br Dienogest DNG Dienogest is a nortestosterone derivative w

Dienogest (DNG) Dienogest is a 19-nortestosterone derivative with two special structural changes [Fig. 1a]: [a] At the cabon-17 position there is a cyanomethyl group instead of an ethinyl group; [b] A double bond is present between carbons 9 and 10. DNG is the only progestogen that combines properties of both 17α-hydroxyprogesterone and 19-nortestosterone derivatives [8], [9]. Dienogest is rapidly and almost completely absorbed, leading to a bioavailability of 90%; about 10% of DNG is free. Approximately 90% of DNG is bound to plasma albumin with no binding to SHBG or CBG. Metabolism of DNG by hydroxylation and conjugation results in inactive metabolites. Unchanged DNG is SB 242084 due to the rapid excretion of its metabolites [23]. The plasma half-life of DNG is approximately 10h. The steady-state is reached after two to three days and is not influenced by SHBG levels. There is no relevant accumulation of DNG [9]. The use of 20mg DNG orally daily for 24 weeks does not negatively influence lipid and carbohydrate metabolism, liver enzymes or hemostasis [10]. Evaluating the antiandrogenic effect of DNG it was estimated that it has about 30% to 40% of the antiandrogenic potency of cyproterone acetate, the most potent antiandrogenic progestin [8], [9], [24]. The important effect of a progestogen is to transfer a proliferative endometrium into a secretory state. The strong progestational effect of DNG on the endometrium has been demonstrated in clinical studies controlling endometrial safety by endometrial biopsy in postmenopausal women treated with estrogen in combination with DNG. When comparing estradiol valerate/DNG with estradiol/norethisterone acetate over twelve cycles, estradiol valerate/DNG appeared to be as effective as estradiol/norethisterone acetate. However, the number of days of bleeding was significantly lower estradiol valerate/DNG compared to estradiol/norethisterone acetate [11]. Overall, DNG itself or in combination with estradiol valerate has no negative effect on lipid or carbohydrate metabolism. DNG does not interfere with the vascular system (arterial and venous). Therefore, DNG is suitable for clinical application in perimenopausal and postmenopausal women.
Drospirenone (DRSP) DRSP, a derivative of 17α-spirolactone [Table 1 and Fig. 1b] has a pharmacodynamic profile similar to progesterone [Table 2]. DRSP is rapidly absorbed after oral intake and reaches peak concentration in 1–2h. Its bioavailability is around 76% and it has a half-life of 25–33h. Steady-state is achieved flowing seven daily administrations of 3mg DRSP in combination with 30μg ethinyl estradiol [EE]. Pharmacology and pharmacokinetics has been described previously [25]. Most of the circulating DRSP is bound to plasma albumin – similar to DNG – and it has no active metabolites. Excretion of DRSP is complete after 10 days, with trace amounts excreted unchanged in urine and feces. The affinity of DRSP for the mineralocorticoid receptor is approximately 5-times that of aldosterone [12]. DRSP increases the sodium/potassium excretion ratio in a dose- dependent manner and is 8–10-times more effective than spironolactone [13], [14]. The natriuretic effect has been shown to be long-lasting. The antigonadotropic potency of DRSP is 5–10-fold higher than that of progesterone, and significantly greater than that of spironolactone, but about one-third of the potency of cyproterone acetate [15]. DRSP was developed for oral hormonal contraception. At first with 30μg EE and 3mg DRSP and later with 20μg EE and an extended regimen (24/4); thereafter, it was formulated for HT with 2mg DRSP and 1mg estradiol. The use of 2mg DRSP together with 1mg estradiol controls endometrial proliferation and avoids any preneoplastic changes. It was shown, that DRSP leads to an atrophic endometrium. These favourable effects on the endometrium of postmenopausal women are due to the proapoptotic action of DRSP in the glandular epithelium [12].