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Management of Hot Flushes Due to Endocrine Therapy for Prostate Carcinoma

Management of Hot Flushes Due to Endocrine Therapy for Prostate Carcinoma

ABSTRACT: Endocrine manipulation plays a crucial role in the treatment of advanced prostate carcinoma. Recent enthusiasm for earlier use of endocrine therapy has increased the significance of diminishing treatment-related side effects, particularly vasomotor hot flushes, to ensure long term patient compliance. Treatments that lower serum testosterone, such as orchiectomy or luteinizing hormone-releasing hormone (LHRH) analogs, cause hot flushes in over half of men. Lack of regulatory feedback in the hypothalamus from circulating serum testosterone is the presumed mechanism of hot flushes in these men. Most often, hot flushes are only mildly bothersome and can be tolerated without the need for treatment. However, if flushes are particularly annoying or problematic, treatment should be offered. Small doses of diethylstilbestrol (DES) are effective in relieving hot flushes but cause gynecomastia. Megestrol acetate, at a dose of 20 mg bid, completely eliminates hot flushes in most men, and the dose can be progressively lowered in some. [ONCOLOGY 10(9):1319-1322, 1996]

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 (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 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 progesterones 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 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
[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.

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