Assisted reproduction - Ovulation and the early luteal phase

Infertility is an increasing worldwide challenge that affects 15% of all couples of reproductive age. It is defined as a disease of couples who do not achieve a clinical pregnancy after 12 months of unprotected intercourse. In Denmark, 10.5% of all children are born after fertility treatment, and improvement of fertility treatment can potentially benefit many patients and reduce socio-economic costs. In line with this, research will increase knowledge and enhance the quality of fertility treatment offered. The overall aim of this thesis was to study ovulation and the luteal phase in order to contribute with additional information on pregnancy and live birth in relation to pre- or post-ovulation insemination. Furthermore, we wanted to explore the dose response relationship between hCG trigger and luteal progesterone (P4). Finally, we explored the correlation between timing of post trigger hCG luteal phase support to P4 values during the mid-late luteal phase. The present PhD thesis is based on three studies. Study I was a retrospective cohort study based on data from the clinical treatment database at the Fertility Clinic, Odense University Hospital. It described the pregnancy, clinical pregnancy rate, live birth rate, and gender ratio in insemination cycles related to whether insemination was performed before or after ovulation. We included a total of 6701 cycles, divided into two groups: 3870 cycles without ovulation at the time of insemination and 2831 cycles with ovulation at the time of insemination. The results showed that the pregnancy, clinical pregnancy, and live birth rate were comparable between the two groups; moreover, the gender ratio was also comparable. These findings can be transferred to daily clinical practice, suggesting that ultrasonography at the time of insemination to visualize ovulation is redundant.
Study II and Study III were part of an RCT allocating patients undergoing GnRH antagonist co-treatment for IVF/ICSI into Study II (RCT I) or Study III (RCT II), depending on the number of follicles on the day of randomization, the day of last ultrasonography, before Oocyte pick up (OPU). In the study, patients had a total of eight blood samples performed during the luteal phase. Study II (RCT 1) explored the dose response correlation between the hCG trigger bolus and the endogenous P4 production-during the luteal phase. Patients with a total of ≤ 11 follicles ≥ 12 mm were randomized into three intervention groups using different doses of hCG for ovulation trigger: 5000 IU, 10,000 IU, and 6500 IU. The luteal phase support consisted of 17-α-OH-P4 to distinguish the exogenous P4 from the endogenous P4 production. A control group received 6500 IU hCG and 180 mg vaginal P4 for luteal phase support. In total, 94 patients completed the study. The results showed a significant hCGP4 dose-response relationship during the mid and late luteal phases. Furthermore, the capacity of a corpus luteum to produce P4 increased with increasing hCG trigger doses. Based on the current findings, 6500 or 10,000 IU hCG is recommended for trigger in non-OHSS risk patients in order to obtain the most optimal serum P4 level during the mid-late luteal phase.
Study III (RCT II) explored the timing and dosing of luteal hCG support after a GnRH agonist trigger in women with a total of 12-25 follicles ≥ 12 mm on the day of randomization, on the last ultrasonography before OPU. Patients received either one bolus of 1500 IU hCG for luteal phase support after OPU, or 1000 IU hCG after OPU, followed by 500 IU hCG 5 days later. A control group had 6500 IU hCG for ovulation trigger. All three groups received standard vaginal luteal phase support, and overall, a total of 69 patients completed the study. In patients with a total of 12-25 follicles ≥ 12 mm on the day of randomization, splitting the hCG luteal phase support dose into 1000 IU hCG on OPU+500 IU hCG on OPU+5, which resulted in a more optimal serum P4 profile during the mid-late luteal phase. Taken together, the findings of this thesis increase the knowledge on ovulation, hCG trigger, hCG for luteal phase support, and luteal serum P4. The results also confirm that insemination can be performed 36 hours after hCG trigger, irrespective of whether or not ovulation took place at the time of insemination without affecting pregnancy, clinical pregnancy, or live birth rates. Further, the findings emphasize the importance of individualizing the hCG trigger dose and the timing of hCG in luteal support during IVF treatment to optimize the serum P4 level at peri-implantation. Thus, a bolus of 6500 or 10,000 IU hCG is recommended for ovulation trigger in low to normal responder patients who are not considered to be at risk of developing OHSS. With regard to hCG for luteal phase support after GnRH agonist trigger, dividing the support into 1000 IU hCG on the day of OPU and 500 IU hCG on OPU+5 resulted in a more optimal mid-late-luteal P4 level. The findings of the studies support individualization not only in terms of the hCG bolus used for trigger, but also as regards the hCG bolus(es) used for luteal phase support after GnRH agonist trigger.