Spironolactone was mentioned specifically in two cohort studies and one case–control study. In one cohort study carried out in the USA, an excess risk for pharyngeal cancer was found, which persisted with longer follow-up. No evidence for an association with breast cancer was found in the other cohort study, and use of spironolactone was not associated with thyroid cancer in one case–control study. All three studies were based on small numbers of cases.

In five case–control studies of renal-cell carcinoma, use of potassium-sparing diuretics was not clearly identified as a risk factor independently of hypertension.

Spironolactone was tested by oral administration in one study in rats. Increased incidences of thyroid follicular-cell adenomas and Leydig-cell tumours of the testis were reported. Spironolactone reduced the incidence of 7,12-dimethylbenz[a]anthracene-induced mammary tumours in rats.

No data were available on the genotoxicity of spironolactone.

The metabolic pathway of spironolactone is complex and can be divided into two main routes: those in which the sulfur moiety is retained and those in which the sulfur moiety is removed by dethioacetylation.

Hyperkalaemia is the most common side-effect of exposure to spironolactone in humans, and a number of endocrine effects have been observed, the most common of which is gynaecomastia in men.

Spironolactone is transformed to a reactive metabolite that can inactivate adrenal and testicular cytochrome P450 enzymes. It also has anti-androgenic activity.

Spironolactone is a microsomal enzyme inducer. Studies on thyroid function have shown increased hepatic activity of uridine diphosphate-glucuronosyl transferase, decreased plasma triiodothyronine and thyroxine concentrations, increased thyroid-stimulating hormone concentrations and increased thyroid weights and follicular-cell hypertrophy and/or hyperplasia.

At relatively high doses, spironolactone induced resorption of embryos in rats and mice when given during the second week of gestation. Spironolactone reduced fertility in mice and delayed the onset of puberty when administered to young female rats. Prenatal treatment of rats with spironolactone caused a reduction in the weight of the prostate and seminal vesicles in male offspring.

There is inadequate evidence in humans for the carcinogenicity of spironolactone.

There is limited evidence in experimental animals for the carcinogenicity of spironolactone.

Spironolactone is not classifiable as to its carcinogenicity to humans (Group 3).

Previous evaluations: Vol. 24 (1980); Suppl. 7 (1987)