Conception and pharmacodynamic profile of drospirenone

• Published in: Steroids 2003-11, Vol.68 (10), p.891-905
• Main Authors: Elger, Walter, Beier, Sybille, Pollow, Kunhard, Garfield, Robert, Shi, Shao Qing, Hillisch, Alexander
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - chemistry; Androgen Antagonists - metabolism; Androstenes - pharmacology; Animals; Antiandrogens; Biological and medical sciences; Blood Pressure; Central Nervous System - metabolism; Circulation; CNS; Contraception; Dose-Response Relationship, Drug; Drospirenone; Estrogens; Ethinyl Estradiol - pharmacology; Female; Fertilization; Fundamental and applied biological sciences. Psychology; History; Humans; Kidney - metabolism; Male; Mineralocorticoid Receptor Antagonists - pharmacology; Models, Chemical; Models, Molecular; NG-Nitroarginine Methyl Ester - metabolism; Pregnancy; Progestins; Protein Binding; Rats; Rats, Wistar; Renin-Angiotensin System; Sex Factors; Time Factors; Vertebrates: endocrinology
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2003.08.008

Progesterone is more than a progestin. Beyond functions in cycle and pregnancy, progesterone binds with high affinity to the mineralocorticoid receptor (MR) acting as an antagonist, with obvious significance for electrolyte homeostasis, an array of MR-related functions in the circulation as well as in the CNS. Progesterone induces natriuresis at physiological concentrations. Lack of antimineralocorticoid activity with conventional progestins may account for sodium and water retention, minor elevation of blood pressure and “pill hypertension” in susceptible women on oral contraceptives. Ethinylestradiol (EE) contributes to this problem by distinct activation of the renin–angiotensin–aldosterone (RAAS) system. Drospirenone (DRSP: 6β,7β,15β,16β-dimethylene-3-oxo 17α-pregn-4-ene-21,17 carbolactone) is the first synthetic progestin with antialdosterone activity. DRSP and progesterone bind to PR in uterine (affinity of both is about 30% of R5020) and MR in kidney cytosol (affinity about 230 and 100% of aldosterone, respectively). Intrauterine administration of DRSP in silastic tubes induced maximum local progestational effects in rabbits. At systemic subcutaneous (s.c.) administration (McPhail-assay) full endometrial transformation was obtained at 1mg per animal per day. At 1–3 mg DRSP per animal per day subcutaneously, pregnancy maintenance after ovariectomy, antiovulatory activity, and antimineralocorticoid activity were seen in the respective assays in rats. The latter activity indicates about eight-fold higher potency than spironolactone. DRSP decreased blood pressure in male hypertensive rats, whereas an increase was noted under conventional progestins. DRSP also prevented hypertension and fetal growth retardation in pregnant rats after l-NAME, an inhibitor of nitric oxide synthase. DRSP has antiandrogenic activity. Feminizing effects were recorded during sexual differentiation in male fetuses at high doses. Powerful antiandrogenic effects were also seen in gonad intact and testosterone substituted castrated male rats. The antiandrogenic potency of DRSP is superior to that of spironolactone but below that of cyproterone acetate. Endometrial transformation, inhibition of ovulation, and antimineralocorticoid, i.e. natriuretic effects and mild antiandrogenic effects were recorded at the same range of oral doses (0.5–4 mg per day) in humans. Combined with EE (3 mg DRSP+30 μg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight com