antifungals (azoles) and testosterone levels

[Guest guest]

Thanks for sending abstracts Mandi - they were waaaaay over my head but

managed to find a few more that were a bit easier to read and here is

my outline (for what it's worth, there is probably loads I don't get so

feel free to jump in and correct me):

- fluconazole (I think this is generic name for Diflucan?)

affected testosterone and fertility (lowered them) in RABBITS in the

study below, but the effects were not permanent and reversed to

original levels after 2 months

- in humans, one study found levels of testosterone INCREASED

significanly after fl treatment. However, another study in man found

ketaonazole desreased testosterone levels, but fluconazole had NO

EFFECT on those...

the conclusion being..... ???? b***r all! science has no answers on this one. or does it?

btw included one abstracts that showed liver toxicity/increase in

volume from azoles antifungals. but then again, this was in rats....

Natasa

2: Arzneimittelforschung. 2002;52(8):636-40.

Effect of fluconazole on the fertility of male rabbits.

el-Medany AH, Hagar HH. Department of Pharmacology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

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 ... on fertility

in sexually mature male rabbits... 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.

PMID: 12236053 [PubMed - indexed for MEDLINE]

3: Br J Clin Pharmacol. 1992 Jul;34(1):75-8.

Contrasting effects of fluconazole and ketoconazole on phenytoin and

testosterone disposition in man.

Touchette MA College of Pharmacy and Allied Health Professions, Wayne State University,

Detroit, MI 48202.

Nine healthy male subjects received oral fluconazole 400 mg daily, ketoconazole

200 mg twice daily or no treatment for 6 days according to a randomized,

cross-over design. ....... AUC(0,10) values for the testosterone precursors androstenedione

and 17 alpha-hydroxyprogesterone were significantly higher in the fluconazole

treatment phase as were concentrations of luteinizing hormone. The mechanism and

clinical significance of the increase in testosterone concentration caused by

fluconazole remains to be determined. (???)

possible difference in mice, rabbits and man?????

Publication Types:

Clinical Trial Randomized Controlled Trial

PMID: 1633070 [PubMed - indexed for MEDLINE]

Antimicrob Agents Chemother. 1988 May;32(5):646-8.

Fluconazole and testosterone: in vivo and in vitro studies.

Hanger DP, Jevons S, Shaw JT Pfizer Central Research, Sandwich, Kent, United Kingdom.

Fluconazole (UK-49,858), a novel bis-triazole antifungal agent, was given orally

to groups of 10 male volunteers at doses of 25 and 50 mg/day for 28 days. Blood

samples for testosterone estimation were taken from these and from a placebo

group at several time points on days 1, 14, and 28 of the study, and the assay

results demonstrated that the compound had no significant effect on circulating

testosterone levels. Similarly, in studies with rat Leydig cells in vitro,

fluconazole at concentrations up to 10 micrograms/ml was found to be only a weak

inhibitor of testosterone production, whereas ketoconazole caused more than 50%

inhibition at 0.1 microgram/ml. It is concluded that fluconazole, in contrast to

ketoconazole, has little effect on the biosynthesis of testosterone by mammalian

cells.

Publication Types: Clinical Trial

Controlled Clinical Trial

PMID: 2840013 [PubMed - indexed for MEDLINE]

TOXICITY - IN RATS !

1: Toxicol Appl Pharmacol. 2006 Apr 25; [Epub ahead of print]

Gene expression profiling in liver and testis of rats to characterize the

toxicity of triazole fungicides.

Tully DB, Office of Research and Development, U.S. Environmental Protection Agency,

Research Triangle Park, NC 27711, USA.

Four triazole fungicides were studied using toxicogenomic techniques to identify

potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14

days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon.

Following exposure, serum was collected for hormone measurements, and liver and

testes were collected for histology, enzyme biochemistry, or gene expression

profiling. Body and testis weights were unaffected, but liver weights were

significantly increased by all four triazoles, and hepatocytes exhibited

centrilobular hypertrophy. Myclobutanil exposure increased serum testosterone

and decreased sperm motility, but no treatment-related testis histopathology was

observed. We hypothesized that gene expression profiles would identify potential

mechanisms of toxicity and used DNA microarrays and quantitative real-time PCR

(qPCR) to generate profiles. Triazole fungicides are designed to inhibit fungal

cytochrome P450 (CYP) 51 enzyme but can also modulate the expression and

function of mammalian CYP genes and enzymes. Triazoles affected the expression

of numerous CYP genes in rat liver and testis, including multiple Cyp2c and

Cyp3a isoforms as well as other xenobiotic metabolizing enzyme (XME) and

transporter genes. For some genes, such as Ces2 and Udpgtr2, all four triazoles

had similar effects on expression, suggesting possible common mechanisms of

action. Many of these CYP, XME and transporter genes are regulated by

xeno-sensing nuclear receptors, and hierarchical clustering of CAR/PXR-regulated

genes demonstrated the similarities of toxicogenomic responses in liver between

all four triazoles and in testis between myclobutanil and triadimefon. Triazoles

also affected expression of multiple genes involved in steroid hormone

metabolism in the two tissues. Thus, gene expression profiles helped identify

possible toxicological mechanisms of the triazole fungicides.

PMID: 16643972 [PubMed - as supplied by publisher]