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2 Table of Contents Title Page Table of Contents Introduction Uh Oh. This Wasn't Supposed to Happen. 4 What Did Studies of Testosterone Therapy Really Tell Us?... 6 Andrew Sullivan s "The He Hormone" Piece...8 As Simple As Possible But Not Simpler..10 The Diverse Treatment Options Available for "Low T".. 15 Three Complex Truths about Testosterone Therapy...18 More Research into the Dangers of Testosterone Therapy..20 Marketing Testosterone Therapy to Men: Like Shooting Fish in a Barrel...22 Androgel.24 Androderm.25 Axiron.26 Delatestryl..27 Depo-Testosterone.28 Fortesta 29 Striant..30 Testim.31 Testopel..32 Conclusion 33 Resources for Testosterone Victims and Their Families.34 Disclaimer.35

3 Introduction For thousands of years, marketers have sold products by appealing to the yearning men have for virility and longevity. This search for the proverbial Fountain of Youth has led to great discoveries. It has pushed humanity to discover exciting therapies, drugs and treatments for many ailments. However, this collective passion for anti-aging has also led society down dangerous paths and caused incalculable harm to thousands. If you or another man in your life suffered a cardiac event, stroke or heart attack while taking testosterone therapy (for "Low T"), this ebook can help you understand the legal actions underway against manufacturers of testosterone products, such AndroGel, Androderm, Axiron, Delatestryl, Depo-Testosterone, Fortesta, Striant, Testim and Testopel. Research has linked these "Low T" drugs with many serious side effects, such as pulmonary embolism, stroke, heart attacks and sudden death. These symptoms afflict men who use black market drugs and FDA approved medications alike. The Low T market is a booming, highly lucrative drug market, worth billions of dollars a year to manufacturers. But science shows that these drugs can lead to substantial dangers for certain men. The side effects of Low T products have been categorically undersold. This ebook offers a comprehensive discussion of the testosterone crisis. It aims to put the story in context and help victims understand what is at stake. Among other things, it will cover: An explanation of low testosterone therapy; A layman's guide to the role testosterone plays in the body -- what testosterone does, what disorders disregulate it, and what good science can tell us about the hormone; The scope and scale of the damage from testosterone side effects, and what is being done to punish companies that have promoted dangerous products; An overview of the state of testosterone lawsuits; A primer on the main testosterone products, including AndroGel (the most popular Low T drug), Androderm, Axiron, Delatestryl, Depo-Testosterone, Fortesta, Striant, Testim and Testopel; Scientific research on testosterone therapy, including a famous study done on veterans that researchers stopped after they noted a 30% increase in cardiovascular problems among people taking Low T products; An analysis of the social and cultural implications. Why do men opt for this therapy in the first place? What is the root cause of the seeming epidemic of Low T? What can be done in the future to prevent similar legal and medical crises? By the end of the book, you will have a very clear understanding of the testosterone crisis as well as access to important resources that you can use to obtain compensation, clarity and peace of mind.

4 Uh Oh. This Wasn't Supposed to Happen. Researchers don't normally like to pull the plug on multi-million dollar studies. But when the death rates among the treatment group due to stroke, heart attack and sudden death spike by 30%, "pulling the plug" makes all the sense in the world. A study on the health benefits/risks of testosterone therapy in older men made national headlines. Researchers at University of Texas's Southwest Medical Center in Dallas hoped to find proof that Low T therapy saved lives or, at the very least, improved the quality of the lives of men receiving treatment. Instead, they unearthed an association that sent ripples across a billion dollar industry. The researchers had been following 8,700 + older veterans, who were taking testosterone replacement therapy to treat a variety of conditions. The conventional wisdom at the time had been that Low T drugs could cause side effects, but that the benefits of replenishing testosterone outpaced the drawbacks by a lot. Thus, the "cost benefit analysis" generally favored intervention. However, researchers found themselves staring at a shocking statistical reality the patients on testosterone therapy were 30% more likely to suffer from cardiovascular disease. That stat forced researchers to shut down the trial at once and prompted a surge of consumer anxiety. Sadly, the study neither ended industry bad practices, nor did it even slow the growth of the Low T therapy movement. In fact, most doctors who prescribed Low T drugs in the U.S. never heard about the University of Texas study. Why not? Why does the Low T industry continue to expand? What can be done to regulate this industry? One might think that a drug associated with a dramatic increase in heart disease would be either pulled off the shelves immediately or at least very closely monitored. Consider, for instance, the converse situation. Imagine if a drug maker created a medicine and gave that drug to 8,700 men. Follow up studies then showed that the treatment group enjoyed a 30% reduction in cardiovascular events and strokes. Undoubtedly, the pharmaceutical industry (and the medical establishment) would not hesitate to call such a medicine a "wonder drug" and begin prescribing it by the metric ton to the ever-worried American populous. A 30% increase (or decrease) of a serious illness across a wide swath of a patient population should be newsworthy. Yet the University of Texas study's headlines came and went. Millions of American men continue to take their testosterone therapy, obliviously. And the Low T drug makers continue to rake in billions of dollars of profits every year. How did this all happen? What can good science actually say about the real "cost benefit analysis" of testosterone therapy? Furthermore, how can patients and their families who have

5 only limited medical knowledge of the complex scientific debate advocate for themselves, given all the conflicting medical and scientific opinions on this topic? First things first, we need to establish basic facts about testosterone therapy and get a clear understanding about the science behind the drug.

