Drospirenone--a new progestogen with antimineralocorticoid activity, resembling natural progesterone.
In the second half of a normal menstrual cycle, progesterone levels rise. Progesterone binds to its specific receptor, but also to the mineralocorticoid receptor; thus progesterone acts as a mineralocorticoid antagonist. For this reason, natriuresis is slightly enhanced in the luteal phase, and, as a reflection of the negative sodium balance, plasma renin and aldosterone rise by 20-50%. This rise is of a compensatory nature, and prevents further sodium losses. All conventional synthetic progestogens, whether they are derivatives of 17alpha-hydroxyprogesterone or 19-nortestosterone, lack the antimineralocorticoid effect of natural progesterone. Ethinylestradiol, as the estrogenic component of combined oral contraceptives, is a sodium-retaining drug. This effect is mainly due to a significant increase of the hepatic synthesis of renin substrate (angiotensinogen). Even with low-dose oral contraceptives, systolic and diastolic blood pressure may be raised in susceptible individuals. Drospirenone is a new progestogen, derived from 17alpha-spirolactone, and the relationship between its progestogenic and its antimineralocorticoid potency is almost identical to that of natural progesterone. In an early preclinical study in 12 normal young women, it was found that the oral administration of 2 mg drospirenone for 6 days led to a cumulative sodium loss of 84 mmol and a significant rise in plasma renin and aldosterone, compared with placebo. In a second experiment, it was found that 2 mg drospirenone given from cycle days 5 to 25 to six regularly menstruating women suppressed ovulation and led to a slight natriuresis without a change in blood pressure, while renin and aldosterone levels slightly increased. The natriuresis and the increase in renin and aldosterone levels did not occur in six other women who received 1 mg cyproterone acetate (a progestogen with antiandrogenic properties), instead of drospirenone. Consequently, an oral contraceptive was designed containing 30 microg ethinylestradiol and 3 mg drospirenone (Yasmin, Schering AG, Berlin, Germany) in the hope of developing a contraceptive that might prevent the sodium retention brought about by the effect of ethinylestradiol. In a 6-month study involving 20 regularly menstruating women, it was shown that the addition of drospirenone to ethinylestradiol did indeed prevent the small rise in body weight and blood pressure observed in some women taking a conventional oral contraceptive. In all studies conducted so far with Yasmin, cycle control and tolerability have been found to be good. In conclusion, Yasmin may become an especially well-tolerated combined oral contraceptive, due to the striking similarity between its progestogenic component drospirenone and progesterone.
Oelkers
W
W
Department of Medicine Klinikum Benjamin Franklin, Freie Universitat Berlin, Germany.
D000736:Androstenes; D003280:Contraceptives, Oral, Synthetic; D005260:Female; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists; D045167:Progesterone Congeners
D000736:Androstenes; D003280:Contraceptives, Oral, Synthetic; D000451:Mineralocorticoid Receptor Antagonists; D045167:Progesterone Congeners; C035144:drospirenone