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Web Topic 5.6: Drugs Related to Sex Hormones

[Referenced on textbook p. 148]

The identification of sex hormones and their role in sexual physiology and behavior has led to the development of several classes of drugs. These drugs exert their effects by mimicking or blocking the actions of sex hormones, or by preventing their synthesis (see Figure 1 and Web Activity 5.6).

Figure 1  How drugs interact with hormones.

Receptor Agonists Mimic Hormones

Drugs that mimic the actions of sex hormones generally do so by binding to and activating the receptors that are the normal targets of hormone action. Such drugs are called receptor agonists (see Figure 1B). The natural agonists for a given receptor—the androgen receptor, for example—are, of course, the hormones that normally activate that receptor in the human body, such as testosterone and DHT. In some cases, these natural hormones (or exact synthetic copies of them) are used in clinical medicine; examples are the use of oxytocin to induce labor and of FSH (made by recombinant DNA technology) to treat infertility.

Often, however, natural hormones are unsuitable for use as drugs. They may not be well absorbed from the gut, or their half-life in the body may be too short. Numerous artificial receptor agonists have been developed that overcome these problems. Examples include the synthetic estrogens and progestins that are the active ingredients in oral contraceptive pills (see Chapter 12).

Receptor Antagonists Block Hormone Effects

Drugs that bind to hormone receptors but fail to activate them are called receptor antagonists or “blockers” (see Figure 1C). These drugs work by preventing the natural hormones from gaining access to their receptors. An example is the drug cyproterone, an antagonist of the androgen receptor that interferes with the action of testosterone and other androgens. It is used to treat androgen-dependent cancers, such as cancer of the prostate, and is also sometimes used to reduce the sex drive of sex offenders (“chemical castration”; see Chapter 15). Another example is the progestin receptor antagonist mifepristone or RU-486. This drug prevents progesterone from playing its usual role in sustaining pregnancy; thus mifepristone is used to induce abortion (see Chapter 12).

Some Drugs Have Mixed Effects

The distinction between receptor agonists and receptor antagonists is often blurred. Take the drug leuprolide (Lupron), a synthetic analog of the hormone GnRH. Technically, leuprolide is a GnRH agonist: it binds to GnRH receptors on LH- and FSH-secreting cells in the anterior lobe of the pituitary gland, causing them to secrete their hormones. But the GnRH receptors are designed to respond to the normal pulsatile secretion of GnRH. When leuprolide is present continuously, the receptors become desensitized and stop secreting gonadotropins, so the long-term action of leuprolide is as a GnRH antagonist. As a result, the testes reduce their secretion of testosterone. Thus leuprolide, like cyproterone, is used in the treatment of prostate cancer. It can also be used to delay puberty when puberty begins too early (see Chapter 6).

Mixed agonist–antagonist effects are commonly seen with drugs that bind to the estrogen receptor. Part of the reason for this is that the estrogen “receptor” is, in reality, two slightly different molecules, which are present in different proportions in different tissues. Also, another class of molecules, called coregulators, is involved in cellular responses to estrogens and other steroid hormones, and the nature of these molecules may vary from tissue to tissue.

To see the practical importance of these mixed effects, consider two drugs that act on estrogen receptors, tamoxifen and raloxifene. Both of these drugs are estrogen receptor agonists in some tissues and antagonists in other tissues. Tamoxifen is an antagonist in breast tissue, and is therefore an important drug in the treatment and prevention of breast cancer, but it is an agonist in the uterus, so it increases the risk of endometrial cancer (see Chapter 3). Raloxifene is an agonist in bone tissue, so it helps prevent osteoporosis, but it is an antagonist in the breast and uterus, and it is being investigated for use in the prevention of cancers of both those tissues. Drugs such as tamoxifen and raloxifene are known as selective estrogen receptor modulators, or SERMs. The development of new SERMs that exhibit the desired actions of estrogens, but not the undesired ones, is an area of intense research.

There is concern about the possible health effects of hormones or hormone-like compounds that exist as pollutants in the environment, or that are administered to livestock. This matter is discussed in Box 5.5.

Enzyme Inhibitors Block the Production of Hormones

Drugs that block the synthesis of sex hormones do so by binding to the enzymes that catalyze the production of the hormones, thus inhibiting their action (see Figure 1E). An example is the class of drugs known as aromatase inhibitors, which prevent the synthesis of estrogens from androgens. We have already described the use of these drugs in a research context to block the conversion of testosterone to estradiol in the brains of experimental animals. Aromatase inhibitors are coming to play an increasing role in the treatment of breast cancer, especially for advanced or recurrent disease. By cutting off the supply of estrogens at the source, aromatase inhibitors can have therapeutic effects that are as good as or better than those of receptor modulators such as tamoxifen. Letrozole (Femara) and anastrozole (Arimidex) are examples of aromatase inhibitors that have been approved for this use. Of course, by depleting estrogen levels throughout the body, these drugs may have undesired side effects. Furthermore, breast cancer cells often cease to express estrogen receptors at some point in the disease. If this happens, all estrogen-related drugs lose their efficacy.

Another example of a medically important enzyme inhibitor is finasteride (Proscar). This drug inhibits the enzyme 5α-reductase and thereby decreases the conversion of testosterone to DHT. Since DHT is required for maintenance of the prostate gland, finasteride is an effective treatment for enlargement of the gland (see Chapter 4).

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