Recombinant follicle stimulating hormone is effective in poor responders to highly purified follicle stimulating hormone

Ovarian stimulation in cases of poor ovarian responsiveness is an important challenge in in-vitro fertilization (IVF) programmes. Despite improvements in oocyte number and quality, an ideal ovarian stimulation strategy has yet to be defined. Here, the results of ovarian stimulation with recombinant follicle stimulating hormone (rFSH) in 28 poor responders to highly purified FSH (FSH-HP) with high basal concentrations of FSH are reported. The protocols used on the FSH-HP and rFSH cycles were identical with the sole exception of the FSH preparation: triptorelin 0.1 mg/day (gonadotrophin-releasing hormone, GnRH-agonist short protocol) and the starting FSH dose of 300 IU/day were administered from day 2 of the menstrual cycle. Ovarian outcome was classified as 'normal', 'intermediate' and 'poor', depending on the number of mature oocytes retrieved and the peak serum oestradiol concentration. Nine of the 28 subjects had an intermediate ovarian response to re-stimulation with rFSH. In the 26 patients who received human chorionic gonadotrophin on both cycles, re-stimulation resulted in a significant increase (P < 0.05) in the mean number of mature oocytes (2.4 +/- 1.4 versus 1.7 +/- 0.8), mean peak oestradiol concentration (606 +/- 252 versus 443 +/- 32 pg/ml) and fertilization rate (73.0 versus 53.3%). Four pregnancies were achieved. It is concluded that rFSH in a GnRH-agonist short protocol improves the ovarian outcome in poor responders to FSH-HP with high basal concentrations of FSH.     

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.     

Previous cycle cancellation due to poor follicular development as a predictor of ovarian response in cycles stimulated with gonadotrophin-releasing hormone agonist-gonadotrophin treatment

BACKGROUND: There is scanty information analysing the predictive value of a poor response, in terms of cancellation of the IVF cycle because of poor follicular development, as a predictor of ovarian response in a subsequent treatment cycle. This study, where logistic regression analysis was used, was undertaken to investigate the relative power of the woman's age, basal FSH, and previous cycle cancellation both as single and combined predictors of ovarian response in an IVF program where pituitary desensitization is routinely used. METHODS: One hundred and twenty-nine consecutive patients having their first cycle of IVF/ICSI treatment cancelled because of poor follicular response and undergoing a second attempt within 6 months after the failed treatment cycle were initially selected (group 1). Group 2 comprised 129 patients undergoing the first cycle of IVF/ICSI treatment and who were randomly selected from our assisted reproductive treatment program matching by BMI and indication for IVF/ICSI to those in group 1. RESULTS: Cancellation rate was significantly higher but ovarian response significantly lower in group 1 as compared with group 2. As indicated by the AUC(ROC) determined with ROC analysis, such a poor outcome in patients having a previous IVF/ICSI cycle cancelled due to poor response was observed whatever the level of basal FSH. In a logistic regression analysis and according to the odds ratio values, the predictive capacity of a previous poor response was 9 and 7.6 times higher than the predictive capacity of age and basal FSH, respectively. Any two or all three variables studied did not improve the predictive value of previous cycle cancellation alone. CONCLUSIONS: The history of an IVF/ICSI cancelled cycle due to poor follicular response in a standard stimulation protocol is a better predictor of cancellation in subsequent treatment cycles than age or FSH. The poor ovarian response associated with previous cycle cancellation occurs whatever the level of basal FSH.     

Simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue (F-G-test) allows effective drug regimen selection for IVF

