Hormones are substances made by glands in the body that function as
chemical signals. They affect the actions of cells and tissues at
various locations in the body, often reaching their targets by
traveling through the bloodstream.
Androgens (male sex hormones) are a class of hormones that control
the development and maintenance of male characteristics.
Testosterone and dihydrotestosterone (DHT) are the most abundant
androgens in men. Almost all testosterone is produced in the
testicles; a small amount is produced by the adrenal glands.
Prostate cancer cells may also have the ability to produce
testosterone.
How do hormones stimulate the growth of prostate cancer?
Androgens are required for normal growth and function of the
prostate, a gland in the male reproductive system that helps make
semen. Androgens are also necessary for prostate cancers to grow.
Androgens promote the growth of both normal and cancerous prostate
cells by binding to and activating the androgen receptor, a protein
that is expressed in prostate cells. Once activated, the androgen
receptor stimulates the expression of specific genes that cause
prostate cells to grow.
Early in their development, prostate cancers need relatively high
levels of androgens to grow. Such prostate cancers are referred to
as androgen dependent or androgen sensitive because treatments that
decrease androgen levels or block androgen activity can inhibit
their growth.
Most prostate cancers eventually become "castration resistant,"
which means that they can continue to grow even when androgen levels
in the body are extremely low or undetectable.
What types of hormone therapy are used for prostate cancer?
Hormone therapy for prostate cancer also called androgen suppression
therapy or androgen deprivation therapy can block the production and
use of androgens (3). Currently available treatments can:
Reduce androgen production by the testicles
Block the action of androgens in the body
Block the production of androgens throughout the body
"Androgen production in men. Drawing shows that testosterone
production is regulated by luteinizing hormone (LH) and luteinizing
hormone-releasing hormone (LHRH). The hypothalamus releases LHRH,
which stimulates the release of LH from the pituitary gland. LH acts
on specific cells in the testes to produce the majority of
testosterone in the body. Most of the remaining androgens are
produced by the adrenal glands. Androgens are taken up by prostate
cells, where they either bind to the androgen receptor directly or
are converted to dihydrotestosterone (DHT), which has a greater
binding affinity for the androgen receptor than testosterone."
Treatment Options for an Enlarged Prostate
Treatments that reduce androgen production by the testicles are the
most commonly used hormone therapies for prostate cancer. These
include:
Orchiectomy, a surgical procedure to remove one or both testicles.
Removal of the testicles can reduce the level of testosterone in the
blood by 90 to 95 percent. This type of treatment, called surgical
castration, is permanent and irreversible. A type of orchiectomy
called subcapsular orchiectomy removes only the tissue in the
testicles that produces androgens, rather than the entire testicle.
Drugs called luteinizing hormone-releasing hormone (LHRH) agonists,
which prevent the secretion of a hormone called luteinizing hormone.
LHRH agonists, which are sometimes called LHRH analogs, are
synthetic proteins that are structurally similar to LHRH and bind to
the LHRH receptor in the pituitary gland. (LHRH is also known as
gonadotropin-releasing hormone or GnRH, so LHRH agonists are also
called GnRH agonists.)
Normally, when androgen levels in the body are low, LHRH stimulates
the pituitary gland to produce luteinizing hormone, which in turn
stimulates the production of androgens by the testicles. LHRH
agonists, like the body’s own LHRH, initially stimulate the
production of luteinizing hormone. However, the continued presence
of high levels of LHRH agonists actually causes the pituitary gland
to stop producing luteinizing hormone, which prevents testosterone
from being produced. Treatment with an LHRH agonist is called
medical castration (sometimes called chemical castration) because it
uses drugs to lower androgen levels in the body to the same extent
as surgical castration (orchiectomy). But, unlike orchiectomy, the
effects of these drugs on androgen production are reversible. Once
treatment is stopped, androgen production usually resumes.
LHRH agonists are given by injection or are implanted under the
skin. Two LHRH agonists, leuprolide and goserelin, are approved to
treat prostate cancer in the United States.
When patients receive an LHRH agonist for the first time, they may
experience a phenomenon called "testosterone flare." This temporary
increase in testosterone level occurs because LHRH agonists briefly
cause the pituitary gland to secrete extra luteinizing hormone
before blocking its release. The flare may worsen clinical symptoms
(for example, bone pain, ureter or bladder outlet obstruction, and
spinal cord compression), which can be a particular problem in men
with advanced prostate cancer. The increase in testosterone is
usually countered by giving another type of hormone therapy called
antiandrogen therapy (described below) along with an LHRH agonist
for the first few weeks of treatment.
Drugs called LHRH antagonists, which are another form of medical
castration. LHRH antagonists (also called GnRH antagonists) act by
preventing LHRH from binding to its receptors in the pituitary
gland, which in turn prevents the secretion of luteinizing hormone,
causing the body’s androgen levels to drop. Unlike LHRH agonists,
LHRH antagonists do not cause a testosterone flare.
