Woman: An Intimate Geography (34 page)

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Authors: Natalie Angier

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BOOK: Woman: An Intimate Geography
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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 Göttingen. 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 transformations 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 estro-

 

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gen 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. Estr
one
has one hydroxyl group, estra
di
ol two, and es
tri
ol 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.

 

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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, soft-hearted, 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.

 

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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.

 

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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

 

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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.
But it is not enough to make estrogen. The means to understand the hormone must be present too. Estrogen speaks to the body through an estrogen receptor, a protein that recognizes it and surrounds it and then changes shape, as a blanket's shape is changed when someone is lying beneath it. In its altered shape, the receptor activates genetic changes within the cell, turning some genes on, others off. The shifts in gene activity in turn change the state of the cell, and eventually the organ of which the cell is part.
So we know that a given organ is sensitive to estrogen if the cells of that organ contain estrogen receptors. And we are, it seems, outlandishly sensitive to estrogen. As aromatase is everywhere, so too are estrogen receptors. Look in the cells of the liver, bone, skin, blood vessels, bladder, brain. Look anywhere; estrogen receptors are everywhere. The trick nowadays, says Benita Katzenellenbogen, who has studied estrogen biochemistry for twenty-five years, is to find a tissue that
doesn't
have estrogen receptors. Maybe the spleen, she shrugs.
It goes on. The estrogen story is like
Masterpiece Theatre
, highbrow soap. In 1996 scientists realized that we have not just one type of estrogen receptor, as they had thought for decades, but two, each a distinct molecular character but each capable of clasping estrogen and allowing the cell to react to the hormone. The proteins are called estrogen receptor-alpha and estrogen receptor-beta. Some cells of the body are alpha-rich, some beta-rich, some doubly blessed. And within any given cell there may be thousands of copies of each receptor type. Thousands of alpha receptors, thousands of betas. In some cells, tens of thousands. That's why it takes so little hormone to get such a big response: entire armies of receptor proteins stand ready and able to detect whatever tiny amount of estrogen may be floating by.
In different tissues, estrogen receptors do very distinct things that is, they turn on a different set of genes in the liver than they do in the bone or the breast or the pancreas. For the most part, we don't have a clue which genes are activated by estrogen. But we do know some things. In the liver, for example, the coupling of estrogen and estrogen receptor stimulates the synthesis of blood clotting factors. It thickens

 

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