Pharmacodynamics<unk>  is a potent progestogen and a weak androgen and estrogen. That is, it is a potent agonist of the progesterone receptor (PR) and a weak agonist of the androgen receptor (AR) and the estrogen receptor (ER).<unk>  itself has insignificant affinity for the ER; its estrogenic activity is from an active metabolite that is formed in very small amounts, ethinylestradiol (EE), which is a very potent estrogen.<unk>  and its metabolites have negligible affinity for the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) and hence have no glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity. Progestogenic activity<unk>  is a potent progestogen and binds to the PR with approximately 150% of the affinity of progesterone. In contrast, its parent compounds, testosterone, nandrolone (19-nortestosterone), and ethisterone (17α-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR. Unlike<unk> , its major active metabolite 5α-dihydronorethisterone (5α-DHNET), which is formed by transformation via 5α-reductase, has been found to possess both progestogenic and marked antiprogestogenic activity, although its affinity for the PR is greatly reduced relative to<unk>  at only 25% of that of progesterone.<unk>  produces similar changes in the endometrium and vagina, such as endometrial transformation, and is similarly antigonadotropic, ovulation-inhibiting, and thermogenic in women compared to progesterone, which is in accordance with its progestogenic activity. Androgenic activity<unk>  has approximately 15% of the affinity of the anabolic–androgenic steroid (AAS) metribolone (R-1881) for the AR, and in accordance, is weakly androgenic. In contrast to<unk> , 5α-DHNET, the major metabolite of<unk> , shows higher affinity for the AR, with approximately 27% of the affinity of metribolone. However, although 5α-DHNET has higher affinity for the AR than<unk> , it has significantly diminished and in fact almost abolished androgenic potency in comparison to<unk>  in rodent bioassays. Similar findings were observed for ethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone (19-nortestosterone) in rodent bioassays. As such, it appears that the ethynyl group of<unk>  at the C17α position is responsible for its loss of androgenicity upon 5α-reduction.<unk>  (0.5 to 3 mg/day) has been found to dose-dependently decrease circulating SHBG levels, which is a common property of androgens and is due to AR-mediated suppression of hepatic SHBG production. The drug also has estrogenic activity, and estrogens are known to increase SHBG hepatic production and circulating levels, so it would appear that the androgenic activity of<unk>  overpowers its estrogenic activity in this regard.<unk>  is bound to a considerable extent (36%) to SHBG in circulation. Although it has lower affinity for SHBG than endogenous androgens and estrogens,<unk>  may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects. Estrogenic activity Ethinylestradiol (EE), the metabolite of<unk>  responsible for its estrogenic activity.<unk>  binds to the ERs, the ERα and the ERβ, with 0.07% and 0.01% of the relative binding affinity of estradiol. Due to these very low relative affinities, it is essentially inactive itself as a ligand of the ERs at clinical concentrations. However,<unk>  has been found to be a substrate for aromatase and is converted in the liver to a small extent (0.35%) to the highly potent estrogen ethinylestradiol (EE), and for this reason, unlike most other progestins,<unk>  has some estrogenic activity. However, with typical dosages of<unk>  used in oral contraceptives (0.5 to 1 mg), the levels of EE produced are low, and it has been said that they are probably without clinical relevance. Conversely, doses of 5 and 10 mg of<unk> , which are used in the treatment of gynecological disorders, are converted at rates of 0.7% and 1.0% and produce levels of EE that correspond to those produced by 30 and 60 μg dosages of EE, respectively. The levels of EE formed by 0.5 and 1 mg of<unk>  have been estimated based on higher dosages as corresponding to 2 and 10 μg dosages of EE, respectively. At high doses,<unk>  may increase the risk of venous thromboembolism due to metabolism into EE. Neurosteroid activity Like progesterone and testosterone,<unk>  is metabolized into 3,5-tetrahydro metabolites. Whether these metabolites of<unk>  interact with the GABAA receptor similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone like allopregnanolone and 3α-androstanediol, respectively, is a topic that does not appear to have been studied and hence requires clarification. Steroidogenesis inhibition<unk>  is a substrate for and is known to be an inhibitor of 5α-reductase, with 4.4% and 20.1% inhibition at 0.1 and 1 μM, respectively. However, therapeutic concentrations of<unk>  are in the low nanomolar range, so this action may not be clinically relevant at typical dosages.