Woman

by Natalie Angier

  A hormone is not only complex, it is small, a desirable feature in a molecule that would act as a bio-troubadour, always in voluble transit. This concision is true regardless of whether the nut of the hormone, its structural core, is built of grease, as the sex hormones are, or of meat, as the peptide hormones such as oxytocin and serotonin are.

  Let's take a zoom lens to the sex hormones, also called the sex steroid hormones. The word steroid lately has been pluralized into idiocy, so that when we think of steroids we think of anabolic steroids, the drugs that bodybuilders and other athletes take, at their peril, in an effort to inflate their strength and bulk. Such drugs are usually a synthetic version of testosterone, and thus they are steroid hormones, but the class of steroid hormones is much more inclusive and more interesting than locker-room dope.

  If you've ever looked at a diagram of a steroid molecule, and if your high school chemistry teacher didn't entirely annihilate your capacity to appreciate molecular aesthetics, you surely appreciated the steroid's rigorous beauty. A steroid is built of four rings of carbon atoms, arranged so they touch each other like mosaic tiles. Those rings lend stability to the hormone; they do not dissolve easily and so will not fall apart in your blood or in the thick sea of your brain. Moreover, the steroid rings are amenable to modification. Decorations can be added to their side, each new flounce changing the steroid's meaning and power. Testosterone and estrogen look surprisingly similar, yet they differ enough in their minor appendages to communicate quite distinct messages to a recipient tissue.

  Steroids are ancient in nature and play communicative roles in many organisms. Molds secrete steroids. A female mold releases a steroid hormone that will induce a neighboring mold to grow the equivalent of male reproductive organs. Once the solicitee has complied with the request and enmaled himself, he releases another steroid hormone into his surroundings, which induces the female to grow toward him. Come and get it! he cries, and she comes, and she gets it. Plants such as soy and yams have steroid and steroidlike hormones, and in fact a diet rich in these phytoestrogens can help palliate some of the symptoms of menopause. Certain species of aquatic insects synthesize the stress hormone Cortisol in such high concentrations that they knock out any fish attempting to eat them. Mexican beetles are like walking birth control pills, generating estrogen and progesterone that some scientists suspect are intended to curb the population of their natural predators. Pigs love steroid hormones; during courtship, a male pig will spit on his sowheart's face and in so doing expose her to a pungent steroid compound that causes her to freeze with rear legs conveniently parted. All of which might help explain the now quaint term male chauvinist pig—yessir, a bit of spit and the little woman is yours!

  There are hundreds, if not thousands, of varieties of steroid and steroidlike hormones in nature. By definition, a steroid hormone is an elaboration of that ubiquitous and unfairly maligned molecule cholesterol. Cholesterol is a steroid in structure, but it is a no-frills steroid and not in itself a communications vehicle. Only with chemical embellishment does it assume the mercurial role of hormone. All steroid hormones in vertebrates are built of cholesterol. The choice of cholesterol as the foundation for these hormones makes sense, because the body brims with it. Even if you never touch cholesterol-rich food such as eggs, oil, and meat, your liver continues to make cholesterol around the clock, and with reason. Cholesterol is an essential component of the plasma membrane, the fatty, protective coat surrounding every cell. At least half of the average cell's membrane consists of cholesterol, much more than half in neurons. Without cholesterol, your cells would fall apart. Without cholesterol, new cells could not be manufactured. There would be no way of replacing the cells of the skin, gut, and immune system, which die by the millions each day. Cholesterol is the fat of the earth and the fat of the brain.

  The steroid hormones, then, are pieces of ourselves, of the skin of our cells. When our cells wish to communicate, they paradoxically turn to the stuff of membranes, the original isolationists. The plasma membrane separates one cell from another, just as a membrane walled off from its environment the mother of us all, the first single-celled organism, some 3.8 billion years ago. The plasma membrane gave birth to selfhood and organismic loneliness. To reconnect, to speak as one cell, one self, to another, there can be no better language than that of the plasma membrane itself.

