Birgit Alsbjerg

GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients

STUDY QUESTION Does a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger? SUMMARY ANSWER A GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS. WHAT IS KNOWN ALREADY A GnRHa trigger is an alternative to hCG in GnRH antagonist co-treated cycles. STUDY DESIGN, SIZE, DURATION Two RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles ≥11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles ≥11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles ≥11 mm was ≤14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval-or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5-or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data. MAIN RESULTS AND THE ROLE OF CHANCE In women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (≤14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22). LIMITATIONS, REASONS FOR CAUTION Although the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles ≥11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs. WIDER IMPLICATIONS OF THE FINDINGS Although a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles ≥11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS.

The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives

In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates.

Early luteal phase endocrine profile is affected by the mode of triggering final oocyte maturation and the luteal phase support used in recombinant follicle-stimulating hormone-gonadotropin-releasing hormone antagonist in vitro fertilization cycles.

OBJECTIVE To assess endocrine differences during early luteal phase according to mode of triggering final oocyte maturation with or without luteal phase support (LPS). DESIGN A prospective randomized study. SETTING University center for reproductive medicine. PATIENT(S) Four oocyte donors each underwent four consecutive cycles. INTERVENTION(S) To avoid interpatient variation, each donor underwent the same stimulation regimen. However, different modes of triggering final oocyte maturation and LPS were administered: A) 10,000 IU hCG and standard LPS; B) GnRH agonist (GnRHa; 0.2 mg triptorelin), and 35 hours later 1,500 IU hCG, and standard LPS; C) GnRH agonist (0.2 mg triptorelin) and standard LPS; and D) GnRH agonist (0.2 mg triptorelin) without LPS. MAIN OUTCOME MEASURE(S) Blood sampling was performed on the day of ovulation trigger, ovulation trigger + 1 day, and ovum pick-up + 5 days. Serum E2, FSH, LH, and P were measured. RESULT(S) The early luteal phase steroid levels following GnRHa trigger and modified luteal phase support (B) were similar to those seen after hCG trigger (A). However, significant differences were seen between groups A and B compared with C and D, as well as between groups C and D. CONCLUSION(S) Administration of a single bolus of GnRHa effectively induced LH and FSH surges in oocyte donors stimulated with recombinant FSH and cotreated with a GnRH antagonist. However, gonadotropin and steroid levels differed significantly according to the type of luteal phase support used after GnRHa trigger. EUROPEAN COMMUNITY CLINICAL TRIAL SYSTEM (EUDRACT) NUMBER 2009-009429-26.

Pregnancy loss after frozen-embryo transfer—a comparison of three protocols

OBJECTIVE To compare the reproductive outcome of three protocols for frozen ET treatment. DESIGN Retrospective follow-up study. SETTING Two public clinics and one private clinic. PATIENT(S) Four thousand four hundred seventy frozen ET cycles between 2006 and 2010. INTERVENTION(S) Thawing of embryos and ET. MAIN OUTCOME MEASURE(S) Pregnancy test rate, clinical pregnancy rate, and pregnancy loss rate. RESULT(S) The natural cycle followed by P (NC + P) was used in 26% of cycles, the natural cycle with hCG (NC + hCG) in 10%, and the substituted cycle with estrogen and P (E + P) in 64% of cycles. The rate of transfers after thawing was similar in all groups (87.2%, 73.9%, and 87.2%, respectively). There was a significantly higher positive pregnancy test rate in the E + P (34.3%) and NC + hCG (35.5%) cycles as compared with the NC + P cycles (26.7%). However, the clinical pregnancy rate was similar in all groups (27.7%, 29.1%, and 24.3%, respectively). Moreover, no differences were seen between groups regarding the live-birth rate (20.1%, 23.5%, and 20.7%, respectively). A logistic regression analysis showed that the type of protocol was the only predictor of pregnancy loss, while age, irregular cycles, endometrial thickness, number, and quality of embryos transferred did not correlate to pregnancy loss. CONCLUSION(S) A higher positive pregnancy test rate was obtained in E + P frozen ET cycles in comparison with other protocols; however, due to an increased preclinical and clinical pregnancy loss, comparable clinical pregnancy, and delivery rates are reported for the three protocols.

GnRHa trigger for final oocyte maturation: is HCG trigger history?

Since the introduction of the gonadotrophin-releasing hormone analogues (GnRHa) protocol, it has become possible to trigger final oocyte maturation with a bolus of GnRHa. This leads to a significant reduction or complete elimination of ovarian hyperstimulation syndrome compared with human chorionic gonadotrophin (HCG) trigger. Early trials showed a severe luteal phase insufficiency after GnRHa trigger despite the application of standard luteal phase support protocols. Subsequent research has led to modifications of the luteal phase support, resulting in reproductive outcome comparable to that seen after HCG trigger in normal- and high-responders. GnRHa trigger facilitates a tailored approach to subsequent luteal phase support, taking into account the ovarian response to stimulation. In the future, GnRHa is likely to be used for trigger in all women co-treated with GnRH antagonists.

