Hormonal Therapy for Cancer
Hormones are chemical messengers that regulate specific body functions. They are produced by various glands in the body and enter the bloodstream, where they travel to other tissues and exert their influence. Certain hormones can influence the growth of cancerous tumors. Hormonal therapy is used in cancer treatment to augment or interfere with the activity of these hormones.
Hormones are responsible for many functions in our bodies. For example, the thyroid gland secretes thyroid hormone, which has a role in the regulation of body temperature, reproduction, bone health, and glucose metabolism—just to name a few. The parathyroid gland secretes parathyroid hormone, which is the single most important hormone controlling the calcium balance of the blood. The gonads (testes in men and ovaries in women) produce the steroidal sex hormones: estrogen, progesterone, and testosterone, which are responsible for the secondary sex characteristics. These examples, which represent only a handful of the hormones circulating in our bodies, illustrate how essential hormones are to health.
How Does Hormonal Therapy Work?
Some tumors arise in tissues that are sensitive to hormonal growth control. Tissues that are greatly affected by hormones include the breast and prostate. Estrogen promotes growth of some
breast cancers, while testosterone promotes growth of some
Since the growth of certain tumors is dependent on specific hormones, it makes sense that altering—either by increasing or decreasing—the levels of hormones in the body can affect a tumor's growth. Hormonal therapy attempts to control a tumor in these hormone-sensitive tissues by manipulating the activity of the hormones.
Hormones and hormone antagonists exert their power in a number of different ways. Some agents act directly on cancerous cells. Other agents act indirectly on hormone-producing glands, increasing or decreasing the production of their respective hormones.
Some cancer cells have hormone receptors on their surfaces. These receptors act like loading docks. The hormones attach to the cancer cell at the receptor and facilitate the tumor’s growth. How responsive a tumor is to hormonal therapy depends on a number of factors, including the amount of hormone receptors present on or in the tumor’s cells.
What Is Hormonal Therapy Used For?
Hormonal therapy is used for cancers that grow in hormone-sensitive tissues. Breast cancer and prostate cancer are the most common targets of hormonal therapy. Hormonal therapy is also used for
What Are the Types of Hormonal Therapy?
Drugs used in hormonal therapy fall into the following broad classifications:
- Estrogens and anti-estrogens
- Androgens and anti-androgens
- Gonadotropin-releasing hormone (GnRH) analogues
- Aromatase inhibitors
Estrogens and Anti-estrogens
One of estrogen's normal physiologic functions is to promote the development of female secondary sex characteristics. In adults, estrogen continues to stimulate the growth of cells in the glandular ducts of the breasts and the endometrial lining of the uterus.
Common estrogens and anti-estrogens used for hormonal therapy are selective estrogen receptor modulators and diethylstilbestrol (DES).
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are both estrogenic and anti-estrogenic. That is, they act like estrogen on some parts of the body, such as bones, but block the effect of estrogen on other tissues, such as the breast. A SERM works by binding to estrogen receptors in the body. Not all parts of the body have these receptors, and not all receptors are alike. The estrogen receptors in bone are different than the estrogen receptors in breast tissue. This allows SERMs to have one effect in one kind of tissue and different effect on another type of tissue.
Examples of SERMs include the following:
- Tamoxifen—This is most frequently used in combination with other treatments for women with resected breast cancer, meaning that the initial lesion has been removed.
- Toremifene—This is used in the treatment of metastatic breast cancer.
Raloxifene—This is currently used to treat
osteoporosis. It is also used to help reduce the risk of breast cancer in postmenopausal women with osteoporosis..
DES is a synthetic estrogen. It used to be the primary hormonal therapy for postmenopausal metastatic breast cancer. However, it has largely been replaced by tamoxifen, which has similar efficacy, but lower toxicity. DES is associated with a risk of developing life-threatening blood clots. DES is sometimes used in metastatic breast cancer that is hormonally sensitive, but has not responded to multiple other hormonal therapies. DES is also used in men with metastatic prostate cancer.
DES was prescribed from the early 1940s until 1971 to help pregnant women at risk for premature delivery. Researchers later discovered that DES is linked to an increased risk of clear cell carcinoma of the vagina among daughters of women who used this drug during their pregnancies.
Androgens and Anti-androgens
Androgens are hormones found in both men and women, but they are commonly referred to as male sex hormones. They promote the development and maintenance of male sex characteristics. Androgens play an essential role in reproductive and sexual function in men.
Androgens are used in women with metastatic breast cancer. While their exact mechanism of action is unknown, the theory is that androgen administration redirects the synthesis of estrogens that occurs in the adrenal glands. This indirectly results in a lowering of the estrogen level in the blood.
Examples of androgens include:
Anti-androgens are used in men with metastatic prostate cancer. They are androgen receptor antagonists, meaning that anti-androgens bind to the androgen receptor and prevent dihydrotestosterone from binding. Dihydrotestosterone stimulates new growth of prostate cells, including cancerous prostate cells. These medications are generally used with
Examples of anti-androgens include:
Progestin is the synthetic form of progesterone.