To determine whether preliminary assessment of ovarian reserve by simultaneous evaluation of basal follicle-stimulating hormone (FSH) and oestradiol response to gonadotrophin releasing hormone (GnRH) analogue (F-G-test) can be used to tailor individually the drug regimen for ovarian stimulation, the in-vitro fertilization (IVF) results of 238 patients were retrospectively analysed. Sixty-two women with abnormal response to the test (DeltaE2 <180 pmol/l and/or FSH >9.5 mIU/ml) had commenced buserelin nasal spray in the mid-luteal phase and discontinued it on cycle day 1. Ovarian stimulation was started on cycle day 3 with 375 IU/day of gonadotrophin. Fifty-three patients completed the treatment cycle (group A). A total of 176 women with normal response to the test (DeltaE2 >180 pmol/l and FSH <9.5 mIU/ml) had continued the GnRH analogue throughout the stimulation cycle and a starting dose of 225 IU/day of gonadotrophin was used from cycle day 3. A total of 158 patients completed the treatment cycle (group B). Group A had significantly higher age (34.9 +/- 4.2 versus 33.2 +/- 4.2) (P < 0.05) and basal FSH (9.2 +/- 3.8 versus 7.0 +/- 2.2) (P < 0.05) and required a higher total dose of gonadotrophin. The numbers of oocytes retrieved and embryos transferred were significantly lower. However, fertilization, clinical pregnancies, and implantation rates were similar in both groups. It was concluded that simultaneous evaluation of basal FSH and oestradiol response to GnRH analogue can be useful in identifying subcategories of women with reduced ovarian reserve who may benefit from reduced GnRH analogue administration and a higher starting dose of gonadotrophin.     

Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study

BACKGROUND: In primates, androgens can play a synergistic role with FSH in promoting the early follicular recruitment, which is critical in assisted reproduction technique programmes. OBJECTIVE: To assess whether poor responders can benefit from androgen application. METHODS: Inclusion criteria were a previous poor ovarian response to controlled ovarian stimulation and a decreased hormonal ovarian reserve. Selected women were randomized to receive either transdermal application of testosterone (n = 24) or placebo (n = 25) gel for 15 days before FSH treatment for a second IVF cycle. Similar GnRH analogue and equivalent FSH daily doses were used in both cycles. The primary outcome was the total number of oocytes retrieved. RESULTS: Testosterone gel application resulted in a significant increase in plasma testosterone levels but did not significantly improve the antral follicle count. Furthermore, after gel application, the main parameters of the ovarian response (numbers of pre-ovulatory follicles, total and mature oocytes and embryos) did not significantly differ between testosterone and placebo-treated patients. CONCLUSION: No significant beneficial effects of androgen administration on the ovarian response to FSH could be demonstrated. However, subsequent clinical trials are needed to determine whether an optimal dose and/or a longer duration of testosterone administration may be helpful.     

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.     

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.     

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.     

Serum IGF-1 concentrations following pituitary desensitization do not predict the ovarian response to gonadotrophin stimulation prior to IVF

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is known to play a role in ovarian follicular development augmenting the action of FSH. Low intrafollicular concentrations have been detected in women who respond poorly to gonadotrophins. This study addresses the relationship between serum IGF-1 levels following pituitary desensitization and ovarian response to gonadotrophin stimulation. METHODS: This is a case-control study of 78 patients undergoing IVF-embryo transfer treatment. Thirty-nine strictly-defined poor responder patients requiring 50 or more ampoules (75 IU FSH) to reach oocyte retrieval were compared with 39 age-matched normal responders, requiring fewer than 50 ampoules. IGF-1 concentrations were determined by extraction radioimmunoassay on serum samples obtained after pituitary desensitization but prior to gonadotrophin stimulation. RESULTS: Despite highly significant differences in measures of ovarian response between groups, the mean serum IGF-1 concentration was not statistically significantly different between poor and normal responders [(31.5 nmol/l [95% confidence interval (CI) 28.5-34.5] versus 34.5 nmol/l (95% CI 31.8-37.2)] respectively. No correlation between oocyte number or total gonadotrophin used and serum IGF-1 concentration was observed. CONCLUSION: Whilst IGF-1 influences ovarian follicular development this study suggests that serum IGF-1 does not predict ovarian response and does not differentiate between critically-defined poor and normal responders.     

Young age does not protect against the adverse effects of reduced ovarian reserve--an eight year study

BACKGROUND: Ovarian reserve significantly influences IVF outcome. Low response to ovarian stimulation due to reduction of ovarian reserve is occasionally encountered in young women. The aim of this study was to evaluate the outcome of IVF treatment in young patients with reduced ovarian reserve. METHODS AND RESULTS: Between January 1993-2001, 762 consecutive patients satisfied the definition of reduced ovarian reserve (raised early follicular phase FSH or gonadotrophin stimulation cycles where three or fewer oocytes were retrieved after routine FSH stimulation) and were included in the study. They were classified into three age groups: young (< or = 30 years), intermediate (31-38 years) and older (>38 years). The three age groups were similar with respect to basal (day 3) serum FSH and estradiol concentrations, cause of infertility and number of previous treatment cycles. Implantation (13, 9.6 and 9.8%), clinical pregnancy (11.8, 10.2 and 10%) and live birth (7.4, 7.3 and 6.8%) rates were not significantly different in the three age groups respectively (P > 0.05). CONCLUSION: This study shows that younger patients with reduced ovarian reserve have a poor outcome of IVF treatment similar to their older counterparts. Such information may be helpful in counselling these patients who otherwise might anticipate an outcome related to their chronological age.     

