizing hormone concentrations, a decrease was observed 2 days after the pre-ovulatory HCG injection and was maintained at almost undetectable levels throughout the entire luteal phase in both conception and non-conception cycles of group I and group II. This study demonstrates that different doses of GnRH antagonist do not have any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given.     

Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix

Luteinizing hormone (LH) is mandatory for the maintenance of the corpus luteum. Ovarian stimulation for IVF has been associated with a defective luteal phase. The luteal phases of two groups of patients with normal menstrual cycles and no endocrinological cause of infertility were retrospectively analysed in IVF cycles. Thirty-one infertile patients stimulated with human menopausal gonadotrophins (HMG) for IVF to whom the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix 0.25 mg was also administered to prevent the LH surge (group I) were compared with 31 infertile patients stimulated with HMG alone (group II). Despite differences in the stimulation outcome, luteal LH serum concentrations were similar in the two groups. LH values dropped from 2.3 +/- 1 IU/l on the day of human chorionic gonadotrophin (HCG) administration to 1.1 +/- 0.7 IU/l on day HCG +2 in group I (P < 0.0001) and from 5.1 +/- 3 to 1.2 +/- 1.7 IU/l (P < 0.0001) in group II. In the mid-luteal phase, LH concentrations were low in both groups. Our results suggest that suppressed LH concentrations in the early and mid-luteal phase may not be attributed solely to the GnRH-antagonist administration. Pituitary LH secretion may be inhibited by supraphysiological steroid serum concentrations via long-loop feedback and/or by the central action of the exogenously administered HCG via a short-loop mechanism.     

High doses of gonadotrophin-releasing hormone antagonist in in-vitro fertilization cycles do not adversely affect the outcome of subsequent freeze-thaw cycles.

The clinical application of gonadotrophin-releasing hormone (GnRH) antagonists instead of GnRH agonists, to prevent spontaneous premature luteinizing hormone surge during ovarian stimulation for assisted reproduction treatment has been advocated. A recent, double-blind, dose-finding study, including six dosages of the GnRH antagonist ganirelix, in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (FSH), has indicated that high doses of GnRH antagonist (1 or 2 mg once daily) are associated with a low implantation rate. This follow-up study reports on the pregnancy rate after replacement of cryopreserved embryos obtained in stimulation cycles of the above-mentioned trial. Ovarian stimulation was initiated on day 2 of the cycle, with daily injections of 150 IU recombinant FSH. Ganirelix (0.0625, 0.125, 0.25, 0.5, 1.0 or 2.0 mg) was administered once daily from stimulation day 6 onwards, up to and including the day of human chorionic gonadotrophin. Retrieved oocytes were fertilized by in-vitro fertilization (IVF) or intracytoplasmic sperm injection and a maximum of three fresh embryos was transferred. Excess embryos were frozen, and subsequently used in either natural or programmed cycles. Until June 1998, 11 ongoing pregnancies (12-16 weeks after embryo transfer) were achieved from 46 cycles in which embryos had been first frozen (23.9% per transfer). Six of these 11 patients had been treated with a high dose of ganirelix (1.0 or 2.0 mg) during the IVF cycles in which the embryos were obtained. In conclusion, our data suggest that high dosages of ganirelix do not adversely affect the potential of embryos to establish clinical pregnancy in freeze-thaw cycles.     

Ovarian stimulation in previous failures from in-vitro fertilization: distinction of two groups of poor responders

Forty-three patients who responded poorly to previous stimulation with clomiphene citrate (CC)/human menopausal gonadotrophin (HMG) for IVF were followed during 70 further cycles. Eighteen patients had a normal FSH response to CC in the previous cycle, while 25 had an abnormal FSH response. Three stimulation protocols were used: buserelin/HMG, CC/HMG and HMG only. No difference between the two groups was observed in the dose of HMG used for any stimulation protocol. More cycles were cancelled due to a poor response in the abnormal response group compared to the normal response group. In the completed cycles, the maximum oestradiol level and number of oocytes retrieved were lower in the abnormal response group compared to the normal response group. The total pregnancy rate per patient, including spontaneous conceptions during the study period, was lower in the abnormal response group compared to the normal response group, 4 versus 33%. We conclude that poor responders with an abnormal FSH response to CC have a latent ovarian failure with a low chance of success in further IVF attempts.     

Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH

BACKGROUND: Treatment of poor-responder patients to controlled ovarian stimulation for assisted reproduction, who have normal basal FSH concentrations, is one of the most difficult challenges in reproductive medicine. This study investigated the usefulness of testosterone pretreatment in such patients. METHODS: Prospective, therapeutic, self-controlled clinical trial including 25 consecutive infertile patients who had a background of the first and second IVF treatment cycle cancellations due to poor follicular response, in spite of vigorous gonadotrophin ovarian stimulation and having normal basal FSH levels. In the third IVF attempt, all patients received transdermal testosterone treatment (20 microg/kg per day) during the 5 days preceding gonadotrophin treatment. RESULTS: Twenty patients (80%) showed an increase of over fivefold in the number of recruited follicles, produced 5.8+/-0.4 (mean+/-SEM) oocytes, received two or three embryos and achieved a clinical pregnancy rate of 30% per oocyte retrieval. There were 20% cancelled cycles. CONCLUSION: Pretreatment with transdermal testosterone may be a useful approach for women known to be low responders on the basis of a poor response to controlled ovarian stimulation but having normal basal FSH concentrations.     

