Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome - a prospective randomized double-blind clinical trial.

BACKGROUND: Ovarian hyperstimulation syndrome remains a serious complication during in vitro fertilization cycles if high dose human chorionic gonadotropin (hCG) is used to trigger ovulation in high responder patients. Though much of this risk is mitigated with trigger using gonadotropin releasing-hormone (GnRH) agonist alone, it may result in lower birth rates. GnRH-agonist trigger and adjuvant low dose hCG has been proposed to improve birth rates, but timing of this hCG support to corpus luteum function has never been fully described. In this randomized, prospective trial, we explore differences in live birth rates and incidence of ovarian hyperstimulation syndrome (OHSS) in high-responder patients undergoing in vitro fertilization (IVF) receiving low dose hCG at the time of GnRH-agonist (dual trigger) or hCG adjuvant at the time of oocyte retrieval. Does the timing of hCG support make a difference? RESULTS: Thirty-four subjects high-responder patients were randomized to receive low-dose hCG at the time of GnRH-agonist trigger (Group 1) and 37 received low-dose hCG at the time of oocyte retrieval (Group 2). There were no differences in the baseline characteristics and outcome of ovarian stimulation between the two groups. There were no differences in the live birth rates between Group 1 and Group 2 by intention-to-treat (14/34, 41.2% versus 21/37, 56.8%, p = 0.19) or per-protocol (14/26, 53.8% versus 19/31, 61.3%, p = 0.57) analyses. There was a slightly higher incidence of OHSS in Group 2 compared to Group 1 although the difference was not statistically significant (3/31, 9.7% versus 1/26, 3.8%). All the cases of OHSS in Group 2 were moderate while the one case of OHSS in Group 1 was mild. CONCLUSIONS: For high responder patients receiving GnRH-agonist trigger, low dose hCG supplementation allowed high pregnancy rates after fresh embryo transfer, regardless of whether it was given at the time of trigger or at oocyte retrieval. Dual trigger may be preferable to reduce the risk of OHSS.

Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger.

STUDY QUESTION: Are there factors predicting the number of total and mature oocytes retrieved after controlled ovarian hyperstimulation (COH) utilizing a gonadotropin-releasing hormone (GnRH) antagonist protocol and a GnRH agonist (GnRHa) to induce oocyte maturation? SUMMARY ANSWER: Peak estradiol (E2) level, post-trigger LH and progesterone and the magnitude of LH rise are independent predictors of the total number of oocytes and mature oocytes retrieved. WHAT IS KNOWN ALREADY: Despite multiple follicular development in high responders, oocyte retrieval after a GnRHa trigger in a small subset of patients fails to obtain a substantial number of total oocytes or mature oocytes. STUDY DESIGN, SIZE AND DURATION: A retrospective chart review of all autologous and oocyte donation cycles utilizing a GnRHa antagonist protocol where GnRHa was used for the induction of oocyte maturation between 1 April 2003 and 31 December 2011. PARTICIPANTS/MATERIALS, SETTING AND METHODS: A total of 508 autologous and donor IVF/ICSI cycles utilizing a GnRH antagonist protocol for COH and GnRHa for the induction of oocyte maturation at a university-based tertiary fertility center. MAIN RESULTS AND THE ROLE OF CHANCE: Peak E2 on the day of trigger (r = 0.19, P < 0.001), post-trigger LH (r = 0.12, P = 0.009) and progesterone (r = 0.47, P < 001) and LH rise (r = 0.18, P < 0.001) all positively correlated with the number of total and mature oocytes retrieved. The true incidence of empty follicle syndrome was 1.4% (7/508). There was no post-trigger LH or progesterone cut-off value for the prediction of oocyte yield. However, all cases of empty follicle syndrome occurred in patients with post-trigger LH <15 IU/l and P ≤ 3.5 ng/ml. The findings of this study may also be due to chance since it was a retrospective study and not prospectively designed. LIMITATION, REASONS FOR CAUTION: This is a retrospective chart review and therefore subject to bias. Serum hormone measurements were performed between 8 and 12 h after GnRHa trigger rather than a standardized time period following trigger administration. Therefore, peak levels of LH may have been missed due to the short ascending limb of LH rise lasting approximately 4 h after GnRHa trigger. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study can be generalized to high responders utilizing a GnRH antagonist protocol for COH and a GnRHa for the induction of oocyte maturation. The use of alternative stimulation regimens or medications will limit the ability to generalize the results of this study to other populations. STUDY FUNDING/COMPETING INTEREST(S): This study was not funded, and there are no conflicts of interest. TRIAL REGISTRATION NUMBER: n/a.

