LH subsequently stimulates secretion of T, predominantly by the testes (Figure 1).11,12 Sustained pituitary overstimulation eventually downregulates and desensitizes GnRH receptors, causing a decrease in hormone levels.13 The overall effect of ADT on hormone levels in prostate cancer differs between treatments. Orchiectomy reduces T and dihydrotestosterone (DHT) but is accompanied by significant rises in both LH and follicle-stimulating hormone (FSH).14,15 GnRH agonists cause an initial surge in LH, FSH, T, and DHT; over time these hormones are suppressed. 16 However, FSH gradually rises during GnRH agonist treatment

and results in a FSH “escape.”17 Figure 1 Gonadotropin-releasing hormone (GnRH), Inhibitors,research,lifescience,medical secreted in pulses from the hypothalamus, stimulates release of luteinizing hormone (LH) from the pituitary gland, along with adrenocorticotropic hormone (ACTH) and prolactin. LH subsequently stimulates secretion … Hence, these distinct modes of action of GnRH agonists produce Inhibitors,research,lifescience,medical different clinical effects. The initial agonist-induced T surge can exacerbate clinical symptoms (clinical flare) in advanced prostate cancer.18 An appreciable proportion of patients (~ 12%) receiving GnRH agonists

fail to achieve castrate T levels ≤ 50 ng/dL.19 T microsurges associated with buy Adriamycin repeat injections also occur with agonists.19 In a Inhibitors,research,lifescience,medical study with goserelin, microsurges (T surges above a castration threshold of 18.5 ng/dL after ≥ 1 repeat injection) occurred in 17.7% to 27% of patients.20 The clinical implications of microsurges are currently unclear. Loss of GnRH receptor sensitivity during long-term agonist therapy can allow renewed T production manifesting as a late breakthrough T escape.19,21 Inhibitors,research,lifescience,medical GnRH agonists usually cause partial FSH suppression.22,23 FSH stimulates prostate cancer cell growth in vitro.24 FSH receptors are present on prostate tumors25 and the

surface of tumor blood vessels 26; they are expressed at higher levels on prostate versus Inhibitors,research,lifescience,medical normal tissue.27 FSH signaling may also contribute to progression of CRPC.28 FSH promotes RANK (receptor activator of nuclear factor κB) expression on CD141+ cells, indicating the acquisition of osteoclast precursor cell characteristics.29 The exact significance of the role of FSH is still being defined. Long-term T control has been suggested to reduce mortality risk among patients with and metastatic disease.10 In 129 patients with metastatic prostate cancer receiving a GnRH agonist, those with high T levels at 6 months had a 1.33-fold increase in mortality risk.10 How May Changing Prostate Cancer Screening Guidelines Impact Use of AdT? PSA is the most utilized biomarker for diagnosing prostate cancer. It is a serine protease inhibitor that was discovered and purified in 1979.30 Thirteen years later, two large studies reported the utility of using PSA screening for prostate cancer.