Fertility and ovarian function are preserved in women treated with an intensified regimen of cyclophosphamide, adriamycin, vincristine and prednisone (Mega-CHOP) for non-Hodgkin lymphoma

BACKGROUND: Intensive chemotherapy is widely used to improve the outcome of aggressive non-Hodgkin lymphoma (NHL). Since these regimens may cause premature ovarian failure (POF), the ovarian function was studied in 13 consecutive women aged < or =40 years, treated with four cycles of intensified CHOP (cyclophosphamide 2000-3000 mg/m2 per cycle doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 (maximum 2 mg) and prednisone 100 mg/day were given every 3 weeks). METHODS: Patients aged <60 years with aggressive NHL were eligible for participating in a non-randomized phase II study if they had stage I, II, B, bulky, or stages III, IV disease with the age-adjusted international prognostic index of low-intermediate to high-risk score. Seven patients were concomitantly treated with D-TRP6-GnRH analogue (Decapeptyl; Ferring, Germany) for minimizing gonadal toxicity. RESULTS: With a median follow-up of 70 months only one patient had POF, while 12 patients retained fertility and eight conceived spontaneously delivering 12 healthy babies. CONCLUSION: It appears that high-dose cyclophosphamide does not affect the ovarian function or fertility in patients exposed to this medication during four consecutive cycles of intensified CHOP.     

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.     

Ovarian stimulation by clomiphene citrate and hMG in combination with cetrorelix acetate for ICSI cycles

BACKGROUND: The introduction of GnRH antagonists such as cetrorelix acetate has made possible the simplification of ovarian stimulation. However, the most effective protocol for their administration has not yet been clearly defined. METHODS: Forty women with male-factor infertility undergoing 40 ICSI cycles were included in the study. Clomiphene citrate at 100 mg a day was given from cycle day 3 through day 7. hMG at 150 IU was given on cycle days 4, 6 and 8, and was adjusted from day 9 according to the follicular and hormone responses. Cetrorelix acetate at 2.5 mg was administered when the leading follicle reached 14 mm. The remaining 0.5 mg was divided into two 0.25 mg injections for possible later use. Serum FSH, LH, estradiol and progesterone levels were measured daily from the day of cetrorelix acetate injection until hCG was given. RESULTS: Serum LH level was suppressed effectively for 4 days. Four patients (10%) needed one or two additional injections of 0.25 mg cetrorelix acetate. No premature LH surge was detected in any of the women treated. Sixteen women became pregnant (40%), of which 14 pregnancies (35%) were ongoing at the time of writing. CONCLUSIONS: This study demonstrates that this new protocol is feasible for couples with male-factor infertility undergoing ICSI.     

Basal and stimulation day 5 anti-Mullerian hormone serum concentrations as predictors of ovarian response and pregnancy in assisted reproductive technology cycles stimulated with gonadotropin-releasing hormone agonist--gonadotropin treatment

BACKGROUND: Anti-Müllerian hormone (AMH) has been recently proposed as a marker for ovarian ageing and poor ovarian response to controlled ovarian hyperstimulation in assisted reproduction cycles. The present study was undertaken to investigate the usefulness of baseline cycle day 3 AMH levels and AMH serum concentrations obtained on the fifth day of gonadotropin therapy in predicting ovarian response and pregnancy in women undergoing ovarian stimulation with FSH under pituitary desensitization for assisted reproduction. METHODS: A total of 80 women undergoing their first cycle of IVF/intracytoplasmic sperm injection (ICSI) treatment were studied. Twenty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, 60 women were randomly selected from our assisted reproduction programme matching by race, age, body mass index, basal FSH and indication for IVF/ICSI to those in the cancelled group. For each cancelled patient, three IVF/ICSI women who met the matching criteria were included. RESULTS: Basal and day 5 AMH serum concentrations were significantly lower in the cancelled than in the control group. Receiver-operating characteristic (ROC) analysis showed that the capacity of day 5 AMH in predicting the likelihood of cancellation in an assisted reproduction treatment programme was significantly higher than that for basal AMH measurement. However, the predictive capacity of day 5 AMH was not better than that provided by day 5 estradiol. In addition, neither basal nor day 5 AMH or estradiol measurements were useful in the prediction of pregnancy after assisted reproductive treatment. CONCLUSIONS: AMH concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproduction are better predictors of ovarian response than basal AMH measurements. However, AMH is not useful in the prediction of pregnancy. Definite clinical applicability of AMH determination as a marker of IVF outcome remains to be established.