Androgens like testosterone and particularly DHT are importantly involved in the development and progression of prostate cancer. They act as growth factors in the prostate gland, stimulating cell division and tissue growth. In accordance, therapeutic modalities that reduce androgen signaling in the prostate gland, referred to collectively as androgen deprivation therapy, are able to significantly slow the course of prostate cancer and extend life in men with the disease. Although antiandrogens are effective in slowing the progression of prostate cancer, they are not generally curative, and with time, the disease adapts and androgen deprivation therapy eventually becomes ineffective. When this occurs, other treatment approaches, such as chemotherapy, may be considered.
The most common methods of androgen deprivation therapy currently employed to treat prostate cancer are castration (with a GnRH modulator or orchiectomy), nonsteroidal antiandrogens, and the androgen synthesis inhibitor abiraterone acetate. Castration may be used alone or in combination with one of the other two treatments. When castration is combined with a nonsteroidal antiandrogen like bicalutamide, this strategy is referred to as combined androgen blockade (also known as complete or maximal androgen blockade).Enzalutamide, apalutamide, and abiraterone acetate are specifically approved for use in combination with castration to treat castration-resistant prostate cancer. Monotherapy with the nonsteroidal antiandrogen bicalutamide is also used in the treatment of prostate cancer as an alternative to castration with comparable effectiveness but with a different and potentially advantageous side effect profile.
High-dose estrogen was the first functional antiandrogen used to treat prostate cancer. It was widely used, but has largely been abandoned for this indication in favor of newer agents with improved safety profiles and fewer feminizing side effects.Cyproterone acetate was developed subsequently to high-dose estrogen and is the only steroidal antiandrogen that has been widely used in the treatment of prostate cancer, but it has largely been replaced by nonsteroidal antiandrogens, which are newer and have greater effectiveness, tolerability, and safety. Bicalutamide, as well as enzalutamide, have largely replaced the earlier nonsteroidal antiandrogens flutamide and nilutamide, which are now little used. The earlier androgen synthesis inhibitors aminoglutethimide and ketoconazole have only limitedly been used in the treatment of prostate cancer due to toxicity concerns and have been replaced by abiraterone acetate.
In addition to active treatment of prostate cancer, antiandrogens are effective as prophylaxis (preventatives) in reducing the risk of ever developing prostate cancer. Antiandrogens have only limitedly been assessed for this purpose, but the 5α-reductase inhibitors finasteride and dutasteride and the steroidal AR antagonist spironolactone have been associated with significantly reduced risk of prostate cancer. In addition, it is notable that prostate cancer is extremely rare in transgender women who have been on feminizing hormone therapy for an extended period of time.
The 5α-reductase inhibitors finasteride and dutasteride are used to treat benign prostatic hyperplasia, a condition in which the prostate becomes enlarged and this results in urinary obstruction and discomfort. They are effective because androgens act as growth factors in the prostate gland. The antiandrogens chlormadinone acetate and oxendolone and the functional antiandrogens allylestrenol and gestonorone caproate are also approved in some countries for the treatment of benign prostatic hyperplasia.
5α-Reductase inhibitors like finasteride, dutasteride, and alfatradiol and the topical nonsteroidal AR antagonist topilutamide (fluridil) are approved for the treatment of pattern hair loss, also known as scalp hair loss or baldness. This condition is generally caused by androgens, so antiandrogens can slow or halt its progression.
Antiandrogens are used in the treatment of androgen-dependent skin and hair conditions including acne, seborrhea, hidradenitis suppurativa, hirsutism, and pattern hair loss in women. All of these conditions are dependent on androgens, and for this reason, antiandrogens are effective in treating them. The most commonly used antiandrogens for these indications are cyproterone acetate and spironolactone.Flutamide has also been studied extensively for such uses, but has fallen out of favor due to its association with hepatotoxicity.Bicalutamide, which has a relatively minimal risk of hepatotoxicity, has been evaluated for the treatment of hirsutism and found effective similarly to flutamide and may be used instead of it. In addition to AR antagonists, oral contraceptives containing ethinylestradiol are effective in treating these conditions, and may be combined with AR antagonists.
