Towards an Improved Understanding of the Effects of Elevated Progesterone Levels on Human Endometrial Receptivity and Oocyte/Embryo Quality during Assisted Reproductive Technologies

Kalakota, Nischelle R.; George, Lea C.; Morelli, Sara S.; Douglas, Nataki C.; Babwah, Andy V.

doi:10.3390/cells11091405

Cited by 20 publications

(13 citation statements)

References 88 publications

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“…An imbalance of steroid hormones is related to many pregnancy complications, such as preeclampsia, caused by insufficient P4 [ 69 ]. A premature increase in P4 levels is related to abnormal implantation and decreased pregnancy rates [ 70 , 71 , 72 , 73 ]. Due to the paracrine effect of P4 on endometrial cells, the proliferation of endometrial cancer cells is inhibited [ 26 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

Progesterone Induces Apoptosis and Steroidogenesis in Porcine Placental Trophoblasts

Liu

Ding

Yang

et al. 2022

Animals

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Placentation and placental steroidogenesis are important for pregnancy and maternal–fetal health. As pregnancy progresses, the main site of progesterone (P4) synthesis changes from the corpus luteum to the placenta, in which placental trophoblasts are the main cell type for P4 synthesis. Therefore, this study investigated the effects of P4 on apoptosis and steroidogenesis in porcine placental trophoblasts and the underlying molecular mechanisms. Porcine placental trophoblasts were treated with different concentrations of P4 for 48 h in a serum-free medium in vitro. Cell number, steroidogenesis, and relevant gene and protein expression levels were detected. A high dose of P4 (10.0 μM) significantly increased P4 (p < 0.01), androstenedione (p < 0.05), testosterone (p < 0.05), and estradiol (p < 0.05) production in porcine placental trophoblasts compared with that in control cells, while a low dose of P4 (1 × 10−3 μΜ) had no marked impact on steroid production. The mRNA expression of apoptosis-related genes (CASP3, CASP8, and Bax) (p < 0.05) and steroidogenesis-related genes (CYP11A1, CYP19A1, and StAR) (p < 0.01) was upregulated, and the expression of HSD3B and HSD17B4 was inhibited (p < 0.05) in the porcine placental trophoblasts treated with high doses of P4. Low doses of P4 had a lighter effect on gene expression than high doses. The expression of apoptosis-related proteins CASP3 (p < 0.05), and Bax (p < 0.01) and steroidogenesis-related proteins CYP19A1 (p < 0.05) and StAR (p < 0.01) was raised, but the proliferation-related protein CCND2 (p < 0.01) was downregulated in the pTr cells treated with high dose of P4. In comparison, a low dose of P4 inhibited the expression of Bax, CYP11A1 (all p < 0.01), and CCND2 (p < 0.05), but the expression of CASP3 (p < 0.05) and StAR (p < 0.01) was upregulated. In summary, excessive P4 can induce the apoptosis of porcine placental trophoblasts and lead to abnormal steroidogenesis in the placenta and hormone imbalance.

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Section: Discussionmentioning

confidence: 99%

Progesterone Induces Apoptosis and Steroidogenesis in Porcine Placental Trophoblasts

Liu

Ding

Yang

et al. 2022

Animals

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“…Our study revealed that members of the ADGR gene family are dynamically expressed across the natural menstrual cycle and early mouse pregnancy. Their expression also appears to be altered by ovarian stimulation, during which supraphysiologic levels of E2 and an early rise in P4 are seen (Kalakota et al 2022). The differential gene expression observed between the proliferative and secretory phase of the menstrual cycle, along with changes in expression seen with OS suggest that ADGR expression is hormonally regulated by E2 and P4.…”

Section: Discussionmentioning

confidence: 99%

“…Ovarian stimulation (OS), utilized for the development of multiple ovarian follicles for IVF, induces supraphysiologic levels of E2 and an early rise in P4 (Kalakota et al 2022). These hormonal changes induce morphological, biochemical, and functional genomic modifications that disrupt receptivity and decrease implantation rates following fresh embryo transfers (Kalakota et al 2022). Thus, with fresh embryo transfers, when the cultured embryo is returned to the uterine cavity, it may encounter a non-receptive endometrium, resulting in implantation failure.…”

Section: Introductionmentioning

confidence: 99%

Endometrial adhesion G protein-coupled receptors are dynamically expressed across the menstrual cycle and expression is altered by ovarian stimulation

Kalakota

Lemenze

George

et al. 2022

Preprint

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Ovarian stimulation (OS), utilized for the development of multiple ovarian follicles for IVF, induces supraphysiologic levels of E2 and an early rise in P4 that disrupt endometrial differentiation and decreases implantation rates or result in placental insufficiency and pregnancy complications. To improve pregnancy rates and reduce the risk of pregnancy complications associated with IVF, it is crucial to advance our molecular understanding of the molecular regulation of endometrial differentiation. Previous studies from our laboratory suggest G protein-coupled receptors (GPCRs) are important regulators of endometrial differentiation. To investigate this further, using a retrospective dataset, we identified all GPCRs expressed across the proliferative and secretory phase of the menstrual cycle and found that many members of the adhesion G protein-coupled receptor (ADGR) family are dynamically expressed. For each ADGR subfamily exhibiting differentially-expressed genes across the cycle, their expression was investigated by RT-PCR in the non-pregnant mouse uterus and decidua on E7.5 of pregnancy. For those genes expressed in the E7.5 decidua, their expression was further quantified by qPCR across early mouse pregnancy. The RT-PCR screen revealed expression of 13 ADGRs (4 of the 9 subfamilies) in E7.5 decidua and among these genes, many were differentially expressed between E0.5 and E5.5 or 6.5 and between E5.5 and E6.5. The dynamic expression of the ADGRs across the menstrual cycle and in early mouse pregnancy, suggests these ADGRs are E2- and/or P4-regulated genes. We therefore hypothesized that for these ADGR genes, mRNA expression would be disrupted in an OS cycle. This hypothesis was tested on endometrial biopsies collected in the secretory phase from prospective cohorts of women in natural and OS cycles. Consistent with the retrospective dataset, our data revealed that members of the ADGR gene family are expressed in the secretory phase of the natural menstrual cycle and for the first time, we show that their expression is altered by ovarian stimulation.

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“…As one of the most important sex steroids and key cyclical reproductive hormones with major impacts on the female organs of vertebrate species, progesterone (PRG) is mainly produced by the corpus luteum (CL) of the ovaries. Besides its reproductive significance, PRG can also be generated from the adrenal cortex, Leydig cells of the male testes, adipose cells and neuronal and glial cells [ 1 , 2 , 3 , 4 , 5 , 6 ], reaffirming its wide range of physiological effects, especially in the metabolic systems, central nervous systems and reproductive systems in both genders [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. PRG was first purified almost a century ago as an ovarian steroid with hormonal function for pregnancy [ 8 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions

et al. 2023

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Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.

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Towards an Improved Understanding of the Effects of Elevated Progesterone Levels on Human Endometrial Receptivity and Oocyte/Embryo Quality during Assisted Reproductive Technologies

Cited by 20 publications

References 88 publications

Progesterone Induces Apoptosis and Steroidogenesis in Porcine Placental Trophoblasts

Progesterone Induces Apoptosis and Steroidogenesis in Porcine Placental Trophoblasts

Endometrial adhesion G protein-coupled receptors are dynamically expressed across the menstrual cycle and expression is altered by ovarian stimulation

Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions

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