“Reducing chemistry is very slow compared to oxidizing. These slow ones are exploring the Earth. They watched the Draco Tavern grow up in front of them. They'll see it turn to dust. They'll be here a long time."
Taper rapped what I was sitting on. “This shell—"
“They're in pressure suits. So's Speedy. They have to be protected from oxygen."
“They're all streamlined,” he noted. “Even that tree stump has a teardrop silhouette,” turning his camera on Quizzical.
I said, “Just being a slow one wouldn't slow down weather. Comes a hurricane, or a flood, they'd just have to wait it out."
Taper asked, “May I talk to Speedy?"
“I'll give you his e-mail address. Have you got a story now? Or is it all too slow?"
“May I have the other e-mail addresses?"
“I'll ask first."
* * * *
Taper came back in January. This time he hurried through Siberia's endless freezing night to reach the tavern. The airlock for humans is there because Siberia in winter isn't a habitable planet.
The tavern was crowded; a liner was in. He stood there taking it in for a few minutes, recording with the camera on his forehead. Then he hung up some of his gear and wove his way through the crowd and the divergent environments.
Speedy was past the jelly lock and ten centimeters inside. Taper smiled down at the smoothed-out turtle shape. He ran a hand over Speedy's head. Then he fished out a keyboard and began typing.
I was at his elbow. “How's it going, Mr. Taper? Got a story yet?"
He laughed. “Not today. If I made a lifetime project of this, I might have something to show the execs. Mr. Schumann, this doesn't take every minute of my time. I've kept four interviews going for seven months without ever skipping lunch. When I'm an old man, these guys could save my reputation."
“This last ship,” I said, “brought three more."
“Addresses?"
“They haven't logged in yet. Come back in the summer and I'll introduce you."
* * * *
WELCOME TO EARTH!
THANK YOU. WE ARE BRICKS, A MULTIPLE MIND.
TAPER, A HUMAN.
CAN YOU TELL US WHAT OF EARTH IS WORTH SEEING?
LOTS! YOU COULD WATCH NIAGARA FALLS EAT ITS WAY WEST. WATCH REDWOODS GROW. RIDE A GLACIER.
Copyright (c) 2005 Larry Niven
[Back to Table of Contents]
* * *
Testosterone Replacement: Beyond Viagra to Successful Aging
by Fran Van Cleave
The world's best-known hormone needs a good press agent. Blamed for every malady from war to prostate cancer to prematurely dead athletes, testosterone is the Prometheus of the endocrine glands, carrying the fire of life to both men and women. Necessary not just for potency and sexual desire (though that is certainly reason enough to replace it), this unjustly vilified hormone now appears to be vitally important for the heart, the brain, and indeed one's very sense of self. In an aging population awash in estrogen and synthetic anti-androgens, and afflicted by one expensive Band-Aid cure after another, testosterone is finally being recognized as of far greater importance than “natural Viagra."
Viagra, by the way, does zero for the libido. It is a vasodilator approved for erectile dysfunction, or ED as the TV commercials so blithely call it.
History
Humans have sought a cure for the maladies of aging since Adam found his first gray hair, and most cures have focused on the “essence of maleness.” Two thousand years ago, a Roman physician, Aretaeus of Cappadocia, wrote an essay on the vitality of man residing in the testes. The Greek physician Galen believed that life was a function of heat derived from sperm at conception, and that aging occurred when that heat begins to dissipate. A thousand years later, the Chinese attempted to extract this male essence from the urine of young men, using it to treat infertility, impotence, and enlarged prostates. In the nineteenth century, French physiologist and former Harvard professor Charles-Edouard Brown-Séquard took this a step further by “drinking an extract of crushed dog testicles” with which he claimed to have “recovered the strength and vigor of a young man.” After his article about this appeared in The Lancet, doctors emptied their prescription pads writing for his new potion. Unfortunately for Brown-Séquard, it didn't actually work, and he became the butt of many jokes. Just after World War I, France was again swept by anti-aging fever in the person of Russian émigré Dr. Serge Veronoff, who transplanted ape testicles into aging Parisians. Not to be outdone in the realm of quackery, an American doctor named John Romulus Brinkley offered the same procedure to his patients, but with goat testicles—presumably these were easier to obtain—and became so wealthy from the practice, he bought a radio station and ran for governor of Kansas.