6 What Did Studies of Testosterone Therapy Really Tell Us? The U of T study analyzed records of 8,700 veterans using a procedure known as coronary angiography to examine coronary arteries. The study found that, among the 1,200 men taking testosterone, their risk of suffering a heart attack, stroke or sudden death over a certain period of time was about one-in-four. The other men studied had a one-in-five risk. But what can those numbers actually tell scientists about testosterone risks? In an editorial that accompanied the publishing of the study in the Journal of the American Medical Association (JAMA), University of Pennsylvania s Dr. Anne Cappola noted that "The important question is the generalizability of the results of the study to the broader population of men taking testosterone." The study was also just a single study -- and an observational one, at that. As any good critic of epidemiology will note, observational studies are only useful for generating hypotheses, not for proving or disproving them. Many doctors, in fact, did not seem all that concerned about the findings: cardiologist Dr. Michael Ho, who helped direct the study, noted that: "these [men] were sick, older veterans." He implied that the Low T therapy might harm this cohort of men, yet potentially be benign or beneficial to other cohorts of men. In other words, the study had subtle ramifications that the always-ready-to-oversimplify media was all too happy to ignore. Dr. Bradley Anawalt, a University of Washington endocrinologist who also examined the data, also expressed only vague concern: "this is a modestly cautionary study about giving testosterone to men over 60 [who have other risk factors]." Did these doctors downplay the implications too much, or were they just being cautious? On the one hand, it is very important to avoid extrapolating too much from the results of any study, even a carefully controlled one. On the other hand, again, imagine the reaction if an identical study had found that testosterone therapy caused a 30% decrease in the risk of cardiovascular events for the cohort in question. What would the press think of that study? What would doctors and researchers say? More importantly, how would pharmaceutical companies react? Based on the modern history of the pharmaceutical industry -- Davis & Crump has catalogued the sordid tales of other drugs, like Granuflo, Lipitor and Risperdal in other ebooks -- odds are high that the industry would jump on the news of such a "huge breakthrough" and start selling testosterone therapy as a wonder drug capable of curing all ills. The muted reaction of medical professionals to this study was both dramatic and suggestive.

7 The sad point is that the medical and pharmaceutical establishment appears happy to ignore results that are financially and logistically inconvenient. Conversely, when a study appears to vindicate a conventional position, the powers-that-be overstate its relevance. What gets lost here is scientific integrity. This is a real shame. Quite possibly, this selective analysis is a deep (albeit, indirect) root cause of suffering for hundred of thousands of American men. This discussion of the science of testosterone therapy begs deeper questions: How did the "testosterone therapy craze" get started? Was there ever good scientific justification for it? How much research supports testosterone therapy? How much seems to refute it -- or at least suggests that it could be dangerous to certain groups of men?

8 Andrew Sullivan s "The He Hormone" Piece American culture today is saturated with advertisements for testosterone therapy. Industry analysts expect that the Low T industry may bloom into a $5 billion a year dynamo by What created and fed this market? Low T historians point to at least one pivotal moment: the publication of a highly influential article on the power of testosterone replacement, "The He Hormone," published in 2004 in The New York Times Magazine. Conservative blogger and author, Andrew Sullivan, penned the piece. Sullivan was (and remains) a powerful thought leader, someone with a hard-won reputation for "speaking truth to power" and for defending controversial positions. He has earned enmity from both the left and the right of the political spectrum. At the age of 35, Sullivan complained of constant feelings of lethargy and depression. He had been taking anti-hiv drugs for years, and his doctor checked his blood work. Per Sullivan, his T levels had dropped "below those of most 8-year-olds," a fact that "shocked" his doctor. Based on his physician s recommendations, Sullivan started taking testosterone and witnessed huge improvements in his energy and mood. At the age of 50, he recently boasted: "I have energy, I am leaner and have more muscle mass, and I am motivated to work out and can sustain [my] focus." Sullivan attributes this stamina and good feeling to his testosterone implants, which he still gets -- four implants, every month. Sullivan's experience is compelling, and "The He Hormone" is definitely worth a read, if for no other reason than because it explains testosterone science using simple, powerful metaphors. However, the plural of anecdote is not data. In other words, just because one person (or many even thousands) feels better on a particular drug or therapy does not mean that the therapy will offer universal benefits. Science is not just about coming up with cool ideas about how the world works: it is also about trying really hard to falsify those hypotheses. It is not about saying: "I took this pill; it made me Superman; therefore, everyone needs to take this pill." Science is about making educated guesses about how the world works, and then ruthlessly testing those ideas in highly controlled settings to try to refute them. No hypothesis has ever been "proven" according to this philosophy. What happens is that scientists "fail to disprove" their guesses, leaving them as winners by default. Unfortunately, this means that real science is a back-breaking, slow, expensive, often painful process. Years of careful research can be fatally undermined by a single "uncomfortable" study or observation. That is how science is supposed to work. In any event, Sullivan, who is HIV positive, immediately noted a stunning physical and emotional transformation when he first started taking his "manhood supplement." He noted that

