Peak Oestradiol Concentrations Research Articles

P-376 Letrozole to minimise exposure to elevated serum estradiol during superovulation for breast cancer patients prior to chemotherapy. Real world experience from a statewide oncofertility service

Abstract Study question How effective is co-treatment with letrozole in supressing peak E2 in a real world setting? Summary answer We observed greater than anticipated supra-physiological serum estadiol concentrations in our cohort. What is known already Breast cancer occurs frequently in women of reproductive age, many of whom request oocyte or embryo cryopreservation before chemo/radiotherapy. Oncofertility treatment requires superovulation with resultant elevation of serum estradiol above concentrations seen physiologically. In order to avoid possible stimulation of estrogen receptor positive breast cancers, co-administration of letrozole is frequently recommended. A 67% lower mean serum estradiol in a letrozole treated group compared with an untreated superovulated comparison group has been reported in the literature, suggesting a protective mechanism. Peak E2 concentration across 4 cohorts of patients co-treated with letrozole has been reported to be 103 – 2350 (mean 564). Study design, size, duration We performed a retrospective cohort study of women referred for fertility preservation following diagnosis of breast cancer to the Fertility Research Centre at The Royal Hospital for Women, Sydney between Jan 2020 and Jan 2024. Women were identified from hospital outpatient paper and electronic medical records. 145 new referrals were received by our centre, with 88 patients undergoing 107 cycles. Participants/materials, setting, methods 145 women aged between 19 and 44 with newly diagnosed breast cancer were referred to our Statewide, multidisciplinary, public oncofertility service for consideration of treatment and review at our fertility multidisciplinary team meeting. Our oncofertility database and outpatient clinical records were used to identify new referrals to the service. Electronic and paper medical records including the ART database were used to obtain cycle information, blood results and demographic information Main results and the role of chance Peak estradiol concentrations (pMol/L) 35% of cycles resulted in peak E2 > 2000. 11% of cycles resulted in peak E2 > 4000 and 2% of cycles resulted in peak E2 > 7000. We calculated a mean E2 of 1837. The mean anti-mullerian hormone was 20.3 pMol/L and mean antral follicle count 19.7. The mean BMI was 24.7. The average stimulation length was 13 days (7-16 days) with an average cumulative gonadotrophin dose of 2769 IU. Average number of MII oocytes per cycle was 7.2. 16 % of patients elected to preserve embryos. The fertilisation rate was 50%, with 61% of fertilised eggs resulting in frozen blastocytes. There have been 2 pregnancies and one live birth to date. 32% of cycles had a germline genetic result prior to OPU, with 20% having a positive BRCA gene mutation. Breast cancer hormone status 56% were Estrogen Receptor positive. 38 % were Progesterone Receptor positive, 18% were HER2 positive, 24% were hormone receptor negative Complications 5% of cycles were cancelled prior to OPU, 8% of cycles resulted in no oocyte or embryo available for freezing. 3% of cycles were reviewed for OHSS symptoms with 2 confirmed cases of OHSS secondary to administration of Zoladex <24hrs following OPU. Limitations, reasons for caution This is a retrospective cohort study in a single academic centre. Our current study duration is too short to permit determination of recurrence rates of breast cancer in the letrozole treated cohort. Wider implications of the findings The impact of short, transient elevation of circulating estradiol during superovulation is uncertain, however it is prudent to try to minimise exposure of ER positive breast cancers to estrogen. Alternative strategies for limiting this phenomenon should be explored, more evidence is needed on oncological and fertility outcomes in this population. Trial registration number N/A

Evaluation of the Impact of Letrozole in Combination with the GnRH Antagonist Ovarian Stimulation Protocol in Patients Expected to Have a Poor Ovarian Response (POSEIDON Groups 3 and 4).

Background and Objectives: The objective of this study was to evaluate the impact of adjuvant letrozole administration during ovarian stimulation using the gonadotropin-releasing hormone (GnRH) antagonist protocol on treatment outcomes in women categorized into POSEIDON groups 3 and 4. Materials and Methods: This retrospective cohort study analyzed data from patients classified into POSEIDON groups 3 and 4 who underwent fresh embryo transfer subsequent to intracytoplasmic sperm injection following a GnRH antagonist stimulation protocol between January 2017 and December 2021. Patients were divided into two groups: the GnRH-LZ group, who received letrozole at a dosage of 5 mg/day for five consecutive days, and the GnRH-ant group, who did not receive adjuvant letrozole. The primary outcome measure of the study was a comparative analysis of live birth rates between the two groups. Results: A total of 449 patients were deemed suitable for final analysis and were allocated into two groups: 281 patients in the GnRH-ant group and 168 patients in the GnRH-LZ group. Live birth rates were found to be comparable in both groups (11% vs. 9%, p = 0.497). Letrozole administration significantly reduced the total amount of gonadotropins required (2606.2 ± 1284.5 vs. 3097.8 ± 1073.3, p < 0.001), the duration of ovarian stimulation (11.2 ± 3.9 vs. 10.2 ± 3, p = 0.005), and the serum peak estradiol concentration (901.4 ± 599.6 vs. 463.8 ± 312.3, p < 0.001). Conclusions: Adjuvant letrozole administration did not demonstrate a significant impact on live birth rates among women categorized into POSEIDON groups 3 and 4. However, this approach may offer potential cost reductions by diminishing the necessity for exogenous gonadotropins and shortening the duration of ovarian stimulation.

