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

Nguyen, Phuong; Lee, Rita S.F.; Conley, Alan J; Sneyd, James; Soboleva, T. K.

doi:10.1016/j.jsbmb.2011.10.003

Cited by 15 publications

(13 citation statements)

References 26 publications

(48 reference statements)

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“…Thus, the Δ‐5 pathway seemed to be the preferred route in the production of androgens . When ∆‐5 metabolites are converted into ∆‐4 metabolites by 3β‐hydroxysteroid dehydrogenase (3βHSD), there is no conversion back into ∆‐5 metabolites . In theca cells and granulosa cells, LH bioactivity increases the expression of 3βHSD .…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18] When Δ-5 metabolites are converted into Δ-4 metabolites by 3b-hydroxysteroid dehydrogenase (3bHSD), there is no conversion back into Δ-5 metabolites. 19 In theca cells and granulosa cells, LH bioactivity increases the expression of 3bHSD. 2,20 If the Δ-5 pathway in humans is the preferred route to androstenedione, the hCG effect would rather enhance the production of progesterone and 17-OH-progesterone as terminal products of the Δ-4 pathway.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose–response study

Thuesen

Smitz

Loft

et al. 2013

Clinical Endocrinology

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Supplementation with hCG resulted in a clear dose-related response for androgens, progesterone and 17-OH-progesterone. Oestradiol concentration reached maximum levels with an hCG dose of 100 IU/day, suggesting saturation of aromatase function. No difference between the groups was observed for DHEA, supporting that the stimulatory effects of hCG doses on androgens and oestrogen production were mainly induced via the Δ-5 pathway. SHBG, being a biomarker of oestrogen/androgen balance, was not changed by increasing hCG.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose–response study

Thuesen

Smitz

Loft

et al. 2013

Clinical Endocrinology

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“…This is the case not only in human adrenal ZR, but also in both gonads and the tumor. Previous mathematical modeling of relative enzyme activity confirms that progressive limitation of HSD3B activity relative to CYP17 raises DHEA production, and does not lower it 30 .…”

Section: ): the Problemmentioning

confidence: 80%

The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

Bird

Abbott

2016

The Journal of Steroid Biochemistry and Molecular Biology

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Given prostate cancer is driven, in part, by its responsiveness to androgens, treatments historically employ methods for their removal from circulation. Approaches as crude as castration, and more recently blockade of androgen synthesis or receptor binding, are still of limited use long term, since other steroids of adrenal origin or tumor origin can supersede that role as the ‘castration resistant’ tumor re-emerges. Broader inhibition of steroidogenesis using relatively nonselective P450 inhibitors such as ketoconazole is not an alternative since a general disruption of steroid biosynthesis is neither safe nor effective. The recent emergence of drugs more selectively targeting CYP17 have been more effective, and yet extension of life has been on the scale of months rather than years. It is now becoming clear this shortcoming arises from the adaptive capabilities of many tumors to initiate local steroid synthesis and/or become responsive to novel early pathway adrenal steroids that are synthesized when lyase activity is not selectively blocked, and ACTH rises in the face of declining cortisol feedback. Abiraterone has been described as a lyase selective inhibitor, yet its use still requires co-administration of prednisone to suppress such a rise of ACTH and fall in cortisol. So is creation of a selective lyase inhibitor even possible? Can C19 steroid production be achieved without a prominent decline in cortisol and corresponding rise in ACTH? Decades of scientific study of CYP17 in humans and nonhuman primates, as well as nature’s own experiments of gene mutations in humans, reveal ‘true’ or ‘isolated’ 17,20 lyase deficiency does quite selectively prevent C19 steroid biosynthesis whereas simple 17 hydroxylase deficiency also suppresses cortisol. We propose these known outcomes of natural mutations should be used to guide analysis of clinical trials and long term outcomes of CYP17 targeted drugs. In this review, we use that framework to re-evaluate the basic and clinical outcomes of many compounds being used or in development for treatment of castration resistant prostate cancer. Specifically, we include the nonselective drug ketoconazole, and then the CYP17 targeted drugs abiraterone, orteronel (TAK-700), galaterone (TOK-001), and VT464. Using this framework, we can fully discriminate the clinical outcomes for ketoconazole, a drug with broad specificity, yet clinically ineffective, from that of abiraterone, the first CYP17 targeted therapy that is limited by its need for prednisone co-therapy. We also can identify potential next generation CYP17 targeted drugs now emerging that show signs of being far more 17,20 lyase selective. We conclude that a future for improved therapy without substantial cortisol decline, thus avoiding prednisone co-administration, seems possible at long last.

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“…The resulting complexity makes it difficult to predict how changing the flux down the pathway for the synthesis of one steroid affects the synthesis of other steroids. Therefore, we have developed a mathematical model to simulate how the interacting pathways of steroid synthesis function, and to predict the changes in steroid balance in response to alterations in the activity of one of the key enzymes, 3b-HSD, or in the availability of the common precursor substrate, pregnenolone (Nguyen et al, 2012). Such models should lead to a better understanding of how steroid synthesis can be regulated and integrated with metabolism or redox state in any steroidogenic organ.…”

Section: Discussionmentioning

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

Cited by 15 publications

References 26 publications

Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose–response study

Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose–response study

The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature

Multilevel regulation of steroid synthesis and metabolism in the bovine placenta

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