Should Cochrane reviews be performed during the development of new concepts?

Cochrane reviews are internationally recognized as the highest standard in evidence-based health care. A Cochrane analysis conducts systematic reviews of primary research in human health care, and the analysis includes a comprehensive search of all potentially relevant studies and the use of explicit, reproducible criteria in the selection of studies for review. Thus, Cochrane reviews, undoubtedly provide many useful clinical guidelines. In this opinion paper, however, it is questioned at what level of clinical development of a new strategy a Cochrane review should be conducted in order not to draw premature conclusions that may not be sustained later on. Previous examples of this are debated together with the most recent Cochrane review regarding GnRH agonist triggering of final oocyte maturation, in which debatable conclusions are drawn from early studies, when the concept was still under development. We question the current policy of meta-analysis and recommend that in the future, the meta-analysts should await the results of a sufficient number of well-performed studies with an established new regime before an analysis is performed in order to avoid too early and possibly biased conclusions.

GnRH agonist to induce oocyte maturation during IVF in patients at high risk of OHSS.

The aim of this retrospective study was to evaluate the effectiveness of gonadotrophin-releasing hormone agonist (GnRHa) to trigger oocyte maturation in patients with polycystic ovarian syndrome (PCOS) or previous high response. The outcome of ovarian stimulation and IVF in patients using GnRHa to trigger oocyte maturation after co-treatment with GnRH antagonist (study group) was compared with patients using human chorionic gonadotrophin (HCG) to trigger oocyte maturation after a dual pituitary suppression protocol with oral contraceptive pill (OCP) and GnRHa overlap (control group). All patients received intramuscular progesterone for luteal support but patients in the study group received additional supplementation with oestradiol patches. The mean number of oocytes, proportion of mature oocytes and fertilization rate were similar between the study and control groups. Implantation rate (38.6% versus 45.1%), clinical pregnancy rate (69.6% versus 60.9%) and delivery rate (62.5% versus 56.5%) were similar in the study and control groups respectively. There was one case of moderate ovarian hyperstimulation syndrome (OHSS) in the control group and none in the study group. GnRHa is effective in triggering oocyte maturation in patients with PCOS or previous high response. Further randomized studies are required to evaluate its effectiveness in the prevention of OHSS in this group of patients.

Trends in the incidence of births and multiple births and the factors that determine the probability of multiple birth after IVF treatment.

BACKGROUND: We aimed to review trends in the probability of birth and multiple birth before and after the legal restriction limiting the maximum allowable number of embryos transferred, and to examine factors that determine the probability of multiple birth following IVF treatment. METHODS: We analysed data relating to 7170 IVF and 530 intracytoplasmic sperm injection cycles reaching embryo transfer undertaken by 4417 women at a single tertiary referral assisted conception centre in the UK between 1984 and 1997. Probability of birth, and of proportion of multiple births among those who gave birth, was explored using logistic regression analysis. RESULTS: Between 1984 and 1997 there was a significant increase in probability of birth but no change in the probability of multiple birth. The trend in probability of birth was almost wholly explained by the significant increase in number of embryos created per cycle. Pooling all the data, risk factors for increased chance of birth and multiple birth were: younger age (<35 years), diagnoses other than tubal infertility, fewer than three previous unsuccessful cycles, previous IVF live birth and a large number of embryos created. Given these factors, increasing the number of embryos transferred did not increase the chance of a birth, but did increase the chance of a multiple birth. CONCLUSIONS: The probability of birth has increased and the probability of multiple birth has remained unchanged, despite legislation limiting the number of embryos transferred in the UK. Efforts should be made to reduce the incidence of multiple births by transferring fewer embryos, especially in the presence of good prognostic factors for birth.

Progestogen therapy during pituitary desensitization with gonadotropin-releasing hormone agonist prevents functional ovarian cyst formation: a prospective, randomized study.

