Progesterone-Receptor Antagonists and Statins Decrease De Novo Cholesterol Synthesis and Increase Apoptosis in Rat and Human Periovulatory Granulosa Cells In Vitro1

Rung, Emilia; Friberg, Peter; Shao, Ruijin; Larsson, D. G. Joakim; Nielsen, Eva Ch.; Svensson, Per‐Arne; Carlsson, Björn; Carlsson, Lena; Billig, Håkan

doi:10.1095/biolreprod.104.033878

Cited by 42 publications

(34 citation statements)

References 38 publications

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“…Progesterone receptor modulators, including mifepristone, have been shown to induce apoptosis and DNA fragmentation in endometrial cells (Prange-Kiel et al, 2000) and granulosa cells (Rung et al, 2005). To our knowledge, there is no study of mifepristone or UPA on DNA integrity.…”

Section: (A) (B)mentioning

confidence: 96%

An in vitro study of the effect of mifepristone and ulipristal acetate on human sperm functions

Huang

et al. 2014

Andrology

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SUMMARYUlipristal acetate (UPA) and mifepristone are currently well-established agents for emergency contraception. Both drugs are selective progestogen receptor modulators which have been shown to have better efficacy than the widely used levonorgestrel in prevention of pregnancy. However, there is only limited information on the action of UPA on sperm function. The present study compared the in vitro biological effects of mifepristone and UPA on human sperm functions. Spermatozoa from semen samples with normal semen parameters were isolated. Capacitated spermatozoa were pre-incubated with 0.04, 0.4, 4 and 40 lM mifepristone or UPA for 1 h. Sperm motility, viability, DNA integrity, capacitation, spontaneous acrosome reaction, spontaneous hyperactivation, zona pellucida (ZP) binding capability and intracellular calcium concentration ([Ca 2+ ] i ) were determined. The effects of mifepristone and UPA on progesterone-induced acrosome reaction, hyperactivation and [Ca 2+ ] i were also studied. Our results showed that mifepristone and UPA dose-dependently suppressed progesterone-induced acrosome reaction, hyperactivation and [Ca 2+ ] i at concentrations ≥0.4 lM in human spermatozoa. Both compounds did not affect sperm motility, viability, DNA integrity, capacitation, spontaneous acrosome reaction, spontaneous hyperactivation, ZP binding capability and [Ca 2+ ] i . This study demonstrated that UPA and mifepristone modulate human sperm functions by acting as progesterone antagonists. The results enable us to gain a better understanding of the mechanisms by which mifepristone and UPA work for emergency contraception, and provide a scientific basis for their clinical application.

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Section: (A) (B)mentioning

confidence: 96%

An in vitro study of the effect of mifepristone and ulipristal acetate on human sperm functions

Huang

et al. 2014

Andrology

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“…Levels of cholesterol in cumulus cells and/or oocytes were compared by assessing the incorporation of [1-14 C]acetate into cholesterol using a protocol adapted from previous reports (Friberg et al, 2007;Rung et al, 2006;Rung et al, 2005). Briefly, for comparing cholesterol synthesis in WT, Bmp15 -/-, and DM COCs, 150 COCs of each genotype were cultured in medium supplemented with 10 Ci [1-14 C]acetic acid, sodium salt (Amersham Biosciences, Buckinghamshire, UK) for 5 hours.…”