Antiandrogens generally are not used to treat acne in males due to the high risk of feminization (e.g., gynecomastia) and sexual dysfunction.
Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high. It is commonly seen in women with PCOS, and also occurs in women with intersex conditions like congenital adrenal hyperplasia. Hyperandrogenism is associated with virilization – that is, the development of masculine secondary sexual characteristics like male-pattern facial and body hair growth (or hirsutism), voice deepening, increased musclemass and strength, and broadening of the shoulders, among others. Androgen-dependent skin and hair conditions like acne and pattern hair loss may also occur in hyperandrogenism, and menstrual disturbances, like amenorrhea, are commonly seen. Although antiandrogens do not treat the underlying cause of hyperandrogenism (e.g., PCOS), they are able to prevent and reverse its manifestation and effects. As with androgen-dependent skin and hair conditions, the most commonly used antiandrogens in the treatment of hyperandrogenism in women are cyproterone acetate and spironolactone. Other antiandrogens, like bicalutamide, may be used alternatively.
Certain antiandrogens combine multiple of the above mechanisms. An example is the steroidal antiandrogen cyproterone acetate, which is a potent AR antagonist, a potent progestogen and hence antigonadotropin, a weak glucocorticoid and hence anticorticotropin, and a weak androgen synthesis inhibitor.
Antiandrogens marketed for clinical or veterinary use
The above table includes AR antagonists, androgen synthesis inhibitors, and progestins marketed for use as or widely used as antiandrogens, but does not include GnRH agonists, GnRH antagonists, 5α-reductase inhibitors, or estrogens. For these types of antiandrogens, see the tables in their respective articles instead.
The side effects of antiandrogens vary depending on the type of antiandrogen – namely whether it is a selective AR antagonist or lowers androgen levels – as well as the presence of off-target activity in the antiandrogen in question. For instance, whereas antigonadotropic antiandrogens like GnRH modulators and cyproterone acetate are associated with pronounced sexual dysfunction and osteoporosis in men, selective AR antagonists like bicalutamide are not associated with osteoporosis and have been associated with only minimal sexual dysfunction. These differences are thought related to the fact that antigonadotropins suppress androgen levels and by extension levels of bioactivemetabolites of androgens like estrogens and neurosteroids whereas selective AR antagonists similarly neutralize the effects of androgens but leave levels of androgens and hence their metabolites intact (and in fact can even increase them as a result of their progonadotropic effects). As another example, the steroidal antiandrogens cyproterone acetate and spironolactone possess off-target actions including progestogenic, antimineralocorticoid, and/or glucocorticoid activity in addition to their antiandrogen activity, and these off-target activities can result in additional side effects.
A number of antiandrogens have been associated with hepatotoxicity. These include, to varying extents, cyproterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, and ketoconazole. In contrast, spironolactone, enzalutamide, and other antiandrogens are not associated with hepatotoxicity. However, although they do not pose a risk of hepatotoxicity, spironolactone has a risk of hyperkalemia and enzalutamide has a risk of seizures.
AR antagonists act by directly binding to and competitively displacing androgens like testosterone and DHT from the AR, thereby preventing them from activating the receptor and mediating their biological effects. AR antagonists are classified into two types, based on chemical structure: steroidal and nonsteroidal. Steroidal AR antagonists are structurally related to steroid hormones like testosterone and progesterone, whereas nonsteroidal AR antagonists are not steroids and are structurally distinct. Steroidal AR antagonists tend to have off-target hormonal actions due to their structural similarity to other steroid hormones. In contrast, nonsteroidal AR antagonists are selective for the AR and have no off-target hormonal activity. For this reason, they are sometimes described as "pure" antiandrogens.