OBJECTIVES: We sought to assess whether the use of norethindrone and gonadotropin-releasing hormone agonist therapy in the early follicular phase reduces the occurrence of functional ovarian cysts and shortens the duration of pituitary desensitization. We also assessed whether the use of norethindrone impairs implantation rates after in vitro fertilization treatment. STUDY DESIGN: We performed a prospective, randomized, single-blind study involving 117 patients who were randomized to receive norethindrone 24 hours before gonadotropin-releasing hormone agonist therapy (n = 63, treatment group) or gonadotropin-releasing hormone agonist alone (n = 54, control group) for pituitary desensitization. RESULTS: The incidence of functional ovarian cyst formation after 1 week of gonadotropin-releasing hormone agonist therapy was significantly lower in the treatment group compared with the control group. Furthermore, the duration of pituitary suppression was significantly shorter in the treatment group than in the control group. There were no significant differences between the 2 groups in the follicular response and embryo quality. Adjusted for age, the implantation rate (22% vs 9%, P =.02) and clinical pregnancy rate (34% vs 18%, P =.04) were significantly higher in the treatment group than in the control group. CONCLUSION: A combination of norethindrone and gonadotropin-releasing hormone agonist therapy is therefore more effective in achieving prompt pituitary suppression and should be considered for routine use during in vitro fertilization cycles.

Cumulative probability of clinical pregnancy and live birth after a multiple cycle IVF package: a more realistic assessment of overall and age-specific success rates?

OBJECTIVE: To provide an assessment of pregnancy and live birth probabilities for women presenting for in vitro fertilisation treatment for the first time, when committed in advance to have up to three cycles of treatment in one year. DESIGN: Up to three cycles of in vitro fertilisation within one year, committed in advance. SETTING: A tertiary referral centre for assisted reproduction. PARTICIPANTS: Two hundred and thirty-two women, undergoing a total of 536 cycles of in vitro fertilisation or intracytoplasmic sperm injection between August 1993 and December 1995. METHODS: Analysis of cumulative clinical pregnancy and live birth rates for women having IVF treatment for the first time and undertaking a three-cycle package, using the life-table approach. MAIN OUTCOME MEASURES: Cumulative clinical pregnancy and live birth rates. RESULTS: The cumulative probabilities of clinical pregnancy and live birth after two cycles of treatment were 38.2% and 33.2%, respectively, compared with 54.2% and 48.2%, respectively, after three cycles of treatment. Cumulative clinical pregnancy and live birth rates after three cycles of treatment for women up to the age of 40 years were 57.8% and 51.3%, respectively. Cumulative clinical pregnancy and live birth rates declined with increasing age (P = 0.02 and P= 0.01, respectively). CONCLUSION: The three-cycle package encourages couples to have multiple treatment cycles, thereby improving their ultimate chances of a live birth. The cumulative clinical pregnancy and live birth rates after such a package provide a more realistic assessment of overall and age-specific success rates after multiple treatment cycles.

The outcome of in-vitro fertilization treatment in women with sonographic evidence of polycystic ovarian morphology.

This study compared the outcome of a course of up to three cycles of in-vitro fertilization (IVF) treatment in 46 women (97 cycles) who had polycystic ovaries (PCO) seen on ultrasound scan, but who had no clinical symptomatology associated with polycystic ovary syndrome, with that of 145 women (332 cycles) who had normal ovarian morphology on ultrasound examination. All 191 women had normal early follicular phase serum follicle stimulating hormone (FSH) concentrations, were less than 40 years of age and used the long protocol of pituitary suppression with gonadotrophin-releasing hormone agonist therapy. On average, the women with PCO produced more follicles, oocytes and embryos than the women with normal ovaries, but the fertilization, cleavage and miscarriage rates were similar. Adjusted for age, the odds of achieving a pregnancy within three cycles of treatment in a woman with PCO were 69% higher than those of a woman with normal ovaries [odds ratio (OR): 1.69, 95% confidence interval (CI) 0.99-2.90, P = 0.05)] and the odds of achieving a live birth were 82% higher (OR: 1.82, 95% CI 1.05-3.16, P = 0.03). There is, therefore, evidence that outcome of IVF treatment for women with PCO seen on ultrasound examination may be better than that for women with normal ovaries.

The pattern of changes in ovarian stromal and uterine artery blood flow velocities during in vitro fertilization treatment and its relationship with outcome of the cycle.

