INHIBITION OF PLACENTAL 3β-Hydroxy-Steroid DEHYDROGENASE BY NATURALLY OCCURRING STEROIDS. A POTENTIAL MECHANISM REGULATING OESTROGEN SYNTHESIS FROM UNCONJUGATED PRECURSORS

Townsley, John D.

doi:10.1530/acta.0.0790740

Cited by 38 publications

(20 citation statements)

References 4 publications

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“…Furthermore, the inhibition parameter K i of a substrate to the metabolism of the other substrates is equal to the affinity of 3␤-HSD for it (K m ). Thus, this model of the 3␤-HSD reactions is consistent with the experimental results in [7,12] which showed that the inhibition parameter K i of a substrate to the metabolism of the other substrates is not significantly different from the affinity (K m ) of 3␤-HSD for that substrate. Similarly, the inhibition parameter (K i ) of a product to the reactions …”

Section: Rates Of Reactions Catalyzed By 3ˇ-hsdsupporting

confidence: 89%

“…From these sequences of reactions, 5 -3␤-hydroxysteroids (P5, 17OH-P5, DHEA) are converted into 4 -3-ketosteroids (P4, 17OH-P4, A4, respectively). In a mixed substrate environment, substrates competitively inhibit each other for access to the enzyme [7,12]. Furthermore, the activity of 3␤-HSD is inhibited by its own catalytic products [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis

Nguyen

Lee

Conley

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Rates Of Reactions Catalyzed By 3ˇ-hsdsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis

Nguyen

Lee

Conley

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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“…These steroids are present in amniotic fluid [14,24] and may suppress the conversion of pregnenolone to progesterone by dispersed human placental cells [9], Their effect is likely non competitive [11]. The effects of the C19 steroids are unlikely to be due to aromatization.…”

Section: Discussionmentioning

confidence: 99%

“…We showed that dispersed cells prepared from human chorion con verted exogenous pregnenolone to progester one more effectively than amnion or decidual cell preparations and that this activity was influenced by estrogen [8]. In placental cells [9] and homogenates [10][11][12], several ste roids influence the conversion of pregneno lone to progesterone. It is likely that these steroids have a direct effect on the 3ßHSD: isomerase enzyme, although longer-term ac tions have not been explored.…”

Section: Introductionmentioning

confidence: 96%

Effects of Steroids on Progesterone Output by Explants of Human Chorion

Powell¹,

Mitchell²,

Challis³

1986

Gynecol Obstet Invest

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Human chorion can synthesize and metabolize progesterone, and changes in progesterone synthesis by chorion at term might be important in the processes leading to parturition. We examined whether other steroids present within the maternal compartment and amniotic fluid during late pregnancy influence progesterone output by explants of chorion. We also sought differences in steroid effects on progesterone output in association with labor. Explants were prepared from chorion collected after the spontaneous onset of labor and vaginal delivery and chorion collected after cesarean section without active labor. To study the short-term effects of steroids on progesterone output by chorion, explants were incubated for 4 h with 3 µM pregnenolone and 3 µM of a potential interacting steroid. Other explants were preincubated for 24 h with steroid, then rinsed and incubated for 4 h with 3 µM pregnenolone and 3 µM of the same steroid as during preincubation. Under these conditions, dehydroepiandrosterone and androstenedione inhibited progesterone output by explants of chorion obtained at spontaneous labor and at cesarean section. Testosterone also inhibited progesterone output, but only in cesarean section chorion. If explants were preincubated for 24 h with steroid and then rinsed and incubated for 4 h with pregnenolone only, progesterone synthesis returned to control values. This finding indicates that the mechanism of action of these inhibitory steroids is likely through an effect on 3Β-HSD activity and not due to a change in the rate of enzyme synthesis. We also noted apparent stimulatory effects of steroids. When explants were preincubated with pregnenolone sulfate and then incubated for 4 h with 3 µM pregnenolone only or with 3 µM pregnenolone +3 µM pregnenolone sulfate, there was an increase in media progesterone concentrations. To examine the effects of steroids on basal progesterone synthesis, we incubated explants for 24 h with 3 µM steroid without addition of exogenous pregnenolone. 5Α-dihydrotestosterone in spontaneous vaginal chorion and 5Α-pregnanediol in cesarean section chorion caused an increase in media progesterone concentrations. Progesterone concentrations increased during 24-hour incubations with 20Α-dihydroprogesterone and pregnenolone sulfate; the effect of pregnenolone sulfate was greater in chorion collected at spontaneous labor than at elective cesarean section. Addition of pregnenolone sulfate with pregnenolone during 24-hour incubations and during the 2nd incubation of 4 h further increased progesterone accumulation in the media. We conclude that several steroids can modify net progesterone output by explants of chorion in the presence of endogenous or exogenous precursors and that the steroid effects vary with the type of delivery.

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“…Products of the synthetic pathways, such as progesterone, testosterone, oestrone, and oestradiol, can also inhibit the activity of 3b-HSD in a concentration-dependent manner (Townsley, 1975;Raimondi et al, 1990). As the steady state concentration of a particular steroid depends on both the rate of synthesis and the rate of metabolism, product inhibition of 3b-HSD also depends on both the rates of synthesis and metabolism.…”

Section: Kinetic Regulation Of the Steroidogenic Enzymesmentioning

confidence: 99%

Multilevel regulation of steroid synthesis and metabolism in the bovine placenta

Nguyen

Conley

Soboleva

et al. 2012

Molecular Reproduction Devel

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SUMMARYSteroid hormones play critical roles in almost all physiological processes in male and female reproduction. In a normal pregnancy, the concentrations of steroid hormones in maternal and foetal blood vary with gestation in response to changing needs. The placenta plays a central role in producing the appropriate steroids to support the pregnancy by coordinating its own steroidogenic activity with that of the corpus luteum and responding to foetal signals. Although much is known about the steroidogenic potential of the bovine placenta, far less is known about how the placenta integrates the synthesis of steroids with their subsequent metabolism and clearance to achieve appropriate local and peripheral concentrations of steroids in maternal and foetal blood at each stage of gestation. This review focuses on the current knowledge of the temporal and spatial regulation and compartmentalization of the biochemical pathways by which potent steroid hormones are synthesized and metabolized in the bovine placenta. The aim is to increase our understanding of how the balance of synthesis and metabolism determines placental steroid output as it changes with development and differentiation, and how this is regulated in response to the variations in the foetal signals and luteal secretory activity. The review highlights knowledge gaps and suggests that mathematical modelling can help understand the effect of different levels of regulation on the steroidogenic output of an organ, such as the bovine placenta.

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INHIBITION OF PLACENTAL 3β-Hydroxy-Steroid DEHYDROGENASE BY NATURALLY OCCURRING STEROIDS. A POTENTIAL MECHANISM REGULATING OESTROGEN SYNTHESIS FROM UNCONJUGATED PRECURSORS

Cited by 38 publications

References 4 publications

Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis

Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis

Effects of Steroids on Progesterone Output by Explants of Human Chorion

Multilevel regulation of steroid synthesis and metabolism in the bovine placenta

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