  The word hormone wasn't coined until 1905, and the first one wasn't isolated until the 1920s, but people have known about steroid hormones indirectly for millennia, thanks to the external nature of one particular hormone factory, the testicles. Males, including human ones, were the hapless recipients of the first experiments in endocrinology. Game animals were castrated to make their behavior more manageable and their meat tastier. Men were castrated to render them trustworthy. The Old Testament describes the use of eunuchs to guard the consorts of Hebrew kings and princes. Men also were castrated as punishment for sexual crimes or sexual miscalculations. In the twelfth century, Peter Abelard, the great theologian and philosopher, had his testicles excised for having run off with his beloved student, Heloise. Abelard bitterly mourned his stolen manhood and wrote of it in a memoir, My Great Misfortune. (For her part, Heloise was sent unscathed to a nunnery, her gonads beyond reach or medieval understanding. Later she rose to prominence as the head of a convent called the Paraclete, founded by her former lover.)

  The role of the testicles in cultivating the many changes of puberty also was known for centuries. Boys with promising soprano voices were accordingly gelded before adolescence to prevent their vocal cords from thickening and their pitches from lowering. According to contemporary accounts, the best of the castrati were magnificent to hear, for they combined the sweetness and luster of a woman's timbre with the power afforded by a man's comparatively large lungs. Castration mania reached a peak in the seventeenth and eighteenth centuries, when thousands of parents had their sons orchiectomized in hopes of stardom and wealth; ever and obnoxiously are stage parents among us. But by the nineteenth century, tastes and operatic singing techniques had changed, and the diva soprano supplanted the castrato as the keeper of the angel's registers.

  Castration continued in the laboratory, however, as Arnold Adolph Berthold fathered the modern science of endocrinology in the mid-nineteenth century with a series of landmark rooster experiments at the University of Gottingen. He removed the testicles of young male chickens, an operation that if allowed to run its course would give rise to capons. Famed among poultry fanciers for their soft and flavorful flesh, capons lack the plumage, sexual bombast, and tendency to crow exhibited by full-fledged roosters. But Berthold's birds didn't stay neutered for long. He took the excised testicles and implanted them inside the young birds' bellies, and lo, the birds matured into perfectly normal roosters, all crest, comb, and cock-a-doodle-do. Dissecting the animals, he observed that the transplanted gonads had taken root in their new position, doubled in size, and sprouted a blood supply; they were even filled with sperm, as adult testes should be. Because the nerves to the testes had been irreparably damaged in the course of the transplantation, Berthold concluded that the testicles were not exerting their impact on the body by grace of the nervous system. Instead, he correctly surmised, some sort of substance, some eau vitale, must be traveling from the gonadal tissue through the bloodstream to other parts of the body, thus transforming cockerel into cock. What that substance might be he had no way of determining.

  The male body gave birth to hormone research, but the female body reared it to maturity. In the 1920s, scientists began experimenting with extracts from the urine of pregnant women, seeking interesting compounds. They tested the urine on the genital tracts of rats, and they found that something in the pee had a dramatic effect on the rat uterus and vagina. The endometrial layer of the rat's uterus thickened, while the lining of the vagina became cornified—a nifty, graphic word meaning that the cells lengthened into shapes resembling cobs of corn. Organic chemists sought the source of such transformation
s and in 1929 isolated the world's first hormone, estrone. Estrone is an estrogen, the family of hormones that we call female hormones, although both sexes—all sexes—have them. There are at least sixty forms of estrogen in the body, any body, but three hold sway: estrone, estradiol, and estriol. They are named for the number of hydroxyl groups (pairs of hydrogen and oxygen atoms) that festoon each hormone's torso. You can teach your baby daughter to count with estrogens. Estrone has one hydroxyl group, estradiol two, and estriol three. Counting hydroxyl groups is a chemist's way of naming names, not a biologist's; the number of hydroxyl groups doesn't predict anything about the molecule's behavior. More doesn't mean better, fewer doesn't mean duller. But the chemists got there first, so they got to play Adam.

