Pharmacodynamics<unk>  acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively), activating these receptors with EC50 values of approximately 0.01 nM, 1 nM, and 10 nM, respectively. It has negligible affinity for the estrogen receptor. The medication has relatively high affinity for the mineralocorticoid receptor, but in spite of this, it has no mineralocorticoid or antimineralocorticoid activity. The intrinsic activities of<unk>  in activating the PR and the AR have been reported to be at least equivalent to those of progesterone and dihydrotestosterone (DHT), respectively, indicating that it is a full agonist of these receptors. Relative affinities (%) of<unk>  and related steroids Progestogen ' ' ' ' ' Progesterone 50 0 0 10 100 Chlormadinone acetate 67 5 0 8 0 Cyproterone acetate 90 6 0 6 8<unk>  115 5 0 29 160 Megestrol acetate 65 5 0 30 0 Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , estradiol for the , dexamethasone for the , and aldosterone for the . Sources: Progestogenic activity<unk>  is a potent agonist of the progesterone receptor with similar affinity and efficacy relative to progesterone. While both<unk>  and its deacetylated analogue<unk>  bind to and agonize the PR,<unk>  has approximately 100-fold higher binding affinity and transactivation potency in comparison. As such, unlike<unk> ,<unk>  is not used clinically, though it has seen some use in veterinary medicine. The oral dosage of<unk>  required to inhibit ovulation (i.e., the effective contraceptive dosage) is 10 mg/day, whereas 5 mg/day was not sufficient to inhibit ovulation in all women. In accordance, the dosage of<unk>  used in oral contraceptives in the past was 10 mg per tablet. For comparison to<unk> , the dosage of progesterone required to inhibit ovulation is 300 mg/day, whereas that of the 19-nortestosterone derivatives norethisterone and norethisterone acetate is only 0.4 to 0.5 mg/day. The mechanism of action of progestogen-only contraceptives like DMPA depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as DMPA, inhibit follicular development and prevent ovulation as their primary mechanism of action. The progestogen decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation. A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus. Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophic. These changes in the endometrium could, theoretically, prevent implantation. However, because DMPA is highly effective in inhibiting ovulation and sperm penetration, the possibility of fertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.<unk>  and related steroids at the progesterone receptor Compound (nM) (nM)a (nM)b Progesterone 4.3 0.9 25<unk>  241 47 32<unk>  1.2 0.6 0.15 Footnotes: a = Coactivator recruitment. b = Reporter cell line. Sources: Oral potencies of<unk>  and related steroids Progestogen (mg/day) (mg/cycle) (mg/day) (mg/day) (mg/day) Progesterone 300 4200 200–300 – 200 Chlormadinone acetate 1.7 20–30 10 2.0 5–10 Cyproterone acetate 1.0 20 1.0 2.0 1.0<unk>  10 50 5–10 ? 5.0 Megestrol acetate ? 50 ? ? 5.0 Abbreviations: OID = ovulation-inhibiting dosage (without additional estrogen). TFD = endometrial transformation dosage. ODP = oral dosage in commercial contraceptive preparations. ECD = estimated comparable dosage. Sources: Antigonadotropic and anticorticotropic effects<unk>  suppresses the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG) axes at sufficient dosages, resulting decreased levels of gonadotropins, androgens, estrogens, adrenocorticotropic hormone (ACTH), and cortisol, as well as levels of sex hormone-binding globulin (SHBG). There is evidence that the suppressive effects of<unk>  on the HPG axis are mediated by activation of both the PR and the AR in the pituitary gland. Due to its effects on androgen levels,<unk>  can produce strong functional antiandrogenic effects, and is used in the treatment of androgen-dependent conditions such as precocious puberty in boys and hypersexuality in men. In addition, since the medication suppresses estrogen levels as well,<unk>  can produce strong functional antiestrogenic effects similarly, and has been used to treat estrogen-dependent conditions such as precocious puberty in girls and endometriosis in women. Due to low estrogen levels, the use of<unk>  without an estrogen poses a risk of decreased bone mineral density and other symptoms of estrogen deficiency. Oral<unk>  has been found to suppress testosterone levels in men by