Management of Hot Flushes Due to Endocrine Therapy for Prostate Carcinoma

Introduction

Since the pioneering work of Huggins and Hodges in the early 1940s,[1] endocrine manipulation has been the mainstay of treatment for patients with metastatic carcinoma of the prostate. Although the methods of endocrine manipulation have changed, the goal of therapy remains the same, ie, deprivation of androgens from the malignant cell. Historically, endocrine manipulation has been reserved for patients with evidence of symptomatic metastatic disease. Recently, however, there has been increasing enthusiasm for earlier use of endocrine treatment. Consequently, more patients receive hormonal therapy and, often, for a longer duration. Although contemporary methods of endocrine treatment for prostate cancer pose little risk of serious or life-threatening side effects, hot flushes due to vasomotor instability can be an annoying, sometimes problematic side effect.

When hormonal therapy is used in patients with metastatic disease, the duration of therapy may be only 1 or 2 years because of the limited life expectancy of these individuals. In contrast, when endocrine manipulation is used as primary therapy for localized cancer or much earlier in the course of the disease, the intent may be to continue treatment for many years or even decades. Tolerance of side effects, then, becomes an issue of major importance with regard to patient compliance.

This article reviews the incidence and presumed etiology of hot flushes caused by endocrine therapy for prostate carcinoma. The variation in the frequency of this side effect with different hormonal treatments is also discussed. Finally, methods for the treatment or prevention of hot flushes are considered.

Causes of Hot Flushes

Hot flushes are a natural consequence of the decreasing estrogen levels that occur in women at menopause. In men, serum testosterone levels decrease somewhat with aging because of Leydig cell dysfunction. However, hot flushes are not observed in men in the normal physiologic setting. Hot flushes do occur frequently in men undergoing endocrine therapy for carcinoma that lowers serum testosterone levels to the castrate range.

Vasomotor hot flushes are characterized by a subjective sensation of increased temperature, usually in the upper body and face. A visible reddening of the skin may be observed because of peripheral vasodilation. Typically, this is followed by profuse sweating. The entire episode may last only a few minutes.

The episodes often occur spontaneously but also may be triggered by external factors, such as changing from a standing to a recumbent position or alterations in the external environmental temperature.[2] Men frequently report the occurrence of a hot flush when they first get into bed at night. Ingestion of hot liquids has also been reported to trigger hot flushes.

Suppression of serum testosterone is a major factor in the development of hot flushes in men. The exact levels to which testosterone must be suppressed before hot flushes occur is uncertain. Physiologic decreases in testosterone coincident with aging rarely cause hot flushes, and most endocrine therapies for prostate cancer are designed to cause profound suppression to the castrate range. Nonetheless, the exact physiologic mechanism that accounts for hot flushes is poorly defined. Initially, the increased gonadotropin levels that occur after orchiectomy were presumed to account for the induction of hot flushes.[3] However, the frequent development of hot flushes after administration of luteinizing hormone-releasing hormone (LHRH), which profoundly decreases serum luteinizing hormone (LH) levels, implies that the physiologic alteration occurs in the hypothalamus rather than the pituitary gland.

Hypothalamic catecholamine appears to be the neurotransmitter for LHRH release.[4,5] The lack of regulatory feedback from circulating serum testosterone lowers the release of endogenous opioid peptides in the hypothalamus. Consequently, the catecholamine concentration is increased. The proximity of the thermoregulatory system within the hypothalamus to the LHRH neurons may allow for a direct effect of the increased intra-hypothalamic catecholamines on physiologic thermoregulation.[6]

Hot Flushes and Endocrine Therapies

The goal of endocrine treatment in men with carcinoma of the prostate is deprivation of androgen from the prostate cancer cell. This may be accomplished by lowering of serum testosterone levels or prevention of uptake of androgens by the cell.

Fortunately, endocrine therapy for prostate carcinoma can be offered to men with little or no risk of serious side effects. With LHRH analogs or orchiectomy, side effects of therapy are a consequence of the lowering of serum testosterone. A decrease in muscle mass, weight gain, and lack of beard growth may be observed, but these changes are usually relatively subtle and well tolerated. The impotence that occurs from lowering of serum testosterone levels can be treated by various mechanical methods or vasoactive drugs. However, the accompanying loss of libido diminishes the motivation for treatment of impotence in most men.

Hot flushes have rarely been a cause for the discontinuation of endocrine therapy in men treated for prostate cancer but can be quite troublesome. An understanding of the basic physiologic mechanism underlying the induction of hot flushes in men allows one to predict, to some degree, the frequency of this side effect with various forms of hormonal therapy.

