Antiandrogens, or androgen blockers, first discovered in the 1960s, prevent androgens like testosterone and dihydrotestosterone (DHT) from expressing their biological effects in responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors or affecting androgen production.
Antiandrogens can be prescribed to treat an assortment of androgen-dependent conditions. In men, antiandrogens are most frequently used to treat prostate cancer. In women, antiandrogens are used to decrease levels of male hormones causing symptoms of hypoandrogenism.
Antiandrogens present in the environment have become a topic of concern. Many industrial chemicals, including phthalates and pesticides exhibit antiandrogenic effects in animal experiments. Certain plant species have also been found to produce antiandrogens. In animal studies, environmental antiandrogens can harm reproductive organ development in fetuses exposed in utero as well as their offspring.
Antiandrogens are used to treat an array of medical conditions that are dependent on the androgen pathway. Antiandrogens are often prescribed for men with prostate cancer, benign prostatic hyperplasia, hypersexuality, and male contraception. For women, antiandrogens are often prescribed for severe cases of acne, amenorrhea, seborrhea, hirsutism, androgenic alopecia, hidradenitis suppurativa, hyperandrogenism, and for trans women undergoing sex reassignment.
Antiandrogens in males can result in hyposexuality (diminished sexual desire or libido), reduced activity or function of the accessory male sex organs, and slowed or halted development or reversal of male secondary sex characteristics.
Antiandrogens are often indicated to treat severe male sexual disorders, such as hypersexuality (excessive sexual desire) and sexual deviation such as paraphilia (a disorder involving intense recurrent sexual urges), since lowering male hormone levels decreases libido. As a part of a program for registered sex offenders recently released from prisons, the offender is sometimes administered antiandrogen drugs to reduce the likelihood of repeat offenses by reducing sexual drive. On occasion, antiandrogens are used as a male contraceptive agent.
Decreasing the body’s response to androgen can have beneficial effects in treating prostate cancer. Prostate cancer is the most commonly diagnosed form of cancer found in men. Some prostate cancer cells require androgens for growth. To counteract cancer cell proliferation, antiandrogens are used for hormone therapy called androgen deprivation therapy. Some antiandrogens suppress androgen production while others inhibit androgens from binding to the cancer cells’ androgen receptors. These two classes of drugs can be prescribed separately or can be used together for a complete/combined androgen blockade. When the body is deprived of androgens, the therapy is termed castration-based therapy as the lack of androgens mimics castration. By competing with circulating androgens for binding sites on prostate cell receptors, antiandrogens promote apoptosis and inhibit prostate cancer growth. Hormone therapy antiandrogen drugs can be prescribed as monotherapy or in addition to radical radiotherapy or prostatectomy. Antiandrogen monotherapy generally causes fewer side effects in males, although it may block androgen less effectively than combined therapies. Monotherapy is often preferred by men as it is less likely than combined therapies to diminish libido or cause tenderness of the breasts, diarrhea, and nausea.
Androgen-deprivation therapy has been shown to cause initial reduction of prostate tumors. However, antiandrogens can cause prostate cancer tumors to become androgen-independent. Androgen independence occurs when cells that are not reliant on androgen proliferate and spread, while cells that require androgen for survival undergo apoptosis. The cells that do not require androgen become the basis of the tumors, and cause recurring tumors a few years after the initial disappearance of the prostate cancer. Once prostate cancer becomes androgen independent, hormone therapy will most likely no longer benefit the individual and a new treatment approach will be needed.
In one study, the efficacy of reducing prostate cancer cells by castration was compared to combined androgen blockade in which castration is combined with an antiandrogen. Flutamide, nilutamide, bicalutamide, enzalutamide, and apalutamide are non-steroidal, "pure" antiandrogens. Flutamide has several side effects that the newer bicalutamide does not. Used in combination with castration, nilutamide and flutamide were found to have minimal effect on prolonging survival while bicalutamide significantly prolonged life in prostate cancer patients. As a result, since 2007 combined androgen blockade with bicalutamide has been used as an effective, safe, and cost-efficient treatment of prostate cancer.
5α-reductase inhibitors such as finasteride, dutasteride, and alfatradiol are antiandrogenic as they prevent the conversion of testosterone to dihydrotestosterone (DHT). DHT is 3–5 times more potent than testosterone or other androgens (except in skeletal muscle tissue, where testosterone is the main androgen). They are unique because they do not counteract the effects or production of other androgens other than DHT. Dihydrotestosterone is necessary for development of both external male sex organs and the prostate. 5α-reductase inhibitors are most often used to treat benign prostatic hyperplasia since the resulting decrease in dihydrotestosterone inhibits proliferation of prostate cells.