about 30% (from 831 ng/dL to 585 ng/dL) at a dosage of 20 mg/day, by about 45 to 75% (average 60%; to 150–400 ng/dL) at a dosage of 60 mg/day, and by about 70 to 75% (from 832 to 862 ng/dL to 214–251 ng/dL) at a dosage of 100 mg/day. Dosages of oral<unk>  of 2.5 to 30 mg/day in combination with estrogens have been used to help suppress testosterone levels in transgender women. Very high dosages of intramuscular<unk>  of 150 to 500 mg per week (but up to 900 mg per week) can suppress testosterone levels to less than 100 ng/dL. The typical initial dose of intramuscular<unk>  for testosterone suppression in men with paraphilias is 400 or 500 mg per week. Androgenic activity<unk>  is a potent full agonist of the AR. Its activation of the AR may play an important and major role in its antigonadotropic effects and in its beneficial effects against breast cancer. However, although<unk>  may produce androgenic side effects such as acne and hirsutism in some women, it rarely does so, and when such symptoms occur, they tend to be mild, regardless of the dosage used. In fact, likely due to its suppressive actions on androgen levels, it has been reported that<unk>  is generally highly effective in improving pre-existing symptoms of hirsutism in women with the condition. Moreover,<unk>  rarely causes any androgenic effects in children with precocious puberty, even at very high doses. The reason for the general lack of virilizing effects with<unk> , despite it binding to and activating the AR with high affinity and this action potentially playing an important role in many of its physiological and therapeutic effects, is not entirely clear. However,<unk>  has been found to interact with the AR differently compared to other agonists of the receptor such as dihydrotestosterone (DHT). The result of this difference appears to be that<unk>  binds to the AR with a similar affinity and intrinsic activity to that of DHT, but requires about 100-fold higher concentrations for a comparable induction of gene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration. Thus, this may explain the low propensity of<unk>  for producing androgenic side effects.<unk>  shows weak androgenic effects on liver protein synthesis, similarly to other weakly androgenic progestins like megestrol acetate and 19-nortestosterone derivatives. While it does not antagonize estrogen-induced increases in levels of triglycerides and HDL cholesterol, DMPA every other week may decrease levels of HDL cholesterol. In addition,<unk>  has been found to suppress sex hormone-binding globulin (SHBG) production by the liver. At a dosage of 10 mg/day oral<unk> , it has been found to decrease circulating SHBG levels by 14 to 18% in women taking 4 mg/day oral estradiol valerate. Conversely, in a study that combined 2.5 mg/day oral<unk>  with various oral estrogens, no influence of<unk>  on estrogen-induced increases in SHBG levels was discerned. In another, higher-dose study, SHBG levels were lower by 59% in a group of women treated with 50 mg/day oral<unk>  alone relative to an untreated control group of women. In a massive-dose study of oral<unk>  (1,000 mg/day), the medication decreased SHBG levels by about 80%. Unlike the related steroids megestrol acetate and cyproterone acetate,<unk>  is not an antagonist of the AR and does not have direct antiandrogenic activity. As such, although<unk>  is sometimes described as an antiandrogen, it is not a "true" antiandrogen (i.e., AR antagonist). Glucocorticoid activity As an agonist of the GR,<unk>  has glucocorticoid activity, and as a result can cause symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency at sufficiently high doses. It has been suggested that the glucocorticoid activity of<unk>  may contribute to bone loss. The glucocorticoid activity of<unk>  may also result in an upregulation of the thrombin receptor in blood vessel walls, which may contribute to procoagulant effects of<unk>  and risk of venous thromboembolism and atherosclerosis. The relative glucocorticoid activity of<unk>  is among the highest of the clinically used progestins. Steroidogenesis inhibition<unk>  has been found to act as a competitive inhibitor of rat 3α-hydroxysteroid dehydrogenase (3α-HSD). This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone,
Medroxyprogesterone acetate
Hydroxyprogesterone acetate
Desoxymethyltestosterone
Retroprogesterone
Gestodene
Lipoidal estradiol
Hydroxyprogesterone caproate
Cloxestradiol acetate