Pharmacodynamics<unk>  has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and weak glucocorticoid activity. Relative affinities (%) of and metabolites Compound 67–172 3–76 0 8 0 0 0 33 4 ? 2 ? ? ? 72 15 ? 6 ? ? ? Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , for the , for the , aldosterone for the , for , and cortisol for . Sources: Progestogenic activity<unk>  is a progestogen, or an agonist of the progesterone receptor. It is highly potent in its progestogenic activity, with about 330 times the potency of progesterone in the Clauberg test and about 2,000 to 10,000 times the oral potency of progesterone in the McPhail assay. For comparison, the potencies of medroxyprogesterone acetate and CPA in the Clauberg assay were about 330- and 1,000-fold that of progesterone, respectively. The progestogenic activity of<unk>  is responsible for its functional antigonadotropic and antiestrogenic effects and for its contraceptive effects. The oral ovulation-inhibiting dosage of<unk>  in women is 1.5 to 4 mg/day and its endometrial transformation dosage is 25 mg/cycle. In one study of ovulation inhibition,<unk>  was 68% effective at 1 mg/day, 85% effective at 2 mg/day, and 100% effective at 4 mg/day. The effective dosage of<unk>  as a progestogen-only pill for contraception is 0.5 mg/day. Inhibition of ovulation is incomplete at this dosage and contraceptive effects are instead mainly achieved via progestogenic changes in the endometrium and cervix. In rabbit bioassays, PR activation was similar for<unk>  and its major active metabolites 3α-hydroxychlormadinone acetate (3α-OH-CMA) and 3β-hydroxychlormadinone acetate (3β-OH-CMA). Antigonadotropic effects Testosterone levels with 50 mg/day allylestrenol or 50 mg/day<unk>  orally over 12 weeks in men with benign prostatic hyperplasia. Due to its progestogenic activity,<unk>  has antigonadotropic effects, and hence can inhibit the secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. As a result,<unk>  suppresses ovulation and gonadal sex hormone production and can strongly decrease circulating testosterone and estradiol levels at sufficiently high dosages. The medication at a dosage of 50 mg/day has been found to suppress testosterone levels by about 76 to 85% (to approximately 50–100 ng/dL) and estradiol levels by about 55 to 59% (to approximately 7–8 pg/mL) in men with BPH. As such,<unk>  has powerful functional antiandrogenic and antiestrogenic effects via its antigonadotropic effects. Antiandrogenic activity<unk>  is a potent antiandrogen, or antagonist of the androgen receptor (AR), with about 30 to 40% of the affinity of CPA for the receptor and about 20% of the antiandrogenic potency of CPA in animals. Like other progestins with antiandrogenic activity such as CPA, megestrol acetate, and spironolactone, but unlike nonsteroidal antiandrogens such as flutamide and bicalutamide,<unk>  is not a silent antagonist of the AR but rather a weak partial agonist with the<unk> acity to activate the receptor in the absence of more efficacious agonists such as testosterone. In rabbit bioassays, AR antagonism was similar for<unk>  and 3α-OH-CMA but lower for 3β-OH-CMA. Both the antigonadotropic and antiandrogenic actions of<unk>  are thought to be involved in its effectiveness in the treatment of prostate cancer. When low-dose<unk>  is combined with EE, as in combined birth control pills, the antiandrogenic activity of<unk>  is reinforced, due to a large increase in sex hormone-binding globulin (SHBG) levels and consequent fall in free testosterone levels induced by EE. Unlike 19-nortestosterone progestins like levonorgestrel,<unk>  does not antagonize the EE-induced increase in SHBG levels. Other activity Similarly to other 17α-hydroxyprogesterone derivatives such as CPA, medroxyprogesterone acetate, and megestrol acetate,<unk>  has weak affinity for the glucocorticoid receptor (comparable to that of progesterone) and weak glucocorticoid activity, and has the potential to cause adrenal insufficiency upon abrupt discontinuation at sufficient dosages. However, the medication shows significant glucocorticoid activity only at dosages much higher than those present in birth control pills. In rabbit bioassays, GR activation was highest for<unk>  but less for 3α-OH-CMA and not observed with 3β-OH-CMA (suggesting that it may, in contrast, be a lower efficacy partial agonist or antagonist of the GR).<unk>  has no affinity for the estrogen or mineralocorticoid receptors and has no estrogenic or antimineralocorticoid activity. Unlike progesterone but similarly to other progestins,<unk>  has no known neurosteroid activity (e.g., GABAA receptor modulation) or sedative effects.<unk>  has been reported to be a competitive inhibitor of 5α-reductase. However, it seems to shows very low potency in this action, with 0.0% inhibition of the enzyme at a concentration of 1 μM, and in relation to this, has been said not to have an important influence on the enzyme.<unk>  may also act weakly as a testosterone biosynthesis inhibitor at high dosages. Unlike 19-nortestosterone progestins,<unk>  does not inhibit enzymes in the cytochrome P450 system, which may give it a lower risk of drug interactions. Certain progestins have been found to stimulate 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). Progesterone and<unk> , in contrast, act neutrally in this assay. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies. Pharmacokinetics The oral bioavailability of<unk>  is 100%, which is due to low first-pass metabolism. In combination with 30 μg EE, a single 2 mg oral dose of<unk>  produced maximal serum levels of 1.6 ng/mL after about 1 to 2 hours and chronic administration produced steady-state levels of 2.0 ng/mL. Steady-state concentrations of<unk>  are achieved after 7 to 15 days. The distribution half-life of<unk>  is about 2.5 hours. The medication is highly lipophilic and is taken up into and accumulated in fat and some female reproductive tissues, although this may only occur at high dosages (e.g., ≥10 mg/day). The volume of distribution of<unk>  is unknown, but that of the closely related steroid CPA is very large at 1,300 L. The plasma protein binding of<unk>  is 96.6 to 99.4%, with about 1 to 3% free. It is bound to albumin, with no affinity for SHBG or corticosteroid-binding globulin.<unk>  is extensively metabolized in the liver by reduction, hydroxylation, deacetylation, and conjugation. Reduction occurs at the C3 ketone with preservation of the δ4(5) double bond, hydroxylation is at the C2α, C3α, C3β, and C15β positions, and conjugation includes glucuronidation and sulfation. The main metabolites of<unk>  are 2α-OH-CMA, 3α-OH-CMA, and 3β-OH-CMA, with the latter two being important active metabolites. Other metabolites of<unk>  are inactive. The elimination half-life of<unk>  has been reported to be 25 to 34 hours after a single dose and 34 to 39 hours after multiple doses, although some publications have reported its half-life to be as long as 80 to 89 hours. Enterohepatic reabsorption of<unk>  occurs. The medication has been found to be excreted 33 to 45% in urine and 24 to 41% in feces, as well as in bile. Only 74% of a dose is excreted 7 days after administration, which is due to accumulation of<unk>  in tissues and low clearance.
Chlormadinone acetate
Methenmadinone acetate
Chlormethenmadinone acetate
Bolandiol dipropionate
Hydroxyprogesterone heptanoate
Ethinylestradiol sulfate
Ethinylestradiol sulfonate
Androstenediol dipropionate