Pharmacodynamics<unk>  has progestogenic activity, possibly some antiprogestogenic activity, and has antiandrogenic activity. The medication does not interact with the estrogen receptor, the glucocorticoid receptor, or the mineralocorticoid receptor, and hence has no estrogenic, glucocorticoid, or antimineralocorticoid activity. Because of its relatively high selectivity as a progestogen,<unk>  may have favorable safety and tolerability compared to various other progestins. Relative affinities (%) of<unk>  and metabolites Compound<unk>  5 10 0 1 0 0 0 9α,10β-Dihydrodienogest 26 13 ? ? ? ? ? 3α,5α-Tetrahydrodienogest 19 16 ? ? ? ? ? Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , estradiol for the , dexamethasone for the , aldosterone for the , for , and cortisol for . Sources: Progestogenic activity<unk>  is an agonist of the progesterone receptor (PR), and hence is a progestogen. It has relatively weak affinity for the PR in vitro in human uterine tissue, about 10% that of progesterone. Despite its low affinity for the PR however,<unk>  has high progestogenic activity in vivo. In addition, although its metabolites, such as 9α,10β-dihydrodienogest and 3α,5α-tetrahydrodienogest, have greater affinity for the PR than does<unk>  itself, the medication is not considered to be a prodrug. + Progestogen (mg/cycle) (mg/day) /ratio Chlormadinone acetate 25 1.7 1.5 Cyproterone acetate 20 1.0 2.0<unk>  6 1.0 0.6 Norethisterone 120 0.4 30 Norethisterone acetate 50 0.5 10 Norgestimate 7 0.2 3.5 Levonorgestrel 5 0.06 8.3 Desogestrel 2 0.06 3.3 Gestodene 3 0.04 7.5 Drospirenone 50 2.0 2.5 Nomegestrol acetate 100 5.0 2.0<unk>  has been described as "special" progestogen, possessing low or moderate antigonadotropic efficacy but strong or very strong endometrial efficacy. In relation to its endometrial activity,<unk>  is said to be one of the strongest progestogens available. The high endometrial activity of<unk>  underlies its ability to stabilize the menstrual cycle when combined with either ethinylestradiol or estradiol valerate (which has lower relative effects on the uterus compared to ethinylestradiol) in birth control pills, and also its use in the treatment of endometriosis. The combination of most other progestins with estradiol or an estradiol ester like estradiol valerate as birth control pills was unsatisfactory due to a high incidence of irregular menstrual bleeding. This is a property that ethinylestradiol does not share with estradiol, because of its resistance to metabolism in the endometrium and hence its greater relative effects in this part of the body. In contrast to other progestins, due to its high endometrial efficacy, the combination of<unk>  with estradiol valerate in birth control pills is able to prevent breakthrough bleeding, and is uniquely able to treat heavy menstrual bleeding. The absence of withdrawal bleeding, otherwise known as "silent menstruation", also may occur.<unk>  has antiovulatory potency that is similar to that of 17α-hydroxyprogesterone derivatives like cyproterone acetate but endometrial potency that is much stronger and similar to that of gonane 19-nortestosterone progestins like levonorgestrel. Unlike other progestogens, except in the case of its strong effects in the uterus,<unk>  has been described as lacking antiestrogenic effects, and does not antagonize beneficial effects of estradiol, for instance in the metabolic and vascular systems.<unk>  showed some possible antiprogestogenic activity in one animal bioassay when administered before but not at the same time as progesterone. The minimum effective dose of oral<unk>  required to inhibit ovulation is 1 mg/day. The inhibition of ovulation by<unk>  occurs mainly via a direct peripheral action in the ovary of inhibiting folliculogenesis as opposed to a central action of inhibiting gonadotropin secretion. Oral therapy with 2 mg/day<unk>  in cyclical premenopausal women reduced serum progesterone levels to anovulatory levels, but circulating levels of luteinizing hormone and follicle-stimulating hormone were not considerably affected. At this dosage, estradiol levels are reduced to early follicular phase levels of about 30 to 50 pg/mL. Such levels are insufficient for reactivation of endometrioses, but are sufficient to avoid menopausal-like symptoms such as hot flashes and bone loss. This is in contrast to gonadotropin-releasing hormone analogues (GnRH analogues), which suppress estradiol levels to lower concentrations and readily induce menopausal-like symptoms.