Orchiectomy

Surgical removal of the testes is a simple, safe procedure that results in rapid suppression of serum testosterone levels. Within 12 to 24 hours after orchiectomy, serum testosterone is in the castrate range.[7] Although orchiectomy has been a mainstay of treatment for over 50 years, in the past hot flushes were rarely addressed as a clinical problem.[8] Frequently, patients presenting with hot flushes underwent an extensive evaluation for a presumed infectious process before the association with orchiectomy was recognized. More contemporary studies indicate that hot flushes occur in about half of men after orchiectomy.

Hot flushes typically begin within a few months after surgery. A generally held, but undocumented observation is that the frequency of hot flushes diminishes with time and the problem becomes less severe years after surgery. No correlation has been found between preorchiectomy serum testosterone levels and the incidence of post-treatment hot flushes.

Estrogens

Oral administration of estrogen, usually diethylstilbestrol(Drug information on diethylstilbestrol) (DES), had long been considered the medical alternative to surgical orchiectomy in the treatment of prostate carcinoma. The effectiveness of oral DES is well documented, and a dose of 3 mg/d provides therapeutic results comparable to those achieved with orchiectomy. Lower doses generally suppress serum testosterone, but the castrate range is not reached reliably with 1 mg/d.[9]

In recent years, the side effects associated with DES have led to the acceptance of LHRH analogs as the primary medical alternative to surgical orchiectomy.[10] Oral DES frequently causes painful gynecomastia in men, which is only partially prevented by pretreatment breast irradiation. Of more consequence has been the association of oral DES with thrombotic cardiovascular events. Myocardial infarction, deep venous thrombosis, and pulmonary embolism are increased in incidence in men taking 3 mg of DES daily. The incidence of these side effects is less well documented with lower doses, and the effectiveness of prophylactic measures is not well understood. However, the expense of LHRH analogs and contemporary pressures for cost-efficient medical care have refocused attention on the use of DES in patients with prostate cancer.

An advantage of therapy with DES or other estrogens(Drug information on estrogens) is the lack of hot flushes associated with their use. Although serum testosterone levels are profoundly suppressed, the estrogen itself provides regulatory feedback to the hypothalamus. In fact, as discussed below, estrogens or progesterone(Drug information on progesterone)s are effective treatments for hot flushes induced by other methods of endocrine therapy for prostate cancer.

LHRH Analogs

Administration of powerful synthetic analogs of LHRH have the paradoxical effect of decreasing serum levels of LH. The presumed mechanism of action is saturation of the receptors within the pituitary gland. After an initial period of stimulation, serum levels of LH and, consequently, of testosterone are profoundly suppressed.[11] The castrate range is achieved reliably within 3 to 4 weeks of the administration of a depot preparation of an LHRH analog, such as leuprolide acetate (Lupron). More recently, 3-month depot preparations, such as goserelin(Drug information on goserelin) acetate (Zoladex), that provide comparable endocrinologic and therapeutic results have been developed and marketed.[12]

The development of LHRH analogs led to the widespread clinical recognition of hot flushes as a treatment-related side effect of endocrine therapy for prostate cancer. Prospective studies evaluating the use of LHRH analogs in the early 1980s showed that up to two-thirds of men receiving LHRH analogs reported hot flushes when specifically asked about their occurrence.[13] The available data suggest that this side effect is observed slightly more frequently in men treated with an LHRH analog than in those who undergo surgical orchiectomy, although the physiologic mechanism for the etiology of hot flushes (discussed above) implies that they should occur with equal frequency. As with orchiectomy, hot flushes usually are observed within several months of the initiation of LHRH treatment.

Antiandrogens

Three antiandrogens (flutamide, nilutamide [Anandron], and bicalutamide(Drug information on bicalutamide) [Casodex]) have received FDA approval for treatment of carcinoma of the prostate in combination with either an LHRH analog or orchiectomy. It is beyond the scope of this paper to debate the efficacy of combination therapy compared with orchiectomy or LHRH analogs alone.[14-16] Antiandrogens per se do not lower serum testosterone levels, however, and, when used alone, provide progression-free survival rates that are inferior to those seen with orchiectomy or LHRH analogs used alone.

There is no apparent effect of antiandrogens, either positive or negative, on the incidence of hot flushes. Antiandrogens prevent the uptake or intracellular metabolism of androgens but seen to have no central effect that increases the incidence of hot flushes. Likewise, antiandrogens are not a treatment for hot flushes.