OBJECTIVES: To assess the effect of short-term (2-3 weeks) pituitary suppression and controlled ovarian stimulation on ovarian and uterine artery Doppler measurements during the in vitro fertilization (IVF) treatment cycle and to compare the pattern of these changes between conception and non-conception cycles as well as between patients with normal and those with polycystic ovaries. DESIGN: Prospective observational study of women undergoing IVF treatment. SUBJECTS: Women using the long-treatment buserelin protocol who did not have uterine fibroids, ovarian cysts or endometrioma. METHODS: Serial transvaginal color and pulsed Doppler measurements of ovarian stromal and uterine artery blood flow velocity were carried out in the early follicular phase of the menstrual cycle, on the day of pituitary suppression and on the day of administration of human chorionic gonadotropin (hCG). The main outcome measures were the ovarian stromal and uterine artery blood flow peak systolic velocity (PSV) and pulsatility index (PI). RESULTS: A total of 105 patients were recruited but six patients were excluded from the analysis because they had only one stage of the measurements performed. There was a significant decline in mean ovarian stromal artery PSV after 2-3 weeks of gonadotropin releasing hormone (GnRH) agonist therapy but no effect on ovarian stromal artery PI. The mean uterine artery PSV or PI did not change significantly after 2-3 weeks of GnRH agonist therapy. There was a significantly higher mean ovarian stromal artery PSV in conception cycles compared to non-conception cycles in the early follicular phase and on the day of pituitary suppression, but not on the day of hCG administration. There were no differences between conception and non-conception cycles in the mean uterine artery PSV or PI. Women with polycystic ovaries had a higher mean ovarian artery PSV on all the three occasions of measurement. CONCLUSION: These data suggest that assessment of ovarian blood flow before commencement of gonadotropin stimulation may play a role in assessing cycles likely to result in pregnancy.

Value of ovarian stromal blood flow velocity measurement after pituitary suppression in the prediction of ovarian responsiveness and outcome of in vitro fertilization treatment.

OBJECTIVE: To evaluate whether ovarian stromal blood flow velocity after pituitary suppression is predictive of ovarian response and the outcome of IVF treatment in patients with normal basal serum FSH levels and to compare the predictive value of this test with age, early follicular phase serum FSH level, E2 level, and FSH:LH ratio. DESIGN: Prospective observational study of women undergoing IVF treatment. SETTING: A tertiary referral center for assisted reproduction. PATIENT(S): Eighty-eight women who received the long buserelin acetate treatment protocol. INTERVENTION(S): Transvaginal color and pulsed Doppler measurement of the ovarian stromal peak systolic velocity (PSV) after pituitary suppression and measurement of the basal serum FSH level, E2 level, and FSH:LH ratio. MAIN OUTCOME MEASURE(S): Number of mature oocytes retrieved and pregnancy rate. RESULT(S): Ovarian stromal PSV was the most important single independent predictor of ovarian response in patients with a normal basal serum FSH level, when compared with age, basal FSH level, E2 level, or FSH:LH ratio. Patients in group 2 (PSV > or = 10 cm/s) had a significantly higher median number of mature oocytes retrieved (11 versus 5.5) and a higher clinical pregnancy rate (35.3% versus 11.3%) than patients in group 1 (PSV <10 cm/s), even after controlling for age. CONCLUSION(S): Ovarian stromal blood flow velocity, after pituitary suppression is confirmed, is predictive of ovarian responsiveness and the outcome of IVF treatment.

Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation syndrome.

OBJECTIVE: To explore the value of serum vascular endothelial growth factor (VEGF) concentrations during IVF cycles in predicting the risk of ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective study. SETTING: London Women's Clinic. PATIENT(S): One hundred seven women undergoing IVF. Mild OHSS developed in 10 women, moderate OHSS in 7, and severe OHSS in 3. INTERVENTION(S): Serum VEGF concentrations were measured before treatment, after pituitary desensitization, and on the days of hCG administration, oocyte collection, and ET. MAIN OUTCOME MEASURE(S): Serum VEGF concentrations. RESULT(S): Serum VEGF concentrations were higher in women in whom OHSS developed. The increase in the VEGF concentration that occurred between the day of hCG administration and the day of oocyte collection (the "VEGF rise") was an important marker of OHSS. The VEGF rise was higher in women in whom OHSS developed. A higher VEGF rise predicted all cases of OHSS and moderate/severe cases of OHSS with a sensitivity of 100% and a specificity of 60%. A likelihood ratio test showed that adding the VEGF rise or the VEGF concentration on the day of oocyte collection to a regression model as a continuous variable to the number of follicles, the E2 concentration, and the presence of polycystic ovaries significantly contributed to predicting the risk of OHSS. CONCLUSION(S): The results support the role of VEGF as an important nonsteroidal index of ovarian response. The VEGF rise may have an advantage over the E2 concentration, the number of follicles, and the number of oocytes, which individually predict only 15%-25% of cases of OHSS.

