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 the blood. We need good, clot-ready blood to keep us from hemorrhaging during those predictable times of blood loss—during menstruation, of course, but also when the egg bursts from the ovarian follicle, when an embryo burrows into the uterine wall like the chirpy parasite it is, and during childbirth. Because of estrogen's capacity to raise clotting factor synthesis, birth control pills and estrogen replacement therapy can on rare occasions cause clots to appear and travel to undesirable locations, such as the lungs.
The marriage of estrogen and receptor in the liver also stimulates the production of high-density lipoprotein, familiar to many of us as HDL, the so-called good cholesterol that we like to see on our medical charts as a big number, the bigger the sweeter, and inhibits low-density lipoprotein, or LDL, the "bad" cholesterol. High-density lipoprotein is not really cholesterol but a carrier of cholesterol, able to absorb cholesterol particles and other fats from the blood and donate them to tissues if needed, or to the liver for processing and excretion if not. The lipoprotein thus may serve as a fine source of energy transfer between mother and offspring during pregnancy and breastfeeding. Ever anticipating fecundity, estrogen tells the liver habitually to favor the production of HDL over that of low-density lipoprotein. (Intense exercise can have a similarly promotional effect on the liver's outlay of HDL; the rigors of chronic activity inspire the same anabolic spirit that reproduction does, the same need to scavenge available blood lipids for the sake of creating new cells.)
Estrogenesis, Part 17. Once again we've underestimated our steroid heroine. Estrogen, it turns out, doesn't need a receptor to make itself understood. Yes, it connects with alpha and beta. But that connection and the consequent shape-shifting of the receptors take time. Estrogen also can work almost instantaneously. It may, for example, rattle cell membranes just by touching them. As estrogen drifts through a cell membrane, it briefly opens tiny pores that allow ions to flow into and out of the cell. The membrane's charge changes— zap!—but then quickly reverts. For most tissues of the body, such transient fluctuations mean nothing. But for some organs, flux is the crux of strength. Think of the heart. The heart pumps blood to an electrochemical metronome, its pacemaker powered by ion flux. Estrogen just might help keep the transmembrane current of cardiac tissue flowing strongly and smoothly. Premenopausal women, whose bodies are bathed in estrogen, have hearts like bulls, and rarely suffer heart attacks. Undoubtedly some of the reason for the cardiopleasures of estrogen is indirect, for as we have seen, estrogen gives us high-density lipoprotein, which helps clear cholesterol from the blood before it can clog the arteries sclerotic. But here we see another possible reason that the heart loves estrogen: for the transient jolt. Estrogen as Edison. It gives the body a buzz.
And so we have at least two broad categories of responses to estrogen stimulation: one swift and transient, the other statelier, more thoughtful. Estrogen, we didn't know the half of you. Is there anything you can't do?
For one thing, sit still. Estrogen is a moving target. Even as it has, under scrutiny, revealed new talents, it has lost some that were previously ascribed to it. For years scientists thought that the hormone was essential to the raw beginnings of life. Studying embryonic development in such pliant "model animals" as the pig, researchers observed that right around the time when an embryo was about to implant in the uterus, whoosh! the cluster of cells released a burst of estrogen. The hormonal surge appeared to mark the transition between provisional pig—the blastocyst—and confirmed pig—the embryo. Nobody knew what that early-stage estrogen was doing, but obviously it was doing something big. When scientists experimentally blocked estrogen synthesis during embryo implantation, they killed the pig-in-progress.
There were other reasons for believing in the importance of estrogen to mammalian embryogenesis. A fetus can survive just fine without androgen or androgen receptors; Jane Carden and other women with androgen insensitivity syndrome are the unblemished adult evidence of that. But without estrogen? Nobody had ever found a person who lacked all traces of estrogen circuitry. Until the mid-1990s, a conceptus without estrogen was simply inconceivable.
The man was twenty-eight years old and six foot nine and sick of being asked if he played basketball. He didn't. He couldn't. His knees were too knocked, his feet were too splayed, and his gait was too awkward. What he could and did do was keep growing. He'd grown an inch since he was twenty-six. He wore a size 19 shoe, six sizes bigger than the biggest shoe you can find in an ordinary men's footwear department. And as the man grew, his gait worsened, which is why he finally consulted a doctor. The doctor referred him to an endocrinologist, who determined that the young man had bones that were both too young and too old for him. Too young, because the ends of them hadn't fused together, as they usually do in late adolescence; too old, because the bone shafts were full of holes. He had a serious case of osteoporosis. He had other problems as well, including insulin resistance like that seen in a diabetic. His blood estrogen levels were elevated, but he wasn't feminized, the way men are when they have a disease that results in excess estrogen production; he didn't have gynecomastia, and his voice wasn't high. He looked like a very tall, knock-kneed, but indisputably masculine fellow.