9 before he started the therapy: "I weighed around 165 pounds. I now weigh 185 pounds. My collar size went from a 15 to 17.5 in a few months; my chest went from 40 to 44. My appetite in every sense of that word expanded beyond measure. Going from napping two hours a day, I now rarely sleep in the daytime and have enough energy for daily workouts and [my] work schedule. I can squat more than 400 pounds. Depression, once a regular feature of my life, is now a distant memory. I feel better able to recover from life s curveballs, more persistent, more alive. These are the long term effects. They are almost as striking as the short term ones." Sullivan s essay is a fascinating study of the sheer power that testosterone has on human development, psychology and physicality. It is hard to overstate the profound influence this hormone has with respect to differentiating the two sexes. Indeed, as Sullivan notes, it has played a huge, underappreciated role in the development of human culture and civilization itself. Sullivan reflects: "Without testosterone, humans would always revert to the default sex, which is female. The Book of Genesis is therefore exactly wrong. It isn't women who are made out of men. It is men who are made out of women. Testosterone, to stretch the metaphor, is Eve's rib." Testosterone helps defines a man as a male: it is, in some sense, the quintessence of "maleness." Testosterone replacement therapy can also clearly lead to short term benefits potentially significant ones in certain men who obtain the treatment. So it is easy to understand why the market for the supplementation has expanded.

10 As Simple As Possible But Not Simpler In addition to discovering and codifying the theory of relativity, physicist Albert Einstein coined some brilliant, pithy statements, including the admonition to make problems as simple as possible but not any simpler. Testosterone researchers and journalists have failed to heed Einstein, however. One unfortunate consequence of the way in which our society communicates the benefits (and side effects) of medications is that, collectively, people tend to oversimplify biological systems. Many men, for instance, likely read Sullivan s column (or heard other positive reports about testosterone therapy) and developed the following simple mental understanding: Low testosterone levels! Lead to weakness/low energy/low libido/health problems! So if you take extra testosterone! You will feel more energetic and younger/higher libido/more industrious. This reasoning sounds like common sense, but it leads to three dangerous assumptions: Dangerous Assumption #1. There is a direct relationship between testosterone levels and health. Dangerous Assumption #2. Testosterone therapy seems to be able to improve several body systems; therefore, it must be "generally healthy" for all body systems. Dangerous Assumption #3. This drug therapy appears to work for XYZ people in such-andsuch trials; therefore, the results are generally applicable to the entire male population. Patients, researchers and doctors all have fallen victim to these assumptions. Yet the science, as even Sullivan points out, does not describe a linear relationship between testosterone levels and health. For instance, as Sullivan noted, men who overdose on testosterone supplementation ironically can see their own endogenous (internally produced) testosterone levels plummet, since the body likes to preserve homeostasis. In other words, the body balances its hormone levels. If a man gets a lot of testosterone through injections or patches, his body might recognize this overabundance and shut down his internal production to compensate. This process, in turn, can cause a whole raft of problems in the body, including, ironically, the same problems that the testosterone was supposed to fix (e.g. loss of libido, low energy, hormonal imbalances, etc). Here is another subtle problem: just because testosterone might alleviate some medical problems does not mean that its effects are entirely positive or benign. A drug can increase libido, help build muscle tissue and enhance performance while at the same time damage the liver and predispose the patient to heart disease or blood clotting problems. Likewise, the "cost benefit analysis" may work out well for certain patients but not for others. For instance, patients who are HIV positive, like Sullivan, might really need the hormone for