Section: Analysis Of De-novo Cholesterol Biosynthesismentioning

confidence: 99%

Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells

et al. 2008

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*Oocyte-derived bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) are key regulators of follicular development. Here we show that these factors control cumulus cell metabolism, particularly glycolysis and cholesterol biosynthesis before the preovulatory surge of luteinizing hormone. Transcripts encoding enzymes for cholesterol biosynthesis were downregulated in both Bmp15-/-and Bmp15 -/-Gdf9 +/-double mutant cumulus cells, and in wild-type cumulus cells after removal of oocytes from cumulus-cell-oocyte complexes. Similarly, cholesterol synthesized de novo was reduced in these cumulus cells. This indicates that oocytes regulate cumulus cell cholesterol biosynthesis by promoting the expression of relevant transcripts. Furthermore, in wild-type mice, Mvk, Pmvk, Fdps, Sqle, Cyp51, Sc4mol and Ebp, which encode enzymes required for cholesterol synthesis, were highly expressed in cumulus cells compared with oocytes; and oocytes, in the absence of the surrounding cumulus cells, synthesized barely detectable levels of cholesterol. Furthermore, coincident with reduced cholesterol synthesis in double mutant cumulus cells, lower levels were also detected in cumulus-cell-enclosed double mutant oocytes compared with wild-type oocytes. Levels of cholesterol synthesis in double mutant cumulus cells and oocytes were partially restored by co-culturing with wild-type oocytes. Together, these results indicate that mouse oocytes are deficient in synthesizing cholesterol and require cumulus cells to provide products of the cholesterol biosynthetic pathway. Therefore, oocyte-derived paracrine factors, particularly, BMP15 and GDF9, promote cholesterol biosynthesis in cumulus cells, probably as compensation for oocyte deficiencies in cholesterol production.

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“…This mechanism would account for P4's ability to induce StAR expression in MA-10 (41) and promote cholesterol and P4 synthesis in human and rat granulosa cells (42). Because PGRMC1 also binds to PAIRBP1, how this interaction is influenced by P4 and how this might affect the formation of the PAIRBP1-INSIG1-SCAP complex remains an open question.…”

Section: Pgrmc1 Transduces P4's Antimitotic Action In These Cellsmentioning

confidence: 99%

Progesterone Membrane Receptor Component 1 Expression in the Immature Rat Ovary and Its Role in Mediating Progesterone’s Antiapoptotic Action

et al. 2006

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Progesterone receptor membrane component-1 (PGRMC1) interacts with plasminogen activator inhibitor RNA binding protein-1 (PAIRBP1), a membrane-associated protein involved in the antiapoptotic action of progesterone (P4). In this paper, the first studies were designed to assess the ovarian expression pattern of PGRMC1 and PAIRBP1. Western blot analysis revealed that spontaneously immortalized granulosa cells (SIGCs) as well as granulosa and luteal cells express both proteins. Luteal cells were shown to express more PGRMC1 than granulosa cells. Immunohistochemical studies confirmed this and demonstrated that PGRMC1 was present in thecal/stromal cells, ovarian surface epithelial cells, and oocytes. PAIRBP1 was also expressed in thecal/stromal cells and ovarian surface epithelial cells but not oocytes. Furthermore, PAIRBP1 and PGRMC1 were detected among the biotinylated surface proteins that were isolated by avidin affinity purification, indicating that they localized to the extracellular surface of the plasma membrane. Confocal microscopy revealed that both of these proteins colocalize to the plasma membrane as well as the cytoplasm. The second studies were designed to assess PGRMC1's role in P4's antiapoptotic actions. These studies showed that overexpression of PGRMC1 increased 3H-P4 binding and P4 responsiveness. Conversely, treatment with a PGRMC1 antibody blocked P4's antiapoptotic action. Taken together, the present findings indicate that both PAIRBP1 and PGRMC1 show a similar expression pattern within the ovary and colocalize to the extracellular surface of the plasma membrane. At the plasma membrane, these two proteins interact to form a complex that is required for P4 to transduce its antiapoptotic action.

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Progesterone-Receptor Antagonists and Statins Decrease De Novo Cholesterol Synthesis and Increase Apoptosis in Rat and Human Periovulatory Granulosa Cells In Vitro1

Cited by 42 publications

References 38 publications

An in vitro study of the effect of mifepristone and ulipristal acetate on human sperm functions

An in vitro study of the effect of mifepristone and ulipristal acetate on human sperm functions

Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells

Progesterone Membrane Receptor Component 1 Expression in the Immature Rat Ovary and Its Role in Mediating Progesterone’s Antiapoptotic Action

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