Eventually he ended up in the office of Dr. Eric P. Smith of the University of Cincinnati College of Medicine, who saw in the patient's symptoms evidence of what medicine had thought was impossible: the man was deaf to estrogen. Smith knew about experiments with mice at Rockefeller University. The researchers had created genetically engineered mice that lacked estrogen receptors. They were so-called ERKO mice—their Estrogen Receptor genes had been Knocked Out, or deactivated. The biologists had worried that such a manipulation would prove fatal—that without the ability to respond to estrogen, the ERKO mice would die in utero. But no, they lived, they were born, they seemed just about normal. Smith decided to check his patient's DNA to see
whether his estrogen receptor genes were mutated as well. Had nature done to this man what the Rockefeller researchers had done to their mice? Nature had. Both copies of the tall man's estrogen receptor gene were defective. The genes couldn't direct the synthesis of estrogen receptor protein. The man had aromatase, so he made estrogen, plenty of it. But he couldn't make estrogen receptors. All that estrogen was going to waste, falling on cellular ears that could not hear.
From the first recorded case in history of an absence of estrogen receptors, Smith and his colleagues concluded several things, which they reported in the New England Journal of Medicine: that estrogen is essential to the maturation and preservation of bones not only in women, as had been known, but also in men; that estrogen metabolism affects glucose metabolism and therefore the risk of diabetes; and that, contrary to dogma, estrogen is not essential to fetal survival. Fetal mice don't need it, and fetal humans don't need it. Estrogen, we overrated you.
"What the evidence now suggests," says Evan Simpson, of the University of Texas, "is that estrogen doesn't seem to be important to fetal development, but that it is more important than we thought to maintaining the body later in life."
I court caveats. Before we dismiss estrogen as an embryonic incidental, let's recall the latest finding: that genes have not one but at least two estrogen receptors. The man with no estrogen receptors and the mice who donated theirs to science turn out to lack only the alpha estrogen receptor. They still have their beta estrogen receptors, and so they may not be as unresponsive to estrogen as originally supposed. Nature loves redundancy. If something is critical enough, nature hires understudies. The understudies may not be perfect, but they'll do in a pinch. Estrogen receptor-beta is unquestionably a poor preserver of adult skeletal mass, and so the man with no alpha receptors has bones that look like kitchen sponges. But did he truly ignore estrogen when he was a desperate embryo, dangling between song and silence? Or did his beta receptors keep him alive, allow him to implant and to unfold, because they knew they were his last hope and that life cannot begin without estrogen?
Maybe, maybe not. This is the story of estrogen, the septuagenarian serial. Built of grease, estrogen darts from our grasp. We don't yet understand it. We can't quite control it. And when it comes to its impact on our behavior and sexuality, estrogen generously, slyly returns the courtesy. It doesn't control us, and its favorite phrase is maybe.
11. VENUS IN FURS
ESTROGEN AND DESIRE
A FEMALE RAT can't mate if she is not in estrus. I don't mean that she doesn't want to mate, or that she won't find a partner if she's not in heat and sending forth the appropriate spectrum of olfactory and auditory enticements. I mean that she is physically incapable of copulating. Unless she is in estrus, her ovaries do not secrete estrogen and progesterone, and without hormonal stimulation, the rat can't assume the mating position known as lordosis, in which she arches her back and flicks aside her tail. The lordosis posture changes the angle and aperture of the vagina, making it accessible to the male rat's penis once he has mounted her from behind. There is no rat's version of the Kama Sutra. An ovariectomized female won't assume lordosis, and hence she can't mate—unless, that is, she is given hormone shots to compensate for the loss of the natural ablutions of the ovarian follicle.
In a female guinea pig, a membrane normally covers the vaginal opening. It takes the release of sex hormones during ovulation to open up the membrane and allow the guinea pig to have sex.
For both the rat and the guinea pig, as well as for many other female animals, mechanics and motivation are intertwined. Only when she is in heat is the female driven to seek a mate, and only when she is in heat can her body oblige her. Estrogen controls her sexual appetite and sexual physics alike.
A female primate can copulate whenever she pleases, whether she is ovulating or not. There is no connection between the mechanics of her reproductive tract and the status of her hormones. Estrogen does not control the nerves and muscles that would impel her to hoist her rear end in the air, angle her genitals just so, and whip her tail out of the way, if she has one. A female primate does not have to be capable of becoming pregnant in order to partake of sex. She can have sex every day, and if she's a bonobo, she will have sex more than once a day, or once an hour. A female primate has been unshackled from the tyranny of hormones. In an almost literal sense, the key to her door has been taken away from her ovaries and placed in her hands.