This sort of thing tended to scare away scientists who valued their reputations, but in spite of that, solid work was done. In the 1920s, Fred Koch, an organic chemist who lived close to the Chicago stockyards, was able to extract a substance from bull testicles which, when injected into capons, turned them into roosters. Other scientists isolated and crystallized the testosterone molecule. In the 1930s, a Yugoslav scientist named Leopold Ruzicka discovered that testosterone enters the blood rapidly after the Leydig cells of the testes produce it, which explained why Brown-Séquard and the Parisian doctors had had such limited success with animal glands. After Ruzicka found that testosterone could be synthesized from cholesterol, he was awarded the Nobel Prize.
Testosterone's Activity In the Body
“Hormone” comes from the Greek word for impulse, and according to Dorland's Illustrated Medical Dictionary, refers to a chemical substance, which has a specific regulatory effect on the activity of a certain organ. An androgen, or masculinizing hormone, testosterone is a structural steroid—a very loose term for fat-like substances whose progenitor is cholesterol—affecting every cell in the body. The normal range for an adult male is wide: from 350 to 1000 nanograms per deciliter of blood.
Most of that, however, is inactive. When the hypothalamus signals a need for testosterone, production proceeds apace in the Leydig cells and to a lesser extent, in the adrenal glands (in women, the ovaries and the adrenals make testosterone). About 97% of circulating testosterone is bound to proteins, either a blood protein called albumin, or another known as SHBG, sex hormone binding globulin. Under some circumstances, the 20 to 40% bound to albumin may be useful physiologically, but the only portion you can truly count on to be active is the unbound “free” testosterone, which constitutes only 1 to 3% of the total. Not much, is it? With age, total testosterone shows little or no decrease, but the percentage of free testosterone declines—in some cases drastically.
The hormonal system is complicated, but its regulation through a negative feedback loop can be simplified thusly: testosterone forms three important byproducts 1) androstenedione (a weak androgen), 2) dihydrotestosterone (DHT, the strong testosterone, implicated in baldness), and 3) estradiol (the most potent human estrogen). The hypothalamic signaling process for testosterone production is inhibited by estradiol, and to a lesser extent by DHT.
Between production and destruction, testosterone does many other things besides masculinize the body and lead the unsuspecting mind into a politically incorrect fantasy life. It promotes growth of bone and muscle; improves oxygen uptake in tissues, helps control blood sugar[1]; maintains the immune system; improves mental concentration and mood; regulates cholesterol; and increases production of nitric oxide, which dilates blood vessels and can be thought of as an endogenous nitroglycerin tablet.[2]
Lest you think this last activity occurs in only one part of the body, let me add that there are more receptors for testosterone in the heart than in any other tissue. Not that strange when you think about it, since testosterone is a powerful muscle-building hormone, and the heart is the hardest-working muscle in the human body.
Does this mean that a lack of testosterone might be bad for the heart? Might this lack actually be a
causative factor in cardiovascular disease? How could that be, when for so many years, conventional wisdom has held that the presence of testosterone is a major factor in heart disease, and quite possibly the primary reason men die at a younger average age than women?
Fascinatingly, many studies have found a correlation between low levels of testosterone and heart disease. The well-known Caerphilly Heart Disease Study, conducted in Wales on 2,512 men, found heart disease, higher insulin levels, and lower levels of HDL (the heart-protective “good cholesterol") all associated with significantly low levels of testosterone.[3]
It's possible that low testosterone could be a result of heart disease instead of the cause. In China, doctors intrigued by these studies decided to treat heart disease with testosterone. In the Wu study[4], 60 of the 62 elderly male volunteers had had a heart attack within the five years prior to the study, and all had documented angina. Half of the participants were given testosterone, the other half placebo. Of those receiving testosterone, 77% experienced relief from anginal pain, while 6% of the placebo group reported this improvement. This self-reporting was verified by echocardiography, which showed an improvement in coronary blood flow in 69% of the testosterone group versus 8% on placebo. These results were provocative, though clearly rigorous proof demanded larger and more detailed studies.