One LHRH antagonist, degarelix, is currently approved to treat
advanced prostate cancer in the United States. It is given by
injection.
Estrogens (hormones that promote female sex characteristics).
Although estrogens are also able to inhibit androgen production by
the testicles, they are seldom used today in the treatment of
prostate cancer because of their side effects.
Treatments that block the action of androgens in the body
include:
Antiandrogens, which are drugs that compete with androgens for
binding to the androgen receptor. By competing for binding to the
androgen receptor, antiandrogens reduce the ability of androgens to
promote prostate cancer cell growth. Because antiandrogens do not
block androgen production, they are rarely used on their own to
treat prostate cancer. Instead, they are used in combination with
orchiectomy or an LHRH agonist. Use of an antiandrogen drug in
combination with orchiectomy or an LHRH agonist is called combined
androgen blockade, complete androgen blockade, or total androgen
blockade.
Antiandrogens that are approved in the United States to treat
prostate cancer include flutamide, enzalutamide, bicalutamide, and
nilutamide. Antiandrogens are given as pills to be swallowed.
Treatments that block the production of androgens throughout the
body include:
Drugs that prevent the production of androgens by the adrenal glands
and prostate cancer cells themselves, as well as by the testicles.
Neither medical nor surgical castration blocks the adrenal glands
and prostate cancer cells from producing androgens. Even though the
amounts of androgens they produce are small, these amounts can be
enough to support the growth of some prostate cancers.
Drugs that prevent the adrenal glands (as well as the testicles and
prostate cancer cells) from making androgens, which are called
androgen synthesis inhibitors, can lower testosterone levels in a
man's body to a greater extent than any other known treatment. These
drugs block testosterone production by inhibiting an enzyme called
CYP17. This enzyme, which is found in testicular, adrenal, and
prostate tumor tissues, plays a central role in allowing the body to
produce testosterone from cholesterol.
Nutrition and Prostate Health
Three androgen synthesis inhibitors are approved in the United
States. All are given as pills to be swallowed. Two of these,
ketoconazole and aminoglutethimide, are approved for indications
other than prostate cancer but are sometimes used as second-line
treatments for castration-resistant prostate cancer. The third,
abiraterone acetate, is approved to treat metastatic
castration-resistant prostate cancer.
How is hormone therapy used to treat prostate cancer?
Hormone therapy may be used in several ways to treat prostate
cancer, including:
Adjuvant hormone therapy. Hormone therapy that is given after other
primary treatments to lower the risk that prostate cancer will come
back is called adjuvant hormone therapy. Men with early-stage
prostate cancer that has an intermediate or high risk of recurrence
may receive adjuvant hormone therapy after radiation therapy or
prostatectomy (surgery to remove all or part of the prostate gland).
Factors that are used to determine the risk of prostate cancer
recurrence include the tumor's grade (as measured by the Gleason
score), the extent to which the tumor has spread into surrounding
tissue, and whether or not tumor cells are found in nearby lymph
nodes.
Men who have adjuvant hormone therapy after prostatectomy live
longer without having a recurrence than men who have prostatectomy
alone, but they do not live longer overall. Men who have adjuvant
hormone therapy after external beam radiation therapy for prostate
cancer live longer, both overall and without having a recurrence,
than men who are treated with radiation therapy alone.
Neoadjuvant hormone therapy. Hormone therapy given before other
treatments is called neoadjuvant hormone therapy. Men with
early-stage prostate cancer that has an intermediate or high risk of
recurrence often receive hormone therapy before or during radiation
therapy, in addition to receiving hormone therapy after radiation
therapy. Men who receive hormone therapy in combination with
radiation therapy live longer overall than men who receive radiation
therapy alone. The use of neoadjuvant hormone therapy (alone or in
combination with chemotherapy) before prostatectomy has not been
shown to prolong survival and is not a standard treatment.
Hormone therapy alone. Hormone therapy is sometimes used alone for
palliation or prevention of local symptoms in men with localized
prostate cancer who are not candidates for surgery or radiation
therapy. Such men include those with a limited life expectancy,
those with advanced local tumor stage, and/or those with other
serious health conditions.
Hormone therapy used alone is also the standard treatment for men
who have a prostate cancer recurrence documented by CT, MRI, or bone
scan after treatment with radiation therapy or prostatectomy.
Hormone therapy is often recommended for men who have a
"biochemical" recurrence a rapid rise in prostate-specific antigen (PSA)
level especially if the PSA level doubles in fewer than 12 months.
However, a rapid rise in PSA level does not necessarily mean that
the prostate cancer itself has recurred. The use of hormone therapy
in the case of a biochemical recurrence is somewhat controversial.
