Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

Gal, M.; Orly, Joseph

doi:10.4137/cmrh.s14036

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…Our study clearly indicates that KCZ indeed inhibits ovulation probably by dual effects on follicular functions. First, KCZ attenuates the activity of the steroidogenic cytochromes 13 , 15 – 17 that is in agreement with earlier studies showing that other inhibitors of steroidogenesis, such as aminoglutethimide and cyanoketone, inhibited ovulation in eCG/hCG-treated rats. 21 Second, KCZ profoundly arrested development of the Graafian follicles and interfered with the expected expression of granulosa cells CYP11A1.…”

Section: Discussionsupporting

confidence: 90%

“…KCZ is a known inhibitor of the ovarian steroidogenic P450s, namely CYP11A1, CYP17A1, and CYP19A1. [13][14][15][16][17][18][19][20] The present study using the superovulating rat model shows that KCZ is also effective in vivo while exerting inhibitory effect on ovarian steroidogenesis induced by eCG/hCG treatments. Furthermore, despite the fact that the half-life of KCZ in the circulation is relatively short, 11 administration of a gel formula of the drug before the gonadotropin stimulation maintained its inhibitory effect for 48 hours of the eCG treatment.…”

Section: Discussionmentioning

confidence: 99%

“…KCZ is a known inhibitor of the ovarian steroidogenic P450s, namely CYP11A1, CYP17A1, and CYP19A1 13–20. The present study using the superovulating rat model shows that KCZ is also effective in vivo while exerting inhibitory effect on ovarian steroidogenesis induced by eCG/hCG treatments.…”

Section: Discussionmentioning

confidence: 99%

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Ketoconazole Inhibits Ovulation as a Result of Arrest of Follicular Steroidogenesis in the Rat Ovary

Gal

Orly

2014

Clin Med�Insights�Reprod�Health

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OBJECTIVEKetoconazole (KCZ) is a known inhibitor of steroidogenic P450 enzymes in the adrenal cortex and the gonads. Previous studies examined the potential clinical use of KCZ for attenuation of ovarian response to gonadotropin treatments. This study aimed to use the superovuating rat model to explore the effect of KCZ on ovarian steroidogenesis, follicular function, and development toward ovulation.METHODSPrepubertal rats were treated with equine chorionic gonadotropin (eCG)/human CG (hCG) resulting in multiple follicular development and ovulation. The effect of KCZ on this model was examined by administration of KCZ-gel formula and subsequent analyses of ovarian steroidogenesis, rate of ovulation, morphometric assessments of follicular parameters, and cell-specific steroidogenic maturation of the treated ovaries.RESULTSWhen applied shortly before gonadotropin stimulation, KCZ markedly reduced ovarian progesterone, androstenedione, and estradiol levels down to 18.7, 36.5, and 19.0%, respectively (P < 0.001). A single KCZ-gel administration of 6, 12, and 24 mg/rat resulted in reduction of ovulated ova/ovary down to 8.6 ± 4.9, 5.1 ± 4.3, and 2.4 ± 3.2, respectively, as compared to 13.6 ± 4.4 ova found in the oviduct of control-gel-injected animals (P < 0.001). An alternative protocol made use of small KCZ doses injected in non-gel formula (5 mg/dose/8 hours), commenced with the eCG administration and terminated 24 hours later; this treatment readily inhibited the ovulation rates to 6.6 ± 6.6 as compared to 16.5 ± 4.1 ova/ovary in the control group (P < 0.01). By contrast, KCZ failed to inhibit ovulation if administered 24 hours after eCG injection. Anovulation by KCZ resulted from arrest of follicular development at the stage of 800–840 μm Graafian follicles as compared to 920 μm of peri-ovulatory follicles (OFs) observed in the control group, P = 0.029. In addition, absence of CYP11A1 expression was evident in the granulosa cell layers of the growth-arrested follicles, which also lacked mucified mature cumulus cell complexes.CONCLUSIONThese results suggest that KCZ-mediated inhibition of follicular maturation probably results from impaired steroidogenesis at early phase of follicular development toward ovulation. Hence, attenuation of folliculogenesis by KCZ may be harnessed to modulate gonadotropin-ovarian stimulation in fertility treatments.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Ketoconazole Inhibits Ovulation as a Result of Arrest of Follicular Steroidogenesis in the Rat Ovary

Gal

Orly

2014

Clin Med�Insights�Reprod�Health

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“…1; Table 1). Similarly, it blocks various steps of steroidogenesis in the gonads (27,28,29), leading to the potential side effect of hypogonadism in men, if used in the long term.…”

Section: Currently Available Steroidogenesis Inhibitorsmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Daniel

Newell‐Price

2015

European Journal of Endocrinology

111

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Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.

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“…It was therefore no surprise that while its use resulted in inhibition of 17-hydroxylase activity, general suppression of all adrenal steroids also occurred. Studies in H295R cells have clearly shown that ketoconazole not only inhibits CYP17A1, but also CYP11A1, CYP21A2, CYP11B1 and CYP19 64; 65 . As such, while ketoconazole treatment has been used as a way of preventing C19 steroid production as an adjunct to anti-cancer treatments for breast and prostate cancer, it is not by any means a selective treatment that achieves our goal of doing so while maintaining sufficient cortisol output .…”

Section: ) Clinical Realitiesmentioning

confidence: 99%

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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Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

Cited by 13 publications

References 37 publications

Ketoconazole Inhibits Ovulation as a Result of Arrest of Follicular Steroidogenesis in the Rat Ovary

Ketoconazole Inhibits Ovulation as a Result of Arrest of Follicular Steroidogenesis in the Rat Ovary

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

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

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