Regulation of Progesterone Levels during Pregnancy and Parturition by Signal Transducer and Activator of Transcription 5 and 20α-Hydroxysteroid Dehydrogenase

Piekorz, Roland P.; Gingras, Sébastien; Hoffmeyer, Angelika; Ihle, James N.; Weinstein, Yacob

doi:10.1210/me.2004-0302

Cited by 128 publications

(120 citation statements)

References 44 publications

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“…The AKR1C2 is also known as the bile acid binding protein because one of its functions may be to transport bile acids from the canalicular to the polar end of hepatocyte (Stolz et al, 1993). AKR1C1 which possesses 20α-HSD activity, has been suggested to play an important role in reductive inactivation of progesterone into 20α-hydroxyprogesterone and deficiency of this enzyme has been shown to cause a delay in parturition (Piekorz et al, 2005). Although much is known about the substrate specificity and tissue distribution of AKR1C enzymes, their physiological roles still remains elusive.…”

Section: Akr1c1-c4 -Hydroxysteroid Dehydrogenasesmentioning

confidence: 99%

“…Hence, it is difficult to draw direct parallels between human and murine enzymes. To date, only one knockout model of the enzyme of this family, namely 20α-HSD, has been reported, and this led to a decrease in the survival of pups and an increase in the duration of the estrous cycles and pregnancy (Ishida et al, 2007;Piekorz et al, 2005). Development of specific inhibitors and fluorogenic substrates that can be used to interrogate the role of individual AKR1C isoforms, as well as serve as potential drug candidates is under way (Byrns et al, 2008;Bauman et al, 2005;Yee et al, 2006).…”

Section: Akr1c1-c4 -Hydroxysteroid Dehydrogenasesmentioning

confidence: 99%

See 1 more Smart Citation

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Barski

Tipparaju

Bhatnagar

2008

Drug Metabolism Reviews

436

340

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The Aldo-Keto Reductase (AKR) superfamily comprises of several enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism and detoxification. Substrates of the family include glucose, steroids, glycosylation end products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (β/α) 8 barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the Phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.

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Section: Akr1c1-c4 -Hydroxysteroid Dehydrogenasesmentioning

confidence: 99%

Section: Akr1c1-c4 -Hydroxysteroid Dehydrogenasesmentioning

confidence: 99%

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Barski

Tipparaju

Bhatnagar

2008

Drug Metabolism Reviews

436

340

View full text Add to dashboard Cite

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“…It is well known that the activity of 20aHSD rises at the end of pregnancy and that PRL represses its expression (Albarracin et al 1994). The key role of 20aHSD as a critical component of luteolysis at the end of pregnancy was evidenced most strikingly by the development of the 20aHSD knockout mouse, in which circulating P 4 levels remain elevated and parturition is significantly delayed (Piekorz et al 2005). PGF2a, after binding to its receptor, acts through a cascade of signaling events involving hormones, cytokines, and possible disruptions of intracellular growth factor signaling (Orlicky et al 1992, Olofsson et al 1996.…”

Section: Introductionmentioning

confidence: 99%

Hypothyroidism prolongs corpus luteum function in the pregnant rat

Hapon¹,

Motta²,

Ezquer³

et al. 2007

Reproduction

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It has been shown that hypothyroidism in the rat produces a prolongation of pregnancy associated with a delay in the fall of circulating progesterone (P 4 ) at term. The aim of the present work is to determine whether the delayed P 4 decline in hypothyroid mother rats is due to a retarded induction of P 4 degradation to 20aOH P 4 or to a stimulation of its synthesis, and to investigate the possible mechanisms that may underlie the altered luteal function. We determined by RIA the circulating profile of the hormones (TSH, PRL, LH, P 4 , PGF2a, and PGE2) involved in luteal regulation at the end of pregnancy and, by semiquantitative RT-PCR, the expression of factors involved in P 4 synthesis (CytP450scc, StAR, 3bHSD, PRLR) and metabolism (20aHSD, PGF2aR, iNOS and COX2). Our results show that the delay in P 4 decline and parturition is the resultant of retarded luteal regression, caused by a combination of decreases in luteolytic factors, mainly luteal PGF2a, iNOS mRNA expression and also circulating LH, and increased synthesis or action of luteotrophic factors, such as luteal and circulating PGE2 and circulating PRL. All these changes may be direct causes of the decreased 20aHSD mRNA and protein (measured by western blot analysis) expression, which in the presence of unchanged expression of the factors involved in P 4 synthesis results in elevated luteal and circulating P 4 that prolonged pregnancy and also may favor longer survival of the corpus luteum.

