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Steroid hormones: from sexual differentiation to cancer control
by Dr. Richard Wassersug, Dalhousie University
Steroid hormones, which are almost chemically identical, control the development of female and male reproductive organs. But they can also stimulate reproductive-related cancers. While "chemical castration" can inhibit the growth of certain cancers, it's unlikely that a single, cure-all, anti-cancer drug will ever be found.
Although she is unmistakably a woman and he a man, they hardly looked so different when they were embryos. What is the chemistry that accounts for the differences between sexually mature males and females?
Sexual differentiation and maturation depends on female and male steroid hormones, collectively identified as estrogens and androgens, which are derived from cholesterol through a series of chemical reactions. For males, these reactions yield testosterone, the most abundant androgen in circulation. For females, similar chemical reactions convert cholesterol to estradiol, the most active female estrogen. Estradiol can also be produced directly from testosterone.
Dr. Richard Wassersug is a Professor in the Department of Anatomy and Neurobiology at Dalhousie University, and an Adjunct Professor in the Australian Research Centre for Sex, Health and Society at LaTrobe University in Melbourne, Australia. He has worked with the Discovery Channel's Daily Planet TV show, and as a regular "science panelist" for CBC radio in Atlantic Canada. Dr. Wassersug has spent most of his career studying the biology of tadpoles, and has published on everything from fossil crocodiles to frogs raised on the MIR space station. His current research is increasingly focused on sexuality and cancer, and he is now a visiting scholar in the Women, Gender and Sexualities Studies Program at Boston University.
More similar than different
What’s surprising is how similar testosterone and estradiol are. He and she may look very different, but testosterone and estradiol have the same basic four-ring structure. With two exceptions, these molecules are identical.
In order to activate the biological processes that control how females and males appear and function, estrogens and androgens must bind to receptor molecules located on or inside cells. There are several different receptors for both estrogens and androgens, but they too have large portions that are identical. Both males and females produce estradiol and testosterone, and both sexes have estrogen and androgen receptors. What’s more, estradiol and many of its precursors can, to some extent, bind to androgen receptors. And many of the precursors to testosterone can, to some extent, bind to estrogen receptors.
How steroids can cause cancer
There is good and bad news in the similarity of estrogens and androgens, which explains why steroid chemistry is a thriving research area within the pharmaceutical industry. The basic issue is the fact that certain cancers — linked to the organs that make him a “he” and her a “she” — can be stimulated by these hormones. Thus, during puberty, estradiol is essential for her breast development, while testosterone promotes the growth of his prostate gland. But the same estradiol can cause some breast cancer cells to proliferate. And testosterone can stimulate the growth of prostate cancer cells.
Dr. Charles Huggins MD received the 1966 Nobel Prize in Medicine for recognizing that one could slow the growth of certain cancers by cutting off their supply of estradiol and testosterone. At first, Dr. Huggins showed that he could extend the lives of prostate cancer patients through surgical castration. By removing patients’ testicles, he removed the main source of testosterone in their bodies. Soon, though, he and his colleagues realized that high doses of an estrogenic compound could shut down the regulatory pathway that signaled the testicles to produce testosterone. In other words, surgical castration wasn’t necessary; chemical castration could do the job.
But here is the bad news. Shutting down the growth of cancer cells is not the same as killing those cells outright. Androgen deprivation for prostate cancer — and estrogen deprivation for breast cancer — are, sadly, too often not curative. The problem is that the receptors for these molecules can mutate, and that different estrogens and androgens can bind to a greater or lesser extent to these receptors.
Mixed signals
This means that a steroid hormone that signals "stop" when bound to one receptor may signal "go" when bound to another. Thus, estradiol can inhibit prostate cancer growth in the early stages of the disease. It can even cause the death of cancer cells when it binds to one type of receptor. But it can promote cancer cell growth when it binds to certain other receptors.
This paradox has prompted a major effort by the pharmaceutical industry to develop drugs that can bind selectively to some — but not all — steroid receptors, either to turn them on or shut them off. It would be premature, however, to expect that a single compound could cure reproductive-related cancers in all patients. The problem is that steroid chemistry is too complex and diverse in the chaotic environment of aggressive cancer cells.
Just as the sexual relationships between men and women are invariably more complicated than people may hope for when they spot a potential partner, so too is the molecular biology of steroid hormones and their receptors. 