The updated Cochrane review 2014 on GnRH agonist trigger: repeating the same errors

Cochrane reviews are powerful tools, internationally recognized as the highest standard in evidence-based health care. A Cochrane analysis makes use of precise, reproducible criteria in the selection of studies for review. In the context of a previous Cochrane review (2010) on the subject of gonadotrophin-releasing hormone agonist (GnRHa) trigger, we questioned whether a review should be conducted during the research phase when new concepts are being developed. Recently, an updated Cochrane review was published, reaching the same general conclusion as the first one, i.e., GnRHa triggers lower the chance of pregnancy in fresh autologous IVF and intracytoplasmic injection treatment cycles. We argue that the new review repeats previous errors by compiling data from studies that were not comparable as different luteal phase protocols were used. From the clinical point of view, the luteal support used is the variable which affects the pregnancy rate and not the use of the GnRHa trigger for final oocyte maturation. Therefore, a meaningful comparison between GnRHa and HCG trigger must be confined to outcome measures that are not affected by the luteal support used. We conclude that the updated review falls short of addressing meaningful clinical and fundamental questions in the context of GnRHa trigger.

GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients

Dear Sir, We read with interest the retrospective report by Seyhan et al. (2013) presenting five cases of early ovarian hyperstimulation syndrome (OHSS) in OHSS high-risk patients, following GnRHa trigger and modified luteal phase support with one bolus of 1500 IU hCG. As we have performed the majority of randomized controlled trials (RCTs) in this field, we feel an urge to further comment on the paper, although the report was previously accompanied by an editorial (Bodri, 2013). Seyhan et al. (2013) in their two-centre retrospective analysis included 23 patients at risk of developing OHSS, defined as ‘a high number of follicles ≥12 mm during the late follicular phase’. Patients received a GnRHa trigger followed by a bolus of 1500 IU hCG on the day of oocyte retrieval (Humaidan et al., 2005; Humaidan, 2009; Humaidan et al., 2010). If a decision was made to go ahead with an embryo transfer a standard luteal phase support was added to the protocol. A total of six patients (26%) developed severe OHSS of whom five patients developed early onset OHSS (22%). Of these patients three had their embryo transfer cancelled and two received a dual embryo transfer. The authors analyzed possible risk factors of OHSS and concluded that the only significant parameter was the number of follicles measuring 10–14 mm on the day of trigger, being significantly higher in the patients who developed severe early OHSS. This made the authors conclude that it would be prudent to avoid hCG luteal rescue and instead freeze all embryos in women with a total of ≥18 follicles with 10–14 mm diameters. GnRHa trigger followed by a modified luteal phase support with one bolus of 1500 IU hCG was developed by our group through a series of trials (Humaidan et al., 2005; Humaidan et al., 2010) mainly involving normal responder patients. However, in our RCT from 2010, including 302 patients (Humaidan et al., 2010), more than one-third of the patients in the GnRHa triggered as well as the hCG triggered groups had .14 follicles ≥11 mm on the day of trigger, a level previously suggested to distinguish between the OHSS risk patient and the patient at low risk of OHSS (Papanikolaou et al., 2006). No patient developed OHSS in the GnRHa triggered group versus 2% after hCG trigger. In our latest RCT including a total of 384 patients (Humaidan et al., 2013) we randomized 118 patients considered at risk of OHSS to either GnRHa trigger followed by the previously described modified luteal phase support or trigger with 5000 IU hCG. Risk of OHSS was a priori determined as the presence of 15–25 follicles ≥11 mm on the day of triggering final oocyte maturation. Importantly, patients with .25 follicles were excluded from this study based on the results of a previous pilot study in OHSS risk patients (Humaidan, 2009). In this new large RCT, no OHSS case was seen after GnRHatrigger and modified luteal phase support when compared with two moderate late-onset OHSS cases (3.4%) after hCG trigger. Reassuringly, no statistical difference in ongoing clinical pregnancy rates between the two trigger concepts was observed. Thus, in patients with up to 25 follicles, we feel quite confident with the use of GnRHa trigger followed by a modified luteal phase support with one bolus of 1500 IU hCG. Above 25 follicles we recommend a ‘freeze all’ policy. If for some reason a decision to perform a fresh transfer is made in this type of OHSS high-risk patient, it is our clinical experience that luteal supplementation with hCG postGnRHa trigger should only be performed in the well-informed patient with great caution and employing a lower dose of hCG. Regarding the Seyhan et al. paper (2013) our main concern and utter surprise is the fact that the authors still decided to proceed with a bolus of 1500 IU hCG in patients who had as many as 50–65 oocytes retrieved. This conduct seems to us unethical, jeopardizing the health of the patient when it would have been more prudent to ‘freeze all’ after GnRHa trigger without any risk whatsoever of OHSS development in the patient. Although GnRHa trigger and modified luteal phase support has allowed fresh transfer in OHSS risk patients, there is clearly an upper biological limit above which it would be unrealistic to believe that all OHSS cases could be avoided. In these cases we call upon the sound clinical judgment of the treating clinician. We also question the upper cut-off value of ≥18 follicles measuring 10–14 mm suggested by Seyhan et al. (2013), as these results derive from a retrospective analysis including 23 OHSS risk patients only. Moreover, in their paper, this cut-off value is severely jeopardized by the discrepancy between the follicular count on the day of trigger and the actual number of oocytes retrieved in several of their patients. In conclusion, GnRHa trigger followed by a modified low-dose early luteal hCG support will provide patients who on the day of trigger have developed up to 25 follicles .11 mm with the opportunity to proceed to fresh embryo transfer with good ongoing pregnancy rates and no OHSS according to the results of our latest RCT. However, until ongoing studies have defined the minimal hCG activity needed in patients with .25 follicles ≥11 mm, we firmly recommend GnRHa trigger followed by a ‘freeze all’ policy to avoid any risk of OHSS development.