<unk>  appears to have similar effects in the breasts as norethisterone acetate, and may likewise increase the risk of breast cancer when combined with an estrogen in postmenopausal women, although this has yet to be confirmed in clinical studies. Antigonadotropic effects Testosterone levels with 2, 5, or 10 mg/day<unk> , 10 mg/day oral cyproterone acetate, or placebo in healthy young men.<unk>  has been found to suppress testosterone levels in men by 43% at 2 mg/day, 70% at 5 mg/day, and 81% at 10 mg/day. The suppression of testosterone levels with 10 mg/day<unk>  was comparable to that with 10 mg/day cyproterone acetate. In general, progestogens are able to suppress testosterone levels in men by a maximum of about 70 to 80% at sufficiently high doses. Antiandrogenic activity<unk>  is one of the only 19-nortestosterone derivative progestins that does not have androgenic properties. In fact, it is actually an antagonist of the androgen receptor (AR), and hence has antiandrogenic activity. The antiandrogenic activity of<unk>  in the Hershberger test is about 30 to 40% of that of cyproterone acetate. It may be able to improve androgen-dependent symptoms such as acne and hirsutism. Metabolites of<unk> , such as 9α,10β-dihydrodienogest and 3α,5α-tetrahydrodienogest, show greater affinity for the AR than does<unk>  itself.<unk>  has no affinity for sex hormone-binding globulin (SHBG), and hence does not displace testosterone or estradiol from this plasma protein or increase the free fractions of these hormones. Other activities<unk>  does not inhibit or induce CYP3A4, unlike many other related progestins. Because of this, it may have a lower propensity for drug interactions.<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 and progestins in clinical studies. Pharmacokinetics<unk>  is rapidly absorbed with oral administration and has high bioavailability of approximately 90%. Peak levels of<unk>  occur within approximately 2 hours after an oral dose. The pharmacokinetics of<unk>  are linear; single oral doses of<unk>  were found to result in maximal levels of 28 ng/mL with 1 mg, 54 ng/mL with 2 mg, 101 ng/mL with 4 mg, and 212 ng/mL with 8 mg. The corresponding area-under-the-curve levels were 306, 577, 1153, and 2293 ng/mL, respectively.<unk>  reaches steady-state concentrations within 6 days of continuous administration, and does not accumulate in the body. The plasma protein binding of<unk>  is 90%, with a relatively high free fraction of 10%. It is exclusively bound to albumin, with no binding to SHBG or corticosteroid-binding globulin. The lack of affinity of<unk>  for SHBG is in contrast to most other 19-nortestosterone progestins. The volume of distribution of<unk>  is relatively low at 40 L.<unk>  is metabolized in the liver. Metabolic pathways of<unk>  include reduction of its Δ4-3-keto group, hydroxylation mainly via CYP3A4, removal of its C17α cyanomethyl group, and conjugation. The metabolites of<unk>  are quickly excreted and are said to be mostly inactive. The elimination half-life of<unk>  is relatively short at approximately 7.5 to 10.7 hours. The short half-life of<unk>  relative to other 19-nortestosterone progestins is in part due to its lack of binding to SHBG and hence prolongation in the circulation. The clearance of<unk>  is 3 L/h. It is eliminated mainly in the urine, both as sulfate and glucuronide conjugates and as free steroid.
Dienogest
Nafarelin
Estropipate
Degarelix
Protollin
Gestodene
Tesamorelin
Macimorelin