Endocrinology: The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone

To evaluate the relative importance of follicle stimulatinghormone (FSH) and luteinizing hormone (LH) in follicular developmentand oocyte fertility in the human species, the use of recombinanthuman FSH, human menopausal gonadotrophin (HMG), and very highlypurified urinary human FSH (FSH-HP) plus oestradiol valeratefor ovarian stimulation and in-vitro fertilization (IVF) werecompared in three cycles in a woman with isolated congenitalgonadotrophin deficiency who had never been treated with ovarianstimulating agents. The total number of ampoules of gonadotrophinsused was lower in the HMG treatment cycle. Ovarian responseand IVF outcome in the three treatment cycles were as follows:(i) HMG cycle: normal follicular growth, normal pattern of oestradioland inhibin through the menstrual cycle, high fertilizationrate (93%); (ii) recombinant FSH cycle: normal follicular growth,low oestradiol and abnormal inhibin, finally poor rate of fertilization(28%); (iii) FSH-HP plus oestradiol valerate cycle: normal folliculargrowth, normal pattern of inhibin and poor fertilization rate(27%). Luteal plasma progesterone concentrations were much higherin the HMG treatment cycle. This case shows that FSH is theonly factor required in order to induce follicular growth inthe human, although LH or a product derived from its actionmay assist in order to achieve full follicular maturity andoocytes capable of fertilization. Though oestradiol might havea mediatory role in the process of follicular maturation, ourresults favour a direct primary role of LH in complete maturationof the follicle.     

Does growth hormone-releasing factor assist follicular development in poor responder patients undergoing ovarian stimulation for in-vitro fertilization?

Treatment with growth hormone-releasing factor (GRF) has been reported to improve the ovarian response to gonadotrophins in women who respond poorly to ovarian stimulation during in-vitro fertilization (IVF). The efficacy and tolerability of GRF were studied in a randomized, double-blind, placebo-controlled trial involving 196 patients. Following down-regulation with a gonadotrophin-releasing hormone agonist (GnRHa), patients were randomized to receive GRF (500 microg twice daily; n = 96) or placebo (n = 100) in addition to follicle stimulating hormone (FSH); treatment was continued until human chorionic gonadotrophin was given, or for a maximum of 14 days. GRF had no significant effect on the mean number of follicles with a diameter of >/=16 mm (GRF: 3.26 +/- 2.29; placebo: 3.27 +/- 2.30; P = 0.95), the number of FSH ampoules required to achieve ovarian stimulation (GRF: 55.2 +/- 16. 4; placebo: 54.9 +/- 17.2; P = 0.50), or on secondary measures of ovarian response and treatment outcome. There were, however, significant increases in circulating growth hormone (GH) and insulin-like growth factor (IGF)-1 concentrations. GRF was well tolerated. It is concluded that, despite producing significant increases in GH and IGF-1, concomitant treatment with GRF does not improve the ovarian response to FSH in poorly responsive women undergoing IVF.     

Day 5 inhibin B serum concentrations as predictors of assisted reproductive technology outcome in cycles stimulated with gonadotrophin-releasing hormone agonist-gonadotrophin treatment