SUBTLE ENDOMETRIAL ABNORMALITIES DO NOT AFFECT THE PREGNANCY RATE IN FRESH ICSI CYCLES

The study aimed to determine whether the presence of subtle endometrial abnormalities discovered by office hysteroscopy (OH) affects the pregnancy rate in fresh intracytoplasmic sperm injection (ICSI) cycles. A prospective cohort study included women undergoing their first ICSI cycles was performed in assisted reproductive technology unit. Patients were divided into two groups: patients with subtle endometrial abnormalities diagnosed by OH (group 1, n=78), and patients with normal uterine cavity (group 2, n=122). OH was conducted post-menstrual and subtle abnormalities detected included hypervascularization, petechiae, mucosal elevation, micropolyps, pale endometrium and single adhesion band. The main outcome measures were clinical pregnancy and implantation rates The most common subtle abnormality observed was pale endometrium in 35.9% of cases. Both groups were comparable regarding the baseline clinical data and endometrial thickness. Additionally, total amount of gonadotrophins used, duration of stimulation, peak estradiol concentrations, peak endometrial thickness, number of mature follicles and number of embryos transferred were not significantly different between both groups. The implantation rate was similar in both groups (2.35 ± 0.83 vs. 2.22 ± 0.84, p=0.465). Also, the pregnancy rate was similar in both groups (38.5% vs. 33.6%, p=0.067) Subtle endometrial abnormalities diagnosed by OH do not negatively affect pregnancy and implantation outcomes in fresh ICSI cycles.

Intravaginal administration of estradiol benzoate capsule for estrus synchronization in goats.

Estrus synchronization requires multiple treatments of hormonal drugs, requiring considerable time and cost. The aim of the present study was to develop an estrus synchronization protocol using intravaginal administration of estradiol benzoate (EB) capsules in goats. Two types of capsules were prepared: an EB capsule that melted immediately after administration and a sustained-release (SR) EB capsule that dissolved slowly and reached a peak after 24 h. Goats with functional corpus lutea were intramuscularly treated with prostaglandin F2α (PG). At 24 h after PG administration, goats were administered 1 mg of EB solution intramuscularly (PG + 24IM; n = 6) or 1 mg of EB capsule intravaginally (PG + 24EB; n = 6). The SR EB capsule was administered intravaginally at the time of PG administration (PG + SR; n = 6). The control group (n = 6) received only PG. All groups showed estrus within 72 h after PG administration. The onset of estrus did not differ significantly between the PG + 24IM and PG + SR groups but was earlier than in the control group. Estradiol concentration in the PG + SR group peaked at 11.5 ± 6.1 h after EB and PG administration. Peak estradiol concentrations were not significantly different between the PG + 24IM and PG + SR groups (78.0 ± 25.8 and 64.0 ± 38.1 pg/ml, respectively), and were higher than the PG + 24EB and control groups (27.3 ± 8.8 and 14.6 ± 6.1 pg/ml, respectively). These results suggest that intravaginal administration of an EB capsule with a sustained-drug release base is applicable for estrus synchronization, as an alternative to intramuscular administration.

Supraphysiological serum oestradiol negatively affects birthweight in cryopreserved embryo transfers: a retrospective cohort study.

Previous studies have demonstrated a negative relationship between peak oestradiol and low birthweight in IVF. However, it is hard to distinguish which aspect influenced by supraphysiological oestradiol concentrations fundamentally contributes to the low birthweight seen during IVF. This study therefore aimed to investigate whether birthweight was associated with an effect of oestradiol on oocytes. Oocytes are the only component exposed to the high-oestradiol environment in vitrified-warmed embryo transfer (VET) cycles. A retrospective cohort study of 431 infertile women was therefore carried out to evaluate the relationship between peak oestradiol concentration during controlled ovarian stimulation (COS) and birthweight in full-term singletons born after VET. The effect size was calculated using multivariable regression analysis. In this cohort, the mean peak oestradiol concentration was 4186.6±1215.0pg/ml, the mean number of oocytes retrieved was 11.5±5.4, the mean length of ovarian stimulation was 11.3±2.1 days and the mean birthweight was 3441.8±466.1g. The results indicated that peak oestradiol concentration was negatively correlated with birthweight in full-term singletons born after VET (adjusted β -5.0, 95% confidence interval [CI] -9.2 to -0.7). The effect size indicated that for every 100pg/ml increase in peak oestradiol concentration, birthweight decreased by 5.0g. The P for trend value was 0.038. Peak serum oestradiol during COS is negatively associated with birthweight. This model proposes a novel concept as well as new evidence that the effect on birthweight is due to the primary influence of a high oestradiol concentration on oocytes during COS.