Yet she still cycles. Her blood bears estrogen from place to place, including to the portions of the brain where desire and emotion and libido dwell, in the limbic system, the hypothalamus, the amygdala. The female primate has been freed from the rigidity of hormonal control. Now she can take the sex steroid and apply it subtly, to integrate, modulate, and interpret a wealth of sensory and psychological cues. For rats, hormones are thumpish, unmistakable, the world in black and white; for primates, they act like a box of crayons, the sixty-four pack, with a color for every occasion and at least three names for every color. Do you want it in pink, blush, or fuchsia?
"In primates, all the effects of hormones on sexual behavior have become focused on psychological mechanisms, not physical ones," Kim Wallen, of Emory University, says to me. "The decoupling of physical from psychological allows primates to use sex in different contexts, for economic reasons or political reasons." Or emotional reasons, or to keep from getting bored. As Wallen speaks, we watch a group of five rhesus monkeys at the Yerkes Primate Research Center chase two other rhesus monkeys around and around in their enclosure, all seven swearing back and forth at each other in rhesusese, as you can tell because the more they scream, the faster everybody runs. In a primate, Wallen continues, hormone pulses may not make the female bow down in lordosis, but they clearly influence her sexual motivation. He points at the group of rhesus monkeys. The seven samurai are still screaming and running. Several other monkeys look on with rapt anxiety, like bettors at a racetrack. One large, scruffy male ignores everything and picks his teeth. None is doing anything remotely sexual. Rhesus monkeys are Calvinists, Wallen says, prudish and autocratic in matters of sex. When a female rhesus is alone with a familiar male and no other monkeys are there to spy on her, she will mate with the male regardless of where she is in her breeding cycle. But a female under the constraints of the social group does not have the luxury of freewheeling carnality. If she sidles up to a male and begins engaging in a bit of heavy petting, other group members strive to intervene, raucously and snappishly. A female rhesus doesn't often bother defying convention. What does she look like, a bonobo?
Hormones change everything. They tint her judgment and sweep her from Kansas to Oz. When she is ovulating and her estrogen levels soar, her craving overcomes her political instincts and she will mate madly and profligately, all the while out-snarling those who would dare to interfere.
When we think about motivation, desire, and behavior, we accord the neocortex and the thinking brain the greater share of credit. We believe in free will, and we must. Free will, of a sort, is a hallmark of human nature. This is not to say that we start each morning afresh, with an infinity of possible selves awaiting us—that is a figment, alas, and a durable one. Nevertheless, we have what Roy Baumeister, of Case Western Reserve University, calls an "executive function," the dimension of the self that exercises volition, choice, self-control. The human capacity for self-control must be counted among our species' great strengths, the source of our adaptability and suppleness. Very little of our conduct is genuinely automatic. Even when we think we're operating on automatic pilot, the executive function keeps an eye out, checks, edits, corrects the course. If you know how to touch-type, you know that the executive brain is never far removed from the drone brain. When all is well, you type along automatically, your fingers so familiar with the keys that it's as though each digit has a RAM chip embedded in its tip. But the moment you make a mistake, the automaton stops and the executive function kicks in, even before you're quite aware of what went wrong. With its guidan
ce, your finger reaches for the backspace key to correct the error, and you see what happened and you fix things, and a moment later your hands have returned to robot mode. Athletes, surgeons, and musicians perform similar exchanges between intentional and programmatic behaviors hundreds of times a minute; such commerce is the soul of mastery. The human capacity for self-control is limited, and we get into trouble when we overestimate it and embrace the caustic ethos of perfectionism, but volition still deserves our gratitude.
At the same time, we know that there's a macaque darting about in the genomic background and that we feel like monkeys and can act like them too. The moment a young girl enters adolescence, she begins dwelling on sex, consciously, unconsciously, in her dreams, alone in the bath—however or wherever it happens, it happens. Her desire is aroused. The changes of puberty are largely hormonal changes. The shifting of the chemical setting stirs desire. Intellectually, we accept the idea that sexuality is a hormonally inflected experience, but we still resent the connection. If hormones count, we worry that they count too much and that therefore we have no free will, and so we deny that they count, all the while knowing that they count, because we see it in our teenage children and we remember, please goddess, our teenage greed.
Rather than denying the obvious, we should try to appreciate the ways in which estrogen and other hormones affect behavior. Granted, our knowledge of neurobiology is primitive, presimian. We don't understand how estrogen or any other substance works on the brain to elicit desire, or feed a fantasy, or muffle an impulse. But there are enough indirect strands of evidence to knit a serviceable thinking cap with which to mull over estrogen's meaning.
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