Although they are described as antiandrogens and indeed show only such effects generally, most or all steroidal AR antagonists are actually not silent antagonists of the AR but rather are weak partial agonists and are able to activate the receptor in the absence of more potent AR agonists like testosterone and DHT. This may have clinical implications in the specific context of prostate cancer treatment. As an example, steroidal AR antagonists are able to increase prostate weight and accelerate prostate cancer cell growth in the absence of more potent AR agonists, and spironolactone has been found to accelerate progression of prostate cancer in case reports. In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals, it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals. In contrast to steroidal AR antagonists, nonsteroidal AR antagonists are silent antagonists of the AR and do not activate the receptor. This may be why they have greater efficacy than steroidal AR antagonists in the treatment of prostate cancer and is an important reason as to why they have largely replaced them for this indication in medicine.
Nonsteroidal antiandrogens have relatively low affinity for the AR compared to steroidal AR ligands. For example, bicalutamide has around 2% of the affinity of DHT for the AR and around 20% of the affinity of CPA for the AR. Despite their low affinity for the AR however, the lack of weak partial agonist activity of NSAAs appears to improve their potency relative to steroidal antiandrogens. For example, although flutamide has about 10-fold lower affinity for the AR than CPA, it shows equal or slightly greater potency to CPA as an antiandrogen in bioassays. In addition, circulating therapeutic concentrations of nonsteroidal antiandrogens are very high, on the order of thousands of times higher than those of testosterone and DHT, and this allows them to efficaciously compete and block AR signaling.
Notes: (1): Reference ligands (100%) were testosterone for the AR, progesterone for the PR, estradiol for the ER, dexamethasone for the GR, and aldosterone for the MR. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: See template.
Affinities of a selection of androgen receptor ligands at steroid hormone receptors
Notes: (1) Human skin fibroblasts used for assays. (2) Situation in vivo is different for flutamide and spironolactone due biotransformation. (3) Conflicting findings for spironolactone. Sources: See template.
Androgen synthesis inhibitors are enzyme inhibitors that prevent the biosynthesis of androgens. This process occurs mainly in the gonads and adrenal glands, but also occurs in other tissues like the prostate gland, skin, and hair follicles. These drugs include aminoglutethimide, ketoconazole, and abiraterone acetate. Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme, also known as P450scc or CYP11A1, which is responsible for the conversion of cholesterol into pregnenolone and by extension the production of all steroid hormones, including the androgens. Ketoconazole and abiraterone acetate are inhibitors of the enzyme CYP17A1, also known as 17α-hydroxylase/17,20-lyase, which is responsible for the conversion of pregnane steroids into androgens, as well as the conversion of mineralocorticoids into glucocorticoids. Because these drugs all prevent the formation of glucocorticoids in addition to androgens, they must be combined with a glucocorticoid like prednisone to avoid adrenal insufficiency. A newer drug currently under development for treatment of prostate cancer, seviteronel, is selective for inhibition of the 17,20-lyase functionality of CYP17A1, and for this reason, unlike earlier drugs, does not require concomitant treatment with a glucocorticoid.
5α-Reductase inhibitors such as finasteride and dutasteride are inhibitors of 5α-reductase, an enzyme that is responsible for the formation of DHT from testosterone. DHT is between 2.5- and 10-fold more potent than testosterone as an androgen and is produced in a tissue-selective manner based on expression of 5α-reductase. Tissues in which DHT forms at a high rate include the prostate gland, skin, and hair follicles. In accordance, DHT is involved in the pathophysiology of benign prostatic hyperplasia, pattern hair loss, and hirsutism, and 5α-reductase inhibitors are used to treat these conditions. Because 5α-reductase inhibitors selectively prevent the formation of DHT and do not affect testosterone levels, and because DHT is important as an endogenous androgen only in select tissues, 5α-reductase inhibitors have minimal side effects in both men and women, unlike other antiandrogens.
