Individualized luteal phase support normalizes live birth rate in women with low progesterone levels on the day of embryo transfer in artificial endometrial preparation cycles

Supplementation with subcutaneous progesterone in women with low serum progesterone level on the day of embryo transfer normalizes pregnancy rates in artificial cycles.

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VOLUME 117, ISSUE 1, P96-103

Authors:

Elena Labarta, M.D., Giulia Mariani, M.D., Cristina Rodríguez-Varela, Ms.C., Ernesto Bosch, M.D.

Abstract:

Objective

To analyze the impact on live birth rates (LBRs) of the individualized luteal phase support (termed iLPS) in patients with low serum progesterone (P) levels compared with patients without iLPS.


Design

Retrospective cohort study, December 1, 2018, to May 30, 2019.


Setting

Private medical center.


Patient(s)

A total of 2,275 patients checked for serum P on the day of blastocyst transfer were analyzed. During the study period, 1,299 patients showed serum P levels of ≥9.2 ng/mL, whereas 550 showed serum P levels of <9.2 ng/mL and received iLPS. Additionally, a historical group of 426 patients with serum P levels of <9.2 ng/mL but no iLPS were used for comparison.
Eligible patients were aged ≤50 years with adequate endometrium morphology after receiving estrogens. Luteal phase support was provided with micronized vaginal P (MVP) to all women. Patients with personalized initiation of exogenous P according to the endometrial receptivity assay test, polyps, fibroids distorting the cavity, or hydrosalpinx were not included in the analysis.


Intervention(s)

As routine practice since December 2018, patients with low serum P levels received an iLPS with a daily injection of 25 mg of subcutaneous P from the day of embryo transfer (ET) in addition to standard LPS (400 mg of MVP twice a day).


Main Outcome Measure(s)

Live birth rate.


Result(s)

The LBR was 44.9% in the iLPS cases vs. 45.0% in patients with normal serum P levels (crude odds ratio [OR], 1.0; 95% confidence interval [CI], 0.82–1.22). By regression analysis, low serum P levels did not affect the LBR after adjusting for possible confounders (age, oocyte origin, fresh vs. frozen, day of ET, embryo quality, number of embryos transferred) (adjusted OR, 0.99; 95% CI, 0.79–1.25). Similarly, no differences were observed in other pregnancy outcomes between groups.
The LBR was significantly higher in the group of patients who received additional subcutaneous P (iLPS) compared with the historical group with low serum P levels and no iLPS (44.9% vs. 37.3%; OR, 1.37; 95% CI, 1.06–1.78).
In the overall population, patients showing P levels of <9.2 ng/mL on the day of ET were slightly younger and had higher body mass index and lower estradiol and P levels during the proliferative phase compared with patients with P levels of ≥9.2 ng/mL. No differences were observed with regard to the time in between the last dose of MVP and the serum P determination. After a multivariable logistic regression analysis, only body mass index and estradiol levels in the proliferative phase reminded statistically significant.
Significant differences in the LBR were observed between patients with serum P levels of <9.2 ng/mL without iLPS and patients with serum P levels of ≥9.2 ng/mL when using either own or donated oocytes.


Conclusion(s)

Individualized LPS for patients with low serum P levels produces LBRs similar to those of patients with adequate serum P levels.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. 

Comments

Go to the profile of Yossi Mizrachi
19 days ago

Dear Authors,

We have read this paper with great interest. Over the last two decades, vast research has been performed in order to optimize IVF protocols, and individualization has become a major component of controlled ovarian hyperstimulation. For example, different stimulation protocols have been proposed for high and poor responders, endometriosis patients, etc. The luteal phase, however, has been neglected in that sense, and a practice of "one size fits all" has become the rule in the majority of ART programs, as most patients receive the same fixed regimen of LPS. We would like to commend the authors for their effort to individualize luteal phase support, acknowledging that there is a group of patients that might benefit from augmentation of P supplementation.

In artificial endometrial preparation cycles, low mid-luteal serum P level has been associated with a lower live birth rate in multiple studies (1). The fact that P levels are lower in patients with higher BMI implies that this finding is related to poor vaginal absorption or higher volume of distribution, resulting in lower bioavailability. It is hypothesized that serum P level reaches a steady state during artificial cycles, as opposed to the natural pulsatile pattern of P secretion by the corpora lutea in fresh cycles. Therefore, clinicians can evaluate P bioavailability using a single serum measurement. Sufficient supplementation of luteal phase support is crucial, since in artificial cycles the corpus luteum is absent and only exogenous P is available to support implantation and early pregnancy development.

The current study is in agreement with recent studies showing that in artificial cycles, LPS using vaginal-only P supplementation is insufficient for a sub-group of patients, and that a better outcome is achievable with the addition of either oral dydrogesterone (2) or intramuscular P (3). The next step was naturally to identify those patients for whom vaginal P is insufficient and who might benefit from additional supplementation of oral, subcutaneous or intramuscular P. Measurement of serum P level on the day of embryo transfer is apparently suitable for detection of those women and also an appropriate time for intervention, according to the current publication.

We are challenging Labarta et al. on the cut-off level of serum P under which LPS augmentation is required. A level of 9.2 ng/mL corresponded with the 25th percentile in a previous study by the same group (4). However, a more gradual impact of serum P level on the effectiveness of LPS seems more likely. A recent study found similar results with the addition of subcutaneous P in artificial cycles when mid-luteal P level was <10.6 ng/mL (5), while another study found lower birth rates only when serum P level was <5 ng/mL (6). We suggest a marker-based approach in which the need for additional supplementation is evaluated in relation to the serum P level and maybe other patient characteristics, such as BMI and estradiol level (7). This should preferably be evaluated in well-designed RCTs or in well-planned large cohort studies.

Kind Regards, 

Yossi Mizrachi 1, Daniel Lantsberg 1, Ben W Mol 2 3

1 Reproductive Services Unit, The Royal Women’s Hospital, Melbourne, Victoria, Australia

2 Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia.

3 Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK. ORCID ID 0000-0001-8337-550X ben.mol@monash.edu

References:

  1. Melo P, Chung Y, Pickering O, Price MJ, Fishel S, Khairy M et al. Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Fertility and sterility 2021;116:1534-56.
  2. Vuong LN, Pham TD, Le KTQ, Ly TT, Le HL, Nguyen DTN et al. Micronized progesterone plus dydrogesterone versus micronized progesterone alone for luteal phase support in frozen-thawed cycles (MIDRONE): a prospective cohort study. Human reproduction (Oxford, England) 2021;36:1821-31.
  3. Devine K, Richter KS, Jahandideh S, Widra EA, McKeeby JL. Intramuscular progesterone optimizes live birth from programmed frozen embryo transfer: a randomized clinical trial. Fertility and sterility 2021;116:633-43.
  4. Labarta E, Mariani G, Holtmann N, Celada P, Remohí J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Human Reproduction 2017;32:2437-42.
  5. Álvarez M, Gaggiotti-Marre S, Martínez F, Coll L, García S, González-Foruria I et al. Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study. Human Reproduction 2021;36:1552-60.
  6. Volovsky M, Pakes C, Rozen G, Polyakov A. Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles? J Assist Reprod Genet 2020;37:1129-35.
  7. Tajik P, Zafarmand MH, Zwinderman AH, Mol BW, Bossuyt PM. Development and evaluating multimarker models for guiding treatment decisions. BMC Med Inform Decis Mak 2018;18:52.