Pharmacodynamics 20α-Dihydrodydrogesterone (20α-DHD), the main active form of<unk> .<unk>  is a highly selective progestogen, and due to its unique structure, unlike progesterone and many other progestins, binds almost exclusively to the progesterone receptor (PR). The affinity of<unk>  for the PR is relatively low at about 16% of that of progesterone. However, in vivo,<unk>  is comparatively much more potent by the oral route, with an equivalent dose, in terms of endometrial proliferation, that is 10 to 20 times lower than that of progesterone. This is due to pharmacokinetic differences between the two medications, namely improved bioavailability and metabolic stability with<unk>  as well as additional progestogenic activity of its metabolites.<unk>  binds to and activates both of the major isoforms of the PR, the PR-A and PR-B, with a similar selectivity ratio between the two receptors as that of progesterone and with lower efficacy at the receptors relative to progesterone. The major active metabolite of<unk> , 20α-dihydrodydrogesterone (20α-DHD), has progestogenic activity as well but with greatly decreased potency relative to<unk> . As with other progestogens,<unk>  has functional antiestrogenic effects in certain tissues, for instance in the endometrium, and induces endometrial secretory transformation.<unk>  does not bind importantly to the androgen, estrogen, or glucocorticoid receptor. As such, it is devoid of androgenic or antiandrogenic, estrogenic or antiestrogenic, and glucocorticoid or antiglucocorticoid activity. Similarly to progesterone however,<unk>  binds to the mineralocorticoid receptor and possesses antimineralocorticoid activity, but only weakly so. Like other progestins but unlike progesterone, which forms sedative neurosteroid metabolites,<unk>  is not able to be metabolized in a similar way, and for this reason, is non-sedative. The medication and 20α-DHD do not inhibit 5α-reductase.<unk>  has been found to inhibit myometrium contractility via an undefined progesterone receptor-independent mechanism in vivo in pregnant rats and in vitro in human tissue at concentrations at which progesterone and other progestogens do not. Atypical progestogenic profile Due to its progestogenic activity,<unk>  can produce antigonadotropic effects at sufficient doses in animals. However, it does not suppress secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), or inhibit ovulation at typical clinical dosages in humans. Oral doses of<unk>  of 5 to 40 mg/day on days 5 to 25 of the cycle fail to suppress ovulation (assessed by urinary pregnanediol and laparotomy), and one study found that ovulation persisted even in women treated with an oral dosage of as great as 400 mg/day (assessed by visual inspection of the ovaries). Likewise, an intramuscular injection of 100 mg<unk>  in microcrystalline aqueous suspension on the first to third day of the cycle did not interfere with the development of an ovulatory pattern of spontaneous uterine contractions in women. A couple of conflicting studies exist on the issue of ovulation inhibition by<unk>  however, with findings of partial or full inhibition of ovulation by oral<unk> . This included prevention of the mid-cycle LH and FSH peaks and the luteal-phase rise in body temperature and pregnanediol excretion. Nonetheless, the overall consensus among researchers seems to be that<unk>  does not inhibit ovulation in women. The apparent inability of<unk>  to prevent ovulation is in contrast to all other clinically used progestogens except trengestone, which is closely related to<unk> . Similarly to trengestone but also unlike all other clinically used progestogens,<unk>  does not have a hyperthermic effect in humans (i.e., it does not increase body temperature). It has been said that the lack of ovulation inhibition and hyperthermic effect with retroprogesterone derivatives like<unk>  may represent a dissociation of peripheral and central progestogenic activity. However, a related retroprogesterone derivative, trengestone, likewise does not inhibit ovulation or produce a hyperthermic effect but rather has an inducing effect on ovulation. Whereas all other assessed progestins are associated with an increased risk of breast cancer when combined with an estrogen in postmenopausal women, neither oral progesterone nor<unk>  are associated with a significantly increased risk of breast cancer (although the risk of breast cancer is non-significantly higher with<unk> . Similarly, like oral progesterone but in contrast to other progestins,<unk>  does not appear to further increase the risk of venous thromboembolism when used in combination with an oral estrogen.<unk>  may also provide inferior endometrial protection relative to other progestins such as medroxyprogesterone acetate and norethisterone acetate, with a significantly increased risk of endometrial cancer in combination with an estrogen with long-term therapy (>5 years). Other activity<unk>  weakly stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins are also active in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone,<unk> , and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies. Pharmacokinetics Absorption<unk>  and its major metabolite, 20α-DHD, have predictable pharmacokinetics. The single-dose kinetics are linear in the oral dose range of 2.5 to 10 mg. The pharmacokinetics do not change during repeated administration of up to 20 mg<unk>  once daily.<unk>  is readily absorbed with oral administration. The absolute bioavailability of<unk>  is on average 28%. Tmax values vary between 0.5 and 2.5 hours. Steady state is attained after 3 days of treatment. The levels of 20α-DHD, which is the main active metabolite, are also found to peak about 1.5 hours post-dose. A single intramuscular injection of 100 mg<unk>  in microcrystalline aqueous suspension has been found to have a duration of action of 16 to 38 days in terms of clinical biological effect in the uterus in women. This was specifically the time until the onset of withdrawal bleeding in estrogen-treated amenorrheic women. Distribution The plasma protein binding of<unk>  and 20α-DHD are unknown. Based on the plasma protein binding of other progestins however, they are probably bound to albumin and not to sex hormone-binding globulin or corticosteroid-binding globulin. Metabolism The metabolism of<unk>  occurs in the liver. It is virtually completely metabolized. The primary metabolic pathway is the hydrogenation of the 20-keto group mainly by AKR1C1 and to a lesser extent AKR1C3, resulting in 20α-DHD. This active metabolite is a progestogen similarly to<unk> , albeit with much lower potency. With oral administration of<unk> , circulating levels of 20α-DHD are substantially higher than those of<unk> . The ratios of 20α-DHD to<unk>  in terms of peak levels and area-under-the-curve (AUC) levels have been found to be 25:1 and 40:1, respectively. For these reasons, despite the lower relative progestogenic potency of 20α-DHD,<unk>  may act as a prodrug of this metabolite. The metabolism of<unk>  differs from progesterone. Whereas the major metabolite of progesterone is pregnanediol, the corresponding derivative of<unk> , retropregnanediol, cannot be detected in urine with oral administration of<unk> . All of the metabolites of<unk>  retain the 4,6-diene-3-one structure and are metabolically stable. As such, similarly to progesterone,<unk>  does not undergo aromatization. The mean elimination half-lives of<unk>  and 20α-DHD are in the ranges of 5 to 7 hours and 14 to 17 hours, respectively. Excretion<unk>  and its metabolites are excreted predominantly in urine. Total clearance of plasma is at a rate of 6.4 L/min. Within 72 hours, excretion is virtually complete. 20α-DHD is preponderantly present in the urine as a conjugate of glucuronic acid. Approximately 85% of the oral dose is successfully removed from the body within 24 hours. Around 90% of excreted material is 20α-DHD. Miscellaneous The pharmacokinetics of<unk>  have been reviewed.
Dydrogesterone
Haloprogesterone
Hydroxyprogesterone acetate
Gestodene
Vinyltestosterone
Retroprogesterone
Ethinylestradiol
Algestone