Antral Follicle Diameter Variance Within Each Ovary May Be A Predictor For Poor Response In Cases With Normal Ovarian Reserve.

To determine the predictive value of antral follicle diameter variance within each ovary for ovarian response in cases with normal ovarian reserve tests. This is a prospective observational study. One hundred and thirty nine infertile women who underwent ART in IVF-ICSI unit of Zeynep Kamil women and children's Health Training and research hospital between January 2017 to June 2017 were recruited. Blood samples were collected on day 2/day 3 for assessment of serum FSH and estradiol. Trans-vaginal sonography was done for antral follicle count. During antral follicle count, in order to determine antral follicle diameter variance, diameters of the largest and smallest follicles were recorded. Variance was calculated by subtracting the smallest diameter from the largest one. Following ovarian stimulation with antagonist protocol, poor response was determined in cases with total oocyte number≤3. Ovarian reserve tests and antral follicle diameter variance were utilized to predict cases with poor response in women with normal ovarian reserve. Antral follicle diameter variance both in right (AUC=0.737, P<0.001) and left (AUC=0.651, P<0.05) ovaries significantly predicted poor ovarian response. Variance>3.5 mm was found to have 75% sensitivity to predict poor response. Basal serum FSH with estradiol levels and AFC failed to predict poor response (P>0.05). Other significant predictors for poor response were day 5 estradiol level and estradiol level at trigger day (P<0.05). In multivariate regression analysis, both AFC and antral follicle diameter variance in the right ovary were found to be significantly associated with clinical pregnancy, on the other hand peak estradiol concentration and antral follicle diameter variance in the right ovary were significantly associated with poor response. Antral follicle diameter variance may be utilized to predict poor ovarian response in cases with normal ovarian reserve.

The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: a systematic review.

Can controlled ovarian hyperstimulation (COH) for fertility preservation be effectively conducted in women with breast cancer without worsening their prognosis? COH with co-administration of letrozole suppresses oestradiol levels without significantly impacting oocyte yield or decreasing disease-free survival rates. Oestradiol has the capacity to stimulate the proliferation of breast cancer cells. COH can cause oestradiol levels to rise by an order of magnitude above physiological levels. Concern exists regarding the effect of supra-physiological oestradiol levels in women with a recent diagnosis of breast cancer. A systematic review of the literature was performed using MEDLINE (PubMed database), EMBASE and the Cochrane Library. The search was restricted to articles written in English. No restrictions regarding the date of publication were applied. Safety was assessed in terms of relapse rates and cancer-related mortality rates. Peak oestradiol concentrations were recorded for different stimulation protocols. Efficacy was measured in terms of the total number of oocytes collected and proportion of mature oocytes. The primary outcome was mortality/recurrence in premenopausal women with Stage I-IIIB breast cancer who underwent COH in the immediate post-operative period, prior to chemotherapy. This is a systematic review of randomized control trials (RCTs), case control and cohort studies reporting on the primary outcome of mortality/recurrence after COH in women with early breast cancer, or secondary outcomes of oocyte yield and peak oestrogen concentration. Owing to the small number of RCTs available, other study types were included. The last electronic search was run in April 2016. Two prospective non-randomized studies reported relapse and breast cancer-related mortality rates in 397 women with breast cancer, of whom 149 underwent COH. Twelve studies reported the peak oestradiol concentrations of 882 women undergoing COH with letrozole co-administration. Four studies compared the oocyte yield of 248 women who underwent COH plus letrozole with 254 women who underwent standard COH. Two studies compared peak oestradiol concentrations and oocyte yield in 61 women who underwent COH with tamoxifen co-administration and 49 women who underwent COH without tamoxifen. One study compared letrozole and tamoxifen co-administration, and another study compared the co-administration of letrozole and anastrozole. The search identified 1002 records of which 15 were included in the final analysis. There was no evidence of a decline in relapse-free survival rates in the two studies of women with breast cancer who received COH with letrozole co-administration compared with women who did not undergo fertility preservation procedures. The largest of these studies reported recurrences in 6/120 (5.0%) women who received COH plus letrozole compared with 12/217 (5.5%) women who did not undergo COH (mean follow-up 5.0 versus 6.9 years; hazard ratio for recurrence 0.77, 95%CI 0.28-2.13). Conclusions regarding women with breast cancer who received tamoxifen during COH could not be made due to insufficient data. Peak oestradiol concentrations (338-829 pg/ml) were suppressed by letrozole when commenced on Days 2-3, with no decrease in oocyte yield. Tamoxifen does not suppress oestradiol concentrations, but may convey protection via its inhibitory action on the oestrogen receptor. Any statements regarding the safety of COH in women with breast cancer are based on a limited number of observational studies. High quality evidence is unlikely to become available for ethical and practical reasons. Whilst available data do not indicate a decline in disease-free survival, a small effect cannot be excluded. Breast cancers are heterogeneous in their genetic profile and receptor status, making the results of studies difficult to generalize to individual cases. The implication of alterations in other hormone levels such as androgens, progestins or vascular endothelial growth factor secondary to COH in women with breast cancer has not been quantified. The co-administration of 5 mg of letrozole daily commencing on Day 2 and continuing throughout COH is recommended as it reduces peak oestradiol concentrations without significantly decreasing oocyte yield. The use of a GnRH agonist trigger is beneficial as oestradiol concentrations rapidly decrease post-administration and rates of ovarian hyperstimulation are lower than with an hCG trigger, without a corresponding reduction in clinical pregnancy or live birth rates in cryopreservation cycles. The protective effect of tamoxifen has not been evaluated although theoretically may be of benefit due to its action on the oestrogen receptor. None. None.