The present study investigates the usefulness of inhibin A, inhibin B and serum oestradiol concentrations obtained in the fifth day of gonadotrophin therapy in predicting ovarian response and assisted reproductive treatment outcome in women undergoing ovarian stimulation under pituitary desensitization. A total of 80 women undergoing their first cycle of in-vitro fertilization (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 reproductive treatment programme matching by race, age, body mass index, and indication for IVF/ICSI to those in the cancelled group. For each cancelled cycle, three IVF/ICSI women who met the matching criteria were included. Basal follicle stimulating hormone (FSH) concentrations were significantly higher in the cancelled than in the control group, whereas basal inhibin B was significantly higher in the latter. Basal oestradiol concentrations were similar in both groups of patients. On day 5 of gonadotrophin therapy serum concentrations of oestradiol, inhibin A and inhibin B were significantly lower in the cancelled group as compared with controls. Logistic regression analysis showed that the association for day 5 inhibin B (with a predictive value of ovarian response of 91.03%) with cancellation rate was significant, independent of, and stronger than, the effects of any other hormone variable investigated. In addition, day 5 inhibin B concentrations were correlated directly with parameters of ovarian response, ovum retrieval and oocyte and fertilization outcome. However, day 5 inhibin B was not a better predictor of pregnancy than the other hormone variables studied on this day. It is concluded that inhibin B concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproductive treatment are highly predictive of ovarian response.     

Women with poor response to IVF have lowered circulating gonadotrophin surge-attenuating factor (GnSAF) bioactivity during spontaneous and stimulated cycles

BACKGROUND: Up to 13% of IVF cancellations are due to poor responses during down-regulated cycles. Because premature luteinization occurs more frequently in older or "poor responder" patients, defective production of gonadotrophin surge-attenuating factor (GnSAF) may be involved. METHODS: Nine women with normal previous IVF response (NORM) and 9 with previous poor IVF response (POOR) were monitored in a spontaneous cycle (blood samples: days 2, 7, 11, 15 and 20) and then stimulated with recombinant human FSH (rFSH) under GnRH agonist (blood samples: treatment days GnRH agonist + 2, GnRH agonist + 7, day of HCG administration and days HCG + 1 and HCG + 8). LH, FSH, estradiol, progesterone and inhibin-A and -B were assayed in individual samples while GnSAF bioactivity was determined in samples pooled according to day, cycle and IVF response. RESULTS: During spontaneous cycles LH, steroids and inhibins were similar between NORM and POOR women, FSH was elevated in POOR women (4.9 +/- 0.3 versus 6.7 +/- 0.6 mIU/l, P < 0.01) and GnSAF bioactivity was detectable on days 2, 7 and 11 in NORM women only. During IVF cycles inhibin-A and -B rose more markedly in NORM than POOR women. Similarly GnSAF production peaked on day GnRH agonist + 7 in NORM women, but on the day of HCG administration in POOR women. CONCLUSIONS: Defects in ovarian responsiveness to FSH include reduced GnSAF production. This suggests that GnSAF should be investigated as a marker of ovarian reserve once an immunoassay becomes available.     

Ovarian stromal blood flow in the prediction of ovarian response during in vitro fertilization treatment

BACKGROUND: This study evaluated the role of ovarian stromal blood flow in the prediction of the ovarian response of infertile women by comparing age of women, body mass index (BMI), basal FSH concentration, antral follicle count (AFC) and ovarian stromal blood flow indices measured by power Doppler in two-dimensional ultrasound. Patients were aged <40 years with basal FSH <10 IU/l on recruitment for IVF treatment. METHODS: All received a standard regimen of ovarian stimulation in their first IVF cycle. AFC, pulsatility index, resistance index and peak systolic blood flow velocity of ovarian stromal vessels were determined on the second day of the treatment cycle prior to ovarian stimulation. Ovarian response was represented by the number of oocytes, serum oestradiol, and the duration and dosage of gonadotrophins. RESULTS: A total of 136 women were included in the analysis. Basal FSH concentration achieved the best predictive value in relation to the number of oocytes obtained, followed by AFC and BMI. AFC was the only predictive factor of serum oestradiol concentration on the day of HCG while BMI was predictive of the gonadotrophin dosage. CONCLUSION: Ovarian stromal blood flow indices measured by power Doppler ultrasound had no predictive value for the ovarian response.     

Effect of reduced dose of triptorelin at the start of ovarian stimulation on the outcome of IVF: a randomized study.

