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Luteal phase support in assisted reproductive technology

Nature Reviews Endocrinology volume 20, pages 149–167 (2024)Cite this article

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Abstract

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely ‘black-box’ with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the ‘window of implantation’. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.

Key points

  • During in vitro fertilization (IVF) treatment, supraphysiological ovarian stimulation and the resultant high sex steroid levels can disrupt the luteal phase via insufficient progesterone production from the corpora lutea, shortening the luteal phase.

  • Luteal phase support during IVF can support implantation and maintain pregnancy by increasing progesterone levels, which is achieved either by increasing endogenous sex steroid secretion or by directly supplementing with sex steroids.

  • The presence, or not, of the corpus luteum has implications for the degree of luteal phase support required to maintain pregnancy and for the risk of pregnancy complications.

  • A gonadotrophin-releasing hormone receptor agonist (GnRHa) trigger for ovarian maturation is not sufficient to support functional corpora lutea, resulting in a more disrupted luteal phase than a human chorionic gonadotrophin (hCG) trigger.

  • Frozen embryo transfer (FET) can mitigate the effect of the disrupted luteal phase after ovarian stimulation, and is favoured especially if a GnRHa is used to trigger oocyte maturation.

  • FET, especially via methods that do not result in the formation of a functional corpus luteum, can increase the risk of pregnancy complications such as pre-eclampsia compared with fresh embryo transfer cycles.

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Fig. 1: The luteal phase in natural and IVF cycles, and serum progesterone levels in early pregnancy.
Fig. 2: The nuclear progesterone receptor.
Fig. 3: The luteal phase, endometrial receptivity and the window of implantation.

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Author notes

  1. These authors contributed equally: Akanksha Garg, Agata P. Zielinska.

  2. These authors jointly supervised this work: Scott M. Nelson, Andy V. Babwah, Waljit S. Dhillo. and Ali Abbara.

Authors and Affiliations

  1. Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, UK

    Akanksha Garg, Agata P. Zielinska, Arthur C. Yeung, Rebecca Abdelmalak, Runzhi Chen, Aleena Hossain, Alisha Israni, Waljit S. Dhillo & Ali Abbara

  2. Imperial College Healthcare NHS Trust, London, UK

    Akanksha Garg, Agata P. Zielinska, Arthur C. Yeung, Waljit S. Dhillo & Ali Abbara

  3. School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, UK

    Scott M. Nelson

  4. NIHR Biomedical Research Centre, University of Bristol, Bristol, UK

    Scott M. Nelson

  5. The Fertility Partnership (TFP), Oxford, UK

    Scott M. Nelson

  6. Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Andy V. Babwah

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Contributions

A.G., A.P.Z., A.C.Y., R.A., R.C., A.H. and A.I. researched data for the article. A.G., A.P.Z., A.C.Y., S.M.N., A.V.B. and A.A. contributed substantially to discussion of the content. A.G., A.P.Z., A.C.Y. and A.A. wrote the article. S.M.N., A.V.B., W.S.D. and A.A. reviewed and/or edited the manuscript before submission.

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Correspondence to Ali Abbara.

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A.A. and W.S.D. have consulted for Myovant Sciences Ltd. S.M.N. has participated in Advisory Boards and received consultancy or speakers’ fees from Access Fertility, Beckman Coulter, Ferring, Finox, Merck, Modern Fertility, MSD, Roche Diagnostics, and The Fertility Partnership. The other authors report no competing interests.

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Garg, A., Zielinska, A.P., Yeung, A.C. et al. Luteal phase support in assisted reproductive technology. Nat Rev Endocrinol 20, 149–167 (2024). https://doi.org/10.1038/s41574-023-00921-5

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