Drospirenone: a Novel Progestogen with Antimineralocorticoid and Antiandrogenic Activity

Abstract

Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3-oxo-17 alpha-pregn-4-ene-21, 17-carbolactone) is a novel progestogen under clinical development. Drospirenone is characterized by an innovative pharmacodynamic profile which is very closely related to that of progesterone. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This property was demonstrated in castrated, testosterone propionate substituted male rats by a dose-dependent inhibition of accessory sex organ growth (seminal vesicles, prostate). In this model, the potency of drospirenone was about a third that of cyproterone acetate. Drospirenone, like progesterone, shows antimineralocorticoid activity, which causes moderately increased sodium and water excretion. This is an outstanding characteristic which has not been described for any other synthetic progestogen before. Drospirenone is eight to ten times more effective in this respect than spironolactone. The natriuretic effect was demonstrable for at least three weeks upon daily treatment of rats with a dose of 10 mg/animal. Drospirenone is devoid of any estrogenic, glucocorticoid or antiglucocorticoid activity. In summary, drospirenone, like progesterone, c...

Androgens and Adipose Tissue in Males: A Complex and Reciprocal Interplay

“…Recently, we have demonstrated that Drospirenone (DRSP), a progestogen with a modest antiandrogenic activity, widely used for contraception [77–79], strongly inhibits adipose differentiation both in murine (3T3-L1) as well as in human preadipocytes ex vivo . It is important to remark that DRSP is a powerful antagonist of the mineralocorticoid receptor (MR), which is a pivotal factor for the induction of adipogenesis.…”

The association between drospirenone and hyperkalemia: a comparative-safety study

“…Drospirenone is a fourth generation OC and it possesses antimineralocorticoid effects not present in previous generations of OCs. Its antimineralocorticoid potency is approximately eight times greater than spironolactone [3], thus a 3 mg tablet of drospirenone has a similar effect to 20-25 mg of spironolactone [4]. This activity enhances sodium, chloride, and water excretion, while reducing the excretion of potassium, ammonium, and phosphate [5].…”

Efficacy and safety of drospirenone 2 mg/17β-estradiol 1 mg hormone therapy in Korean postmenopausal women

“…Furthermore, DRSP differs from most synthetic progestogens as it demonstrates a similar pharmacological profile to endogenous progestogens [345]. Consequently, DRSP is devoid of any estrogenic, glucocorticoid or anti-glucocorticoid activity but exhibits anti-aldosterone and anti-androgenic properties.…”