Kristine Løssl

Dynamics and mechanisms of chemotherapy-induced ovarian follicular depletion in women of fertile age

OBJECTIVE To study ovarian follicular dynamics during chemotherapy to understand the mechanisms behind chemotherapy-induced ovarian follicular depletion and to evaluate whether pretreatment levels of ovarian reserve markers were predictive of the posttreatment levels. DESIGN Prospective clinical study. SETTING University hospital fertility center. PATIENT(S) Seventeen women (median age 30 years; range 19-35 years) undergoing chemotherapy. INTERVENTION(S) Patients were seen before, frequently during, and after chemotherapy, until 1 year after the end of treatment. Antral follicle count and levels of FSH, LH, E(2), anti-Müllerian hormone (AMH), and inhibin A and B were monitored at each visit. MAIN OUTCOME MEASURE(S) The dynamics of the ovarian reserve markers during chemotherapy and factors predictive of posttreatment ovarian function. RESULT(S) Anti-Müllerian hormone level (mean +/- 2 SEM) dropped from 2.7 +/- 1.0 to 1.1 +/- 0.6 and to 0.4 +/- 0.4 ng/mL immediately after one and two series of chemotherapy, respectively. Inhibin B and antral follicle count decreased after three series whereas FSH reached menopausal levels after four series. High pretreatment AMH levels predicted higher posttreatment AMH levels. CONCLUSION(S) Anti-Müllerian hormone and inhibin B levels immediately declined in response to chemotherapy, and the follicular target of chemotherapy appeared to be growing follicles. High pretreatment AMH levels were predictive of a higher posttreatment AMH level.

Acupuncture on the day of embryo transfer: a randomized controlled trial of 635 patients

This prospective, randomized, controlled and double-blinded trial studied whether acupuncture in relation to embryo transfer could increase the ongoing pregnancy rates and live birth rates in women undergoing assisted reproductive therapy. A total of 635 patients undergoing IVF or intracytoplasmic sperm injection (ICSI) were included. In 314 patients, embryo transfer was accompanied by acupuncture according to the principles of traditional Chinese medicine. In the control group, 321 patients received placebo acupuncture using a validated placebo needle. In the acupuncture group and the placebo group, the ongoing pregnancy rates were 27% (95% CI 22-32) and 32% (95% CI 27-37), respectively. Live birth rates were 25% (95% CI 20-30) in the acupuncture group and 30% (95% CI 25-30) in the placebo group. The differences were not statistically significant. These results suggest that acupuncture administered in relation to embryo transfer has no effect on the outcome of IVF and ICSI.

Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial

BACKGROUND Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top-quality embryos after IVF/ICSI. METHODS Patients were randomized to androgen priming (n = 53): anastrozole 1 mg cycle day (c.d.) 2, 3 and 4, hCG 1250 IU and cetrorelix 3 mg on c.d. 2, rFSH 150 IU from c.d. 5 following a flexible antagonist protocol; or control (n = 50): flexible antagonist protocol. RESULTS The mean (confidence interval) number of top-quality embryos was 1.08 (0.83,1.40) and 1.43 (1.12,1.81) in the priming and control group, respectively, being 32% (-7%, 89%) higher in the control compared to priming group (P = 0.120). Stimulation duration was longer in the priming group (P < 0.001). On the day of hCG administration, the proportion of c.d. 2 antral follicles reaching >or=14 mm was higher in the priming group (P = 0.014), as were serum estradiol (E(2)) (P < 0.001) and E(2) per follicle >or=14 mm (P = 0.005). Pre-ovulatory follicular fluid levels of E(2) (P = 0.007) and testosterone (P = 0.014) were higher in the priming group. The number of oocytes retrieved was similar. The fertilization rate was lower in the priming group (P = 0.007). Ongoing pregnancy rates in priming and control group were 30 and 36% (P = 0.531). CONCLUSIONS Administration of aromatase inhibitor and hCG before COS for IVF/ICSI failed to improve the number of top-quality embryos.