Influence of Menstrual Cycle and Oral Contraceptive Phase on Spinal Excitability

BackgroundRates of musculoskeletal injury differ substantially between the genders, with females more likely to experience conditions such as anterior cruciate ligament (ACL) injuries than males in the same sports. Emerging evidence suggests a significant hormonal contribution. Most research has focused solely on how hormonal fluctuations affect connective tissue, but a direct link between hormonal shifts, ligamentous laxity, and ACL injury has not been borne out. There is also evidence to suggest that sex hormones can modulate the central nervous system, but how this affects neuromuscular control is not well understood. ObjectiveTo determine whether changes in sex hormone concentrations would alter spinal excitability, measured across the menstrual and oral contraceptive pill cycle. We hypothesized that spinal excitability would fluctuate across the menstrual cycle (with increased excitability during the periovulatory phase due to peak estradiol concentration), but that there would be no fluctuation in oral contraceptive users. DesignThis was a prospective cohort study. SettingThe study took place at a biomechanics laboratory at a rehabilitation hospital. ParticipantsA total of 30 healthy women aged 18–35 who were similar in age, body composition, and exercise-training status were included. Fifteen of the women were eumenorrheic and nonusers of oral contraceptives (nonusers), and 15 of the women were taking oral contraceptives (users). Main Outcome MeasuresH-reflex (Hmax/Mmax ratio), serum estradiol, and progesterone concentrations were measured at 3 time points during the menstrual and contraceptive pill cycle. ResultsThe H-reflex (Hmax/Mmax ratio) remained stable across the menstrual and contraceptive pill cycle. Spinal excitability was lower in the users compared with the nonusers across all testing sessions, but this was not statistically significant. ConclusionsOur results suggest that acute fluctuations of endogenous estradiol and progesterone do not modulate spinal excitability. However, long-term exposure to exogenous estrogen and progesterone (oral contraceptives) might have an impact on spinal excitability and neuromuscular control. Further research is necessary to better understand the potential differential effect of endogenous and exogenous sex hormones on spinal excitability.

The Muscle Stretch Reflex throughout the Menstrual Cycle

The significant sex disparity in sports-related knee injuries may be due to underlying differences in motor control. Although the development of sex-specific movement patterns is likely multifactorial, this study specifically focuses on the potential modulatory role of sex hormones. This study aimed to investigate the muscle stretch reflex (MSR) across the menstrual cycle. We hypothesized that the MSR would fluctuate throughout the menstrual cycle and that the lowest response would correspond with peak concentrations of estrogen. Nineteen healthy women age 18-35 yr participated in this study: 8 eumenorrheic women and 11 women taking oral contraceptives. Serum estradiol and progesterone concentrations, anterior knee laxity (AKL), and the MSR response of the quadriceps muscles were measured three times during the menstrual cycle. The MSR response of the rectus femoris (RF) varied significantly across the menstrual cycle in both groups. Specifically, the RF MSR response was 2.4 times lower during the periovulatory phase when compared with the luteal phase (P = 0.007). The same trend was seen in the vastus medialis, but this did not reach statistical significance (P = 0.070). The MSR response of the vastus lateralis did not change significantly across the menstrual cycle (P = 0.494). A mixed model comparison did not show an association between endogenous concentrations of estradiol and progesterone, exposure to hormonal contraceptives or AKL, and the MSR response for any muscle. Our results demonstrate that the RF MSR response varies throughout the menstrual cycle with the lowest response around the time of ovulation. Additional research is needed to clarify the exact relationship between sex hormones, AKL, and MSR response and to determine the specific origin of the change along the monosynaptic reflex arc.