Hyperandrogenism is a condition found in women where ovaries overproduce androgens, which are typically considered male hormones as they are important for the development of male reproductive organs and secondary male characteristics. Antiandrogens can help to counteract androgens that cause skin and hair problems in women. Gonadotropins, pituitary hormones, are involved in ovarian androgen production, and their suppression can result in reduced testosterone production. Antiandrogens can inhibit the release of the gonadotropin luteinizing hormone (LH), suppressing testosterone synthesis in the ovaries. Androgenic alopecia (a type of hair loss and pattern baldness), acne vulgaris, seborrhea, amenorrhea (the absence of menstrual periods), hirsutism (excessive facial and/or body hair in women), and hidradenitis suppurativa can be caused by an excess of androgens.
Hormonal antiandrogen treatment is given to female patients that suffer from multiple symptoms of hyperandrogenism. Acne is the most common of skin disorders that result from male hormone overproduction. Fewer androgens present in a female’s tissues result in a reduction of oil (sebum) production and bumps (comedone). Antiandrogens are usually combined with topical and oral pharmaceuticals to treat severe acne. In women that suffer from hirsutism due to high testosterone levels, antiandrogens are used to slow hair growth, lighten hair color, and thin the hair. For females with androgenic alopecia, antiandrogens can assist in reducing hair shedding and thinning.
The most common antiandrogens used to treat women with hyperandrogenism are spironolactone and cyproterone acetate. Spironolactone, a steroidal antimineralocorticoid diuretic with additional antiandrogen properties, is used primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome. Cyproterone acetate is a potent steroidal antiandrogen that is also a potent progestin and antigonadotropin. Oral contraceptives containing progestins have no effect on androgen levels, but may be combined with spironolactone and cyproterone acetate for the purpose of correcting menstrual irregularities.
Mechanism of action
AR antagonists are classified as steroidal or non-steroidal. Steroidal antiandrogens counteract androgens and thus also affect secondary sex characteristics. Steroidal antiandrogens directly affect gene expression due to their fat-soluble nature that allows them to diffuse through the plasma membrane’s phospholipid bilayer and prevent the binding of testosterone and dihydrotestosterone (DHT) to the androgen receptor. Steroidal antiandrogens include cyproterone acetate and spironolactone.
Non-steroidal antiandrogens, or "pure" antiandrogens, such as flutamide, bicalutamide, and enzalutamide, counter androgens and have no steroidal effects. Antiandrogens inhibit circulating androgens by blocking androgen receptors, suppressing androgen synthesis, or acting in both those ways. The most common antiandrogens are androgen receptor (AR) antagonists which act on the target cell level and competitively bind to androgen receptors.
Inhibition of androgen production occurs through a unique mechanism for each antiandrogen. For example, ketoconazole not only competes with androgens such as testosterone and DHT for androgen receptor binding, but also suppresses androgen synthesis by inhibiting cytochrome P450 and 17,20-lyase, which partake in synthesizing and degrading steroids, including the precursors of testosterone. The result is a decrease in the overall testosterone production of the adrenal cortex. Gonadotrophins, which are pituitary hormones capable of altering androgen synthesis, are also affected by antiandrogens. Antiandrogens can suppress gonadotropin secretion by down-regulating gonadotropin-releasing hormone receptors (GnRHR) in the pituitary gland. A decreased amount of GnRHRs results in gonadotropin-releasing hormone (GnRH) not being able to bind sufficiently. GnRH is responsible for the release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the Leydig cells of the testes and the theca cells of the ovaries to produce testosterone and indirectly estradiol. Therefore, if GnRH cannot bind, testosterone synthesis is not induced in testes or ovaries.
Antigonadotropins, including progestins like cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate and GnRH analogues like leuprorelin and cetrorelix, suppress gonadal androgen production by suppressing gonadotropin secretion from the pituitary gland, and hence are antiandrogens that act as androgen synthesis inhibitors.
Antiandrogens may not bind to or block membrane androgen receptors, which are distinct from the classical nuclear AR.
Exposure to antiandrogens can occur unintentionally due to natural or anthropogenic compounds in the environment. Environmental compounds affecting the endocrine system, termed endocrine disruptors, that antagonistically affect androgen receptors and androgen production can negatively affect animals that come in contact with the compounds as well as their future generations. Certain pesticides and insecticides as well as industrial chemicals possess antiandrogen properties. Some species of plants produce phytochemicals with antiandrogenic effects. Exposure to these environmental antiandrogens has resulted in adverse effects on animals that allude to human health risks.