In 1994, the American M.D. Gerald Phillips at Columbia University College of Physicians and Surgeons decided to do a cross-sectional study of 55 men (mean age 61) who had abnormal stress tests, some of whom also had chest pain.[5 ]Blood samples taken from these men showed a stark inverse relationship between levels of testosterone and severity of cardiovascular disease. Levels of free testosterone showed an even more profound contrast. Low levels correlated with important risk factors for heart attack, e.g. greater tendency for the blood to clot, higher levels of insulin and insulin resistance, and lower levels of HDL. In prior studies with men who had not had heart attacks, Phillips documented low testosterone levels correlating with central obesity ("spare tire syndrome"), high blood pressure, and increased levels of cholesterol, triglycerides, glucose, and clotting factors.
Interestingly, blood clots are also associated with high doses of anabolic steroids.
Anabolic steroid drugs are not the same as testosterone, but resemble the molecule in some ways. As Figure 1 shows, so does the powerful estrogen known as estradiol, which illustrates the dangers of making too much of a mere resemblance! We've all heard news stories of athletes misusing anabolic steroids and paying the physical price with liver damage, clots, and strokes. Those stories are accurate. At low doses, anabolic steroids tend to exert a favorable effect on clot-busting fibrinogen, but at high doses, they clearly increase the tendency of red blood cells to stick together, which means blood clots. Anyone desperate enough to use these black market testosterone impersonators will probably not use them in low doses, and in any case, other problems with these molecules make them unsafe in any quantity.
Normal testosterone levels, on the other hand, hinder blood clots by reducing the amount of a powerful clotting factor called plasminogen activator inhibitor, also known as PAI-1. This substance inhibits the release of one of the blood's chief clot-busting enzymes, tissue-type plasminogen activator or tPA, which helps dissolve the protein known as fibrin, the core of the clot. Testosterone's control of PAI-1 allows tPA to be released from the endothelial cells on the inside of arteries into the bloodstream, where it can vanquish the offending clot before it does any harm.[6]
This may sound confusing, but what it all boils down to is this: the symptoms Phillips documented are no longer seen as independent risk factors for heart disease, but are now being tied together as Syndrome X or Metabolic Syndrome. Which suggests that what we think of as different diseases—obesity, clotting problems, Type II diabetes, cardiovascular disease—are all manifestations of the same disease.
Sounds a lot like aging, doesn't it?
According to a report in the Proceedings of the National Academy of Sciences, testosterone appears to aid in both the prevention and treatment of Alzheimer's disease (women with the disease outnumber men by a factor of almost 2:1, though this may be due in part to the larger number of elderly women). Researchers at the University of Texas-Houston found that testosterone prevented hyperphosphorylation of a brain protein called tau, and this in turn prevents the formation of snarls of filaments in the brain known as neurofibrillary tangles, a hallmark of the disease.[7]
Does testosterone do anything to alleviate America's other expensive and debilitating disease of aging, osteoporosis? Indeed, it does. Testosterone grows and strengthens bone as well as muscle, and studies have confirmed that serum testosterone levels are powerful predictors of bone mineral density and total body bone mineral content in independent-living elderly men.[8] You still have to exercise and take calcium with Vitamin D, but testosterone will get you a lot more mileage from these activities.