Relationship of follicle size and concentrations of estradiol among cows exhibiting or not exhibiting estrus during a fixed-time AI protocol

Cows exhibiting estrus near fixed-time artificial insemination (AI) had greater pregnancy success than cows not showing estrus. The objective of this study was to determine the relationship between follicle size and peak estradiol concentration between cows that did or did not exhibit estrus during a fixed-time AI protocol. Ovulation was synchronized in beef cows by applying the CO-Synch protocol [GnRH (100 μg) on day-9, prostaglandin F2α (PGF2α; 25 mg) on day-2, and a second injection of GnRH 48 h after PGF2α (day 0)] to both suckled (experiment 1) and nonsuckled (experiment 2) cows. Follicle size (day 0) and ovulation (day 2) was determined by ultrasonography. Blood samples were collected every 3 or 4 h beginning at the time of PGF2α injection (0 h). Estrus was detected by visual observation with the aid of estrus-detection patches, and cows that ovulated were classified as exhibited estrus (n = 46) or did not exhibit estrus (n = 63). In both suckled and nonsuckled cows, there was a positive relationship between all cows (P < 0.05) and among those that exhibited estrus (P < 0.05) between follicle size and peak estradiol concentration, but no linear relationship (P > 0.50) between follicle size and peak estradiol concentration was observed among cows not exhibiting estrus. Cows that exhibited estrus had greater (P < 0.01) peak estradiol concentrations than cows that did not exhibit estrus. Suckled cows exhibiting standing estrus had greater (P < 0.001) preovulatory concentrations of estradiol beginning 6 h (replicate 1) or 4 h (replicate 2) after the injection of PGF2α on day-2 compared with cows not exhibiting standing estrus. Nonsuckled cows exhibiting standing estrus had greater (P < 0.001) preovulatory concentrations of estradiol beginning at the injection of PGF2α on day-2 compared with cows not exhibiting standing estrus. Furthermore, cows that exhibited estrus had an increased (P < 0.01) rate in the rise in concentrations of estradiol following the PGF2α to peak estradiol than cows not exhibiting estrus. In summary, follicle diameter had a positive relationship with peak concentrations of estradiol, but only among cows that exhibited standing estrus, and estradiol increased earlier in cows that exhibited estrus compared with cows that did not.

Fertility preservation in patients with haematological disorders: a retrospective cohort study

This study investigated the factors associated with utilization of fertility preservation and the differences in treatments and outcomes by prior chemotherapy exposure in patients with haematological diseases. This study included all 67 women with haematological diseases seen for fertility preservation consultation at two university hospitals between 2006 and 2011. Of the total, 49% had lymphoma, 33% had leukaemia, 7% had myelodysplastic syndrome and 4% had aplastic anaemia; 46% had prior chemotherapy; and 33% were planning for bone marrow transplantation, 33% pursued ovarian stimulation and 7% used ovarian tissue banking; and 48% of patients did not pursue fertility preservation treatment. All five cycle cancellations were in the post-chemotherapy group: three patients with leukaemia and two with lymphoma. Patients with prior chemotherapy had lower baseline antral follicle count (10 versus 22) and received more gonadotrophins to achieve similar peak oestradiol concentrations, with no difference in oocyte yield (10.5 versus 10) after adjustment for age. Embryo yield was similar between those who had prior chemotherapy and those who had not. Half of the patients with haematological diseases who present for fertility preservation have been exposed to chemotherapy. While ovarian reserve is likely impaired in this group, oocyte yield may be acceptable.Women with haematological diseases, particularly haematological cancers, may need therapies that can impact fertility. In this study, women with haematological diseases who presented for fertility preservation consultation were evaluated to assess what factors were associated with the fertility preservation treatments chosen and the outcomes of ovarian stimulation for egg or embryo banking. Of the total patients, 46% had already had prior chemotherapy at the time of consultation, and one-third elected to pursue ovarian stimulation. Women who had prior chemotherapy had lower antral follicle counts and received more gonadotrophins to achieve similar peak oestradiol concentrations suggesting that ovarian reserve is likely impaired after chemotherapy in these women, consistent with the findings of other studies. However, there was no difference in oocyte or embryo yield in women undergoing ovarian stimulation before chemotherapy compared with those undergoing stimulation after chemotherapy, after adjusting for age. Thus while ovarian reserve may be impaired, response to ovarian stimulation and IVF may be acceptable for these women.

Emergency IVF for embryo freezing to preserve female fertility: a French multicentre cohort study