BACKGROUND: Partial pituitary desensitization using gonadotrophin-releasing hormone (GnRH) agonists may be sufficient in women undergoing controlled ovarian hyperstimulation for assisted reproduction. However, the minimal effective agonist dose remains to be determined. The aim of the study was to investigate the effect of a reduced daily dose of triptorelin, administered at the start of ovarian stimulation, on the results of IVF and intracytoplasmic sperm injection. METHODS: A total of 132 patients was randomized in two groups. Pituitary desensitization was obtained in group 1 (66 patients) with a single 3.75 mg injection (i.m.) of triptorelin. In group 2, 66 patients received 100 microg triptorelin daily, which was then reduced to 50 microg at the start of follicle-stimulating hormone (FSH) stimulation. RESULTS: No significant differences were found in terms of pregnancy rate per transfer (38% in group 1 versus 34.9% in group 2), implantation rate (20.2 versus 18%) and abortion rate (8.3 versus 9.1%). The number of FSH ampoules used, as well as the number of days stimulation required, was significantly reduced in group 2 (41 +/- 26 versus 46.6 +/- 25.3, P < 0.03 and 11 +/- 1.3 versus 11.8 +/- 1.5, P < 0.002 respectively). No significant differences were seen in oestradiol concentrations and in follicle number, in the quantity of oocytes collected and fertilized, or in the number of embryos obtained or transferred. CONCLUSION: A reduced dose of triptorelin is enough for pituitary suppression during ovarian stimulation but provides no significant improvement in IVF cycle outcome when compared with depot formulation. The possibility of a shorter treatment protocol requiring lower amounts of gonadotrophins should be considered in view of its economic advantage.     

Low-dose aspirin does not improve ovarian responsiveness or pregnancy rate in IVF and ICSI patients: a randomized, placebo-controlled double-blind study

BACKGROUND: Poor ovarian and endometrial responses to gonadotrophin stimulation in assisted reproduction techniques lead to decreased pregnancy rates. The aim of the present study was to test the hypothesis that low-dose aspirin started prior to controlled ovarian stimulation improves ovarian responsiveness, pregnancy rate (PR) and pregnancy outcome. METHODS: A total of 374 women who were to undergo IVF/ICSI were randomized to receive 100 mg of aspirin (n=186) or placebo (n=188) daily. Treatment was started on the first day of controlled ovarian stimulation. It was continued until menstruation or a negative pregnancy test. Pregnant women continued the medication until delivery. The main outcome measures were the number of oocytes, number and quality of embryos, the clinical PR and pregnancy outcome. RESULTS: The mean (+/-SD) number of oocytes (12.0+/-7.0 versus 12.7+/-7.2), the total mean number of embryos (5.82+/-4.35 versus 5.99+/-4.66), the mean number of top quality embryos (0.99+/-1.39 versus 1.18+/-1.51) and the number of embryos transferred (1.64+/-0.64 versus 1.63+/-0.71) did not differ in the aspirin and placebo groups. Between the aspirin and placebo group, there was no statistically significant difference in clinical PR per embryo transfer (25.3%, n=44 out of 174 versus 27.4%, n=48 out of 175) or clinical PR per cycle initiated (23.7% versus 25.5%). Birth rate per embryo transfer did not differ significantly between the aspirin (18.4%) and placebo (21.1%) groups. The incidence of poor responders [12 (6.5%) versus 13 (6.9%)] was similar in both groups. CONCLUSIONS: The present results indicate that low-dose aspirin treatment does not have any beneficial effect on ovarian responsiveness, PR and pregnancy outcome in unselected women undergoing IVF/ICSI.     

The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients

BACKGROUND: Adequate ovarian response to exogenous gonadotrophins is important for both ovulation induction (OI) and controlled ovarian stimulation (COS). The objective of this study was to analyse the effect of a number of clinical factors that influence ovarian response in non-polycystic ovarian syndrome (non-PCOS) patients. METHODS: A total of 140 OI cycles (52 subjects), where each subject had a single abnormality (elevated FSH, abnormal body mass index (BMI) or > or = 40 years of age), were compared with 54 cycles (15 subjects) where the patients displayed none of these abnormal features (the normal group). Similarly, 275 COS cycles (135 subjects), where each subject displayed a single abnormality, were compared with 79 cycles (40 subjects) in the normal group. RESULTS: For OI, subjects with a high basal FSH generally had an inadequate response with a poor chance of conception. Subjects with an abnormal BMI commonly required dosage adjustment so were more difficult to manage. Their potential for conception was normal. Older women seemed to respond normally with a normal expectation of conception. In the COS group, subjects with a moderately high basal FSH responded and conceived normally. Subjects with an abnormal BMI had an increased risk of an inadequate response leading to cancellation but if the response was adequate then the outlook was good. Older women required more gonadotrophin with a poor response and a low chance of conception. CONCLUSION: The results have better defined the anticipated responses of non-PCOS patients to gonadotrophin stimulation in both OI and COS.     