Progesterone is a hormone secreted by the ovaries and endometrial lining of the uterus. Acting with estrogen, progesterone promotes breast development and growth of endometrial cells during the menstrual cycle.
The exact mechanism of progestin action in cancer treatment is unknown. Some theories suggest that progestins may work by suppressing the production of estrogen from the adrenal glands (an alternate source particularly in postmenopausal women), lowering estrogen receptor levels, or altering tumor hormone metabolism. It is also thought that progestin may directly kill tumor cells.
Progestins are commonly used in the management of advanced
uterine cancer. They can also be used for advanced breast cancer, although this use has been less common because of the numerous antiestrogen treatment options available. Occasionally, progestins are used as hormonal therapy for prostate cancer.
Examples of progestins include:
- Progesterone acetate
Gonadotropin-releasing Hormone (GnRH) Analogues
When released from the hypothalamus in the brain, gonadotropin-releasing hormone (GnRH) analogues
stimulate the pituitary gland to produce gonadotropins. Gonadotropins are hormones that stimulate androgen synthesis in the testes and estrogen synthesis in the ovaries (hormones that can go on to promote cancer cell growth). When GnRH analogues are first administered, they can cause an increase in gonadotropin release. But with continued administration, GnRH will block gonadotropin release, and therefore decrease the synthesis of androgen and estrogen.
GnRH analogues are used to treat metastatic prostate cancer. They are also FDA-approved for treatment of metastatic breast cancer in premenopausal women.
Examples of GnRHs include:
In both men and women, a small amount of androgen is continuously converted into estrogen by the enzyme aromatase. Aromatase inhibitors block the action of aromatase, leaving less estrogen available to stimulate estrogen receptors on cancer cells.
Aromatase inhibitors are used primarily in postmenopausal women. Since ovarian production of estrogen is scant in postmenopausal women, androgen conversion becomes a significant alternate source. In premenopausal women, where the primary source of estrogen is the ovary, aromatase inhibitors are less effective.
Examples of aromatase inhibitors include:
Octreotide is used in the therapy of carcinoid syndrome, which is characterized by skin flushing, abdominal cramps, and diarrhea. The syndrome is usually caused by metastatic intestinal carcinoid tumors that secrete excessive amounts of certain hormones, namely serotonin and vasoactive intestinal peptide.
Thyroid Replacement Therapy (Synthroid or Levothyroxine)
Certain thyroid cancers (papillary and follicular cancers) are very responsive to thyroid hormone levels. Thyroid replacement therapy is typically given after surgery and radioactive iodine treatments. Thyroid replacement has two purposes:
- To provide the hormone your thyroid can no longer make, as a result of the surgery
To suppress any
cells from growing back
The surgical approach to hormonal therapy is to remove the source of the hormone.
The ovaries are the main source of estrogen in premenopausal women.
, surgical removal of the ovaries, may be used in premenopausal women to treat advanced breast cancer.
The testes are the main source of testosterone production. For prostate cancer, orchiectomy, removal of the testes, may be considered in advanced cases.
What Adverse Effects Can Occur With Hormonal Therapy?
Hormonal therapies do have side effects, some of which are severe, but they are usually not life-threatening. Side effects usually occur when the hormonal agents affect tissues in the body other than the target tissues. The goal for future development of hormonal agents will be to design a therapy that will attack only the target tissues, while sparing those associated with side effects.
Each of the drugs used in hormonal therapy carries its own risk of side effects.
Estrogens and Anti-estrogens
One of the more common side effects of estrogen therapy is gastrointestinal upset, manifested by nausea and vomiting. Other side effects include fluid retention, high blood levels of calcium, uterine bleeding, and decreased sex drive. Men may experience
Hot flashes are the most common side effect of SERMs (anti-estrogens). In addition, women may experience vaginal bleeding and discharge, mood swings, and visual disturbances.
Uterine cancer, blood clots, and
are rare, but serious side effects.
Tamoxifen has been associated with a 3-fold increase in endometrial cancer incidence when compared to the general population. However, the absolute risk is very small..
Androgens and Anti-androgens
Androgen's side effects are masculinizing effects, including hirsutism
, male-pattern baldness, voice lowering, acne, and enhanced sex drive.
The most common side effect of anti-androgens is gastrointestinal distress—
, sometimes with abdominal pain and cramping. Gynecomastia frequently occurs in men, but can be controlled with concomitant therapy. A rare, but possibly fatal, complication is liver toxicity. Nilutamide has 2 unique side effects: night blindness and lung toxicity.
Progestins are relatively well tolerated. The major side effects are weight gain and menstrual irregularities.
Gonadotropin-releasing Hormone (GnRH) Analogues
The primary side effects associated with GnRHs are hot flashes, sweating, and nausea. This treatment is also associated with impotence and decreased libido. Some people report transient bone pain if cancer is located in their bones.
Aromatase inhibitors can cause osteoporosis and bone fractures. Other side effects include lack of energy,
high blood pressure
, nausea, vomiting,
, and skin rash.
Octreotide is generally well tolerated, but can cause bradycardia
(slowed heart beat), diarrhea,
(low blood sugar), hyperglycemia (high blood sugar), and hypothyroidism.
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