Endocrine therapy for prostate cancer, also known as androgen suppression therapy or androgen depot therapy, blocks the synthesis and function of androgens, thereby inhibiting the growth of prostate cancer.
Endocrine therapies currently work in three main ways:
- Reducing androgen synthesis in the testes;
- Blocking the action of androgens in the body;
- Blocking the production of androgens in sites other than the testes.
Among these, inhibiting androgen synthesis in the testes is the most commonly used hormonal therapy for prostate cancer and includes the following approaches:
Orchiectomy
Removing the testicles can reduce testosterone levels in the blood by 90 to 95 percent. This treatment, called surgical debulking, is permanent and irreversible.
There is also a type of orchiectomy called submacular orchiectomy, which removes only the androgen-producing tissue from the testicle, not the whole testicle.
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LHRH agonists
Luteinizing hormone-releasing hormone (LHRH) agonists, sometimes referred to as LHRH analogs, are synthetic proteins that are structurally similar to LHRH and bind to LHRH receptors in the pituitary gland.
Normally, when the body’s androgen levels are low, LHRH stimulates the pituitary gland to produce luteinizing hormone, which in turn stimulates the testes to produce androgens. lHRH agonists, like the body’s own LHRH, initially stimulate the production of luteinizing hormone. However, the continued presence of high levels of LHRH agonists actually causes the pituitary gland to stop producing luteinizing hormone, thus preventing testosterone production.
Treatment with LHRH agonists is called pharmacological debulking (sometimes called chemical debulking) because it uses drugs to lower the levels of androgens in the body to the same extent as surgical debulking (orchiectomy). However, unlike orchiectomy, the effects of these drugs on androgens are reversible. Once the medication is stopped, androgen production usually returns to normal.
LHRH agonists are administered either by injection or subcutaneous implantation, and two LHRH agonists (leucovorin and goserelin) are currently approved for the treatment of prostate cancer.
A transient increase in testosterone may occur when a patient is first treated with an LHRH agonist. This transient increase in testosterone levels is due to the ability of LHRH agonists to cause the pituitary gland to produce large amounts of additional luteinizing hormone before going into a suppressed state. This phenomenon may exacerbate certain clinical symptoms in the short term (eg, bone pain, ureteral or bladder outlet obstruction, and spinal cord compression), which is a special condition encountered in patients with advanced prostate cancer.
In the first few weeks of treatment, a regimen called anti-androgen therapy is usually given along with an LHRH agonist to counteract excessive levels of testosterone in the patient’s body.
LHRH antagonists
LHRH antagonists (also known as GnRH antagonists) work by preventing LHRH from binding to pituitary receptors, which in turn prevents luteinizing hormone production, resulting in a decrease in the body’s androgen levels. Unlike LHRH agonists, LHRH antagonists do not cause a transient rise in testosterone.
An LHRH antagonist called degarelix is now approved for the treatment of advanced prostate cancer in the United States.
Estrogens (female sex hormones)
While estrogen can also inhibit testicular production of androgens, it is now rarely used in the treatment of prostate cancer because of its side effects.
Anti-androgen drugs
By competing with androgens for binding receptors, antiandrogens can reduce the androgen-promoting effects of androgens on prostate cancer cell growth. Because antiandrogens do not block androgen production, they are rarely used alone to treat prostate cancer and are often used in combination with orchiectomy or LHRH agonists.
Treatment with anti-androgens in combination with orchiectomy or LHRH agonists is called combined androgen blockade, complete androgen blockade, or overall androgen blockade.
Antiandrogens approved for the treatment of prostate cancer in the United States include flutamide, enzalutamide, bicalutamide, and nilumetide. Anti-androgens are generally administered by mouth.
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Androgen synthesis inhibitors
Neither drugs nor surgical debulking methods can stop adrenal and prostate cancer cells from producing androgens. Although they produce small amounts of androgens, these amounts are sufficient to support the growth of some prostate cancers.
Drugs that stop the adrenal glands (and testicular and prostate cancer cells) from producing androgens, called androgen synthesis inhibitors, reduce testosterone levels in men to a greater extent than any current treatment. These drugs block the production of testosterone by inhibiting an enzyme called CYP17. This enzyme is found in testicular, adrenal, and prostate tumor tissue and plays an important role in the biological process by which the body synthesizes cholesterol into testosterone.
There are currently three androgen synthesis inhibitors approved for marketing in the United States. All are administered orally, with ketoconazole and amiloride approved for indications other than prostate cancer and sometimes as second-line therapy for desmoid-resistant prostate cancer; the third is abiraterone acetate, which has been approved for the treatment of metastatic desmoid-resistant prostate cancer. has been approved for the treatment of metastatic desmoid-resistant prostate cancer.
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