Today, one third of those with fragile-bone fractures are men, and as men live longer, that percentage is bound to increase. The 25 million osteoporosis patients in the U.S. and their yearly accumulation of 1.5 million fractures cost over $10 billion a year to treat, and by 2050, the world's total number of hip fractures (which frequently result in death from secondary pneumonia) is predicted to reach 6.26 million.[9]
So why didn't modern medicine understand the benefits of testosterone a long time ago, and use it to combat these problems? Several reasons. First, it is almost impossible to do a double-blind study and keep it blinded about who is getting the real testosterone. Second, the therapeutic picture was confused by the body's rapid conversion of testosterone to estrogen, creating tremendous dispute over which hormone does what. The third reason has to do with testosterone being a “natural” substance—i.e., it cannot be patented.
The first problem is self-evident, but what's the story on the second one? Most people know that men and women have both “male” and “female” hormones, but why and how does the body change a masculine hormone into a feminine one?
The Battle of the Hormones
As the molecular structures in Figure 1 show, testosterone and estradiol are not nearly so different as one would suppose from their activity in the human body. In males, an enzyme called aromatase converts testosterone to estrogen, and it is a simple process. (Perhaps we should stop calling these molecules “male” and “female.” Men genetically deficient in aromatase show no functional abnormalities save a general lack of sexual desire.) A large testosterone/estrogen ratio, generally ranging between 20 and 40 to 1, is ideal for health and function in men, but increasing age and obesity drop the ratio by increasing levels of aromatase and estradiol production. Estradiol can unlock or displace testosterone at its receptor sites, preventing free testosterone from doing its job. While it's good to be able to switch off the libido occasionally, it's not good to have it stuck in the off position, which too much estradiol does. That's one of the reasons why women on hormone-replacement therapy also need testosterone.
Fatty tissue in both men and women produces estrogen, so for women, being overweight can be thought of as something of a mixed blessing, since this estrogen delays the onset of menopause. This hormone is important in the brains of both sexes for thinking and memory, but its excess brings a surfeit of problems, most strikingly in men: narrowing of coronary arteries and increased risk of heart attack, blood clots, diminished energy, and a faltering sex life. Not too surprisingly, a UCLA study in 1988 found significant correlation between high levels of estrogen in men and impotence, and estrogen's deleterious effect on weight-loss programs adds insult to injury. A man can't even eat a steak without ingesting a little estrogen from the high-potency additives in cattle feed (these were banned in Europe in 1991). Considering the enormous increase in obesity in the United States in the last few decades, it appears that American testosterone is drowning in an ocean of estrogen.
Like so many things in life, hormones are about balance.
Which brings u
s to problem three, the lack of patentability of testosterone. Balance became increasingly problematic with the use of synthetic hormones favored by drug companies.
The Pharmaceutical Model: How Problem-Solving Leads to Problems
Over the years, drug companies have come to rely on a business model that goes something like this: identify a disease, syndrome, or symptom; ferret out its biochemical mechanisms; then develop a chemical that targets those mechanisms, usually through blockage or inhibition. This seems like a logical approach, and it often is, but alien molecules don't process well in human hormonal systems. That's one reason why DES, the artificial estrogen diethylstilbesterol, was such a disaster.
Because testosterone cannot be swallowed without causing liver toxicity as well as a host of other problems (all pain, no gain), most of the early synthetic versions were injectable anabolic steroids. At first it seemed like a good idea to improve on nature by making stronger and longer-lasting chemical hormones.
But as Figure 2 shows, the endocrine system is nothing if not dynamic. While many men experienced improvement of symptoms, particularly at first, this was quickly followed by a severe downturn. Not only did their bodies convert a large portion of these super-potent male hormones to estrogen, they also produced more sex hormone binding globulin, so the poor fellows ended up with a worse testosterone/estrogen ratio and an even smaller percentage of free testosterone than they started with!
Unfortunately, a number of researchers did not measure estrogen levels, and also made no distinction among testosterone esters, anabolic steroids, and bio-identical human testosterone. (Rather than employ the fuzzy, exhausted adjective “natural” to describe the testosterone molecule found in humans, I will use “bio-identical” for clarity.) The wild mood swings of the test subjects were blamed on testosterone. And why not? Everyone knows male hormones are what make people fly into rages and become violent.
Analog SFF, December 2005 Page 21