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“…Piekorz et al [10] recently reported that the parturition of mice lacking the 20α-HSD gene is delayed by 2-3 days and that the pups of these mice die in utero. In their study, the progesterone levels at term of pregnancy were 3-4 times higher than those in wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

“…PGF 2 α -receptor knockout (FP -/-) mice failed to deliver pups due to lack of decline of serum progesterone levels at parturition [9]; at that time, no elevation of 20α-HSD activity was observed [8]. Furthermore, it has recently been reported that 20α-HSD -/-mice exhibited a phenotype similar to FP -/-mice at parturition; notably, the fetuses of the latter mice all died in utero [10]. Thus, expression of 20α-HSD appears to be closely related to functional luteolysis in rodent reproduction.…”

mentioning

confidence: 99%

Reproductive Phenotypes in Mice with Targeted Disruption of the 20.ALPHA.-Hydroxysteroid Dehydrogenase Gene

Ishida

Choi

Hirabayashi

et al. 2007

Journal of Reproduction and Development

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Abstract. In the corpus luteum of rats and mice, 20α-hydroxysteroid dehydrogenase (20α-HSD) catalyzes the conversion of progesterone to a biologically inactive metabolite, 20α-dihydroprogesterone (20α-OHP). The reduction of progesterone by 20α-HSD is believed to be important for functional luteolysis in these rodent species. In addition to the corpus luteum, expression of 20α-HSD has been demonstrated in tissues such as the placenta, endometrial epithelia, and fetal skin, although the roles it plays in the latter tissues remain to be determined. To determine the contribution of 20α-HSD to functional luteolysis and to the rodent reproductive system more generally, we generated a strain of mice with targeted disruption of the 20α-HSD gene. In the 20α-HSD -/-mice we obtained, which lacked the genomic region essential for catalytic reaction, neither 20α-HSD activity in the corpus luteum nor an increase in the serum concentrations of 20α-OHP during pseudopregnancy or pregnancy was detected. The durations of the estrous cycle, pseudopregnancy, and pregnancy were significantly prolonged in the 20α-HSD -/-mice, although the serum progesterone levels decreased to levels low enough for delivery of pups at term of pregnancy. In addition, the number of pups, especially live pups, was markedly decreased in the 20α-HSD -/-mice. These findings suggest that the role of 20α-HSD in functional luteolysis is relatively minor but that it is involved in the survival of newborn mice. Key words: 20α-Hydroxysteroid dehydrogenase (20α-HSD), Luteolysis, Mouse, Ovary, Reproduction (J. Reprod. Dev. 53: [499][500][501][502][503][504][505][506][507][508] 2007) he enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD) is expressed in the rodent corpus luteum, and it catalyzes the conversion of p r o g e s t e r o n e t o i t s i n a c t i v e f o r m , 2 0 α -dihydroprogesterone (20α-OHP). In the estrous cycle of rats, 20α-HSD is thought to play a crucial role in recurrence of unique short cycles through promotion of functional luteolysis [1,2]. The finding that the transcription factors Sp1 and Sp3 stimulate the promoter activity of mouse 20α-HSD

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Regulation of Progesterone Levels during Pregnancy and Parturition by Signal Transducer and Activator of Transcription 5 and 20α-Hydroxysteroid Dehydrogenase

Cited by 128 publications

References 44 publications

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Hypothyroidism prolongs corpus luteum function in the pregnant rat

Reproductive Phenotypes in Mice with Targeted Disruption of the 20.ALPHA.-Hydroxysteroid Dehydrogenase Gene

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