Finally, hormone therapy used alone is also the standard treatment
for men who are found to have metastatic disease (i.e., disease that
has spread to other parts of the body) when their prostate cancer is
first diagnosed. Whether hormone therapy prolongs the survival of
men who have been newly diagnosed with advanced disease but do not
yet have symptoms is not clear. Moreover, because hormone therapy
can have substantial side effects, some men prefer not to take
hormone therapy before symptoms develop.
The length of treatment with hormone therapy for prostate cancer
depends on a man’s risk of recurrence, which is based on the
clinical stage (the amount or spread of cancer in the body), Gleason
score (system of grading prostate cancer tissue based on how it
looks when examined under a microscope), and PSA level. For men with
intermediate-risk prostate cancer, hormone therapy is generally
given for 4 to 6 months; for men with high-risk disease it is
generally given for 2 to 3 years.
Home Remedies for Enlarged Prostate
Many prostate cancers that initially respond to hormone therapy with
LHRH agonists, LHRH antagonists, or orchiectomy eventually stop
responding to this treatment. This is referred to as
castration-resistant prostate cancer. Castration-resistant prostate
cancers need much lower levels of androgen to grow than
androgen-sensitive cancers.
Several potential mechanisms may allow prostate cancer cells to grow
even when androgen levels are very low, including increased
production of androgen receptor molecules within the cells (either
through an increase in the expression of the androgen receptor gene
or an increase in the number of copies of the androgen receptor gene
per cell), a change in the androgen receptor gene such that it
produces a more active protein, and changes in the activities of
proteins that help control the function of the androgen receptor.
Doctors cannot predict how long hormone therapy will be effective in
suppressing the growth of any individual man’s prostate cancer.
Therefore, men who take hormone therapy for more than a few months
will be regularly tested to determine the level of PSA in their
blood. An increase in PSA level may indicate that a man’s cancer has
started growing again. A PSA level that continues to increase while
hormone therapy is successfully keeping androgen levels extremely
low is an indicator that a man’s prostate cancer has become
resistant to the hormone therapy that is currently being used.
What are the treatment options for castration-resistant prostate
cancer?
Treatments for castration-resistant prostate cancer include:
Antiandrogens, such as flutamide, bicalutamide, nilutamide, and
enzalutamide
Androgen synthesis inhibitors, such as ketoconazole,
aminoglutethamide, and abiraterone acetate
Immunotherapy using a cell-based vaccine called sipuleucel-T. This
vaccine uses a man’s own immune cells to fight metastatic prostate
cancer that has become resistant to hormone therapy.
Chemotherapy, most commonly with the drug docetaxel. Another drug,
cabazitaxel, is approved for the treatment of metastatic
castration-resistant prostate cancer that was previously treated
with docetaxel.
Radium 223 dichloride, a radiopharmaceutical approved to treat men
with castration-resistant prostate cancer that has metastasized
(spread) to the bones and is causing symptoms but has not spread to
other organs. This drug collects in certain areas of bone, such as
bone metastases, and gives off radiation that kills cancer cells.
Men with castration-resistant prostate cancer who receive these
treatments will continue to take first-line hormone therapy (e.g.,
an LHRH agonist) to avoid an increase in testosterone level, which
may lead to tumor progression in some men.
Randomized clinical trials have demonstrated that treatment with
abiraterone acetate or enzalutamide prolongs survival among men with
metastatic castration-resistant prostate cancer, whether or not they
have previously received chemotherapy.
What are the side effects of hormone therapy for prostate cancer?
Both medical castration and surgical castration greatly reduce the
amount of androgens produced by the body. Because androgens are used
by many other organs besides the prostate, medical or surgical
castration can have a wide range of side effects:
Loss of interest in sex (lowered libido)
Erectile dysfunction
Hot flashes
Loss of bone density
Bone fractures
Loss of muscle mass and physical strength
Changes in blood lipids
Insulin resistance
Weight gain
Mood swings
Fatigue
Growth of breast tissue (gynecomastia)
Antiandrogens can cause diarrhea, breast tenderness, nausea, hot
flashes, loss of libido, and erectile dysfunction. The antiandrogen
flutamide may damage the liver.
Drugs that stop the adrenal glands from making androgens (i.e., the
androgen synthesis inhibitors ketoconazole, aminoglutethimide, and
abiraterone acetate) can cause diarrhea, itching and rashes,
fatigue, erectile dysfunction (with long-term use), and,
potentially, liver damage.
Estrogens avoid the bone loss seen with other kinds of hormone
therapy, but they increase the risk of cardiovascular side effects,
including heart attacks and strokes. Because of these side effects,
estrogens are rarely used today as hormone therapy for prostate
cancer.
