A 66-year-old man comes to the office for follow-up of metastatic prostate cancer. He was diagnosed 12 months ago, when he was found to have a single bony metastasis. The patient declined orchiectomy and was treated with a long-acting gonadotropin-releasing hormone agonist. While on this therapy, he developed nocturnal pain in the area of the bony metastasis and was found to have a rising level of prostate-specific antigen. Flutamide was then added to his initial therapy and led to significant pain relief and a decrease in the size of the primary tumor. Which of the following mechanisms is the best explanation for the effects of flutamide in this patient?

Question

A 66-year-old man comes to the office for follow-up of metastatic prostate cancer.  He was diagnosed 12 months ago, when he was found to have a single bony metastasis.  The patient declined orchiectomy and was treated with a long-acting gonadotropin-releasing hormone agonist.  While on this therapy, he developed nocturnal pain in the area of the bony metastasis and was found to have a rising level of prostate-specific antigen.  Flutamide was then added to his initial therapy and led to significant pain relief and a decrease in the size of the primary tumor.  Which of the following mechanisms is the best explanation for the effects of flutamide in this patient?

Quizplus · Accepted Answer

11ec160b_3c04_038e_9249_857db128cde4_MD0001_00 Prostate cancer is testosterone-dependent and can be treated in most cases with surgical and/or pharmacologic androgen deprivation. Initial options include bilateral orchiectomy or a gonadotropin-releasing hormone (GnRH) agonist. Pulsatile release of GnRH from the hypothalamus stimulates secretion of LH from the anterior pituitary and leads to increased testosterone production. However, constant GnRH activity causes down-regulation of the GnRH receptors on pituitary gonadotrophin cells, which suppresses LH secretion. Therefore, long-acting GnRH agonists (eg, leuprolide) paradoxically cause a decrease in testicular Leydig cell stimulation (Choice B). The use of long-acting GnRH agonists can be associated with a transient rise in LH and testosterone levels following treatment initiation. As a result, antiandrogens are sometimes prescribed concurrently to limit the tumor-stimulating effects of this initial testosterone rise. Flutamide is a nonsteroid agent that acts as a competitive testosterone receptor inhibitor. Prevention of androgen-receptor binding blocks the stimulatory effect of androgens on the primary tumor and metastases and leads to a reduction in their size (improving symptoms such as bone pain and urinary obstruction). (Choice A) Aromatase inhibitors (eg, anastrozole) decrease the peripheral conversion of androgens to estrogen and are used in postmenopausal women with estrogen receptor-positive breast cancer. They do not lower androgen levels and are not used in the treatment of prostate cancer. (Choice C) Finasteride decreases peripheral conversion of testosterone to dihydrotestosterone by inhibiting 5-α-reductase. It is used for treatment of benign prostatic hyperplasia and male-pattern baldness. (Choice E) Ketoconazole is a weak antiandrogen that decreases synthesis of steroid hormones in the gonads and adrenals. Flutamide does not inhibit testosterone production by Leydig cells. Educational objective: Flutamide is a nonsteroid anti-androgen that acts as a competitive inhibitor of testosterone receptors. It is used in combination with long-acting gonadotropin-releasing hormone agonists for the treatment of prostate cancer. __________ References: Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review. (http://www.ncbi.nlm.nih.gov/pubmed/25523493) Combined androgen blockade in advanced prostate cancer: looking back to move forward. (http://www.ncbi.nlm.nih.gov/pubmed/17956709)

A 66-Year-Old Man Comes to the Office for Follow-Up of Metastatic