Trilostane but not prostaglandin F2α (PGF2α) or cortisol aborts 90-day-pregnant lutectomized sheep☆

Weems, Y.S.; Vincent, D.L.; Lemme, C.; Weems, C.W.

doi:10.1016/s0090-6980(99)00018-0

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…We previously hypothesized that partial inhibition of 3bHSD could possibly augment androgen synthesis because of this block [1]. The current data provide support for this hypothesis and are consistent with a growing body of evidence in vitro [40] and in vivo [41][42][43] showing a so-called paradoxical increase of androgen and/or estrogen secretion in response to inhibition of 3bHSD. Flück et al [44] used microsomal preparations of recombinant human enzymes to demonstrate similarly that androstenedione synthesis was actually increased when 3bHSD type 2 was decreased relative to P450c17.…”

Section: Partitioning and Competition In Steroidogenesissupporting

confidence: 89%

Costs and Consequences of Cellular Compartmentalization and Substrate Competition among Human Enzymes Involved in Androgen and Estrogen Synthesis

Conley

Thomas

Gee

et al. 2012

Biology of Reproduction

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The impact of compartmental expression of steroidogenic enzymes and of changes in flux through delta5 and delta4 metabolism on sex steroid synthesis was investigated by rebuilding pathways using recombinant enzyme expression by infection of insect cells with recombinant baculovirus constructs. Human cytochromes 17alpha-hydroxylase/17,20-lyase (P450c17) and aromatase (P450arom), always coexpressed with their redox partner NADPH-P450 oxidoreductase (CPR) and 3beta-hydroxysteroid dehydrogenase/delta5-4 isomerase (3betaHSD; types 1 or 2), were compartmentally expressed in different cell populations or coexpressed together with pregnenolone (100 nM) as substrate. Estrone was compared among cell compartments expressing different enzyme combinations or in cells coexpressing all enzymes (experiment 1). Additionally, P450c17, 3betaHSD, and CPR were all coexpressed, and androstenedione was measured in cells with different 3betaHSD expression levels or activity using an inhibitor, trilostane (experiment 2). Steroids were measured by immunoassay and mass spectrometry. In experiment 1, partitioning of P450c17, P450arom, and 3betaHSD markedly decreased estrone synthesis in comparison to cells coexpressing enzymes in different combinations. However, partitioning P450arom with 3betaHSD from P450c17 in different cell populations resulted in more estrone than either of the other two-cell compartment models. In experiment 2 (cells coexpressing P450c17, 3betaHSD, and CPR), androstenedione secretion was (paradoxically) higher at lower levels of 3betaHSD, and partial inhibition of 3betaHSD by trilostane also increased androstenedione when 3betaHSD expression was high. We conclude 1) that tissue or cell-specific, partitioned expression of sex steroid synthesizing enzymes limits rather than maximizes estrogen synthesis and 2) that limiting metabolism by 3betaHSD can paradoxically promote androgen synthesis when 3betaHSD expression is high by promoting delta5-steroid flux.

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Section: Partitioning and Competition In Steroidogenesissupporting

confidence: 89%

Costs and Consequences of Cellular Compartmentalization and Substrate Competition among Human Enzymes Involved in Androgen and Estrogen Synthesis

Conley

Thomas

Gee

et al. 2012

Biology of Reproduction

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“…Nonetheless, this behaviour has been observed in vitro in insect cells expressing human recombinant P450c17 with either 3␤-HSD type 1 or type 2 [26] and in reconstituted human enzyme systems [27]. A similar response in A4 synthesis was also reported in in vivo systems, such as in rhesus monkeys during the mid-luteal phase of the menstrual cycle, and in lutectomised and ovarectomized 90-day pregnant ewes, where inhibition of 3␤-HSD by trilostane increased the circulating levels of E2 [14][15][16]. These results were predicted [1] and can be explained in the following way: initial decrease in 3␤-HSD activity decreases P4 and 17OH-P4 synthesis, allowing 17OH-P5 to accumulate, and thereby shift the flux down the 5 pathway towards DHEA production.…”

Section: Discussionsupporting

confidence: 73%

“…With the aim of understanding why inhibition of 3␤-HSD can increase circulating levels of 17␤-estradiol (E2) in rhesus monkey and sheep [14][15][16], we developed a model to test the hypothesis that when the 17,20-lyase activity of P450c17 on 17OH-P4 is negligible in species like these, the synthesis of A4, a substrate for estrogen formation, can be increased by decreasing 3␤-HSD activity. In steroidogenic cells, both 3␤-HSD and P450c17 are membrane bound, and 3␤-HSD can be present in both the mitochondrial and microsomal compartments while P450c17 is present only in the microsomal compartment [11,17].…”

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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“…In these studies, De Bosschere et al [ 16 ] reported that TRL treatment decreased the endometrial wall thickness in dogs with cystic endometrial hyperplasia; De Gier et al [ 17 ] determined that TRL treatment for seven days decreased P4 concentrations in diestric dogs; and Jurzack et al [ 18 ] reported that TRL treatment concurrent with deslorelin administration did not alter ovarian functions. In addition to these studies, the effects of TRL treatment on PT and P4 concentrations have also been investigated in ewes [ 19 , 20 ] and mares [ 21 ]. Hence, further studies are needed to establish and/or re-evaluate the effects of the inhibition of the 3β-HSD enzyme.…”

Section: Introductionmentioning

confidence: 99%

The Efficacy of a 3β-Hydroxysteroid Dehydrogenase Inhibitor for the Termination of Mid-Term Pregnancies in Dogs

Binli

İnan

Büyükbudak

et al. 2022

Animals

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Progesterone (P4) is the only hormone needed to maintain pregnancy in dogs. Therefore, a competitive inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) could be a safe and effective option to terminate pregnancy by inhibiting P4 synthesis. To address this hypothesis, we investigated the efficacy of trilostane (TRL), a competitive inhibitor of 3β-HSD, in terminating pregnancy in dogs. Twenty-one dogs between days 30 and 38 of pregnancy were randomly assigned to one of two treatment groups (trilostane (TRL) and aglepristone (AGL)) and an untreated control (CON) group (n = 7 dogs each). Fetal heart rates (FHRs) (measured at 12 h intervals) and serum P4 concentrations (measured at 6 h intervals) were evaluated. The pregnancy termination rates were 0% and 100% in the TRL and AGL groups, respectively. The decrease in the FHR in the TRL and AGL groups was significantly lower than that observed in the CON group. There was a marked decrease in P4 concentrations in the TRL group 6, 54, and 102 h after the initiation of treatment. The luteal expression of StAR appeared to be weaker in the AGL group than the CON group. In conclusion, although a treatment-induced decrease was observed in plasma P4 concentrations, a seven-day TRL treatment alone was not effective in terminating pregnancies. Further studies are needed on the effects of the prolonged administration of TRL with varying doses and frequencies for the termination of mid-term pregnancy in dogs.

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Trilostane but not prostaglandin F2α (PGF2α) or cortisol aborts 90-day-pregnant lutectomized sheep☆

Cited by 12 publications

References 28 publications

Costs and Consequences of Cellular Compartmentalization and Substrate Competition among Human Enzymes Involved in Androgen and Estrogen Synthesis

Costs and Consequences of Cellular Compartmentalization and Substrate Competition among Human Enzymes Involved in Androgen and Estrogen Synthesis

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

The Efficacy of a 3β-Hydroxysteroid Dehydrogenase Inhibitor for the Termination of Mid-Term Pregnancies in Dogs

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