Progesterone elevation on the day of human chorionic gonadotropin administration is not the only factor determining outcomes of in vitro fertilization

Capsule:
The elevated progesterone on the day of human chorionic gonadotropin triggering has an obvious negative impact on pregnancy outcome only at extremely high progesterone concentrations.

Authors:
Yi-Ru Tsai, M.D., Fu-Jen Huang, M.D., Pin-Yao Lin, M.D., Fu-Tsai Kung, M.D., Yu-Ju Lin, M.D., Yi-Chi Lin, B.Sc., Kuo-Chung Lan, M.D., Ph.D.

Volume 103, Issue 1, Pages 106-111

Abstract:

Objective:
To assess whether progesterone elevation is the only factor in determining outcomes of in vitro fertilization (IVF).

Design:
Retrospective cohort study.

Setting:
Infertility clinic at Kaohsiung Chang Gung Memorial Hospital, Taiwan.

Patient(s):
One thousand five hundred eight women undergoing a total of 1,508 IVF cycles.

Intervention(s):
None.

Main Outcome Measure(s):
Clinical pregnancy and live-birth rates.

Result(s):
Patients were classified into four subgroups according to their progesterone concentration on the day of human chorionic gonadotropin (hCG) triggering. The clinical pregnancy and live-birth rates were statistically significantly associated with the age of the woman, the day of embryo transfer, the progesterone concentration on the day of hCG administration, the number of transferred embryos, and the number of top-quality embryos transferred. However, after omitting the women with the highest progesterone concentration (≥1.94 ng/mL), only four factors—patient age, day of embryo transfer, number of transferred embryos, and number of top-quality embryos transferred—were statistically significantly associated with the clinical pregnancy and live-birth rates.

Conclusion(s):
Progesterone concentration on the day of hCG administration is not the only factor determining the clinical pregnancy and live-birth rates. Fresh embryos from women should be frozen with extremely high progesterone concentrations. Each patient’s general condition and the capacity for frozen-thawed embryo transfer should be considered before implantation.

  • Micah Hill

    Thank you for the article exploring elevated progesterone during IVF and clinical outcomes, a very timely and interesting discussion. Your 180 patients with a P4 > 1.94 had an average P4 of 2.9 with a STDEV of 3.3, indicating most of these patients had P4 levels well over 3 and potentially much much higher. Do you think think some of these patients had actually surged and ovulated through their GnRH agonist or antagonist? This would clinically be a much different group than patients who had not had a GnRH surge.

    Do you use pure FSH in your stimulation, or mixed protocols with some LH activity included?

    It makes sense that elevated P4 on the day of hCG is not the only factor associated with live birth. Its one of many factors from the egg, sperm, lab environment, embryo, and the uterine environment all potentially affecting outcomes.

    • Micah– do you have a cut off at the NIH? we continually debate this topic

      • Micah Hill

        We are currently using a cutoff of 2 based on some data analyses we did in conjunction with the Shady Grove group. We see a drop in pregnancy rates at lower P4 levels, but it becomes very marked over 2 and seems to justify the cost and time delay of freezing. One of my fellows is currently working on a cost analysis of this exact question, which we will hopefully be able to submit to FS soon. He is an engineering PhD now doing REI and developed some formulas which would allow anyone to insert their own fresh and frozen rates and the detriment based on their own P4 assay to assess when to freeze.

        • there was a a great journal club you were on with shapiro group paper on why the uterine environment and prog likely explains the diff between results with day 5 vs day 6 blasts http://youtu.be/9Cw1aeR00sk

    • Kuo-Chung Lan

      Thanks for Dr.Hill’s informative comments.

      We try to answer what factors are associated with increased P4 concentration in our another study (in writing). Indeed, we found total FSH dosage,protocol choice (GnRH agonistor GnRH antagonist), body weight, estradiol values on the day of hCG administration, luteinizing hormone values on the day of hCG administration and the number of dominant follicles were statistically significantly associated with elevated P4 concentration using the last data driven points
      (1.1, 1.5, 1.94 ng/mL) .
      Interesting, Papanikolaou et al. reported the incidence of a progesterone rise (>1.5 ng/ml) was similar between the two analogues[1] However, Bosch et al reported serum progesterone levels were significantly greater in women treated with GnRH agonists versus antagonists (0.84 +/- 0.67 versus 0.75 +/- 0.66 ng/ml; P =0.0003).[2].

      Admittedly, another question is elicited. The occurrence of a breakthrough LH surge despite GnRH-ant or GnRH-a treatment[3,4] is a reassuringly rare event. At the same time, a premature rise in the level of luteinizing hormone (LH) without a concomitant increase in the level of progesterone also had been reported.[5]

      1. Papanikolaou
      EG, Pados G, Grimbizis G, Bili E, Kyriazi L, Polyzos NP, Humaidan P, Tournaye
      H, Tarlatzis B: GnRH-agonist versus GnRH-antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study. Hum Reprod 2012,
      27(6):1822-1828.

      2. Bosch E, Labarta E, Crespo J, Simon C, Remohi J, Jenkins J, Pellicer A: Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.
      Hum Reprod 2010, 25(8):2092-2100.

      3. Reichman DE, Zakarin L, Chao K, Meyer L, Davis OK, Rosenwaks Z: Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles. Fertility and sterility 2014, 102(1):99-102.

      4. Younis JS: “Premature luteinization” in the era of GnRH analogue
      protocols: time to reconsider. Journal of assisted reproduction and genetics 2011, 28(8):689-692.

      5. Dovey S, McIntyre K, Jacobson D, CatovJ, Wakim A: Is a premature rise in
      luteinizing hormone in the absence of increased progesterone levels detrimental
      to pregnancy outcome in GnRH antagonist in vitro fertilization cycles. Fertility and sterility 2011, 96(3):585-589.

      • Micah Hill

        Thank you for taking the time to answer my questions! We have also noticed very similar associations to the ones you describe with elevated P4. I look forward to seeing more papers on the topic!

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