11 energy and general functioning and might not be at risk for big side effects. But older men with a history of heart disease or cardiovascular abnormalities might not be so lucky. In an ideal world, researchers would randomize large groups of men and administer doubleblind, placebo-controlled trials to test the short- and long-term effects of testosterone supplementation. But such experiments would be costly. The time factor alone would create problems. A therapy might seem purely useful or benign for the first 10 years. But, theoretically, this same therapy could predispose men to develop cardiac problems 20 years or 30 years down the line. In other words, it could take 20+ years before certain side effects become observable. At the same, consumers, physicians, and drugmakers all crave therapies that work and that can be implemented as soon as possible. In some sense, this eagerness makes sense, and it is somewhat justifiable. After all, life is full of risk; no one can expect complete safety. Every time a man walks out the door, he could be hit by a car or smashed to smithereens by an asteroid. Advocates of rapid pharmaceutical intervention will also suggest that the costs of inaction can be serious. For instance, consider the following hypothetical situation: 10,000 men with low testosterone are put on supplementation for years. The men in this cohort wind up with a slightly elevated risk of heart disease, clotting and cardiovascular problems. After 20 years of therapy, 9 men who might not otherwise have had heart attacks suffer fatal cardiac events because of the drug. However, 500 of the patients enjoy medical, social and emotional benefits from the therapy that last decades. Had these men never taken Low T drugs, their lives would have been harder/less fulfilling. This hypothetical raises big questions: When do the benefits of "doing nothing" outweigh the benefits of "doing something" that has not been fully scientifically vetted? How do the costs of "doing nothing" compare to the costs of engaging in a speculative therapy? Given the ambiguous state of the science, it is not surprising that advocates have emerged on both sides of the debate. Many smart people want to see testosterone therapy much more closely regulated. They fear the potential for harm. On the other side, many smart people argue the benefits outweigh the potential risks. For instance, Dr. Abraham Morgentaler, a Men s Health contributer, authored a book called "Testosterone for Life: Recharge your Vitality, Sex Drive, Muscle Mass, and Overall Health." He wants more men to participate in Testosterone Replacement Therapy (TRT). In an interview with WebMD, he said: "despite all the recent advertising campaigns, awareness of Low T and its importance for men s health remains very poorly recognized by both the public and by physicians." Dr. Morgentaler also says that "based on dozens of studies [testosterone has important relevance] to health issues, such as diabetes, obesity, metabolic syndrome and osteoporosis." He also observes that: "men with Low T die sooner than men with normal levels of testosterone."

12 Dr. Morgentaler is right that having Low T can be a sign of a lack of health. But his observations don t necessarily suggest that using testosterone therapy will lead to health benefits or longevity. They merely suggest that having Low T is, in and of itself, a risk factor. This begs two questions: 1) What actually causes Low T? 2) What can be done to prevent Low T and/or fix any underlying associated health problems? Doing the opposite of what harms a man, physiologically, may not make him well. For instance, perhaps a bad diet causes both Low T and health problems in a man. Any attempt to fix the Low T without addressing his underlying diet issues would prove woeful. It would like prescribing an ice bath for patient who has a fever and congestion. The bath might get the temperature down (temporarily), but it would not address the underlying infection causing both the fever and the congestion. The link between Low T and health problems might be robust, but is the solution to those health problems "just raise T"? Per Dr. Michael Eisenberg, a urologist at Stanford Hospital and clinics in Palo Alto, "lower testosterone levels have been linked to higher risk of cardiovascular problems, [but] again, it s not clear if low testosterone levels actually cause heart problems." This graph, courtesy Tyler Vigien's website about spurious correlations, shows the general gist of this problem: Many patients, doctors, and even science journalists (who should know better) make the mistake of confusing correlation for causation. For instance, the rates of autism and organic food

13 consumption in the United States over the past decade or so correlate almost astonishingly well. However, no scientist would ever suggest that eating organic food causes autism or that having an autistic kid causes people to want to eat more organic food. The relationship is just there, but it is an artifact. It does not tell us any information about what causes what. Likewise, just because Low T is associated with negative health problems does not mean that the reduction in testosterone, in and of itself, caused the harm. Not does it imply that simply boosting testosterone levels to normal will fix the issues. Those ideas are certainly plausible, but they are not given. As Dr. Sergei Romashkan, a doctor who works at the National Institute on Aging and oversees that agency's clinical trials, famously opined: "The problem is that we don't have any evidence that prescribing testosterone to older men with relatively low testosterone levels does any good." Meanwhile, the risks of such therapies can be pretty scary. For instance, as the WebMD article notes: "testosterone therapy can raise a man s blood cell count. This can lead to thickening of the blood, which may make stroke and clotting more likely." Other side effects that are less common can include: Sleep apnea; Liver damage; Kidney problems; Acne; Breast enlargement; Dozens of other rare but significant conditions. Even Dr. Eisenberg, who consults for drugmakers to produce Testosterone Replacement Therapy, noted in the WebMD article that scientists do not know a lot about the long-term safety of TRT. For instance, some evidence suggests that the therapy may lead to increases in prostate cancer, although the science in that area is thin. Meanwhile, many men experience immediate and psychologically rewarding benefits, at least over the short term. As Dr. Morgentaler notes: "this is one of the very few areas of medicine where a male patient will come to you and say, 'you made me feel like myself again.' I hear from their wives, too, who say 'you gave me my husband back.'" It is wonderful that such a therapy can have such positive effects for people like Andrew Sullivan. However, just because a therapy helps (or at least seems to help) in the short term does not mean that it is not also doing long-term damage like increasing the risk for cardiovascular disease, stroke and clotting. Theoretical questions aside, we need to address several practical questions, such as: What TRT options have been available to people? How do these drugs work?

14 What are the distinctions among the different types of Low T therapies? In the next section, we will address these critical "nuts and bolts" questions.