<unk>  and its major active metabolite 5α-DHNET have been found to act as irreversible aromatase inhibitors (Ki = 1.7 μM and 9.0 μM, respectively). However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages. 5α-DHNET specifically has been assessed and found to be selective in its inhibition of aromatase, and does not affect cholesterol side-chain cleavage enzyme (P450scc), 17α-hydroxylase/17,20-lyase, 21-hydroxylase, or 11β-hydroxylase. Since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike<unk> , 5α-DHNET has been proposed as a potential therapeutic agent in the treatment of ER-positive breast cancer. Other activities<unk>  is a very weak inhibitor of CYP2C9 and CYP3A4 (IC50 = 46 μM and 51 μM, respectively), but these actions require very high concentrations of<unk>  that are far above therapeutic circulating levels (which are in the nanomolar range) and hence are probably not clinically relevant.<unk>  and some of its 5α-reduced metabolites have been found to produce vasodilating effects in animals that are independent of sex steroid receptors and hence appear to be non-genomic in mechanism.<unk>  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 act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies. Antigonadotropic effects Due to its progestogenic activity,<unk>  suppresses the hypothalamic–pituitary–gonadal axis (HPG axis) and hence has antigonadotropic effects. The estrogenic activity of<unk>  at high doses would also be expected to contribute to its antigonadotropic effects. Due to its antigonadotropic effects,<unk>  suppresses gonadal sex hormone production, inhibits ovulation in women, and suppresses spermatogenesis in men. The ovulation-inhibiting dosage of both oral<unk>  and oral<unk> A is about 0.5 mg/day in women. However, some conflicting data exist, suggesting that higher doses might be necessary for full inhibition of ovulation. An intramuscular injection of 200 mg<unk> E has been found to prevent ovulation and suppress levels of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in women. Early studies of oral<unk>  in men employing doses of 20 to 50 mg/day observed suppression of 17-ketosteroid excretion, increased estrogen excretion (due to conversion into ethinylestradiol), suppression of spermatogenesis, libido, and erectile function, and incidence of gynecomastia. A dosage of oral<unk>  of 25 mg/day for 3 weeks in men has been reported to suppress testosterone levels by about 70%, to 100 to 200 ng/dL, within 4 or 5 days, as well as to suppress sperm count and to have no effect on libido or erectile function over this short time period. A single 200 mg intramuscular injection of<unk> E alone or in combination with 2 mg estradiol valerate has been found to produce a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men. Intramuscular injections of 200 mg<unk> E once every 3 weeks have also been found to suppress spermatogenesis in men. Pharmacokinetics The pharmacokinetics of<unk>  have been reviewed. Absorption The oral bioavailability of<unk>  is between 47 and 73%, with a mean oral bioavailability of 64%. Micronization has been found to significantly improve the oral bioavailability of<unk>  by increasing intestinal absorption and reducing intestinal metabolism. A single 2 mg oral dose of<unk>  has been found to result in peak circulating levels of the drug of 12 ng/mL (40 nmol/L), whereas a single 1 mg oral dose of<unk>  in combination with 2 mg estradiol resulted in peak levels of<unk>  of 8.5 ng/mL (29 nmol/L) one-hour post-administration. Distribution The plasma protein binding of<unk>  is 97%. It is bound 61% bound to albumin and 36% bound to SHBG. Metabolism<unk>  has an elimination half-life of 5.2 to 12.8 hours, with a mean elimination half-life of 8.0 hours. The metabolism of<unk>  is very similar to that of testosterone (and nandrolone) and is mainly via reduction of the Δ4 double bond to 5α- and 5β-dihydronorethisterone, which is followed by the reduction of the C3 keto group to the four isomers of 3,5-tetrahydronorethisterone. These transformations are catalyzed by 5α- and 5β-reductase and 3α- and 3β-hydroxysteroid dehydrogenase both in the
Norethisterone
Cloxotestosterone acetate
Androstanolone benzoate
Norvinisterone
Norethandrolone
Oxandrolone
Nandrolone propionate
Ethisterone