This is the first randomized controlled multi-arm trial comparing how three hCG trigger doses impact endogenous progesterone levels in IVF- fresh embryo transfer cycles.

Study Background

WHAT

• Does the ovulation trigger dose of human chorionic gonadotropin (hCG) have an association with the endogenous progesterone of women doing fresh embryo transfer (ET)?

WHY

• Endogenous progesterone (P) is a critical hormone in embryo implantation, especially ~7 days after oocyte retrieval

• Past studies on trigger doses of hCG measured endogenous P with exogenous P vs. looking at endogenous P specifically

• Per authors, vaginal P supplements modestly contribute and tend to reach an upper limit (30-40 nmol/L) when contributing to serum P

WHERE

• Fertility Clinic of Odense University Hospital, Denmark

WHEN

• Screened women between January 2015 - September 2019 for study eligibility

WHO

Female Inclusion Criteria:

• Ages 18-40

• IVF followed by fresh ET

• Normal baseline hormone levels for FSH, LH, E, thyroid, and prolactin

• Using partner sperm or sperm donor

Female Exclusion Criteria:

• BMI < 18 or > 35 kg/m2

• Major organ disease

• Endocrine diseases or coagulation disorders

• Cancelled embryo transfer

• High risk of OHSS or at least twelve follicles that were > 11 mm on last ultrasound before trigger shot

HOW

• Ovarian stimulation via medications (recombinant FSH, urinary FSH, corifollitropin-alfa, rFSH/LH and or HMG alone or in combination; thereafter initiated GnRH antagonist co-treatment)

• Randomization the day before or on ovulation trigger day to:

  • Group 1: 5,000 IU uhCG (Pregnyl)

  • Group 2: 6,500 IU rhCG (Ovitrelle)

  • Group 3: 10,000 IU uhCG (Pregnyl)

  • To give exogenous P as luteal phase support, Groups 1, 2, and 3 took 341 mg of intramuscular 17a-hydroxyprogesterone caproate (Lentogest) every third day

  • Group 4 “Control Group”: 6500 IU rHCG + “standard” luteal phase support of vaginal micronized progesterone (Crinone) twice daily

  • Pregnyl was discontinued and removed from market in March 2018

    • 36% of patients randomized after Pregnyl discontinued

    • Groups 1 and 3 switched from Pregnyl to Ovitrelle pre-filled syringes (4,940 IU and 10,140 IU Ovitrelle, respectively)

  • Randomization into groups via random sequence generator, with block randomization ensuring equal group distribution

• Unblinded: physicians enrolled participants and assigned to intervention

• Medication compliance monitored by forms and empty medications

• Blood samples drawn on eight occasions

  Statistics

• 92 participants needed to provide 80% power (Type II error 20%, P < 0.05); study NOT powered for reproductive outcomes

• see p. 796 for additional statistics

  Results

• 127 women randomized, 94 completed the trial (74%), 33 excluded due to embryo transfer cancellations; no significant differences between groups regarding women excluded

• Baseline characteristics slightly differed between groups: cycle length - one patient had oligomenorrhea in Group 3 - and LH concentrations

• No differences in ovarian stimulation characteristics (FSH/HMG doses, days of stimulation, LH used)

• No differences in # of oocytes retrieved, fertilized, and cleaved

• Groups were similar regarding fertilization (more IVF > ICSI) and sperm source (partner > donor)

• More Day 3 vs. Day 5 embryo transfers in all groups (73% vs. 26%)

• One patient transferred two embryos, all others transferred one

• Medication safety: one patient dropped out due to potential local reaction to intramuscular P injection

• Progesterone outcomes

  • on last day of ultrasound, oocyte retrieval (36 hours after ovulation trigger), groups “relatively equal”

  • differences found between groups on days 8, 10, and 14 post-retrieval (p < 0.001)

  • after adjusting for pregnancy, P values continued to be sig diff

  • strong positive correlation with luteal P concentration and follicle count

    • larger follicles produced more P

    • adjustments based on follicle #s still showed differences between groups

  • Group 2 (Lentogest) vs. Group 4 (Crinone): Group 4 showed increased P from oocyte retrieval through 14 days post-retrieval (p =0.035)

  • Group 1 (5000iu hCG) vs. Group 3 (10,000iu hCG):

    • Group 3’s follicles, sized over 13 mm, produced more progesterone (17.7nmoL/L) on days 2-8 post-retrieval vs. group 1 (p = 0.007)

    • no differences in P levels found in patients within Groups 1 and 3 based on use of uHCG vs. rHCG

  • no differences based on age but decrease in P by 4.05 nmol/L for every 1 kg/m2 BMI increase (p = 0.005)

• Embryo and Pregnancy outcomes:

  • No differences between groups in # of mature fertilized oocytes or good-quality embryos

  • 32% tested (+) for pregnancy; 23% confirmed clinical pregnancy

  • No differences detected in (+) pregnancy test or clinical pregnancy test between groups, though study not powered to detect this outcome

Authors’ Thoughts

• Though similar in early luteal phase, the P increased with higher hCG trigger doses in mid and late luteal phases; the P output from each individual follicle increased with higher hCG trigger doses.

• Using 17a-hydroxyP for LPS distinguished endogenous P production from exogeneous vaginal P, which allowed P levels to be tested as direct reflection of corpus luteum function.

• Trigger doses higher than 5000 IU hCG should be used if fresh transfer intended (5000 IU is sufficient for retrieval and fertilization)

• Trigger doses should be individualized to optimize P concentrations during the implantation period.

This Pharmacist’s (Additional) Thoughts

(+) well-researched and cited

(-) small numbers of patients in each group—> study not powered to detect reproductive outcomes

Conclusions

This study detected statistically significant differences in P production based on hCG trigger doses; additional studies could examine and explore the notable trend of lower births in the 5000 IU hCG group.

Resources

Abdalla HI, Ah-Moye M, Brinsden P, Howe DL, Okonofua F, Craft I. The effect of the dose of human chorionic gonadotropin and the type of gonadotropin stimulation on oocyte recovery rates in an in vitro fertilization program. Fertil Steril. 1987;48(6):958-963. doi:10.1016/s0015-0282(16)59591-0

Pabuçcu E, Pabuçcu R, Gürgan T, Tavmergen E. Luteal phase support in fresh and frozen embryo transfer cycles [published online ahead of print, 2020 Jun 22]. J Gynecol Obstet Hum Reprod. 2020;101838. doi:10.1016/j.jogoh.2020.101838

Svenstrup L, Möller S, Fedder J, et al. Does the HCG trigger dose used for IVF impact luteal progesterone concentrations? a randomized controlled trial. Reprod Biomed Online. 2022;45(4):793-804. doi:10.1016/j.rbmo.2022.04.019

Vuong LN, Ho TM, Pham TD, Ho VNA, Andersen CY, Humaidan P. The early luteal hormonal profile in IVF patients triggered with hCG. Hum Reprod. 2020;35(1):157-166. doi:10.1093/humrep/dez235