Increasing vaginal progesterone gel supplementation after frozen–thawed embryo transfer significantly increases the delivery rate

The aim of this study was to evaluate the reproductive outcome in patients receiving frozen-thawed embryo transfer before and after doubling of the vaginal progesterone gel supplementation. The study was a retrospective study performed in The Fertility Clinic, Skive Regional Hospital, Denmark. A total of 346 infertility patients with oligoamenorrhoea undergoing frozen-thawed embryo transfer after priming with oestradiol and vaginal progesterone gel were included. The vaginal progesterone dose was changed from 90 mg (Crinone) once a day to twice a day and the reproductive outcome during the two periods was compared. The pregnancy rate increased significantly after doubling of the progesterone dose (26.7% (90 mg) versus 38.4% (180 mg); P=0.021). Moreover, the early pregnancy loss rate decreased significantly (67.4% versus 43.7%, respectively; P=0.014), which significantly increased the delivery rate (8.7% versus 20.5%, respectively; P=0.002). Doubling of the vaginal progesterone gel supplementation during frozen-thawed embryo transfer cycles decreased the early pregnancy loss rate, resulting in a significantly higher delivery rate. This study evaluated the reproductive outcome of 346 women with oligoamenorrhoea (cycle length >34 days) or amenorrhoea undergoing oestradiol and progesterone priming prior to frozen-thawed embryo transfer. Patients treated with vaginal progesterone gel (Crinone 90 mg) twice daily had a lower risk of pregnancy loss (43.7%) compared with women treated once a day (67.4%). This resulted in a significantly higher delivery rate (20.5% versus 8.7%, respectively).

The gonadotropin-releasing hormone antagonist protocol--the protocol of choice for the polycystic ovary syndrome patient undergoing controlled ovarian stimulation.

Polycystic ovary syndrome (PCOS) patients are prone to develop ovarian hyperstimulation syndrome (OHSS), a condition which can be minimized or completely eliminated by the use of a gonadotropin‐releasing hormone agonist (GnRHa) trigger. In this commentary paper, we maintain that the gonadotropin‐releasing hormone antagonist protocol should be the protocol of choice for the PCOS patient undergoing ovarian stimulation with gonadotropins for in vitro fertilization. If an excessive ovarian response is encountered, the clinician will always have two options: either to trigger final oocyte maturation with a bolus of GnRHa and supplement the luteal phase with a small bolus of human chorionic gonadotropin in addition to the standard luteal phase support and transfer in the fresh cycle or, alternatively, to trigger with GnRHa and perform a total freeze, resulting in a complete elimination of OHSS and high ongoing pregnancy rates in the subsequent frozen–thawed transfer cycles.

Motivational interviewing: a part of the weight loss program for overweight and obese women prior to fertility treatment

Abstract This is a retrospective study to investigate whether motivational interviewing increases weight loss among obese or overweight women prior to fertility treatment. Women with body mass index (BMI) > 30 kg/m2 approaching the Fertility Clinic, Regional Hospital Skive, were given advice about diet and physical activity with the purpose of weight loss. In addition, they were asked if they wanted to receive motivational interviewing. Among other data, age, height and weight were obtained. Main outcomes were weight loss measured in kg and decrease in BMI. We studied 187 women: 110 received sessions of motivational interviewing (intervention group, n = 110), 64 received motivational support by phone or e-mail only and 13 women did not wish any motivational support (control group, n = 77). The mean weight loss and decrease in BMI was greater in the intervention group compared with the control group (9.3 kg versus 7.3 kg, difference p = 0.01, 3.3 kg/m2 versus 2.6 kg/m2, difference p = 0.02). The mean period of intervention was comparable in the two groups, 7.9 month and 7.3 month, respectively, (difference non significant: NS). The study indicates that motivational interviewing may be a valuable tool in weight loss programs for obese and overweight women prior to fertility treatment.