Predictors of ovarian response in intrauterine insemination patients and development of a dosage nomogram

The objective of this prospective study was to identify predictors of ovarian response in ovulatory patients treated with low-dose recombinant FSH (rFSH), gonadotrophin-releasing hormone antagonist and intrauterine insemination (IUI), and to develop an rFSH dosage nomogram based on the findings. Patients (n = 159) were stimulated with a starting dose of 75 IU rFSH/day. Ten parameters were investigated as possible predictors of the number of mature follicles >or=15 mm: age, spontaneous cycle length, body weight, body mass index, smoking status, total ovarian volume, total number of antral follicles, total Doppler score of the ovarian stromal blood flow, baseline FSH and oestradiol. Simple and multiple linear regressions were used for the statistical analysis. Appropriate ovarian response was defined as two to three mature follicles. Body weight (P = 0.001) and the number of antral follicles (P = 0.004) were the strongest independent predictive factors of the number of mature follicles. In conclusion, body weight and antral follicle count may be used to achieve appropriate ovarian response for IUI in ovulatory patients. Based on this, a simple rFSH dosage nomogram was developed for individual ovarian stimulation prior to IUI.

Quality of life and psychosocial and physical well-being among 1,023 women during their first assisted reproductive technology treatment: secondary outcome to a randomized controlled trial comparing gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist protocols

OBJECTIVE To compare self-reported quality of life, psychosocial well-being, and physical well-being during assisted reproductive technology (ART) treatment in 1,023 women allocated to either a short GnRH antagonist or long GnRH agonist protocol. DESIGN Secondary outcome of a prospective phase 4, open-label, randomized controlled trial. Four times during treatment a questionnaire on self-reported physical well-being was completed. Further, a questionnaire on self-reported quality of life and psychosocial well-being was completed at the day of hCG testing. SETTING Fertility clinics at university hospitals. PATIENT(S) Women referred for their first ART treatment were randomized in a 1:1 ratio and started standardized ART protocols. INTERVENTION(S) Gonadotropin-releasing hormone analogue; 528 women allocated to a short GnRH antagonist protocol and 495 women allocated to a long GnRH agonist protocol. MAIN OUTCOME MEASURE(S) Self-reported quality of life, psychosocial well-being, and physical well-being based on questionnaires developed for women receiving ART treatment. RESULT(S) Baseline characteristics were similar, and response rates were 79.4% and 74.3% in the GnRH antagonist and GnRH agonist groups, respectively. Self-reported quality of life during ART treatment was rated similar and slightly below normal in both groups. However, women in the GnRH antagonist group felt less emotional (adjusted odds ratio [AOR] 0.69), less limited in their everyday life (AOR 0.74), experienced less unexpected crying (AOR 0.71), and rated quality of sleep better (AOR 1.55). Further, women receiving GnRH agonist treatment felt worse physically. CONCLUSION(S) Women in a short GnRH antagonist protocol rated psychosocial and physical well-being during first ART treatment better than did women in a long GnRH agonist protocol. However, the one item on self-reported general quality of life was rated similarly. CLINICAL TRIAL REGISTRATION NUMBER NCT00756028.

Comparison of a ‘freeze-all’ strategy including GnRH agonist trigger versus a ‘fresh transfer’ strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial

Introduction Pregnancy rates after frozen embryo transfer (FET) have improved in recent years and are now approaching or even exceeding those obtained after fresh embryo transfer. This is partly due to improved laboratory techniques, but may also be caused by a more physiological hormonal and endometrial environment in FET cycles. Furthermore, the risk of ovarian hyperstimulation syndrome is practically eliminated in segmentation cycles followed by FET and the use of natural cycles in FETs may be beneficial for the postimplantational conditions of fetal development. However, a freeze-all strategy is not yet implemented as standard care due to limitations of large randomised trials showing a benefit of such a strategy. Thus, there is a need to test the concept against standard care in a randomised controlled design. This study aims to compare ongoing pregnancy and live birth rates between a freeze-all strategy with gonadotropin-releasing hormone (GnRH) agonist triggering versus human chorionic gonadotropin (hCG) trigger and fresh embryo transfer in a multicentre randomised controlled trial. Methods and analysis Multicentre randomised, controlled, double-blinded trial of women undergoing assisted reproductive technology treatment including 424 normo-ovulatory women aged 18–39 years from Denmark and Sweden. Participants will be randomised (1:1) to either (1) GnRH agonist trigger and single vitrified-warmed blastocyst transfer in a subsequent hCG triggered natural menstrual cycle or (2) hCG trigger and single blastocyst transfer in the fresh (stimulated) cycle. The primary endpoint is to compare ongoing pregnancy rates per randomised patient in the two treatment groups after the first single blastocyst transfer. Ethics and dissemination The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committees in Denmark and Sweden. The results of the study will be publically disseminated. Trial registration number NCT02746562; Pre-results.

