Antiandrogen


Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone from mediating their biological effects in the body. They act by blocking the androgen receptor and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids like testosterone, DHT, and nandrolone and selective androgen receptor modulators like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.
Antiandrogens are used to treat an assortment of androgen-dependent conditions. In men, antiandrogens are used in the treatment of prostate cancer, enlarged prostate, scalp hair loss, overly high sex drive, unusual and problematic sexual urges, and early puberty. In women, antiandrogens are used to treat acne, seborrhea, excessive hair growth, scalp hair loss, and high androgen levels, such as those that occur in polycystic ovary syndrome. Antiandrogens are also used as a component of feminizing hormone therapy for transgender women and as puberty blockers in transgender girls.
Side effects of antiandrogens depend on the type of antiandrogen and the specific antiandrogen in question. In any case, common side effects of antiandrogens in men include breast tenderness, breast enlargement, feminization, hot flashes, sexual dysfunction, infertility, and osteoporosis. In women, antiandrogens are much better tolerated, and antiandrogens that work only by directly blocking androgens are associated with minimal side effects. However, because estrogens are made from androgens in the body, antiandrogens that suppress androgen production can cause low estrogen levels and associated symptoms like hot flashes, menstrual irregularities, and osteoporosis in premenopausal women.
There are a few different major types of antiandrogens. These include AR antagonists, androgen synthesis inhibitors, and antigonadotropins. AR antagonists work by directly blocking the effects of androgens, while androgen synthesis inhibitors and antigonadotropins work by lowering androgen levels. AR antagonists can be further divided into steroidal antiandrogens and nonsteroidal antiandrogens; androgen synthesis inhibitors can be further divided mostly into CYP17A1 inhibitors and 5α-reductase inhibitors; and antigonadotropins can be further divided into gonadotropin-releasing hormone modulators, progestogens, and estrogens.

Medical uses

Antiandrogens are used in the treatment of an assortment of androgen-dependent conditions in both males and females. They are used to treat men with prostate cancer, benign prostatic hyperplasia, pattern hair loss, hypersexuality, paraphilias, and priapism, as well as boys with precocious puberty. In women and girls, antiandrogens are used to treat acne, seborrhea, hidradenitis suppurativa, hirsutism, and hyperandrogenism. Antiandrogens are also used in transgender women as a component of feminizing hormone therapy and as puberty blockers in transgender girls.

Males

Prostate cancer

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 males 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, 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. 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 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.

Enlarged prostate

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.

Scalp hair loss

5α-Reductase inhibitors like finasteride, dutasteride, and alfatradiol and the topical nonsteroidal AR antagonist topilutamide 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. Systemic antiandrogens besides 5α-reductase inhibitors are not generally used to treat scalp hair loss in males due to risks like feminization and sexual dysfunction. However, they have been assessed and reported to be effective for this indication.

Acne

Systemic antiandrogens are generally not used to treat acne in males due to their high risk of feminization and sexual dysfunction. However, they have been studied for acne in males and found to be effective. Clascoterone, a topical antiandrogen, is effective for acne in males, albeit modestly, and has been approved by the FDA in August 2020.

Paraphilias

Androgens increase sex drive, and for this reason, antiandrogens are able to reduce sex drive in males. In accordance, antiandrogens are used in the treatment of conditions such as hypersexuality and paraphilias like pedophilia. They have been used to decrease sex drive in sex offenders so as to reduce the likelihood of recidivism. Antiandrogens used for these indications include cyproterone acetate, medroxyprogesterone acetate, and GnRH modulators.

Early puberty

Antiandrogens are used to treat precocious puberty in males. They work by opposing the effects of androgens and delaying the development of secondary sexual characteristics and onset of changes in sex drive and function until a more appropriate age. Antiandrogens that have been used for this purpose include cyproterone acetate, medroxyprogesterone acetate, GnRH modulators, spironolactone, bicalutamide, and ketoconazole. Spironolactone and bicalutamide require combination with an aromatase inhibitor to prevent the effects of unopposed estrogens, while the others can be used alone.

Long-lasting erections

Antiandrogens are effective in the treatment of recurrent priapism.

Women and girls

Skin and hair conditions

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.

High androgen levels

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, voice deepening, increased muscle mass 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, 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.