New Considerations for ADT in Advanced Prostate Cancer and the Emerging Role of GnRH Antagonists

N D Shore; P-A Abrahamsson; J Anderson; E D Crawford; P Lange


Prostate Cancer Prostatic Dis. 2013;16(1):7-15. 

In This Article

GnRH Agonists and Antagonists

Mechanism of Action

GnRH, secreted in pulses from the hypothalamus, stimulates pituitary release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH subsequently stimulates testosterone secretion, predominantly by the testes (Figure 1).[8,9]

Figure 1.

Endocrine control of the prostate gland. ACTH, adrenocorticotropic hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone. Reproduced from Damber et al. 7 with permission from Informa Healthcare.

GnRH agonists and antagonists exhibit different mechanisms of action. Agonists bind to GnRH receptors and produce an initial intense stimulation. This causes marked increases in LH, FSH and testosterone. Sustained pituitary overstimulation will eventually down-regulate/desensitize GnRH receptors with a consequent decrease in hormone levels.[10] In contrast, antagonists block receptors, immediately stopping LH secretion, producing rapid testosterone suppression without the initial LH and testosterone surge.[11]

The overall effect of ADT on hormone levels in PCa differs between treatments (Table 1). Orchiectomy reduces testosterone and dihydrotestosterone (DHT) but is accompanied by significant rises in LH and FSH.[15,16] In contrast, GnRH agonists cause an initial surge in LH, FSH, testosterone and DHT; over time these hormones are suppressed.[11,17] However, FSH gradually rises during GnRH agonist treatment and FSH 'escapes' occur.[11,18] With GnRH antagonists there is a rapid and sustained suppression in LH, testosterone, DHT[12,19] and FSH.[12,20]

Pharmacological Profiles

These distinct modes of action produce different biochemical effects (Table 2). The initial agonist-induced testosterone surge can exacerbate clinical symptoms in advanced PCa[21] and delay the therapeutic effect (agonists generally suppress testosterone to <0.5 ng/ml (<1.7 nmol/l) within 3–4 weeks). Indeed, an appreciable proportion of patients (~5–17%) receiving GnRH agonists fail to achieve castrate testosterone ≤0.5 ng/ml.[22] Testosterone microsurges associated with repeat injections also occur with agonists.[11,23] In a study with goserelin, microsurges (testosterone surges above a castration threshold of 18.5 ng/dl (0.185 ng/ml) after ≥1 repeat injections) occurred in 17.7–27% of patients.[5] The clinical implications of microsurges are currently unclear.

Loss of GnRH receptor sensitivity during long-term agonist therapy can allow renewed testosterone production manifesting as late breakthrough testosterone escapes.[22] In 73 patients with non-metastatic PCa receiving agonists (38.4% also received bicalutamide), duration of androgen-independent progression-free survival (PFS) was correlated to the extent of testosterone breakthrough escape.[24] Mean PFS was significantly lower in patients with breakthrough testosterone >0.32 ng/ml versus those not experiencing breakthrough escape (88 versus 137 months, P<0.003).

GnRH antagonists achieve castration faster than agonists[11,25] and may offer better testosterone control, in terms of the absence of initial testosterone surge or subsequent microsurges.[11] Long-term testosterone control has been suggested to reduce mortality risk among patients with metastatic disease.[26] In 129 patients with metastatic PCa receiving a GnRH agonist, those with high testosterone at 6 months had a 1.33-fold increase in mortality risk.

GnRH antagonists cause profound and persistent FSH suppression[11,20] compared with partial FSH suppression with agonists.[27–29] The therapeutic advantage of persistent FSH suppression with antagonists is not fully understood. However, several studies have linked FSH with PCa. Thus, FSH stimulates PCa cell growth in vitro.[30] FSH receptors occur on prostate tumors[31] and the surface of tumor blood vessels[32] and are expressed at higher levels on prostate versus normal tissue.[33] Also, FSH signaling may contribute to progression of castration-resistant PCa.[34] Elevated FSH may also contribute to increased bone loss during perimenopause by promoting development of osteoclast precursor cells; FSH promotes RANK (Receptor Activator of Nuclear Factor κB) expression on CD14+ cells, indicating the acquisition of osteoclast precursor cell characteristics.[35] The exact significance of FSH is still being defined. Two studies investigated the GnRH antagonist, abarelix, in androgen-independent metastatic PCa progressing after orchiectomy[36] or GnRH agonists.[37] There were no PSA responses but these studies showed that PSA reduction could be achieved, especially in those who had previously received orchiectomy and who had the highest baseline FSH.[38]