A 60-year-old man comes to the office due to 2 months of low back pain unresponsive to over-the-counter analgesics. The pain is worse at night and interferes with sleep. On examination, the lumbar vertebrae are tender to palpation, and the prostate is indurated and firm. After a thorough evaluation, leuprolide therapy is started. Which of the following changes in testosterone (solid line) and dihydrotestosterone (dashed line) levels are most likely to occur in this patient after initiation of therapy?
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This patient's nocturnal back pain, spinal tenderness, and indurated prostate suggest prostate adenocarcinoma with bony metastases. Prostate cancer is an androgen-dependent tumor. Because most androgens (eg, testosterone) in men are made in the Leydig cells of the testes, initial treatment focuses on a systemic reduction in androgen production via surgical or medical orchiectomy.
Androgen production is primarily regulated by the hypothalamic-pituitary-testicular axis. Neurons in the hypothalamus release GnRH into the hypothalamic-pituitary portal system in a pulsatile pattern every 90-120 minutes. This stimulates pituitary gonadotrophs to release luteinizing hormone (LH) into the circulation, which then binds to a surface receptor on Leydig cells and stimulates androgen production.
In medical orchiectomy, a GnRH analogue (eg, leuprolide) is administered to continuously stimulate pituitary gonadotrophs, which leads to down-regulation of the GnRH receptor, lower LH release, and reduced testicular androgen production. However, because GnRH analogues initially stimulate pituitary gonadotrophs prior to the down-regulation of the receptor, most patients have a transient increase in systemic androgens during the first week of therapy (upward portion of graph). This effect is generally blunted by administering a short course of androgen receptor antagonist medication (eg, bicalutamide) during treatment initiation in order to prevent worsening of the underlying prostate cancer.
(Choices A and C) GnRH analogues stimulate the GnRH receptor prior to down-regulation, resulting in a transient increase in LH and systemic androgen production prior to down-regulation of the receptor.
(Choice D) The enzyme 5-alpha reductase converts testosterone to dihydrotestosterone (DHT) in peripheral tissues (eg, skin, liver); as testosterone levels fall, DHT production will decrease concurrently. GnRH analogues have no effect on the activity of 5-alpha reductase, therefore, testosterone and DHT levels rise and fall in synchrony following GnRH administration.
(Choice E) Benign prostatic hyperplasia is typically treated with a 5-alpha reductase inhibitor (eg, finasteride), which reduces the conversion of testosterone to DHT. This class of medications reduces DHT levels while testosterone levels remain largely unaffected.
Educational objective:
Leuprolide is a GnRH agonist used to treat prostate cancer. It initially stimulates pituitary LH secretion, which leads to a rise in androgen levels. However, the GnRH receptor is subsequently down-regulated, which dramatically drops LH release and leads to a long-term decrease in androgen production.