Secretory products of the corpus luteum and preeclampsia

Abstract

Background: Despite significant advances in our understanding of the pathophysiology of preeclampsia (PE), there are still many unknowns and controversies in the field. Women undergoing frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium have been found to have an unexpected increased risk of PE compared to women who receive embryos in a natural FET cycle. The differences in risk have been hypothesized to be related to the absence or presence of a functioning corpus luteum (CL).

Objective and rationale: To evaluate the literature on secretory products of the CL that could be essential for a healthy pregnancy and could reduce the risk of PE in the setting of FET.

Search methods: For this review, pertinent studies were searched in PubMed/Medline (updated June 2020) using common keywords applied in the field of assisted reproductive technologies, CL physiology and preeclampsia. We also screened the complete list of references in recent publications in English (both animal and human studies) on the topics investigated. Given the design of this work as a narrative review, no formal criteria for study selection or appraisal were utilized.

Outcomes: The CL is a major source of multiple factors regulating reproduction. Progesterone, estradiol, relaxin and vasoactive and angiogenic substances produced by the CL have important roles in regulating its functional lifespan and are also secreted into the circulation to act remotely during early stages of pregnancy. Beyond the known actions of progesterone and estradiol on the uterus in early pregnancy, their metabolites have angiogenic properties that may optimize implantation and placentation. Serum levels of relaxin are almost undetectable in pregnant women without a CL, which precludes some maternal cardiovascular and renal adaptations to early pregnancy. We suggest that an imbalance in steroid hormones and their metabolites and polypeptides influencing early physiologic processes such as decidualization, implantation, angiogenesis and maternal haemodynamics could contribute to the increased PE risk among women undergoing programmed FET cycles.

Wider implications: A better understanding of the critical roles of the secretory products of the CL during early pregnancy holds the promise of improving the efficacy and safety of ART based on programmed FET cycles.

Keywords: angiogenesis; corpus luteum; estradiol; estradiol metabolites; frozen-thawed embryo transfer; implantation; placentation; preeclampsia; progesterone; relaxin.

Figure 1.

Schematic representation of the systemic cross-talk (black dashed arrows) between the embryo and the CL during early pregnancy (<10 weeks). The CL produces multiple steroid and polypeptide hormones that control its own lifespan (i.e. paracrine regulation, red dashed arrow), but also that act remotely (i.e. systemic regulation) to guide embryo implantation and placentation. The elaboration of hCG by the trophoblast prevents regression of the CL (i.e. luteolysis). The latter responds to the embryo with the release of proangiogenic and vasoactive substances that further support its growth and development. The CL is mainly composed of two hormone-producing cell types, theca lutein and granulosa lutein cells, that work collaboratively in steroidogenesis. *Although most of the circulating relaxin-2 is produced by granulosa lutein cells, theca cells represent a significant local source of relaxin-2. For further information see text. CL: corpus luteum; E₂: estradiol; EM: ooestrogen metabolites; hCG: human chorionic gonadotropin; P: progesterone; T: testosterone; VEGF: vascular growth factor.

Figure 2.

Potential consequences of the absence of a CL (and its secretory products) in early pregnancy. An unbalanced early hormonal milieu would impair endometrial quality for implantation, placental angiogenesis and development, and prevent the early maternal cardiovascular adaptations required to cope with haemodynamic loads of pregnancy. All these mechanisms would play together increasing the risk of developing preeclampsia as the pregnancy progresses. *Placental hypoxia and stress trigger the release of anti-angiogenic, vasoactive and pro-inflammatory factors into the maternal systemic circulation that further impair the vascular and haemodynamic condition. BP: blood pressure; CL: corpus luteum; GFR: glomerular filtration rate; IVF in-vitro fertilization; LV: left ventricle; PVR: peripheral vascular resistance; RBF: renal plasma flow; UA: uterine artery.

Figure 3.

Proposed physiological roles of relaxin-2 during pregnancy. Relaxin-2 produces its major effects through the activation of its membrane receptor, RFXP1, which in turns leads to an up-regulation of cAMP, NO and gene transcription (e.g. VEGF, MMP and PPARṾ), promoting cardiovascular and renal adaptation, endometrial remodelling, vascularization and placental development. BP: blood pressure; cAMP: cyclic adenosine monophosphate; CO: cardiac output; GFR: glomerular filtration rate; MMP: matrix metalloproteinases; NO: nitric oxide; PlGF: placental growth factor; PPARṾ: peroxisome proliferator-activated receptor gamma; RBF: renal blood flow; SVR: systemic vascular resistance; VEGF: vascular endothelial growth factor.