RESUMEN
Dydrogesterone is widely used for menstrual disorders, endometriosis, threatened and habitual abortion and postmenopausal hormone replacement therapy. Although progestins have a promiscuous nature, dydrogesterone does not have clinically relevant androgenic, estrogenic, glucocorticoid or mineralocorticoid activities. To date, systematic biochemical characterization of this progestin and its active main metabolite, 20α-dihydrodydrogesterone, has not been performed in comparison to progesterone. The objective of this study was to evaluate the selectivity and potential androgenic/antiandrogenic effects of dydrogesterone and its metabolite in comparison to progesterone and medroxyprogesterone acetate by analyzing their interference with AR signaling in vitro. We characterized dydrogesterone and its metabolite for their binding and transactivation of androgen and other steroid hormone receptors and for their potential inhibitory effects against androgen biosynthetic enzymes, 17ß-hydroxysteroid dehydrogenase types 3 and 5 and 5α-reductase types 1 and 2. We found that dydrogesterone resembled progesterone mainly in its progestogenic effects and less in its androgenic, anti-androgenic, glucocorticoid and antiglucocorticoid effects; whereas, 20α-dihydrodydrogesterone showed reduced progestogenic potency with no androgenic, glucocorticoid and mineralocorticoid effects. Effects on the androgen and glucocorticoid receptor differed depending on the technology used to investigate transactivation. Progesterone, but not dydrogesterone and 20α-dihydrodydrogesterone, exerted anti-androgenic effects at the pre-receptor level by inhibiting 5α-reductase type 2. Dydrogesterone, 20α-dihydrodydrogesterone and progesterone inhibited the biosynthesis of testosterone catalyzed by 17ß-hydroxysteroid dehydrogenase types 3 and 5; however, due to their micromolar K(i) values, these activities appeared to be not of relevance at therapeutic levels. Overall, our data show that the anti-androgenic potential of dydrogesterone and 20α-dihydrodydrogesterone is less pronounced compared to progesterone.
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Didrogesterona/farmacología , Progestinas/farmacología , 17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Inhibidores de 5-alfa-Reductasa/farmacología , Sitios de Unión , Unión Competitiva , Línea Celular , Didrogesterona/análogos & derivados , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Humanos , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/química , Receptores de Progesterona/metabolismo , Activación TranscripcionalRESUMEN
BACKGROUND: Blocking the tubuloglomerular feedback mechanism with adenosine A1 receptor antagonists seems to improve diuresis and sodium excretion without compromising the glomerular filtration rate in patients with heart failure. However, the direct cardiac effects of this compound class have not been investigated to date. METHODS AND RESULTS: In total, 111 patients (109 men and 2 women) received a 1-hour infusion of 5, 10, and 15 mg SLV320, an adenosine A1 receptor antagonist, placebo, or 40 mg furosemide. Mean age was 57.9 years, mean ejection fraction was 28.1%, 82 patients were of New York Heart Association class II, and 29 patients were of New York Heart Association class III. Hemodynamic parameters (heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, systemic vascular resistance, right atrial pressure, and cardiac output) were determined. Kidney function was assessed by cystatin C measurements and by analysis of urine output and urine electrolytes. In addition, pharmacokinetics of SLV320 and ex vivo inhibition of adenosine A1 receptor activity were performed. SLV320 was well tolerated, and no serious adverse events were observed. Heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, and cardiac output were not altered by any dose of SLV320. Pulmonary capillary wedge pressure was significantly (P=0.04) decreased by furosemide (-6.2+/-5.9 mm Hg). Systemic vascular resistance was significantly (P=0.04) increased in the furosemide group (+166.70+/-261.87 dynes . s(-1) . cm(-5)), whereas all SLV320 groups showed no significant alterations of systemic vascular resistance. Changes from baseline cystatin C plasma concentrations decreased after 10 mg SLV320 (-0.093+/-0.137 mg/L, P=0.046), whereas furosemide resulted in a significant (P=0.03) increase of cystatin C (+0.052+/-0.065 mg/L) versus baseline. All values represent mean changes+/-SD from baseline at 3 hours postdosing: SLV320 (10 and 15 mg) increased significantly sodium excretion and diuresis compared with placebo during the 0- to 6-hour collection period postdosing. CONCLUSIONS: SLV320 infusion shows no immediate effects on cardiac hemodynamics. SLV320 might improve glomerular filtration rate while simultaneously promoting natriuresis and diuresis. Clinical Trial Registration- clinicaltrials.gov Indentifier: NCT00160134.