Serum vascular endothelial growth factor and Doppler blood flow velocities in in vitro fertilization: relevance to ovarian hyperstimulation syndrome and polycystic ovaries.

OBJECTIVE: To relate changes in serum and follicular fluid vascular endothelial growth factor (VEGF) concentrations to Doppler blood flow velocities within ovarian and uterine blood vessels during IVF cycles and to assess their relation to ovarian hyperstimulation syndrome (OHSS) and polycystic ovaries (PCO)/polycystic ovary syndrome (PCOS). DESIGN: Prospective descriptive study. SETTING: The London Women's Clinic. PATIENT(S): One hundred seven patients receiving a "long" stimulation protocol of IVF. INTERVENTION(S): Doppler blood flows were recorded in ovarian stromal and uterine arteries; serum VEGF was measured in the early follicular phase, after pituitary desensitization, on the day of hCG administration, on the day of oocyte retrieval, and on the day of ET. MAIN OUTCOME MEASURE(S): Serum and follicular fluid VEGF concentrations and Doppler blood flow measurements. RESULT(S): Serum VEGF concentrations rose after hCG administration. The rise was higher in women in whom OHSS developed. Women with PCO/PCOS had higher serum VEGF concentrations throughout the IVF cycle irrespective of whether OHSS developed. Follicular fluid VEGF concentrations were higher in women in whom OHSS developed and in women with PCO/PCOS. Doppler blood flow velocities in the ovarian blood vessels were higher in women in whom OHSS developed. Within ovarian and uterine blood vessels, blood flow velocities were higher in the early follicular phase and on the day of hCG administration in women with PCO/PCOS. A positive correlation was observed between the serum VEGF and E2 concentrations on the days of hCG administration and oocyte retrieval and between the serum VEGF concentration and Doppler blood flow velocities throughout the IVF cycle. CONCLUSION(S): Our results support the role of VEGF as a mediator of OHSS and establish a possible link between VEGF, OHSS, and PCO.

A prospective randomized study to assess the clinical efficacy of gonadotrophins administered subcutaneously and intramuscularly.

The purpose of this study was to compare the clinical efficacy of gonadotrophins administered s.c. or i.m., in a prospective randomized study of women undergoing in-vitro fertilization (IVF) treatment at a tertiary referral centre. In all, 71 patients undergoing a total of 162 IVF treatment cycles were randomized to receive either s.c. (n = 41) or i.m. (n = 30) administration of gonadotrophins. Up to three cycles of IVF were assessed for each patient. The main outcome measures were the number of oocytes retrieved, the total amount of gonadotrophins used, the number of follicles recruited and the cumulative pregnancy and live birth rates. The mean number of oocytes retrieved was 10.5 for each group. The number of days of stimulation was significantly shorter for the s.c. group (11.7 +/- 1.9 days, mean +/- SD) than the i.m. group (12.6 +/- 2.3 days). The cumulative conception and live birth rates after three cycles of treatment were similar between the two groups. Our results suggest that the clinical efficacy of s.c. and i.m. administration of gonadotrophins is comparable. Both routes are well tolerated by patients.

Serum vascular endothelial growth factor concentrations and ovarian stromal blood flow are increased in women with polycystic ovaries.

