Steroidal antiandrogen
| Steroidal antiandrogen | ||
|---|---|---|
Chemical class Steroidal | | |
| Legal status | ||
| In Wikidata | ||
A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure.[1][2][3] They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production.[2][3] SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus.[4] SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose.[2] They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.[2][3]
Medical uses
SAAs are used in clinical medicine for the following indications:[2]
- Prostate cancer in men
- Benign prostatic hyperplasia in men
- seborrhea, and pattern hair loss(androgenic alopecia) in women
- Hyperandrogenism, such as due to polycystic ovary syndrome or congenital adrenal hyperplasia, in women
- As a component of
- Precocious puberty in boys
- Hypersexuality and paraphilias in men and sex offenders
- Priapism in men
Available forms
| Generic name | Class | Type | Brand name(s) | Route(s) | Launch | Status | Hitsa |
|---|---|---|---|---|---|---|---|
| Abiraterone acetate | Steroidal | Androgen synthesis inhibitor | Zytiga | Oral | 2011 | Available | 523,000 |
| Allylestrenol | Steroidal | Progestin | Gestanin, Perselin | Oral | 1961 | Availableb | 61,800 |
| Chlormadinone acetate | Steroidal | Progestin; AR antagonist | Belara, Prostal | Oral | 1965 | Available | 220,000 |
| Cyproterone acetate | Steroidal | Progestin; AR antagonist | Androcur, Diane | Oral, IM | 1973 | Available | 461,000 |
| Delmadinone acetate | Steroidal | Progestin; AR antagonist | Tardak | Veterinary | 1972 | Veterinary | 42,600 |
| Gestonorone caproate | Steroidal | Progestin | Depostat, Primostat | IM | 1973 | Availableb | 119,000 |
| Hydroxyprogesterone caproate | Steroidal | Progestin | Delalutin, Proluton | IM | 1954 | Available | 108,000 |
| Medroxyprogesterone acetate | Steroidal | Progestin | Provera, Depo-Provera | Oral, IM, SC | 1958 | Available | 1,250,000 |
| Megestrol acetate | Steroidal | Progestin; AR antagonist | Megace | Oral | 1963 | Available | 253,000 |
| Osaterone acetate | Steroidal | Progestin; AR antagonist | Ypozane | Veterinary | 2007 | Veterinary | 87,600 |
| Oxendolone | Steroidal | Progestin; AR antagonist | Prostetin, Roxenone | IM | 1981 | Availableb | 36,100 |
| Spironolactone | Steroidal | AR antagonist | Aldactone | Oral, topical | 1959 | Available | 3,010,000 |
| Footnotes: a = Hits = Google Search hits (as of February 2018). b = Availability limited / mostly discontinued. Class: Steroidal = Steroidal antiandrogen. Nonsteroidal = Nonsteroidal antiandrogen. Sources: See individual articles. | |||||||
Pharmacology
Unlike NSAAs, most SAAs show off-target hormonal activity such as
antigonadotropic effects, and are weak partial agonists of the AR with some capacity to activate the receptor.[2] Due to their antigonadotropic effects, SAAs lower androgen levels in addition to directly blocking the actions of androgens at the AR; at sufficiently high dosages, they are able to lower circulating testosterone levels by up to 70 to 80% in men, to just above the castrate range.[8][9][10] However, due to their other hormonal effects, suppression of estrogen levels alongside testosterone levels, and AR activation, SAAs have increased side effects and show lower efficacy in the treatment of prostate cancer relative to NSAAs.[2]
List of SAAs
Marketed
Used specifically as antiandrogens (major)
- fatigue.[citation needed]
- menstrual disturbances.[citation needed]
Used specifically as antiandrogens (minor)
- Chlormadinone acetate (Prostal): A combined AR antagonist and progestogen/antigonadotropin. Also has weak glucocorticoid activity. Widely used in the treatment of prostate cancer in Japan, but little used for this purpose elsewhere.[11] Has largely been replaced by NSAAs. Mostly used throughout the world in oral contraceptives (with ethinylestradiol under the brand names Belara and Belarina). Not available in the United States.