What are the outcomes of French emergency IVF procedures involving embryo freezing for fertility preservation before gonadotoxic treatment? Pregnancy rates after emergency IVF, cryopreservation of embryos, storage, thawing and embryo transfer (embryo transfer), in the specific context of the preservation of female fertility, seem to be similar to those reported for infertile couples undergoing ART. A French retrospective multicentre cohort study initiated by the GRECOT network-the French Study Group for Ovarian and Testicular Cryopreservation. We sent an e-mail survey to the 97 French centres performing the assisted reproduction technique in 2011, asking whether the centre performed emergency IVF and requesting information about the patients' characteristics, indications, IVF cycles and laboratory and follow-up data. The response rate was 53.6% (52/97). Fourteen French centres reported that they performed emergency IVF (56 cycles in total) before gonadotoxic treatment, between 1999 and July 2011, in 52 patients. The patients had a mean age of 28.9 ± 4.3 years, and a median length of relationship of 3 years (1 month-15 years). Emergency IVF was indicated for haematological cancer (42%), brain tumour (23%), sarcoma (3.8%), mesothelioma (n = 1) and bowel cancer (n = 1). Gynaecological problems accounted for 17% of indications. In 7.7% of cases, emergency IVF was performed for autoimmune diseases. Among the 52 patients concerned, 28% (n = 14) had undergone previous courses of chemotherapy before beginning controlled ovarian stimulation (COS). The initiation of gonadotoxic treatment had to be delayed in 34% of the patients (n = 19). In total, 56 cycles were initiated. The mean duration of stimulation was 11.2 ± 2.5 days, with a mean peak estradiol concentration on the day on which ovulation was triggered of 1640 ± 1028 pg/ml. Three cycles were cancelled due to ovarian hyperstimulation syndrome (n = 1), poor response (n = 1) and treatment error (n = 1). A mean of 8.2 ± 4.8 oocytes were retrieved, with 6.1 ± 4.2 mature oocytes and 4.4 ± 3.3 pronuclear-stage embryos per cycle. The mean number of embryos frozen per cycle was 4.2 ± 3.1. During follow-up, three patients died from the consequences of their disease. For the 49 surviving patients, 22.5% of the couples concerned (n = 11) requested embryo replacement. A total of 33 embryos were thawed with a post-thawing survival rate of 76%. Embryo replacement was finally performed for 10 couples with a total of 25 embryos transferred, leading to one biochemical pregnancy, one miscarriage and three live births. Clinical pregnancy rate and live birth per couple who wanted a pregnancy after cancer were, respectively, 36% (95% CI = 10.9-69.2%) and 27% (95% CI = 6.0-61%). The overall response rate for clinics was 53.6%. Therefore, it is not only that patients may not have been included, but also that those that were included were biased towards the University sector with a response rate of 83% (25/30) for a small number of patients. According to literature, malignant disease is a risk factor for a poor response to COS. However, patients having emergency IVF before gonadotoxic treatment have a reasonable chance of pregnancy after embryo replacement. Embryo freezing is a valuable approach that should be included among the strategies used to preserve fertility. No external funding was sought for this study. None of the authors has any conflict of interest to declare.

Energy Expenditure and Plasma F2-Isoprostanes across the Menstrual Cycle

Habitual energy expenditure seems to favorably alter oxidant/antioxidant balance. Sparse evidence suggests that hormones that fluctuate during the menstrual cycle, particularly estrogens, may influence concentrations of oxidative biomarkers and their relation to energy expenditure. We investigated the relation between energy expenditure and plasma free F2-isoprostane concentrations in 259 healthy, regularly menstruating 18- to 44-yr-old participants of the BioCycle Study. Habitual energy expenditure was measured using a baseline International Physical Activity Questionnaire and categorized as low, moderate, or high. Women were followed for one or two subsequent menstrual cycles. Past-week and past-day physical activity were measured during follow-up using questionnaires and diaries, respectively. F2-isoprostane concentrations were measured in blood samples collected at both menses (approximate cycle day 2; low serum estradiol concentration) and the late follicular phase (approximate cycle day 12; peak estradiol concentration). Generalized estimating equations were used to model the energy expenditure/isoprostane association, adjusting for confounders. Habitual energy expenditure was positively associated with F2-isoprostane concentration (adjusted difference in median F2-isoprostane, high versus low energy expenditure: 17.4%; 95% confidence interval (CI)=3.3%-31.4%). This association was not modified by cycle phase (interaction, P=0.61) or differences in peak estradiol concentration across women (interaction, P=0.20). Past-week and past-day physical activity measures were not associated with F2-isoprostane concentration (category trend, P=0.50 and P=0.18, respectively). These results suggest that higher habitual energy expenditure may be associated with higher concentration of F2-isoprostanes in healthy, reproductive-aged women. Estradiol concentration changes during the menstrual cycle do not seem to influence this relationship.

Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism

The aim of this observational preliminary trial was to estimate the association between the most common polymorphism of LH (LH-β variant: v-βLH), with different profiles of ovarian response to recombinant human FSH (rhFSH). A total of 60 normogonadotrophic patients undergoing a gonadotrophin-releasing hormone analogue long down-regulation protocol followed by stimulation with recombinant human FSH (rhFSH) for IVF/intracytoplasmic sperm injection, and in whom at least five oocytes were retrieved were retrospectively included. On the basis of the total rhFSH consumption, patients were divided into three groups: Group A: 22 women requiring a cumulative dose of rhFSH >3500 IU; Group B: 15 patients requiring 2000-3500 IU; Group C (control): 23 women requiring <2000 IU. The presence of v-βLH was evaluated using specific immunoassays. Peak oestradiol concentrations were significantly lower in Group A when compared with both groups B ( P < 0.05) and C ( P < 0.001). Group A had a significantly lower ( P < 0.05) number of oocytes retrieved (7.3 ± 1.5, 11.7 ± 2.4 and 14.7 ± 4.1 in the three groups, respectively). Seven carriers (31.8%) of v-βLH were found in Group A, whereas only one variant (6.7%) was observed in Group B; no variant was detected in Group C. These preliminary results suggest that v-βLH is more frequent in women with ovarian resistance to rhFSH.