The aim of this study was to determine basal serum vascular endothelial growth factor (VEGF) concentrations and Doppler blood flow changes within the ovarian stroma of women with polycystic ovaries (PCO) and women with normal ovaries. Pulsed and colour Doppler blood flows within the ovarian stroma were recorded, and serum VEGF concentrations measured, in the early follicular phase (days 2-3 of a menstrual cycle) in 60 women undergoing ovarian stimulation for in-vitro fertilization. 36 women had normal ovaries, 14 women had PCO as seen on pelvic ultrasound examination and 10 had polycystic ovarian syndrome (PCOS). Mean+/-SD serum VEGF concentrations were significantly higher (P < 0.001) in women with PCO and PCOS (3.4+/-0.7 and 3.2+/-0.66 ng/ml respectively) compared with women with normal ovaries (2.3+/-0.5 ng/ml). Mean peak systolic blood flow velocity (PSV) and time-averaged maximum flow velocity (TAMXV) were significantly higher (P < 0.001) in women with PCO and PCOS compared with women with normal ovaries. The mean PSV were 15+/-4 and 16+/-4 cm/s in women with PCO and PCOS respectively, compared with 9+/-2 cm/s in women with normal ovaries. The TAMXV were 9+/-3 and 11+/-3 cm/s in women with PCO and PCOS respectively compared with women with normal ovaries (5.8+/-1.5 cm/s). Serum VEGF concentrations were positively correlated with PSV (r=0.44, P=0.001) and TAMXV (r=0.45, P < 0.000) in all three groups of women. Higher serum concentrations of VEGF in women with PCO and PCOS may relate to the increased vascularity that underlies the increased blood flow demonstrated by Doppler blood flow velocity measurements in these women. The results may explain the higher risk of ovarian hyperstimulation syndrome in programmes of ovarian stimulation in patients with PCO compared with those with normal ovaries.

Local side effects of subcutaneous and intramuscular urinary gonadotropins for ovarian stimulation in in vitro fertilization: a prospective, randomized study.

OBJECTIVE: To compare the incidence and severity of local side effects of urinary-derived gonadotropins administered s.c. and i.m.. DESIGN: Prospective randomized study of women undergoing IVF treatment. SETTING: Tertiary referral center for assisted reproduction. PATIENT(S): A total of 71 patients were randomized to receive gonadotropins by the s.c. (n = 41) or i.m. (n = 30) route. INTERVENTION(S): One cycle of IVF with gonadotropins administered either s.c. or i.m. for ovarian stimulation. MAIN OUTCOME MEASURE(S): Incidence and severity of local side effects, such as redness, itching, swelling, pain, and bruising. RESULT(S): Pain was the most common side effect, with 55.3% and 70.1% of i.m. and s.c. injections, respectively, resulting in pain. There were no statistically significant differences in the incidence of itching or bruising after i.m. and s.c. injections. Although there was a higher incidence of redness and swelling in the s.c. group compared with the i.m. group, most cases were classified as mild. CONCLUSION(S): There was a significantly higher incidence of some local side effects after s.c. gonadotropin administration but most of these were mild and well tolerated by patients.

Implications of using follicle-stimulating hormone preparations depleted of luteinizing hormone to achieve follicular growth in in vitro fertilization.

We aimed to compare the outcome of in vitro fertilization (IVF) treatment using follicle-stimulating hormone (FSH) containing gonadotropins with human menopausal gonadotropin (hMG) containing gonadotropins for ovarian stimulation. A retrospective analysis of 82 patients undergoing IVF in a private fertility clinic was performed over a specific period of time. Eighteen women received hMG, 20 received Normegon and 44 received FSH. In addition, 17 of these patients received hMG in one cycle and FSH in the other. The main outcome measures studied were duration of treatment, dose of gonadotropins required to achieve optimum follicular growth, number and size of follicles, endometrial thickness, serum estradiol concentrations, number of oocytes retrieved, pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS). At the time of administration of human chorionic gonadotropin (hCG), the mean (+/- SD) serum estradiol concentrations in patients treated with preparations containing FSH and luteinizing hormone (LH) in a ratio of 1:1 was 10,044.3 +/- 5378.8 pmol/l compared with 6819.5 +/- 2597.9 pmol/l in patients treated with preparations with FSH and LH in a ratio of 3:1 and 7369 +/- 4300 pmol/l in patients treated with FSH. The differences between the first and the second two groups were significant (p < 0.05). Endometrial thickness in the three groups of patients were 11 +/- 1.7 mm, 11 +/- 1.5 mm and 9.7 +/- 1.5 mm, respectively (p < 0.001). Comparing cycles of treatment with hMG and FSH in the same patient, we found significantly higher estradiol levels, thicker endometrium, more developing follicles and a shorter duration of treatment in the hMG-treated cycles compared with those in FSH-treated cycles. However, there were no differences between the incidence of OHSS or the pregnancy rates between the three treatment groups. With the advent of recombinant human FSH and the shortage of LH-containing preparations, it is important to note that serum estradiol concentrations on the day of administration of hCG underrepresent the degree of follicular maturation. In the context of the use of a 'long' protocol of gonadotropin-releasing hormone (GnRH) analog therapy and LH-depleted gonadotropin preparations, serum estradiol is no longer a reliable marker of follicle development.