Effect of ketoconazole on steroidogenic human granulosa-luteal cells in culture

Gal, M.; Barr, Ilya; Lior, Mrs.Ofra; Tadmor, O.; Orly, Joseph; Diamant, Yoram Z.

doi:10.1016/0028-2243(91)90059-t

Cited by 14 publications

(10 citation statements)

References 16 publications

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“…Similar to our results, studies using intact cell models observed lack of KCZ effect on 3β-HSD and 17β-HSD7,8,33,36 while the use of cell-free preparations yielded inhibitory effects of the drug at exceedingly high concentrations 16. Similarly, we could not detect any effect of KCZ on 5α-reductase, 3α-HSD, and 20α-HSD.…”

Section: Discussionsupporting

confidence: 89%

“…[5][6][7] In contrast, there are fewer studies on the effects of KCZ on ovarian steroidogenesis and its potential effects related to fertility treatments. For example, we and others have previously found that administration of a low dose of KCZ to polycystic ovarian syndrome patients during superovulation attenuated ovarian folliculogenesis 8,9 and better controlled the hyperstimulated response to gonadotropins. 8 In addition, KCZ was also shown to improve clomiphene responsiveness in PCOS patients.…”

Section: Introductionmentioning

confidence: 86%

“…In addition, KCZ was also shown to improve clomiphene responsiveness in PCOS patients 10. In view of the potentially beneficial use of KCZ in reproduction, several studies attempted to analyze the biochemical basis for the drug effect on the ovary 8,11–18. However, the use of multiple experimental models yielded incomplete and occasionally contradictory information that led us to seek a model providing a complete view of the drug effects on the entire ovarian steroidogenic enzymatic cascade starting from cholesterol down to estradiol synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

Gal

Orly

2014

Clin Med�Insights�Reprod�Health

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OBJECTIVEKetoconazole (KCZ) is an anti-fungal agent extensively used for clinical applications related to its inhibitory effects on adrenal and testicular steroidogenesis. Much less information is available on the effects of KCZ on synthesis of steroid hormones in the ovary. The present study aimed to characterize the in situ effects of KCZ on steroidogenic enzymes in primary rat ovary cells.METHODSFollowing the induction of folliculogenesis in gonadotropin treated rats, freshly prepared ovarian cells were incubated in suspension for up to four hours while radiolabeled steroid substrates were added and time dependent generation of their metabolic products was analyzed by thin layer chromatography (TLC).RESULTSKCZ inhibits the P450 steroidogenic enzymes in a selective and dose dependent manner, including cholesterol side-chain cleavage cytochrome P450 (CYP11A1/P450scc), the 17α-hydroxylase activity of CYP17A1/P450c17, and CYP19A1/P450arom, with IC50 values of 0.3, 1.8, and 0.3 μg/mL (0.56, 3.36, and 0.56 μM), respectively. Unaffected by KCZ, at 10 μg/mL, were the 17,20 lyase activity of CYP17A1, as well as five non-cytochrome steroidogenic enzymes including 3β-hydroxysteroid dehydrogenase-Δ5–4 isomerase type 1 (3βHSD1), 5α-reductase, 20α-hydroxysteroid dehydrogenase (20α-HSD), 3α-hydroxysteroid dehydrogenase (3α-HSD), and 17β-hydroxysteroid dehydrogenase type 1 (17HSD1).CONCLUSIONThese findings map the effects of KCZ on the ovarian pathways of progestin, androgen, and estrogen synthesis. Hence, the drug may have a potential use as an acute and reversible modulator of ovarian steroidogenesis in pathological circumstances.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

Gal

Orly

2014

Clin Med�Insights�Reprod�Health

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“…It has been widely accepted that the androgen-suppressive properties of fluconazole residues mainly on the ability of the drug to selectively block steroidogenesis by inhibiting cytochrome P-450 mixed function oxidase enzymes [18,19]. This means that the steroid hydroxylation step involved with C17-20 lyase (i.e.…”

Section: Discussionmentioning

confidence: 99%

Effect of Fluconazole on the Fertility of Male Rabbits

El-Medany

Hagar

2011

Arzneimittelforschung

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Azole derivatives are currently available for oral treatment of systemic mycosis. They act by affecting the membrane permeability of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell. The present work was conducted to investigate the possible side effects of a newer azole derivative, fluconazole (CAS 86386-73-4), on fertility in sexually mature male rabbits and to elucidate the underlying mechanisms of this effect. Oral administration of fluconazole (50 mg/kg body weight in distilled water) daily for one month to sexually mature male rabbits induced a significant decrease in serum testosterone, semen volume, count and percentage of motile sperms. A significant increase in serum prolactin, follicle stimulating hormone and luteinizing hormone was observed. On the other hand, a non-significant alteration in percentage of abnormal sperm forms was noticed. After one month drug cessation, hormonal profile, sperm counts and percentage of motile sperms were still significantly distorted, and the whole profile reversed back towards normal only after the second month of drug cessation. Testicular biopsies showed no histopathological changes. From the above mentioned results, it can be concluded that fluconazole induced functional and reversible alterations in male fertility. Though the primary brunt of action appears to be operating on testicular level, however, a secondary direct interplay on higher central controls seems obviously contributing. Caution is advised when using azole derivatives in male patients, especially those on prolonged therapy.

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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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Effect of ketoconazole on steroidogenic human granulosa-luteal cells in culture

Cited by 14 publications

References 16 publications

Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

Selective Inhibition of Steroidogenic Enzymes by Ketoconazole in Rat Ovary Cells

Effect of Fluconazole on the Fertility of Male Rabbits

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

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