Estradiol and testosterone levels following a single intramuscular injection of 320 mg polyestradiol phosphate, a polymeric estradiol ester and prodrug, in men with prostate cancer.
In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the hepatic production of sex hormone-binding globulin (SHBG) and by extension circulating SHBG levels.Combined oral contraceptives containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%. However, combined oral contraceptives that contain the particularly androgenic progestin levonorgestrel have been found to increase SHBG levels by only 50 to 100%, which is likely because activation of the AR in the liver has the opposite effect of estrogen and suppresses production of SHBG. Levonorgestrel and certain other 19-nortestosterone progestins used in combined oral contraceptives like norethisterone also directly bind to and displace androgens from SHBG, which may additionally antagonize the functional antiandrogenic effects of ethinylestradiol. In men, a study found that treatment with a relatively low dosage of 20 μg/day ethinylestradiol for 5 weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease free testosterone levels, increased total circulating levels of testosterone by 50% (via reduced negative feedback by androgens on the HPG axis).
Antigonadotropins like estrogens and progestogens were both first introduced in the 1930s. The beneficial effects of androgen deprivation via surgical castration or high-dose estrogen therapy on prostate cancer were discovered in 1941.:56 AR antagonists were first discovered in the early 1960s. The steroidal antiandrogen cyproterone acetate was discovered in 1961 and introduced in 1973 and is often described as the first antiandrogen to have been marketed. However, spironolactone was introduced in 1959, although its antiandrogen effects were not recognized or taken advantage of until later and were originally an unintended off-target action of the drug. In addition to spironolactone, chlormadinone acetate and megestrol acetate are steroidal antiandrogens that are weaker than cyproterone acetate but were also introduced earlier, in the 1960s. Other early steroidal antiandrogens that were developed around this time but were never marketed include benorterone (SKF-7690; 17α-methyl-B-nortestosterone), BOMT (Ro 7-2340), cyproterone (SH-80881), and trimethyltrienolone (R-2956).
The nonsteroidal antiandrogen flutamide was first reported in 1967. It was introduced in 1983 and was the first nonsteroidal antiandrogen marketed. Another early nonsteroidal antiandrogen,DIMP (Ro 7-8117), which is structurally related to thalidomide and is a relatively weak antiandrogen, was first described in 1973 and was never marketed. Flutamide was followed by nilutamide in 1989 and bicalutamide in 1995. In addition to these three drugs, which have been regarded as first-generation nonsteroidal antiandrogens, the second-generation nonsteroidal antiandrogens enzalutamide and apalutamide were introduced in 2012 and 2018, respectively. They differ from the earlier nonsteroidal antiandrogens namely in that they are much more efficacious in comparison.
The androgen synthesis inhibitors aminoglutethimide and ketoconazole were first marketed in 1960 and 1977, respectively, and the newer drug abiraterone acetate was introduced in 2011. GnRH modulators were first introduced in the 1980s. The 5α-reductase inhibitors finasteride and dutasteride were introduced in 1992 and 2002, respectively.Elagolix, the first orally active GnRH modulator to be marketed, was introduced in 2018.