Having adjuvant hormone therapy after radiation therapy worsens some
adverse effects of radiotherapy, particularly sexual side effects
and vitality. Many of the side effects of ongoing hormone therapy
also become stronger the longer a man takes hormone therapy.
What can be done to reduce the side effects of hormone therapy
for prostate cancer?
Men who lose bone mass during long-term hormone therapy may be
prescribed drugs to slow or reverse this loss. The drugs zoledronic
acid and alendronate (which belong to a class of drugs called
bisphosphonates) increase bone mineral density in men who are
undergoing hormone therapy. A newer drug, denosumab, which increases
bone mass through a different mechanism than bisphosphonates, was
approved in 2011 for use in men undergoing hormone therapy for
prostate cancer. However, bisphosphonates and denosumab are
associated with a rare but serious side effect called osteonecrosis
of the jaw.
Exercise may help reduce some of the side effects of hormone
therapy, including bone loss, muscle loss, weight gain, fatigue, and
insulin resistance. Several clinical trials are examining whether
exercise is an effective strategy to reverse or prevent side effects
of hormone therapy for prostate cancer.
The sexual side effects of hormone therapy for prostate cancer can
be some of the most difficult to deal with. Erectile dysfunction
drugs such as sildenafil citrate (Viagraź) do not usually work for
men undergoing hormone therapy because these drugs do not affect
loss of libido (sexual desire).
More information about the sexual side effects of cancer treatment
can be found in the NCI booklet Facing Forward: Life After Cancer
Treatment.
More information about supportive care for other side effects of
hormone therapy can be found in the following PDQ summaries:
Sweats and Hot Flashes
Depression
Fatigue
When most men stop taking a reversible hormone therapy, the sexual
and emotional side effects caused by low levels of androgens will
eventually go away. However, if a man has been taking hormone
therapy for many years, these side effects may not disappear
completely. Some physical changes that have developed over time,
such as bone loss, will remain after stopping hormone therapy.
Patients should be sure to tell their doctor about all medications
they are taking, including over-the-counter herbal medicines. Some
herbal medicines interact with drug-metabolizing enzymes in the
body, which can adversely affect hormone therapy.
Does a reversible hormone therapy have to be taken continuously for
it to be effective?
Researchers have investigated whether a technique called
intermittent androgen deprivation can improve the effectiveness of
hormone therapy for prostate cancer that is, whether it delays the
development of hormone resistance. With intermittent androgen
deprivation, hormone therapy is given in cycles, with breaks between
drug administrations, rather than continuously. An additional
potential benefit of this approach is that the temporary break from
the side effects of hormone therapy may improve a man’s quality of
life.
Two clinical trials of intermittent versus continuous androgen
deprivation found that intermittent therapy reduced some of the side
effects of hormone therapy, including those involving sexual
function. However, the trials did not show any improvement in
overall survival with intermittent therapy.
How is hormone therapy for prostate cancer being tested in
clinical trials?
Treatment in a clinical trial is an option for men with any stage of
prostate cancer. Many questions about the best uses of hormone
therapy still need to be answered. These include whether hormone
therapy added to brachytherapy, a type of internal radiation
therapy, can help improve survival for men with early-stage prostate
cancer. Other questions include whether newer intensive hormone
therapies may improve the outcome of men who are receiving surgery
or radiation therapy for high-risk disease. Researchers are also
testing new hormone therapies to treat castration-resistant prostate
cancer. These include TAK-700 and VT-464, which work in a way
similar to abiraterone acetate.
Another question is the possible value of adding chemotherapy to
hormone therapy as initial treatment for men with hormone-sensitive
metastatic prostate cancer. Currently, chemotherapy is not used in
these men until their disease progresses on hormone therapy (i.e.,
until it becomes hormone resistant). Early results of an
NCI-sponsored trial that was conducted by two cancer cooperative
groups the Eastern Cooperative Oncology Group (ECOG) and the
American College of Radiology Imaging Network (ACRIN) suggest that
men with hormone-sensitive metastatic prostate cancer who receive
the chemotherapy drug docetaxel at the start of standard hormone
therapy live longer than men who receive hormone therapy alone. The
trial results suggested that men with the most extensive metastatic
disease benefit the most from the early addition of docetaxel. A
follow-up analysis will be performed to clarify the effect of this
treatment on men with less extensive metastatic disease.
Information about clinical trials can be found on NCI's website.
NCI's Cancer Information Service (CIS) can also provide information
about clinical trials and help with clinical trial searches.
Where can someone find more information about drugs used in
prostate cancer?
NCI's Drug Information Summaries provide consumer-friendly
information about certain drugs that are approved by the FDA to
treat cancer or conditions related to cancer, including prostate
cancer. For each drug, topics covered include background
information, research results, possible side effects, FDA approval
information, and ongoing clinical trials.
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