Anti-Müllerian hormone testing is useful for individualization of stimulation protocols in oocyte donors

While the age of a donor is a fundamental factor to the success of donor IVF, no serum markers have been demonstrated to be useful in predicting variability of ovarian response in individual donors. Anti-Müllerian hormone (AMH) has been described as an accurate marker of ovarian response in patients undergoing IVF, but has not been applied to oocyte donors. AMH concentrations from 104 anonymous oocyte donors between the ages of 21-32 years were studied and IVF outcome parameters compared. AMH was correlated with several parameters including the number of oocytes retrieved ( r = 0.232, P = 0.024), the peak oestradiol concentrations ( r = 0.235, P = 0.024) and the need to decrease gonadotrophin dose in order to avoid ovarian hyperstimulation syndrome ( r = 0.274, P = 0.007). Receiver operating curve analysis was able to identify an AMH threshold that rendered about 70% sensitivity and 70% specificity for predicting the need to decrease gonadotrophin dosing. The clinical pregnancy rate was 77% per recipient and was not related to the donors' AMH concentrations. For oocyte donors, measurement of AMH appears most useful for determining gonadotrophin sensitivity in order to mitigate symptoms consistent with ovarian hyperstimulation.

The effect of body condition at calving and supplementation with Saccharomyces cerevisiae on energy status and some reproductive parameters in early lactation dairy cows

Improving the energy status of dairy cows during the early post-partum (PP) period by adding a safe dietary supplement such as live yeast culture (YS) may have a positive effect on reproductive function. The objective was to examine potential benefits of YS supplementation on PP energy status and fertility indices of dairy cows managed to have low or high body condition score (BCS, 1–5 scale) at calving. Forty (10 primiparous and 30 multiparous) Holstein/Friesian dairy cows were blocked by yield, parity, BCS, and predicted calving date. Within each block, cows were randomly allocated to a 2 × 2 factorial arrangement of treatments which were: BCS at calving (low ≤3.5 or high ≥3.75; n = 20) and YS supplementation (2.5 g/cow/day for pre-calving and 10 g/cow/day for post-calving × 10 8 CFU of Saccharomyces cerevisiae/g) (supplemented or control; n = 20). Daily milk yield was recorded and weekly milk composition, BCS and BW were assessed from calving to week 10 PP. Forage (100% grass silage pre-calving; 50% grass silage, 50% maize silage post-calving; ad libitum) intake was recorded individually. Concentrate (2 kg of pre-calver nuts ± YS for pre-calving and 8 kg of lactating nuts ± YS for post-calving) feeding was controlled individually. Estimated energy balance PP was calculated on a weekly basis individually as the difference between the net energy (NE) intake and the sum of NE for maintenance and milk production. Insulin and IGF-I concentrations were determined on days 14 and 7 pre-calving and 1, 5, 15, 25 and 35 post-calving. Daily ovarian ultrasonography was performed from day 10 PP to monitor the size and development of the first dominant follicle (>10 mm in diameter with absence of other large growing follicles), first ovulatory follicle and days to first ovulation PP. Pre-ovulatory peak of serum oestradiol concentration was determined during the 2 days before ovulation day. Cows with high BCS (over-conditioned) at calving ingested less NE, produced more milk NE output, and consequently had a significantly ( P < 0.05) exacerbated negative energy balance in comparison with low BCS cows (moderately conditioned) during early lactation. Higher ( P < 0.05) insulin concentrations and a tendency for higher ( P = 0.06) pre-ovulatory peak oestradiol concentrations in low BCS group were detected in the early PP period. Supplementing the diet with YS had no effect ( P > 0.10) on NE intake, NE milk output or energy balance. On the other hand it increased ( P < 0.01) insulin concentration and tended to increase ( P = 0.07) pre-ovulatory peak oestradiol concentrations and the size of first ovulatory follicle ( P = 0.09) early PP. Feeding YS had no effect on energy status of lactating dairy cows with high or low BCS at calving, whilst it improved serum insulin concentration, pre-ovulatory peak of oestradiol and the size of first ovulatory follicle in the early PP period. These observed effects of YS supplementation require to be substantiated with further research.

