Conception and pharmacodynamic profile of drospirenone.
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: 6beta,7beta,15beta,16beta-dimethylene-3-oxo 17alpha-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 1-3mg 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 microg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight compared to conventional oral contraceptives was reduced. DRSP (3 mg per day+15, 20, or 30 microg ethinyl estradiol per day) prevented the mild increase of blood pressure seen under a conventional levonorgestrel-containing contraceptive and even tended to reduce pretreatment blood pressure. Studies on modulation (i.e. inhibition) of glucocorticoid effects at the MR in the CNS remain an unexplored and interesting area for research.
Elger
Walter
W
EnTec GmbH Labor Jena, Adolf Reichweinstrabe 20, 07745 Jena, Germany. w.elger@web.de
Beier
Sybille
S
Pollow
Kunhard
K
Garfield
Robert
R
Shi
Shao Qing
SQ
Hillisch
Alexander
A
D000726:Androgen Antagonists / Q000737:chemistry / Q000378:metabolism; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D002490:Central Nervous System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D005306:Fertilization; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System; D012737:Sex Factors; D013997:Time Factors
D000726:Androgen Antagonists; D000736:Androstenes; D000451:Mineralocorticoid Receptor Antagonists; D004997:Ethinyl Estradiol; C035144:drospirenone; D019331:NG-Nitroarginine Methyl Ester