- Gestonorone caproate (Depostat, Primostat): A pure progestogen/antigonadotropin without any direct AR antagonism or other hormonal activity. Injected intramuscularly. Used in the treatment of benign prostatic hyperplasia in certain countries such as the United Kingdom. Not available in the United States.
- obstetric indications in women.[citation needed]
- menopause. It is an older progestin that has mostly been discontinued and is now rarely used.
- Medroxyprogesterone acetate (Depo-Provera): A progestogen/antigonadotropin without any direct AR antagonism. Also has weak androgenic and glucocorticoid activity and acts as a steroidogenesis inhibitor at very high dosages. Injected intramuscularly. Used as a means of chemical castration for sexual deviation in men, particularly in the United States where cyproterone acetate is unavailable. Studied in the treatment of prostate cancer but never widely used. Has also been used to prevent precocious puberty. Most commonly used as a long-lasting injectable contraceptive in women.
- Megestrol acetate (Megace): A combined AR partial antagonist and progestogen/antigonadotropin. Also has weak androgenic and glucocorticoid activity. Studied in the treatment of prostate cancer but showed poor effectiveness.[12] Mostly used as an appetite stimulant in patients with cachexia.
- Oxendolone (Prostetin, Roxenone): A combined AR antagonist and progestogen/antigonadotropin. Marketed in Japan only for the treatment of benign prostatic hyperplasia. Controversial due to low effectiveness observed in clinical studies.
Used as antiandrogens in veterinary medicine
- Delmadinone acetate (Tardak): A combined AR antagonist and progestogen/antigonadotropin. Also has weak glucocorticoid activity. Used in veterinary medicine only. Marketed in Europe and Oceania for the treatment of androgen-dependent conditions such as benign prostatic hyperplasia in dogs.
- elevated liver enzymes.
Used exclusively as progestins in women
- Dienogest (Visanne, Dinagest): Progestin with some AR antagonist activity. Used as an oral contraceptive (with estradiol valerate as Natazia and Qlaira and with ethinylestradiol as Valette) and in the treatment of endometriosis.
- Drospirenone: Progestin with antimineralocorticoid and AR antagonist activity. Used in combination with estrogen in hormonal replacement therapy and oral contraceptives (with ethinylestradiol as Yasmin, Yasminelle, and Yaz and with estradiol as Angeliq). Also used (as an oral contraceptive) in the treatment of acne.
- Nomegestrol acetate (Lutenyl): Progestin with AR antagonist activity. Used in the treatment of gynecological disorders and in hormonal replacement therapy and oral contraceptives (with estradiol as Naemis and Zoely).
Miscellaneous
- Mifepristone (RU-486; Mifegyne, Mifeprex): An antiprogestogen which is widely used as an abortifacient. Also has antiglucocorticoid and AR antagonist activity. Has been found to produce gynecomastia as a side effect in men at a relatively high rate in clinical studies. Has been studied as a treatment for prostate cancer.
Steroidal
5α-reductase inhibitors finasteride and dutasteride
could also technically be described as "SAAs", but the term is usually reserved to describe AR antagonists (and sometimes progestogenic antigonadotropins).
Not marketed
Under development
- Clascoterone (CB-03-01; Breezula, Winlevi): A pure AR antagonist. Topical without any systemic activity. Under development for the treatment of acne and pattern hair loss (androgenic alopecia).
Development discontinued
- 11α-Hydroxyprogesterone (11α-OHP): Possibly the first antiandrogen to be discovered. Weak antiandrogen used topically. Studied in the 1950s for the treatment of androgen-dependent skin conditions like acne and reportedly showed some effectiveness but was never marketed.
- seborrhea, and hirsutism in the 1960s but was found to produce a very high rate of gynecomastiain males. Development was discontinued in favor of cyproterone acetate, which showed only a low rate of gynecomastia in males.