15 The Diverse Treatment Options Available for "Low T" The Federal Drug Administration (FDA) has approved a variety of options to treat Low T. Here are five common treatments: 1. Patches The patient applies a testosterone patch to his skin, a la a nicotine patch, to slowly allow his body to absorb testosterone and increase/normalize levels of the hormone. 2. Injections A physician injects the patient in the buttocks with a testosterone solution weekly or biweekly. 3. Gels The patient can apply ointments, solutions or gels daily; his body absorbs the testosterone through the skin. 4. Pellets A physician can implant pellets surgically near the hip to release the hormone in a slow, controlled manner over time. 5. Gum tablet Also known as a "buccal tablet," this application mechanism allows the testosterone to be absorbed through the gums. Typically, a patient would take such tablets twice a day. Symptoms of Low Testosterone Different men present different low T symptoms. Common symptoms include: A loss of libido; The inability to maintain an erection; Reduced energy and general lethargy; A decrease in muscle mass; General changes in body composition; Looking more feminine and less masculine; Changes in body fat deposition; Reduction in body hair, as well as evidenced by a reduced need to shave; Psychological distress, such as depression or mood shifts; Fluctuations in other hormone levels, such estrogen and progesterone; Shifts in other metabolic markers and lipid panel numbers.

16 When Is Testosterone Therapy Considered Appropriate? The body strives to maintain its levels of key hormones, like testosterone, through an unconscious process called homeostasis. The body works to keep testosterone, cholesterol levels, sodium, calcium, blood ph and other factors in a constrained, narrow range to prevent problems and maximize fitness. Different men have different genetic programming, so what is considered a "normal" testosterone level for a man will depend on that man's genes and metabolic history. All that said, if a man's T levels drop below 300 nanograms per deciliter, his doctor would diagnose him with "Low T." Many factors can influence a man's testosterone levels, including: His diet; His metabolic and hormonal history; His stage of life development (T levels fluctuate wildly in young male fetuses, in men going through puberty, and in men who experience medical problems or diseases); Whether or not his is sick or injured; Whether or not he his cohabitating with a pregnant woman (a father-to-be may see his sex hormone levels change radically while his partner is pregnant); Stressful events or exciting events can also elicit profound changes in testosterone levels. For instance, when a man watches a football game, his testosterone levels will climb. If his team wins the game or scores, he will experience a boost in testosterone. If his team loses, his testosterone levels will decline. Some researchers believe there may be evolutionary reasons for such changes. A primitive man who succeeded at a hunt might find it beneficial to continue to hunt and build off that "winning streak" to collect more food for himself and his tribe. Conversely, if a man loses at a hunt (or a game), he may need to slow down and conserve his energy to avoid getting killed or burning himself out. Hence, his testosterone levels may drop after a loss. As journalist Matthew Perrone noted in a blockbuster article published in 2012: "Adding to the confusion over what defines "low testosterone," there's not much understanding of whether testosterone replacement therapy actually improves men's symptoms. Evidence of the benefits of testosterone is mixed, and the potential health risks are serious. The largest study conducted to date, a 2008 trial involving 230 patients in the Netherlands, found no improvement in muscle strength, cognitive thinking, bone density or overall quality of life among men taking testosterone. Muscle mass increased 1.2 percent, but not enough to improve physical mobility." What Causes Low T Levels? Researchers have proposed different mechanisms that can cause T levels to drop. For instance: The biochemical signals that go between the testes and the brain can, for different reasons, falter, prompting the brain to biochemically "ask" the testes to limit production of testosterone;

17 Defective testes or gonads can also prompt Low T levels; Medications and diet can change the man s hormonal tone and cause the overproduction or underproduction of sex hormones like estrogen, testosterone, progesterone, etc. The technical name for when the body fails to produce adequate testosterone is "hypogonadism." Some men are born with hypogonadism -- or at least are predisposed to develop it -- or develop it due to a problem with the testes. This is known as "primary hypogonadism." Other men develop Low T indirectly due to problems with the hypothalamus or the pituitary gland in the brain. Other issues that can Low T or hypogonadism include: Heavy metal toxicity damage; Chemotherapy; Genetic problems like Klinefelter's syndrome and Kallmann s syndrome; Too much iron; Several diseases and medications. Clinicians have linked low testosterone levels with other health problems. For instance, Low T levels have been linked with obesity, type 2 diabetes, hypertension, high cholesterol levels, asthma, COPD, and cardiovascular problems. Does that mean that the simple act of losing weight and getting blood sugar under control would elevate testosterone levels back to normal? Would getting testosterone levels back to normal help resolve symptoms of type 2 diabetes and lead to weight loss? Could changing a dietary factor(s) help normalize blood sugar, weight and testosterone levels all at once?