Impact of overweight and underweight on IVF treatment in Chinese women

Objective. To investigate the effects of body mass index (BMI) on ovarian stimulation and the outcome of IVF or ICSI treatment in Asian population who have different characteristics of BMI from white people.Design. In this retrospective study, the first fresh cycles of 1107 Chinese women were classified by BMI: underweight (BMI <18.5 kg/m2), normal weight (BMI: 18.5–23.9 kg/m2) and overweight (BMI ≥ 24 kg/m2). Dose and days of ovarian simulation, cancelled cycles and number of oocytes collected, fertilisation and embryo utilisation rates and pregnancy outcome were compared among BMI groups.Results. It showed that overweight women required more ampoules of gonadotrophin (P = 0.002) and had lower peak oestradiol concentration (P = 0.001), increased cycle cancellation due to insufficient follicle development (P = 0.018) and a higher miscarriage rate (10.5 vs. 5.4%, P = 0.018, OR = 2.006 (95% CI: 1.09–3.69, P = 0.025)) compared with normal weight women. However, no differences were found in clinical pregnancy and live-birth rates. Underweight compared with normal weight women showed no differences in ovarian stimulation and IVF outcome although the clinical pregnancy rate was lower (31.1 vs. 37.3%).Conclusion. At a lower cutoff point of BMI in Chinese women, overweight is associated with increased miscarriage risks and impaired response to ovarian stimulation after IVF and ICSI.

Ovarian stimulation in women with high and low body mass index: GnRH agonist versus GnRH antagonist

This study evaluated women with a high body mass index (BMI) (>40 kg/m(2)) and low BMI (<18 kg/m(2)) undergoing assisted reproduction treatment and determined whether the type of gonadotrophin-releasing hormone (GnRH) analogue used has an impact on cycle parameters and outcome. The study analysed 65 women with high BMI and 118 with low BMI. In the former group, polycystic ovarian syndrome was significantly more prevalent in the agonist long protocol (ALP) group (P=0.01) and gonadotrophin consumption was lower, peak oestradiol concentrations and total number of oocytes retrieved were higher in the ALP group compared with the antagonist (ANT) group. Implantation rate (IR), pregnancy rate (PR) per embryo transfer and early pregnancy loss rate (EPLR) were similar in both stimulation groups, with overall rates of 21.6%, 55.4% and 44.4%, respectively. In women with low BMI, peak oestradiol concentrations, total oocytes retrieved, mature oocytes and transferred embryos were higher in the ALP group compared with ANT group. IR, PR/embryo transfer and EPLR were similar in both groups, with overall rates of 24.3%, 52.5% and 16.1%, respectively. In all patients, no difference was found between ALP and ANT protocols concerning treatment outcome. Contrary to the reasonable EPLR observed in women with low BMI, the high rate found in women with high BMI is remarkable.

Anti-Müllerian hormone testing is useful for individualization of stimulation protocols in oocyte donors

While the age of a donor is a fundamental factor to the success of donor IVF, no serum markers have been demonstrated to be useful in predicting variability of ovarian response in individual donors. Anti-Müllerian hormone (AMH) has been described as an accurate marker of ovarian response in patients undergoing IVF, but has not been applied to oocyte donors. AMH concentrations from 104 anonymous oocyte donors between the ages of 21-32 years were studied and IVF outcome parameters compared. AMH was correlated with several parameters including the number of oocytes retrieved (r=0.232, P=0.024), the peak oestradiol concentrations (r=0.235, P=0.024) and the need to decrease gonadotrophin dose in order to avoid ovarian hyperstimulation syndrome (r=0.274, P=0.007). Receiver operating curve analysis was able to identify an AMH threshold that rendered about 70% sensitivity and 70% specificity for predicting the need to decrease gonadotrophin dosing. The clinical pregnancy rate was 77% per recipient and was not related to the donors' AMH concentrations. For oocyte donors, measurement of AMH appears most useful for determining gonadotrophin sensitivity in order to mitigate symptoms consistent with ovarian hyperstimulation.

Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism

The aim of this observational preliminary trial was to estimate the association between the most common polymorphism of LH (LH-β variant: v-βLH), with different profiles of ovarian response to recombinant human FSH (rhFSH). A total of 60 normogonadotrophic patients undergoing a gonadotrophin-releasing hormone analogue long down-regulation protocol followed by stimulation with recombinant human FSH (rhFSH) for IVF/intracytoplasmic sperm injection, and in whom at least five oocytes were retrieved were retrospectively included. On the basis of the total rhFSH consumption, patients were divided into three groups: Group A: 22 women requiring a cumulative dose of rhFSH >3500 IU; Group B: 15 patients requiring 2000–3500 IU; Group C (control): 23 women requiring <2000 IU. The presence of v-βLH was evaluated using specific immunoassays. Peak oestradiol concentrations were significantly lower in Group A when compared with both groups B ( P< 0.05) and C ( P< 0.001). Group A had a significantly lower ( P< 0.05) number of oocytes retrieved (7.3 ± 1.5, 11.7 ± 2.4 and 14.7 ± 4.1 in the three groups, respectively). Seven carriers (31.8%) of v-βLH were found in Group A, whereas only one variant (6.7%) was observed in Group B; no variant was detected in Group C. These preliminary results suggest that v-βLH is more frequent in women with ovarian resistance to rhFSH.