Pesticides and insecticides
Exposure to pesticides with antiandrogen properties has been found to negatively affect laboratory animals. Androgens are important in fetal development as well as in pubertal development. Exposure during critical periods of development can cause reproductive malformations in males while exposure after birth and before puberty can delay puberty.
Animal studies with vinclozolin, procymidone, linuron, and the DDT metabolite dichlorodiphenyldichloroethylene (p.p’-DDE) have shown irregular reproductive development due to their function as androgen receptor antagonists that inhibit androgen-activated gene expression. Even with low doses of antiandrogenic pesticides, developmental effects such as reduced anogenital distance and induction of areolas were seen in male rats.
Animal studies show that deformities result in offspring exposed to antiandrogens. Male mice can display malformations that resemble the reproductive organs of females as in the case of exposure to vinclozolin or proymidone. Exposure to vinclozolin or procymidone in utero feminized male offspring, as seen in abnormalities of anogenital distance, small or absent sex accessory glands, hypospadias, undescended testes, retained nipples, cleft phallus, and presence of a vaginal pouch. Male mice exposed before puberty to vinclozolin experienced delayed pubertal development visualized by delayed onset of androgen-dependent preputial separation.
Ketoconazole is an imidazole derivative is used as a broad-spectrum antifungal agent effective against a variety of fungal infections. Although ketoconazole is a relatively weak antiandrogen, high doses side-effects lead to reduced levels of androgens from both the testicles and adrenal glands.
Phthalates are mainly found as softeners in plastics, but also perfumes, nail varnish and other cosmetics. Fetuses that are exposed to a mixture of phthalates in utero may show signs of disrupted reproductive development. When Di-n-butyl phthalate (DBP), diisobutyl phthalate (DiBP), benzyl butyl phthalate (BBP), Bis(2-ethylhexyl) phthalate (DEHP) and di-n-pentyl phthalate (DPP) were combined, reductions in both testosterone synthesis and gene expression of steroidogenic pathway proteins were seen. The results in male rats were undescended testes and abnormal development of reproductive tissues.
Parabens are used as preservatives and/or antimicrobial agents and commonly found in food, soap, detergent, toothpaste, disinfectant, cosmetic and pharmaceutical products. Paraben esters, such as butylparaben, have been found to mimic androgen antagonist activity. Antiandrogenic endocrine disruption has been shown in aquatic species, but the mechanism is unknown. Researchers believe parabens have the ability to bind to human androgen receptors but it still remains unclear.
Antiandrogens can also occur naturally in plants.
The best known plant-derived antiandrogen is 3,3'-diindolylmethane found in cruciferous vegetables, which are members of the cabbage family.
The compound N-butylbenzene-sulfonamide (NBBS) isolated from the bark of Prunus africana, the Subsaharan red stinkwood tree, is a specific androgen antagonist and has been used as alternative medicine in benign prostatic hyperplasia.
Licorice, or Glycyrrhiza glabra native to southern Europe, India, and parts of Asia has shown antiandrogen activity in male rats.
Discovery and development
List of antiandrogens
There are a variety of different types of antiandrogens. These include drugs that bind directly to and block the androgen receptor (AR), drugs that directly inhibit the enzymatic biosynthesis of androgens like testosterone and/or DHT, and drugs that suppress the gonadotropin-releasing hormone (GnRH)-induced release of gonadotropins and consequent activation of gonadal androgen production (also known as antigonadotropins). Although the term antiandrogen is generally used to refer specifically to AR antagonists, it may also be used to describe functional antiandrogens like androgen synthesis inhibitors and antigonadotropins.
Steroidal antiandrogens (SAAs)
- 17α-Hydroxyprogesterone derivatives
- 19-Nortestosterone derivatives
- 17α-Spirolactone derivatives
Note that in addition to acting as AR antagonists, most SAAs also act as potent progestogens and therefore antigonadotropins.
Non-steroidal antiandrogens (NSAAs)
Note that, in contrast to most SAAs, NSAAs are pure/selective AR antagonists with no antigonadotropic activity.
Androgen synthesis inhibitors
CYP11A1 (P450scc) inhibitors
These drugs selectively inhibit the synthesis of DHT without affecting that of testosterone.
- Estrogens (e.g., estradiol (and its esters), ethinyl estradiol, conjugated equine estrogens (Premarin), diethylstilbestrol)
- GnRH analogues
- Progestogens (e.g., progesterone, cyproterone acetate, chlormadinone acetate, medroxyprogesterone acetate, megestrol acetate, hydroxyprogesterone caproate, gestonorone caproate, norethisterone (and its esters))
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