18 Three Complex Truths about Testosterone Therapy Most people want simple, easy answers: is testosterone therapy "good" or "bad"? Is it safe or not? But the reality is not black and white. Here are three truths about testosterone science: 1. Doing the opposite of what harmed someone will not necessarily treat him. For instance, perhaps a poor diet and lack of exercise causes a man to develop diabetes, obesity, low testosterone levels and other hormonal/metabolic problems. He might benefit from an improved diet and more exercise, which could cause beneficial changes to his hormonal profile. However, he may not be able to undo all the damage to his body, had he never indulged in a bad diet and sedentary lifestyle from the start. 2. Researchers have a checkered history of understanding chronic metabolic health issues. Despite decades of intense study -- and billions of dollars of effort expended -- the research establishment is not much closer to solving major metabolic puzzles, like cancer, than it was 40 years ago. Meanwhile, once-relatively-rare diseases, like obesity and diabetes, have become epidemic in the United States. Some estimates say that two-thirds of all Americans are now overweight. Yet the research establishment has made little progress -- it has barely been able to slow the acceleration of these epidemics. In 1990s, researchers cut short a famous, massive effort to use hormone replacement therapy to help older women. It turned out that the hormone therapy increased women's risk of cancer and mortality, as opposed to decreasing it. Here is a quote from a 2007 New York Times article about this infamous medical experiment: "By the mid-1990s, the American Heart Association, the American College of Physicians and the American College of Obstetricians and Gynecologists had all concluded that the beneficial effects of H.R.T. were sufficiently well established that it could be recommended to older women as a means of warding off heart disease and osteoporosis. By 2001, 15 million women were filling H.R.T. prescriptions annually; [many] were older women, taking the drug solely with the expectation that it would allow them to lead a longer and healthier life. A year later, the tide would turn. In the summer of 2002, estrogen therapy was exposed as a hazard to health rather than a benefit, and its story became what Jerry Avorn, a Harvard epidemiologist, has called the "estrogen debacle" and a "case study waiting to be written" on the elusive search for truth in medicine." This is not to say that science cannot provide powerful insight into what causes (or potentially might cure) low testosterone and the diseases/symptoms associated with it. However, it does suggest that caution and skepticism should rule the day. 3. Not all men respond to testosterone therapies the same way.

19 As Andrew Sullivan s journey shows, some men who get testosterone replacements claim to feel immediate and palpable benefits. Yet the study on older, chronically sick veterans suggests that, in certain cohorts, the therapy can cause way more harm than good. Not only might different people react differently to the therapy, but also the therapy could have different effects on the same man over time. Testosterone replacement could be benign in an otherwise healthy man in his 40s and 50s. However, if that man develops a chronic illness or metabolic problems or gets older, that same therapy could prove to be dangerous. It might, for instance, provoke a fatal coronary event. Medical problems caused by testosterone therapy might not appear immediately. A single, normal dose of the hormone would be unlikely to suddenly clog the arteries of an otherwise healthy man and kill him. The damage caused by inappropriate hormonal therapies tends to accumulate over time, and evidence of problems may be spare until a health catastrophe hits.

20 More Research into the Dangers of Testosterone Therapy "Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels" -- published in the Journal of the American Medical Association (JAMA) in The authors sought to "assess the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and to determine whether this association is modified by underlying coronary artery disease." They looked at "8709 men with a total testosterone level lower than 300 ng/dl" and concluded that "Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes," with the caveat that "the effects of testosterone therapy on cardiovascular outcomes and mortality are unknown." "Adverse Events Associated with Testosterone Administration" -- published in the New England Journal of Medicine in The researchers examined 209 "community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter" and found that "in this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events." However, they did present the caveat that "The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy." "Testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000 to 2011" -- published in 2014 in the Journal of Clinical Endocrinology & Metabolism. The researchers "evaluated commercial and Medicare insurance claims from the United States and general practitioner healthcare records from the United Kingdom for the years 2000 through 2011." They concluded that "Testosterone testing and use has increased over the past decade, particularly in the United States, with dramatic shifts from injections to gels. Substantial use is seen in men without recent testing and in US men with normal levels. Given widening use despite safety and efficacy questions, prescribers must consider the medical necessity of testosterone before initiation." FDA Safety Alert On January 31, 2014, the Federal Drug Administration issued a safety alert stating that men taking FDA-approved testosterone products might be at heightened risk for stroke, heart attack, pulmonary embolism, other clots and death.

21 "The U.S. Food and Drug Administration (FDA) is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy."

22 Marketing Testosterone Therapy to Men: Like Shooting Fish in a Barrel Most men -- and, indeed, most doctors who treat men -- do not have a sophisticated understanding of how testosterone works in the body, how and why different types of hypogonadism progress, and what the true limitations of the testosterone-related research are. At the same time, men who suffer from Low T related problems do know that "something is wrong." These men want to fix their problems, and savvy marketers are only too happy to assist. The immediate effects of Low T therapy can be seemingly positive. A man suffering in his mid- 30s might care more about relief now and less about a possible heart attack in his 50s. Journalist Matthew Perrone eloquently summed up the problem in a 2012 AP story, Testosterone Marketing Therapy Draws Skepticism: "The latest marketing push by drugmakers is for easy-to-use gels and patches that are aimed at a much broader population of otherwise healthy older men with low testosterone, or androgen deficiency. The condition is associated with a broad range of unpleasant symptoms ranging from insomnia to depression to erectile dysfunction. Drug companies peg this group at about 15 million American men, though federal scientists do not use such estimates. Watson Pharmaceuticals now markets its Androderm patch, which slowly releases testosterone into the bloodstream. Abbott has its gel that can be applied to the shoulders and arms. And Eli Lilly's Axiron is an underarm gel that rolls on like deodorant. Androderm, launched last year, had $87 million in sales, and Axiron, which was launched in 2010, had sales of $48 million last year. "All of a sudden you've got these big players with a lot of money using consumer directed marketing to change the landscape," said Dr. Natan Bar-Chama, a male reproductive specialist at Mount Sinai Hospital in New York. "They see the potential, they see the market growth annually and it's very impressive." But government researchers worry that medical treatments have gotten ahead of the science." Gender roles in the United States have evolved since the stifling 1950s. But sexuality and gender still matter, and many men go to great lengths to: Perform better in athletic competitions; Earn more at work; Enjoy more dynamic sexual relationships; Get promotions/start businesses; Lose fat and have more energy in the short term;

