Ongoing pregnancy rates in intrauterine insemination are affected by late follicular phase progesterone levels

Capsule:
Significant differences in ongoing pregnancy rates with high P levels after stimulated IUI cycles may help clinicians counsel patients about reduced success rates and time insemination to optimize implantation.

Authors:
Antonio Requena, M.D., María Cruz, Ph.D., Alberto Pacheco, Ph.D., Juan Antonio García-Velasco, M.D.

Volume 104, Issue 4, Pages 879-883

Abstract:

Objective:
To determine the relationship between serum P levels on the day of hCG administration and ongoing pregnancy rates.

Design:
Retrospective study.

Setting:
University-affiliated private IVF setting belonging to IVI group in Spain.

Patient(s):
A total of 2,458 couples undergoing IUI.

Intervention(s):
Ovarian stimulation with human recombinant FSH.

Main Outcome Measure(s):
Ongoing pregnancy and miscarriage rates.

Result(s):
Progesterone concentrations were significantly higher given that the E2 concentration increased. Ongoing pregnancy rates were significantly decreased in women with P levels higher than 1.1 ng/mL; similar results were obtained in relation to miscarriage rates.

Conclusion(s):
Significant differences in ongoing pregnancy rates when P levels were elevated on the day of hCG administration may help clinicians to counsel patients about the reduced success rates with IUI and manage the timing of insemination to optimize implantation.

  • Roberto Matorras MD, PhD

    We read with great interest the article of
    Requena et al. entitled “Ongoing pregnancy rates in intrauterine
    insemination are affected by late follicular-phase progesterone levels” ( 1).
    The authors conducted a retrospective study in 2,458 women
    undergoing IUI, with either their partner’s or a donor’s sperm and they concluded
    that in IUI cycles, ongoing pregnancy rates were significantly
    lower in women with progesterone (P) levels >1.1
    ng/mL. They suggest that in IUI cycles the premature
    increase in plasma P could be a sign of premature luteinization as a result of
    a spontaneous LH peak, since unlike in IVF cycles, GnRH agonists were not
    administered in their IUI study, as in a number of IUI programs.

    We would like to make some
    comments regarding the controversial topic of “premature luteinization” (2) in
    the context of IUI, based on our previous experience, in particular, in
    relation to a prospective study performed some years ago in a much smaller IUI population
    (152 women, 208 cycles)(3). Notably, the results were very similar, despite a
    number of differences between the population in Requena et al.’s study and ours
    (namely, we considered IUI performed with partner’s sperm only, much higher
    FSH doses, and especially
    systematic use of GnRH antagonists in all cycles) and the chemiluminescence method used
    for assessing P levels (our measurements being made on an ADVIA Centaur XP™
    Automated Chemiluminescence System).
    We found that pregnancy rates were significantly lower with P values > 1
    ng/ml, and above this threshold, the higher the P value, the lower the
    pregnancy rates. We fully agree with their conclusions and recommendations.

    On the other hand, we would like to underline that there are two different events:
    a) a progresterone rise (defined in our study as P > 1.0 ng/mL), which occurred
    relatively frequently, in spite of GnRH antagonist administration (22.1% in our
    study vs 10.3% in Requena et al. considering a cut-off of P> 1.1 ng/mL and
    without antagonists); and b) a premature LH peak . In our study, we
    systematically searched for a premature LH peak (defined as LH > 10 mUI/mL),
    and as expected – since GnRH antagonists were administered- found a very low
    frequency (4.58%). Moreover, no differences were observed in pregnancy rate in
    the LH peak group (although the number of cases was small).The majority of LH
    peaks had normal P values. Further, the combination of LH peak and P > 1 ng/mL
    occurred only in 1.45% of cases.

    In our opinion, the term “premature luteinization” should be restricted to cases with
    both premature LH surge and P rise, and in other cases the term progesterone
    rise should be employed. This P rise could be related to increased estrogen
    production by the follicle/ ovary. In agreement with this, Requena et al.
    reported that P values became significantly higher with increasing estradiol
    concentration.

    References

    1.
    Requena A, Cruz M, Pacheco A, García-Velasco JA. Ongoing pregnancy
    rates in intrauterine insemination are affected by late
    follicular-phase progesterone levels. Fertil Steril. 2015 ;104:879-83

    2.
    Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P,
    Tarlatzis BC. Is progesterone elevation on the day of human
    chorionic gonadotrophin administration associated with the probability of pregnancy
    in in vitro fertilization? A systematic review and metaanalysis. Hum Reprod Update 2007;13:343–55.

    3. Matorras R, Soler AV, Ramon O, Burgos J, Abanto E, González M, Múgica
    J, Corcóstegui B, Pijoan JI, Exposito A. Prognostic value of serum progesterone and LH values on the day of hCG
    administration in IUI GnRH antagonist cycles. Gynecol Endocrinol. 2012 ;28:157-61.

    Matorras R, Ramón O, Expósito A.
    Human Reproduction Unit.
    Gynecology Department. Cruces Hospital. Basque Country University.

  • Rafael Sanchez

    Very interesting topic.
    It´s there any possibility to avoid the premetaure surge of progesterone

    • Antonio Requena

      Dear Rafael

      Thank you for your comment. We think that this progesterone levels could be induced by the LH surge (in difference to the increase found during a ART cycle). In our opinion, you could try to advance the time for the insemination or cancel the cycle.

      • Rafael Sanchez

        Dear Dr Requena. Thank you for your comments.
        best
        Rafael

  • The results of this study are interesting and clinically relevant to most fertility practices, even though the Progesterone cutoff may not be generalizable given lab-to-lab differences in the P assay. In our practice, when a P of >1.0 is found in the late follicular phase, we do the IUI the next day instead of 2 days after the monitoring visit. It would be interesting to see if doing this could restore pregnancy rates- it may help answer the question from your discussion whether the results seen are due to the effect of P on the endometrium or to a premature LH surge.

    • Antonio Requena

      Dear Alex
      Fully agree with you regarding the managment of these cases with Pg over 1.0.
      In fact we are carring out a prospective random trial in this direction (advance the IUI vs our daily practice of performing it 36 hours later from the triggering).

      • Micah Hill

        This would be a fantastic and potentially very beneficial RCT, glad to hear of it!

        • I agree with Micah- thank you for the reply Antonio. I look forward to seeing the results of that trial when they come out!

          • Antonio Requena

            Dear Micah and Alex,

            thanks for your interestest and you can be sure we will keep you informed about our trial (if FS accepts to publishs ours results!!)

      • Jason M. Franasiak

        This is very interesting! Any consideration to doing 2 IUIs as standard practice? This will ensure coverage over the entire period. I know there are studies with 2 IUIs showing modest or mixed benefit. It would be of interest to tailor it to those with premature progesterone rises.

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