- BOMT (Ro 7-2340): A pure AR antagonist without other progestogenic activity, though with some antigonadotropic activity through an undefined mechanism. One of the earliest antiandrogens. Studied in the treatment of benign prostatic hyperplasia but was never marketed. Was also of interest for the potential treatment of acne, pattern hair loss (androgenic alopecia), and prostate cancer, but was never studied for such uses.
- progonadotropic activity like NSAAs. One of the earliest antiandrogens. Was studied in the treatment of precocious pubertyas well as acne, seborrhea, and hirsutism. Showed surprisingly poor effectiveness in clinical trials and was abandoned in favor of cyproterone acetate.
- Delanterone (GBR-21162): An AR antagonist which was described in the literature in 1977. Was under development for the treatment of acne but showed poor effectiveness in preclinical studies and was abandoned.
- Galeterone (TOK-001, VN/124-1): A dual AR antagonist and steroidogenesis inhibitor which was under development for the treatment of prostate cancer but showed insufficient effectiveness in clinical trials and was discontinued.
- Inocoterone acetate (RU-38882, RU-882): A steroid-like NSAA. It was under development as a topical medication for the treatment of acne but was discontinued due to insufficient effectiveness in clinical trials.
- Metogest (SC-14207): An AR antagonist which was patented in 1975 and briefly investigated for the treatment of acne but was never marketed.
- Rosterolone (SH-434): A pure AR antagonist without other hormonal activity. Developed as a topical antiandrogen without systemic activity. Showed some effectiveness in the treatment of acne, but was never marketed.
- Topterone (WIN-17665): An AR antagonist which was described in the literature in 1977. Developed as a topical antiandrogen. Was under development for the treatment of acne but showed poor effectiveness and was abandoned.
- anabolic–androgenic steroid metribolone(methyltrienolone). Was under investigation for potential clinical use but development was discontinued in favor of NSAAs, which in contrast show a complete lack of intrinsic androgenic activity.
- animal models. Was under development for the treatment of benign prostatic hyperplasia but showed poor effectiveness and a high rate of breast painand gynecomastia in clinical trials and was subsequently abandoned.
- Many spirolactone antimineralocorticoids that were never marketed like dicirenone, mespirenone, mexrenone, prorenone, SC-5233 (spirolactone), spirorenone, and spiroxasone also show varying degrees of activity as AR antagonists.
See also
References
- ISBN 978-1-60761-471-5.
- ^ PMID 10637363.
- ^ PMID 10673793.
- PMID 9750520.
- S2CID 39120534.
- PMID 27429189.
There are many different androgen blockers used for transition care. Spironolactone, an aldosterone receptor antagonist, is frequently used in the United States, whereas cyproterone acetate, a synthetic steroidal antiandrogen with prostogenic properties, is predominantly outside of the United States.
- PMID 21449788., ...) appears to be more effective. ...
... Hormone therapy is prescribed for male-to-female transsexuals to induce breast formation and ... To achieve these goals, the biologic action of androgens must be almost completely neutralized. ... combining this treatment [of administrating estrogens] with ... other medications that suppress androgen action (e.g., cyproterone acetate
- ISBN 978-1-4160-6911-9.
- S2CID 5836155.
- S2CID 22300358.
- ISBN 978-0-08-049789-1.
- ISBN 978-1-60327-829-4.
Further reading
- Akakura K, Furuya Y, Ito H (August 1998). "[Steroidal and nonsteroidal antiandrogens: chemical structures, mechanisms of action and clinical applications]". Nippon Rinsho (in Japanese). 56 (8): 2124–8. PMID 9750520.
- Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M (December 1999). "Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy". Arch Ital Urol Androl. 71 (5): 293–302. PMID 10673793.
- Singh SM, Gauthier S, Labrie F (2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Curr. Med. Chem. 7 (2): 211–47. PMID 10637363.
- Schröder FH, Radlmaier A (2009). "Steroidal Antiandrogens". In V. Craig Jordan, Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 325–346. ISBN 978-1-60761-471-5.