23 Doctors who feel dubious or even outright skeptical about using testosterone therapy might nevertheless fall under the sway of patients who want a quick fix. Doctors are in the service industry, after all. A doctor may feel pressure to "give in" to a patient s demand for testosterone therapy to avoid losing business or getting a negative review on Yelp. Another challenging factor is the time factor. Harm associated with testosterone may not show up for years or even decades. The human mind is not wired to think about risk in that fashion. Finally, testosterone therapy can have both positive and negative effects on the body at the same time, which makes the cost benefit calculus even tougher to measure. Consider cigarettes, which have been rightfully demonized for causing lung cancer and dozens of other awful health conditions. Even cigarettes have short term "benefits" that may seem (for some people) to offset the longer term risks. For instance, they can be soothing and helpful in social situations. Nicotine, one of the key active ingredients in the cigarettes, suppresses the body s production of LPL, an enzyme that plays a critical role in storage of fat. When people quit nicotine, LPL levels tend to shoot up, and excess fat is stored as a result. Nicotine s influence on LPL explains why smokers often lose weight/stay slim until they quit. Unfortunately, this (potentially) positive aspect of nicotine therapy does not counterbalance the long term effects of smoking. Testosterone clearly plays a dynamic role in many body processes, and it defines men not just physically but also sexually and culturally. It is no wonder that testosterone therapy has been such an easy sell -- in some sense, it is literally masculinity in a bottle. Bearing that context in mind, we will now explore some common commercial testosterone therapies and analyze the legal actions taken against drug makers for promoting certain testosterone products.

24 Androgel Approved for use in 2000, Androgel has been marketed to help men who have deficient endogenous testosterone produce more of the hormone. General Information AndroGel is one of the top selling testosterone replacement drugs. It comes in gel form, and it is packaged in two formulations: 1.62% and 1%. The patient applies the gel on the abdomen, shoulder or arms on clean, dry skin areas. The body then absorbs the product over a 24 hour period. Manufacturers say the drug is indicated for men with testicular failure as well as for men who suffer from conditions like idiopathic gonadotropin or LHRH deficiency. Per the manufacturer, a research study on 227 men with hypogonadism found that, at least over a 180 day period, the drug restored mean testosterone levels to normal for 87% of the patients. AbbVie, formerly a division of Abbott Labs, manufactures both AndroGel 1% and AndroGel 1.2% as prescription products. Side Effects The list of potential side effects is impressive. It includes: Acne; Alopecia; Headache; Hypertension; Nervousness; Edema; Gynecomastia; Depression; Reactions at the application site; Abnormal lab tests; Disorders of testis and prostate. Absorptions The formulation is hydroalcoholic; 40% of the testosterone absorbed into the blood is bound to sex hormone binding globulin (SHBG). 2% of the testosterone absorbed remains free and unbounded to other binding molecules. The remainder of the absorbed testosterone binds to albumin and similar proteins in the body, per a Federal Drug Administration (FDA) analysis.

25 In September 2009, the Federal Drug Administration added a "black box" warning label to AndroGel prescriptions, because regulators were concerned about the effects of second-hand exposure to women and children.

26 Androderm In 1995, the Federal Drug Administration (FDA) approved the testosterone replacement drug, Androderm. This drug is delivered a via a transdermal system. General Information Per the manufacturer, men should apply two or four milligrams of the testosterone to their arms, back, legs or stomach. The drug has been approved to treat hypogonadism and manage hypothalamus defect related testosterone disorders as well as primary hypergonadism (i.e. medical issues with the testis). According to the manufacturer, Androderm was tested in a small trial of 94 subjects, 86 of whom enjoyed normalized testosterone levels as a result. Side Effects Some commonly reported side effects include: Redness and itchiness at the side of the patches; Fatigue; Depression; Osteoporosis; Impotence; Loss of male sex characteristics; Lightening of the voice; Loss of muscle; Redistribution of hair. Some of these side effects may seem paradoxical. After all Androderm is a testosterone supplement. So how could it decrease male sex characteristics and/or increase female ones? The answer is that the body is not a simple system. Just because a man suffers from hypergonadism does not necessarily mean that supplementing him with transdermal testosterone will return him to biochemical balance. Perhaps, for some men, supplementation could depress the body s internal production testosterone (known as "endogenous" production). This suppressive effect could lead to a net lower level of testosterone in the body and/or interfere with other biochemical pathways and lead to short term and long term side effects. To understand how the drug affects long term health, researchers need to conduct much larger and more in-depth studies to answer questions like: Do men who take Androderm, long term, live longer? Do these men suffer fewer or more adverse heart events?