  Estrone proved to be relatively weak in its ability to prompt vaginal cornification or endometrial thickening, particularly when compared to estradiol, the principal estrogen in premenopausal women. But because estrone is secreted in abundant amounts by the placenta during pregnancy, and because it was a pregnant woman's urine that gave rise to the modern era of endocrinology, estrone was the first to be found. Soon after, chemists were seized by hormone hysteria and in short order had isolated most of the steroid hormones—the androgens, progesterone, the stress hormones of the adrenal gland—and determined their most obvious functions.

  Yet their truest love remained their first, the estrogens. Chemists created a pharmacopoeia of synthetic estrogens, yanking off side chains here, tacking on methyl groups there. They designed the notorious estrogen compound diethylstilbestrol, or DES, used to prevent miscarriage from the 1940s through the 1960s but now known to be a cause of cancer and other disorders in the children of mothers who took the drug. They invented birth control pills. They made estrogen pills and estrogen patches for menopause, using either a synthetic version of the hormone or "natural" estrone isolated from the urine of pregnant mares, who piss a lot, the way horses do, particularly when they're with foal.

  Estrogens were the first, and they remain, in their way, the finest. They have grown more interesting with time, not less. They are part angel, part anarchist. Estrogens keep us healthy and make us sick. They build our breasts and then corrupt them with tumors. They ripen eggs and nurture new life in the womb, but they also give rise to those ropy purple fibroids that can expand like zucchinis or pumpkins, until we cry aunt and have the uterus abolished.

  How difficult it is to keep track of the contradictions. We are told that women in the industrialized world are steeped in too much estrogen, all kinds of estrogen; that what with our excess fat, our perpetual menstrual cycles rarely broken by pregnancy or lactation, our birth control pills, our taste for alcoholic libations, even estrogenic chemicals in our surroundings, we end up being exposed to far more of the hormone than our ancestors ever were, and this abundance is bad and a source of disease. Then we are told that we don't get enough estrogen, that we weren't supposed to live much past menopause, when our ovaries stop serving up significant doses of estrogen. Therefore we need to take estrogen supplements for years and years. We are told that estrogen keeps our hearts strong, our bones sturdy, and our wits sharp: estrogen as a Marvel comics superheroine. Can we therefore discard the old image of estrogen as the hormone that makes women tender, softhearted, practically filleted?

  I admire estrogen because it is so obliging of our demands and our capriciousness. It is our scapegoat, our whipping bitch. Over the years it has been demonized, glorified, excommunicated, and resurrected, and just like a woman, it can still take a joke. To appreciate estrogen, we need to begin by separating estrogen the hormone—what we know and what we don't know about its powers and constraints—from estrogen the parable, the imagined ingredient in Wicca's medicine chest, source of lunacy and the malign feminine.

  The estrogens are called female hormones, and that is partly inaccurate and partly reasonable. From the age of twelve through fifty, women have three to ten times more estrogen circulating through their bloodstream than men do. In middle age, men and women become closer estrogenic kin, for not only do a woman's levels of the hormone drop, but a man's gradually rise. Keep in mind that regardless of whose hormones are under scrutiny, the concentrations are vanishingly small, measured in laboratory tests in nanograms or picograms—billionths or trillionths of a gram. To obtain one teaspoon of estradiol, we would need to drain the blood of a quarter of a million premenopausal women. By contrast, the blood supply of any one of us contains at least a teaspoon of sugar and several tablespoons of salt. Hormones are peas, and we're all princesses. No matter how many mattresses you put between us and them, hormones still make us squirm.