Concentration of soluble urokinase plasminogen activator receptor (suPAR) in the pre-ovulatory follicular fluid is associated with development of ovarian hyperstimulation syndrome during ovarian stimulation

PurposeInvestigating whether pre-ovulatory follicular fluid (FF) levels of selected proteins differ between women who do or do not develop severe ovarian hyperstimulation syndrome (OHSS) and evaluate whether they potentially could guide a “freeze-all” strategy.MethodsFF was collected during a randomized controlled trial comparing OHSS in antagonist versus agonist protocol including 1050 women in their first assisted reproductive technology (ART) cycle during year 2009–2013. The present sub-study is a matched case-control study comparing FF levels of soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, placental growth factor, vascular endothelial growth factor, and angiopoietins 1 and 2 in OHSS cases (n = 25, severe OHSS, and ≥ 15 oocytes), high-risk controls (n = 25, no OHSS, and ≥ 15 oocytes), and low-risk controls (n = 25, no OHSS, and 5–8 oocytes).ResultsFF level of suPAR differed significantly between the three groups (p = 0.018) with mean (SD) levels of 2.3 (0.4) μg/L, 2.6 (0.8) μg/L, and 2.8 (0.6) μg/L in OHSS cases, high-risk controls, and low-risk controls, respectively. Receiver operating characteristic curve analysis demonstrated that suPAR levels could predict severe OHSS (AUC 0.678; 95% CI 0.553–0.803) with a sensitivity of 64% and a specificity of 66%. None of the other investigated proteins differed between the three groups or between OHSS cases and combined controls.ConclusionThe pre-ovulatory FF level of suPAR was significantly lower in women developing severe OHSS, indicating that the plasminogen activator system could be involved in the pathophysiology of OHSS. However, suPAR did not provide a satisfying predictive value for the prediction of OHSS.

The use of anti‐Müllerian hormone for controlled ovarian stimulation in assisted reproductive technology, fertility assessment and ‐counseling

Ovarian reserve can be determined by serum anti‐Müllerian hormone (AMH) level and/or antral follicle count before controlled ovarian stimulation. The aim of controlled ovarian stimulation is to achieve an appropriate number of mature follicles and avoid complications such as ovarian hyperstimulation syndrome. Measurement of the ovarian reserve is useful for clinicians as it predicts the ovarian response to controlled ovarian stimulation. Further, it assists in giving the patient realistic expectations regarding the treatment. By determining the ovarian reserve, the most appropriate stimulation protocol and gonadotropin dose can be chosen specifically for each woman enabling so‐called “individualized treatment” in line with the personalized treatment concept. Many benefits come with using AMH as a biomarker for ovarian reserve; the hormone is considered fairly cycle independent apart from a small decrease in the late follicular phase and there is no inter‐observer variance. However, the use of AMH also has limitations; since the implementation of AMH in fertility treatment several AMH assays have been developed. This has made direct comparisons of AMH serum levels complicated. Currently, no international standardized assays exist. AMH is a valid predictor of the ovarian response to controlled ovarian stimulation and to some extent the chance of pregnancy in relation to assisted reproductive technology, but AMH is less optimal in prediction of spontaneous pregnancy and live birth after assisted reproductive technology. Accordingly, AMH can be used to optimize gonadotropin stimulation in fertility treatment, but is not recommended as a screening tool in the general population.

Predictive value of plasma human chorionic gonadotropin measured 14 days after Day-2 single embryo transfer

Prediction of pregnancy outcome after in vitro fertilization is important for patients and clinicians. Early plasma human chorionic gonadotropin (p‐hCG) levels are the best known predictor of pregnancy outcome, but no studies have been restricted to single embryo transfer (SET) of Day‐2 embryos. The aim of the present study was to investigate the predictive value of p‐hCG measured exactly 14 days after the most commonly used Day‐2 SET on pregnancy, delivery, and perinatal outcome.