27 Different cohorts of men may have radically different reactions to the drug. For some men, Low T replacement might be benign or helpful. For others, it could cause more harm than good. Axiron Axiron is a testosterone replacement product designed for men to apply under the underarm. Made by pharmaceutical giant, Eli Lilly, Axiron generated nearly $50 million in revenue in Eli Lilly markets the drug to men 30 years old and older the typical age at which male testosterone levels start to drop, at least in modern, Western societies like the United States. General Information According to the manufacturer, Axiron should be applied like a deodorant under the arms for two minutes every morning to clean and dry skin. Like several other Low T supplements delivered via the skin, Axiron can be transferred to other people. Thus, manufacturers urge men to wash their hands with soap and warm water after use. Women and children who come into contact with the solution could, potentially, suffer adverse health effects. The drug maker urges men to "stop using Axiron and call your healthcare provider right away, if you see signs and symptoms in a child or a women that may have occurred through accidental exposure." Side Effects The Axiron website is replete with warnings about the potential dangers and side effects of the drug. Some of these include: Impeded bone growth in children; Gynocomastia; Sleep apnea; Clotting in the legs; Possible increase in the risk of prostate cancer. Eli Lilly spent $100 million in 2011 promoting Axiron and Low T supplementation in general.

28 Delatestryl Delatestryl is a Low T medication used to treat men with hypogonadism -- i.e. men who cannot, for various reasons, produce enough testosterone themselves to avoid unpleasant symptoms and side effects. General Information A doctor injects Delatestryl into the buttocks once a week or on regular schedule (e.g. once a week, once every two weeks, etc.). Unlike transdermal testosterone supplements, like AndroGel and Androderm, Delatestryl is delivered "all at once" into the body via injection. The injection carries its own risks. For instance, a poor injection strategy can cause bleeding, discomfort and infection. As the manufacturer warns, injecting testosterone directly into a vein can have dangerous consequences. Side Effects Some research suggests that Delatestryl can be useful for treating conditions like erectile dysfunction, loss of libido, low energy and Low T levels. But it can have unwanted side effects, some of which paradoxically make the underlying problems worse. Side effects observed have included reduced libido, erectile dysfunction, decrease in semen production, loss or depletion of hair, loss of muscle and increase of fat, and other metabolic changes. Injection vs. Other Application Methods Injecting a testosterone supplement can be simpler and easier than applying a transdermal patch or gel or cream every day. This process can also help patients avoid the annoying and potentially dangerous prospect of getting testosterone gel or cream on members of the family. However, the injection method could be a proverbial double-edged sword. Since a large dose of the drug is taken at one time, the patient might be at a greater risk for an acute reaction. Different men may have different reactions to different types of application processes. Patients should work carefully with their physicians to monitor all effects of testosterone supplementation. Even if certain numbers "look good" in the short term -- and the patient and doctor do not observe serious side effects -- monitoring should continue over the long term to watch for signs of cardiovascular disease, arrhythmias, blood clotting and embolism.

29 Depo-Testosterone Made by Pharmacia & Upjohn, Depo-Testosterone is a Low T treatment designed for men with hypogonadism (i.e. who cannot produce enough natural testosterone) to restore libido and energy levels and to manage other common side effects of hypogonadism. General Information Doctors administer the drug via injection using a formulation called testosterone cypionate. The drug uses similar biochemical mechanisms to the ones employed by most commonly prescribed testosterone gels and creams. Side Effects The side effects of depo-testosterone therapy can be pretty disturbing: Therapy has been associated with myocardial infarctions, ischemic stroke and blood clotting; Prolonged use of Depo-Testosterone has been linked with several disturbing conditions, such as adenomas in liver, kidney disease and prostate cancer. Many patients (and doctors alike) probably assume that drugs, like Depo-Testosterone, are relatively interchangeable with other types of testosterone supplements, like AndroGel, Androderm, Fortesta, etc. However, even slight differences in the formulations of these drugs could have different effects in different patients. The Rise of Depo-Testosterone in Context Could the skyrocketing popularity of drugs like Depo-Testosterone have less to do with their efficacy and more to do with the fact that human beings are social animals inclined to follow trends? The TRT (testosterone replacement therapy) story is built on a vivid premise: men who have "lost their masculinity" can easily and simply take a drug (e.g. an injection) and instantly "feel more like a man" without serious long term side effects. This story would be great, if it were true. For some men, it might be. But this assumption can also lead to serious unintended consequences, like spikes in rates of heart disease and stroke in men who take testosterone supplements.