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Rise of P prior to hCG administration: the clinical dilemma

Dear Colleague,
A 32 y-o,
Unexplained infertility and good ovarian reserve, First IVF cycle.
Stimulated on a long GnRH agonist (Decapeptil 0.1 mg/d) protocol and 150IU rec-hFSH.
Everything was going well, nice synchronous follicle development, good lining build up, gradual nice increase of serum estradiol levels.
On day 8 of the stimulation, U/S scan showed 4-5 follicles 20-22 mm in diameter on each ovary and multiple smaller ones.
E2 is 11500 pmol/L, P4 7.3 nmol/L (2.02 ng/mL).

  1. What's going on?
  2. Is my patient ovulating under the GnRH agonist?
  3. Should I cancel her?
  4. Should I trigger ovulation and go for retrieval?
  5. Should I transfer embryos or freeze all?
  6. If she fails to get pregnant, what's next?
  7. How can I prevent this P4 rise from happening once again?

Background on stimulation protocols from IVF-Worldwide.com

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Answer By Johhny S. Younis

In the pre-GnRH analogue era in an ART setting elevated Progesterone (P) level prior to hCG administration was considered a sign of premature luteinization, a result of premature LH surge. This has been shown to adversely affect endometrial receptivity and clinical pregnancy rate. During the GnRH analogue era and specifically in good responder patients there is growing evidence to show that elevated P prior to hCG administration is not the result of premature LH surge but to excessive response to FSH causing increased ovarian steroidogenic activity and P production. In such a setting P elevation is not as much detrimental to endometrial receptivity and clinical pregnancy rate as has been the case in the pre-GnRH analogue era. The absolute cut-off point of the permissive P level on hCG day or the optimal P/E2ratio in this setting is still under investigation. Moreover, although  controversial, some authors have produced evidence to show that under these circumstances LH addition to the FSH stimulation may reduce elevated P level, by promoting its conversion to androgens, which are then further metabolized to estrogens by the granulosa cells. By this way, hopefully optimizing endometrial receptivity. The story in low responder patients seems to be more complex and still in debate. Furthermore, very few papers have suggested that elevated follicular P level could be from an adrenal origin.     

Taken together, the patient in this case presentation should not be canceled; she is not ovulating or showing signs of premature luteinization but rather signs of excessive steroidogenic activity in response to the rec-hFSH stimulation. I would carry on  trigger the ovulation and perform a fresh transfer unless there are early manifestations of ovarian hyperstimulation syndrome. If she fails to get pregnant I would add LH/LH activity to the FSH stimulation in her next superovulation protocol to try and reduce her elevated P level. Additionally, an adrenal origin of the elevated follicular P level could be investigated or alternately a trial of oral therapy with dexamethasone 0.5 mg/day could be added (before bedtime) to the regimen.  

Professor Johhny S. Younis

Poriya Medical Center, Tiberias, Israel.

Answer By Ariel Weissman

I believe that your patient is a very good responder and what we see is a hyper-response and hyper-function of granulosa cells to stimulation, and premature luteinization or imminent ovulation. I would proceed with oocyte retrieval and if multiple good quality are available, proceed also with ET and transfer a single good quality embryo/blastocyst and freeze all the others.
If the patient does not get pregnant from the fresh or frozen embryos of this cycle I would certainly change the stimulation protocol:
1. Use a milder protocol, probably 100/112.5 IU of FSH.
2. Include LH in the gonadotropin regimen, at least for the second half of stimulation.
3. A GnRH antagonist protocol might work very well for this patient.
4. If P elevation is persistent in subsequent cycles, adjunctive steroids (dexamethasone 0.5 mg/d) might be beneficial. See: Fertil Steril. 1997 May;67(5):959-61.Elevated serum progesterone levels during pituitary suppression may signify adrenal hyperandrogenis. Eldar-Geva T, Margalioth EJ, Brooks B, Algur N, Gal M, Zylber-Haran E, Bar I, Diamant YZ.

For an excellent review on this subject: Reprod Biomed Online. 2010 Oct;21(4):446-9. The source and implications of progesterone rise during the follicular phase of assisted reproduction cycles. Fleming R, Jenkins J.

Ariel Weissman
IVF Units Wolfson Medical center

Answer By Matan Yemini

1 No point for embryo transfer with this level of Progesterone but embryo freezing is one option VS D/C the cycle
2 With the assumption that day 3 Progesterone was <2 , the best explanation is that she missed one day of GnRH and then it stimulate an LH. ( other option is an old Corpus Luteum been effected by the FSH )
3 For next cycle, same protocol is OK but better to go with GnRH antagonist to refuse the risk of same problem.

Dr Matan Yemini
Diamond Institute for Infertility, NJ USA

Answer By Michael Alper

I do not believe that she ovulated but do believe she has luteinization from her response. This could advance the endomtrium to be asynchronous and affect implantation. There appears to be a P4 threshold above which negatively affects implantation. The problem is you need the data from your own center since it depends on the P4 assay itself. The largest data set on this is from IVI. With a P4 of 2.0 ng/ml, the cautious think to do is to do the retrieval, and freeze all the embryos and replace in a frozen/thaw cycle. As to preventing this in future, I would try an antagonist cycle next.

Michael Alper MD
Boston IVF, Harvard Medical School

Answer by Bart C.J.M. Fauser

Many questions;
This indeed seems like extensive premature luteinization.
I would cancel the cycle or freez all (considering presumed negative effects on endometrial receptivity).
I would make sure that there are no compliance issues.
Maybe try antagonist next time.

Bart C.J.M. Fauser, M.D.,Ph.D.
Professor of Reproductive Medicine, Chair, Division Woman & Baby
University Medical Center Utrecht, Utrecht, The Netherlands

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