An elevated basal FSH reflects a quantitative rather than qualitative decline of the ovarian reserve

BACKGROUND: Many cycling women with elevated basal FSH level have been discouraged from undergoing IVF treatment. This is because elevated basal FSH is associated with poorer assisted reproduction treatment outcome. It has been argued that high FSH reflects not only reduced ovarian reserve but also poor oocyte quality. The aim of this study is to assess the value of treating cycling women who have elevated basal FSH and to assess the reasons for the reduction in both pregnancy rate (PR) and live birth rate (LBR). METHODS: Between January 1997 and December 2001, 2057 patients underwent 3401 consecutive IVF/ICSI cycles in which the basal level of FSH (days 2-4) was determined at an earlier cycle. Analysis, however, was only performed for a single cycle per patient. All cases were divided into four cohorts according to FSH levels: group A, FSH <10 IU/ml; group B, 10.1-15 IU/ml; group C, 15.1-20 IU/ml; and group D, FSH >20 IU/ml. Each group was stratified further into subgroups according to age, < or =38 and >38 years. RESULTS: Both PR (A, 32.3%; B, 19.8%; C, 17.5%; and D, 3%) and LBR (A, 24.7%; B, 13.2%; C, 13.8%; and D, 3%) were significantly reduced in the higher FSH level groups. LBR was significantly higher in the younger subgroups (A, 32.2%; B, 21.8%; C, 20%; and D, 16.7%) as compared with the older subgroups (A, 12.1%; B, 8.3%; C, 10.5%; and D, 0%). Higher levels of FSH were significantly associated with more cycle cancellation, a larger amount of gonadotrophin required to achieve follicular maturity, and a lower number of eggs collected, embryos available and embryos transferred. In all cases, however, there was no significant correlation between FSH levels and fertilization rate or miscarriage rate. Younger cycling women with elevated FSH had significantly higher LBR compared with older women with normal FSH (21.2% versus 12.1%). Furthermore, the cumulative LBR after three cycles in these younger patients with elevated FSH levels was 49.3%. CONCLUSION: Although there is a reduction in both PR and LBR associated with higher levels of basal FSH, it is clear that in cycling women, high basal FSH is not a contraindication to IVF treatment, and a respectable PR and LBR can be achieved especially in young women. The reduction in PR and LBR is due to reduced reserve rather than poor oocyte quality. Clinics refusing to treat cycling women with elevated basal FSH levels may be denying these women a reasonable, albeit low, chance of achieving a birth with their own genetic material. Clinicians should use basal FSH levels as a guide to advise patients about their chances of achieving a live birth, not to exclude patients with a predicted lower success rate from a treatment programme.     

The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome

The impact of insulin resistance on the outcome of IVF or intracytoplasmic sperm injection (ICSI) in women with polycystic ovarian syndrome (PCOS) was examined. Insulin sensitivity was measured by the continuous infusion of glucose with model assessment (CIGMA) test. Insulin-resistant (n = 26) and non-insulin-resistant women (n = 30) with PCOS underwent a total of 100 cycles of long-term down-regulation with buserelin acetate, stimulation with human recombinant FSH, and IVF or ICSI. Blood samples were taken throughout ovarian stimulation for hormone assays. Insulin-resistant and non-insulin-resistant women had similar concentrations of FSH, LH, testosterone and androstenedione throughout stimulation, but insulin-resistant women had hyperinsulinaemia and lower sex hormone binding globulin concentrations. Insulin-resistant women also had lower oestradiol concentrations during stimulation and required higher FSH doses, but these differences disappeared after controlling for the higher body weight in the group of insulin-resistant women. Groups had similar number of oocytes collected, similar implantation and pregnancy rates, and the incidence of ovarian hyperstimulation syndrome was also similar. Obesity, independent of hyperinsulinaemia, was related to a lower oocyte count and increased FSH requirement. It is concluded that in PCOS women receiving long-term down-regulation and stimulation with recombinant FSH, insulin resistance is neither related to hormone levels nor to IVF outcome. Obesity, independent of insulin resistance, is associated with relative gonadotrophin resistance.