The following is a timeline of events in the history of antiandrogens:
1941: Hudgins and Hodges show that androgen deprivation via high-dose estrogen therapy or surgical castration treats prostate cancer
1957: The steroidal antiandrogen spironolactone is first synthesized
1960: Spironolactone is first introduced for medical use, as an antimineralocorticoid
1961: The steroidal antiandrogen cyproterone acetate is first synthesized
1962: Spironolactone is first reported to produce gynecomastia in men
1963: The antiandrogenic activity of cyproterone acetate is discovered
1966: Benorterone is the first known antiandrogen to be studied clinically, to treat acne and hirsutism in women
1967: A known antiandrogen, benorterone, is first reported to induce gynecomastia in males
1967: The first-generation nonsteroidal antiandrogen flutamide is first synthesized
1967: Cyproterone acetate was first studied clinically, to treat sexual deviance in men
1969: Cyproterone acetate was first studied in the treatment of acne, hirsutism, seborrhea, and scalp hair loss in women
1969: The antiandrogenic activity of spironolactone is discovered
1972: The antiandrogenic activity of flutamide is first reported
1973: Cyproterone acetate was first introduced for medical use, to treat sexual deviance
1977: The first-generation antiandrogen nilutamide is first described
1978: Spironolactone is first studied in the treatment of hirsutism in women
1980: Medical castration via a GnRH analogue is first achieved
1982: The first-generation antiandrogen bicalutamide is first described
1982: Combined androgen blockade for prostate cancer is developed
1983: Flutamide is first introduced, in Chile, for medical use, to treat prostate cancer
1987: Nilutamide is first introduced, in France, for medical use, to treat prostate cancer
1989: Combined androgen blockade via flutamide and a GnRH analogue is found to be superior to a GnRH analogue alone for prostate cancer
1989: Flutamide is first introduced for medical use in the United States, to treat prostate cancer
1989: Flutamide is first studied in the treatment of hirsutism in women
1992: The androgen synthesis inhibitor abiraterone acetate is first described
1995: Bicalutamide is first introduced for medical use, to treat prostate cancer
1996: Nilutamide is first introduced for medical use in the United States, to treat prostate cancer
2006: The second-generation nonsteroidal antiandrogen enzalutamide is first described
2007: The second-generation nonsteroidal antiandrogen apalutamide is first described
2011: Abiraterone acetate is first introduced for medical use, to treat prostate cancer
2012: Enzalutamide is first introduced for medical use, to treat prostate cancer
2018: Apalutamide is first introduced for medical use, to treat prostate cancer
2018: Elagolix is the first orally active GnRH antagonist to be introduced for medical use
Society and culture
The term antiandrogen is generally used to refer specifically to AR antagonists, as described by Dorfman (1970):
Antiandrogens are substances which prevent androgens from expressing their activity at target sites. The inhibitory effect of these substances, therefore, should be differentiated from compounds which decrease the synthesis and/or release of hypothalamic (releasing) factors, from anterior pituitary hormones (gonadotropins, particularly luteinizing hormone) and from material which acts directly on the gonads to inhibit biosynthesis and/or secretion of androgens.
However, in spite of the above, the term may also be used to describe functional antiandrogens like androgen synthesis inhibitors and antigonadotropins, including even estrogens and progestogens. For example, the progestogen and hence antigonadotropin medroxyprogesterone acetate is sometimes described as a steroidal antiandrogen, even though it is not an antagonist of the AR.
There has been much interest and effort in the development of topical AR antagonists to treat androgen-dependent conditions like acne and pattern hair loss in males. Unfortunately, whereas systemic administration of antiandrogens is very effective in treating these conditions, topical administration has disappointingly been found generally to possess limited and only modest effectiveness, even when high-affinity steroidal AR antagonists like cyproterone acetate and spironolactone have been employed. Moreover, in the specific case of acne treatment, topical AR antagonists have been found much less effective compared to established treatments like benzoyl peroxide and antibiotics.
A variety of AR antagonists have been developed for topical use but have not completed development and hence have never been marketed. These include the steroidal AR antagonists clascoterone, cyproterone, rosterolone, and topterone and the nonsteroidal AR antagonists cioteronel, inocoterone acetate, RU-22930, RU-58642, and RU-58841. However, one topical AR antagonist, topilutamide (fluridil), has been introduced in a few European countries for the treatment of pattern hair loss in men. In addition, a topical 5α-reductase inhibitor and weak estrogen, alfatradiol, has also been introduced in some European countries for the same indication, although its effectiveness is controversial.Spironolactone has been marketed in Italy in the form of a topical cream under the brand name Spiroderm for the treatment of acne and hirsutism, but this formulation was discontinued and hence is no longer available.
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