The Science of Sex: Estrogen

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Two weeks ago, I discussed the theory that estrogen-mimicking pollutants in the environment might be causing men’s sperm counts to decline, threatening their fertility. Hardly had the digital ink dried on my column when two announcements about the health effects of estrogens in women came down the wires. It was a bad news/good news sort of thing. The bad news: a federal panel voted to list medically prescribed estrogens as cancer-causing agents, because of their role in promoting endometrial and breast cancer. The good news: another panel recommended that a drug that interferes with the production of estrogens be approved for first-line use in advanced breast cancer.

First, some background. Estrogens are a group of hormones that shape female sexual development and reproductive physiology. A woman’s ovaries and adrenal glands synthesize estrogens from testosterone and other “male” hormones, converting them via a middleman enzyme: aromatase. But after menopause, the ovaries get out of the estrogen business, leaving a woman with the meager supply provided by her adrenals.


Over fifteen million postmenopausal women in the U.S. take estrogens to alleviate the symptoms of menopause — lovely side effects like vaginal dryness, hot flashes, fatigue and irritability — and stave off osteoporosis and heart disease. But the downside of estrogen treatment is that it raises the risk of breast cancer and endometrial cancer.


As far as endometrial cancer is concerned, adding another hormone, progestin, to the mix effectively eliminates the heightened risk. Hopes were high that progestin might do the same when it came to breast cancer. But a study from the University of Southern California, published in the Journal of the National Cancer Institute in January of this year, found the exact opposite: the combination of progestin and estrogen raises breast cancer risk above that of estrogen treatment alone. Bad news indeed.


Early this month, an advisory panel of the National Toxicology Program recommended that estrogens be added to the federal list of known carcinogens. This doesn’t mean that women should stop taking hormone replacements (or oral contraceptives, most of which also contain estrogens). For the average woman, it seems that the long-term benefits of hormone replacement slightly outweigh the risks: one Dutch study, published this year, suggests that a healthy fifty-five-year-old woman who takes hormone replacement therapy for ten years will prolong her ultimate life expectancy by one month. Still, women who are at increased risk of breast cancer (having a first-degree relative with the disease, for example) should discuss the potential risks and benefits with their doctors before making a decision about treatment.


Now for the good news: another recent announcement also came from a federal advisory panel, this time from a group that recommends drug approvals to the Food and Drug Administration. The panel recommended that the drug letrozole (trade name Femara) should be approved as a first-line treatment for advanced (recurrent or metastatic) breast cancer.


It’s long been known that many breast cancers require the presence of estrogens for their growth — just like breast tissue itself. One of the mainstays of chemical therapy for these tumors has been a class of drugs that block the action of estrogens on the tumor cells. Those drugs — tamoxifen is a widely-used example — bind to the estrogen receptors (the molecules that recognize estrogens) in the tumor cells and effectively blind them to the presence of the hormones.


Femara takes a different approach. It’s part of a relatively new class of drugs that block the activity of the enzyme aromatase in the ovaries and adrenal glands — thus preventing the synthesis of estrogens in the first place. Femara and another “aromatase inhibitor,” Arimidex, had until recently been approved only as second-line drugs, for use when treatments such as tamoxifen fail. Then Arimidex was upgraded to a first-line drug after a study showed that it was as effective as tamoxifen. This November, the results of two studies comparing Femara and tamoxifen were announced: in both reports, Femara prevented progression of the disease for significantly longer than tamoxifen (forty-one versus twenty-six weeks in one study). The FDA committee jumped to recommend promotion of the drug to first-line status.


Unfortunately, none of these treatments is a miracle cure: even with Femara, median survival is only about two years. All too often, breast cancer cells lose their estrogen receptors as the disease progresses, so drugs stop working and cells multiply unhindered. (Though they may still be responsive to regular chemotherapy, which simply targets any dividing cell.)


It’s only the beginning for such research. This column is titled the Science of Sex, but despite the racy sound, that category means so much more than spying on people’s bedrooms. Since the first estrogen was isolated in 1929, sex hormone research has improved the lives of millions of people, particularly women. All the signs are that new, more selective drugs will soon be available, drugs that will offer greater benefits with fewer risks — and better prospects for women as they age.