  Roughly speaking, the different estrogens are produced by different tissues of the body, though there's a lot of overlap, redundancy, and the usual unknowns about who does what when and to what end. Estradiol, the principal estrogen of our reproductive years, is the product of the ovaries. It flows out of the cells of the follicles and from the corpus luteum, the yellow matter that forms like a blister on a ruptured follicle. Estradiol is considered the most potent of the three estrogens, at least according to standard assays of estrogen activity—that is, it makes a rat's vagina cornify so clearly it looks like the waving fields of Iowa. Estriol is generated by the placenta and to a lesser extent by the liver. It is the major "pregnancy estrogen," the source of any charming gestational glow you might have—if you aren't green with nausea. As mentioned above, the placenta also synthesizes estrone. So too does adipose tissue. Fat women often are spared overt symptoms of menopause such as hot flashes and covert ones such as thinning bones; even as their ovaries cease the monthly efflux of estradiol, their peripheral tissue compensates by manufacturing estrone. Very muscular women fare well in menopause too, not only because they're fit and their hearts are hardy and their bones are strengthened by years of weight-bearing exercise, but also because muscle makes modest amounts of estrone. For any postmenopausal woman who forgoes patches or conjugated extracts of horse piss, estrone will be the predominant estrogen until departure. Estrone alone for the merry crone.

  This is a lesson learned only recently, that the body makes and consumes estrogen globally. During the golden age of hormone research, scientists thought that they didn't need to look beyond the gonads: the ovaries made estrogen, the testes made testosterone. Hence the term sex steroids. They thought that the gonads made sex steroids to do sexy things, or rather reproductive things—to control ovulation, for example, and thicken the uterine lining. But no, estrogen's role is not limited to good breeding. The body makes estrogen everywhere, and the body eats estrogen everywhere. Bones make estrogen, and bones eat estrogen. The blood vessels make estrogen and devour estrogen. The brain makes estrogen, and it responds to estrogen in ways we are only beginning to understand. The body loves estrogen. It chews it up and then demands more. The half-life of estrogen' is brief, maybe thirty to sixty minutes, and then it is broken down, to be recycled or eliminated. But there's always more, produced and consumed locally or disseminated transcorporeally.

  Estrogen is like chocolate. It is strong in very small doses, and it can either excite or soothe, depending on which tissue is doing the devouring. Estrogen stimulates the cells of the breast and the uterus, but it calms the blood vessels and keeps them from getting narrow, stiff, and inflamed. Estrogen is also like chocolate because it is a near-universal symbol for Eat me. Rare and mutant is the human who hates chocolate. By the same token, very few parts of the body hate or ignore estrogen. Almost every two-bit organ or tissue wants a bite of it.

  Here is what we've learned about the pervasiveness of estrogen. To make estrogen, you need an enzyme called aromatase. With aromatase, a tissue of the body can transform a precursor hormone into estrogen. The precursor may be testosterone—yes, the "male" hormone, which women make in their ovaries, their adrenal glands, and possibly in places like the uterus and the brain. Or the precursor can be another androgen, like androstenedione, a hormone that deserves much deeper scientific understanding than
it currently can claim. Who knows but that androstenedione is an amplifier of female aggression and anger? Suffice it to say here that women generate androstenedione in the ovaries and adrenals, and that androstenedione can, through the mediating activity of aromatase, be transmuted into the bittersweet cordial estrogen.

  This would all be so much chemistry-set trivia if it weren't for the recent discovery that aromatase is all over the place. The ovaries have aromatase, so the ovaries, which make testosterone, can instantly turn the testosterone into estrogen, and they do, in calendrical spurts, and so women cycle. Other tissues have aromatase too: fat, bones, muscle, blood vessels, brain. The breast has aromatase. Give any of these tissues a bit of precursor hormone, a taste of testosterone, and they'll convert it to estrogen. Not in spurts, not by the menstrual calendar, but sedately, steadily, day after day. Interestingly, aromatase grows more potent with age. Even as most systems of the body slide into decrepitude, aromatase activity picks up its pace, becoming ever more efficient at converting precursors into estrogen. That could explain why older men are more estrogenized than their younger counterparts, and why postmenopausal women don't crumble, don't lie down and die, just because their ovaries no longer give them monthly estradiol highs. Their breasts, bones, blood vessels, are yet creating estrogen. Red wine, redwood, aromatase: how well the years become you.