Pharmacodynamics<unk>  act by binding to and activating the progesterone receptors (PRs), including the PR-A, PR-B, and PR-C. Major tissues affected by<unk>  include the uterus, cervix, vagina, breasts, and brain. By activating PRs in the hypothalamus and pituitary gland,<unk>  suppress the secretion of gonadotropins and thereby function as antigonadotropins at sufficiently high doses. Progesterone interacts with membrane progesterone receptors, but interaction of progestins with these receptors is less clear. In addition to their<unk> c activity, many<unk>  have off-target activities such as androgenic, antiandrogenic, estrogenic, glucocorticoid, and antimineralocorticoid activity.<unk>  mediate their contraceptive effects in women both by inhibiting ovulation (via their antigonadotropic effects) and by thickening cervical mucus, thereby preventing the possibility of fertilization of the ovum by sperm.<unk>  have functional antiestrogenic effects in various tissues like the endometrium via activation of the PR, and this underlies their use in menopausal hormone therapy (to prevent unopposed estrogen-induced endometrial hyperplasia and endometrial cancer). The PRs are induced in the breasts by estrogens, and for this reason, it is assumed that<unk>  cannot mediate breast changes in the absence of estrogens. The off-target activities of<unk>  can contribute both to their beneficial effects and to their adverse effects. Antigonadotropic effects<unk> , similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via activation of the PR in the pituitary gland. This effect is a form of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis) and takes advantage of the mechanism that the body uses to prevent sex hormone levels from becoming too high. Accordingly,<unk> , both endogenous and exogenous (i.e., progestins), have antigonadotropic effects, and<unk>  in sufficiently high amounts can markedly suppress the body's normal production of<unk> , androgens, and estrogens as well as inhibit fertility (ovulation in women and spermatogenesis in men).<unk>  have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high doses. This is notably less than that achieved by GnRH analogues, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%. It is also less than that achieved by high-dose estrogen therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues. The retroprogesterone derivatives dydrogesterone and trengestone are atypical<unk>  and unlike all other clinically used<unk>  do not have antigonadotropic effects nor inhibit ovulation even at very high doses. In fact, trengestone may have progonadotropic effects, and is actually able to induce ovulation, with about a 50% success rate on average. These progestins also show other atypical properties relative to other<unk> , such as a lack of a hyperthermic effect. Androgenic activity Some progestins have androgenic activity and can produce androgenic side effects such as increased sebum production (oilier skin), acne, and hirsutism (excessive facial/body hair growth), as well as changes in liver protein production. Only certain progestins are androgenic however, these being the testosterone derivatives and, to a lesser extent, the 17α-hydroxyprogesterone derivatives medroxyprogesterone acetate and megestrol acetate. No other progestins have such activity (though some, conversely, possess antiandrogenic activity). Moreover, the androgenic activity of progestins within the testosterone derivatives also varies, and while some may have high or moderate androgenic activity, others have only low or no such activity. The androgenic activity of androgenic progestins is mediated by two mechanisms: 1) direct binding to and activation of the androgen receptor; and 2) displacement of testosterone from sex hormone-binding globulin (SHBG), thereby increasing free (and thus bioactive) testosterone levels. The androgenic activity of many androgenic progestins is offset by combination with ethinylestradiol, which robustly increases SHBG levels, and most oral contraceptives in fact markedly reduce free testosterone levels and can treat or improve acne and hirsutism. An exception is progestin-only contraceptives, which do not also contain an estrogen. The relative androgenic activity of testosterone-derivative progestins and other progestins that have androgenic activity can be roughly ranked as follows: * Very high: danazol, ethisterone, gestrinone, normethandrone, norvinisterone * High: levonorgestrel, norgestrel, norgestrienone, tibolone * Moderate: norethisterone and its prodrugs (norethisterone acetate, norethisterone enanthate, etynodiol diacetate, lynestrenol, quingestanol acetate) * Low: desogestrel, etonogestrel, gestodene, norgestimate * Very low or negligible: allylestrenol, dimethisterone, medroxyprogesterone acetate, megestrol acetate, norelgestromin, noretynodrel, norgesterone * Antiandrogenic: dienogest, oxendolone The clinical androgenic and anabolic activity of the androgenic progestins listed above is still far lower than that of conventional androgens and anabolic steroids like testosterone and nandrolone esters. As such, they are only generally associated with such effects in women and often only at high doses. In men, due to their concomitant<unk> c activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects via suppression of testosterone production and levels. Antiandrogenic activity Some<unk>  have antiandrogenic activity in addition to their<unk> c activity. These<unk> , with varying degrees of potency as antiandrogens, include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, medrogestone, megestrol acetate, nomegestrol acetate, osaterone acetate (veterinary), and oxendolone. The relative antiandrogenic activity in animals of some of these<unk>  has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30–40%) ≥ chlormadinone acetate (30%) = drospirenone (30%). Antiandrogenic activity in certain<unk>  may help to improve symptoms of acne, seborrhea, hirsutism, and other androgen-dependent conditions in women. Estrogenic activity A few progestins have weak estrogenic activity. These include the 19-nortestosterone derivatives norethisterone, noretynodrel, and tibolone, as well as the norethisterone prodrugs norethisterone acetate, norethisterone enanthate, lynestrenol, and etynodiol diacetate. The estrogenic activity of norethisterone and its prodrugs are due to metabolism into ethinylestradiol. High doses of norethisterone and noretynodrel have been associated with estrogenic side effects such as breast enlargement in women and gynecomastia in men, but also with alleviation of menopausal symptoms in postmenopausal women. In contrast, non-estrogenic progestins were not found to be associated with such effects. Glucocorticoid activity Some<unk> , mainly certain 17α-hydroxyprogesterone derivatives, have weak glucocorticoid activity. This can result, at sufficiently high doses, in side effects such as symptoms of Cushing's syndrome, steroid diabetes, adrenal suppression and insufficiency, and neuropsychiatric symptoms like depression, anxiety, irritability, and cognitive impairment.<unk>  with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, promegestone, and segesterone acetate and the testosterone derivatives desogestrel, etonogestrel, and gestodene. Conversely, hydroxyprogesterone caproate possesses no such activity, while progesterone itself has very weak glucocorticoid activity. Antimineralocorticoid activity Certain<unk> , including progesterone, drospirenone, and gestodene, as well as to a lesser extent dydrogesterone and trimegestone, have varying degrees of antimineralocorticoid activity. Other progestins might also have significant antimineralocorticoid activity. Progesterone itself has potent antimineralocorticoid activity. No clinically used<unk>  are known to have mineralocorticoid activity. Progestins with potent antimineralocorticoid activity like drospirenone may have properties more similar to those of natural progesterone, such as counteraction of cyclical estrogen-induced sodium and fluid retention, edema, and associated weight gain; lowered blood pressure; and possibly improved cardiovascular health. Neurosteroid activity Progesterone has neurosteroid activity via metabolism into allopregnanolone and pregnanolone, potent positive allosteric modulators of the GABAA receptor. As a result, it has associated effects such as sedation, somnolence, and cognitive impairment. No progestin is known to have similar such neurosteroid activity or effects. However, promegestone has been found to act as a non-competitive antagonist of the nicotinic acetylcholine receptor similarly to progesterone. Other activities 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). Norethisterone, desogestrel, levonorgestrel, and drospirenone strongly stimulate proliferation and medroxyprogesterone acetate, dienogest, and dydrogesterone weakly stimulate proliferation, whereas progesterone, nomegestrol acetate, and chlormadinone acetate act neutrally in the assay and do not stimulate proliferation. It is unclear whether these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies. Pharmacokinetics Oral progesterone has very low bioavailability and potency. Micronization and dissolution in oil-filled capsules, a formulation known as oral micronized progesterone (OMP), increases the bioavailability of progesterone by several-fold. However, the bioavailability of oral micronized progesterone nonetheless remains very low at less than 2.4%. Progesterone also has a very short elimination half-life in the circulation of no more than 1.5 hours. Due to the poor oral activity of oral micronized progesterone, it has relatively weak<unk> c effects. Administration of progesterone in oil solution by intramuscular injection has a duration of about 2 or 3 days, necessitating frequent injections. Transdermal administration of progesterone in the form of creams or gels achieves only very low levels of progesterone and weak<unk> c effects. Due to the poor oral activity of progesterone and its short duration with intramuscular injection, progestins were developed in its place both for oral use and for parenteral administration. Orally active progestins have high oral bioavailability in comparison to oral micronized progesterone. Their bioavailability is generally in the range of 60 to 100%. Their elimination half-lives
Progestogen 
Norgesterone
Antigonadotropin
Catechol estrogen
Androgen
Haloprogesterone
Vinyltestosterone
Androstenediol