The Hormonal Theory of aging is dead
The Hormonal Theory of aging dates back at least one hundred years. It states that because hormones decline with aging, they are the cause of aging. Consequently, replacement of hormones will prevent aging. As with any theory of aging that is even slightly plausible, it gained rapid acceptance. Hormone therapy became highly coveted. In fact, in the early part of the twentieth century, wealthy aging men paid hundreds of thousands of dollars for one of the early forms of "Testosterone replacement"- the transplantation of monkey or goat testicles. Not much has changed. The wealthy are always the victims and financiers - the guinea pigs - of dangerous untested medical technologies. Fortunately, we have learned much about aging and hormones over the years. The Estrogen trials have given us tremendous insight into the aging and replacement of hormones in women. Women lose their sex hormones abruptly during menopause around the age of fifty. Large randomized controlled trials with Estrogen and placebo, following hundreds of thousands of women for decades, showed that Estrogen replacement essentially does nothing. The Hormonal theory of aging for women is dead.
The same lessons are starting to surface with respect to Testosterone. Low Testosterone is not the CAUSE of aging in men. It is the EFFECT of aging. In fact, it has been hypothesized that Testosterone levels decline with age to protect the body from Testosterone's damaging effects. We know that castrated animals live longer than uncastrated animals. We also know that Testosterone increases cellular growth and metabolism. This contradicts recent theories of longevity which espouse cellular repair instead of growth, and decreased metabolism instead of increased metabolism. At best, Testosterone replacement improves the quality of life, but certainly not the quantity. Most gerontologist have likened Testosterone to running your car at 8,000 RPM; you may get better performance temporarily, but you will decrease the life of the car. The fact that it is prescribed in clinics calling themselves "Longevity clinics" or "Anti-aging clinics" is misleading, to say the least.
Despite the academic death of the Hormonal theory of aging, the number of Testosterone prescriptions in aging men has exponentially increased over the past decade. Partly, this is due to the invention of a more user-friendly version of Testosterone - the Testosterone gel. Testosterone can't be taken orally and for years was given by weekly injection. The invention of a gel made Testosterone therapy much more appealing. However, this does not explain the exponential rise of Testosterone use. There is certainly more to this story.
Medicalization of aging
Pharmaceutical companies decided to abandon Testosterone as a "longevity" drug. Instead, they decided to treat a new disease that they themselves created - "low T". They did this by attributing the vague and non-specific symptoms of aging to low Testosterone levels. This is known as medicalization - taking a normal experience of life and labelling it as a disease. Consider the following experiences: depression, low sex drive, restless legs, anxiety in social situations, guilt after eating, lack of focus, or dry eyes. Are these diseases? In their extreme forms, yes. But there is a fuzzy line between normal experience and disease. A spectrum. Where does normal experience end and disease begin? We don't know. Of course, this presents a perfect opportunity for exploitation. As a result, we have the following medicalized diseases: Mild depression, Hypoactive Sexual Drive Disorder, Restless Leg Syndrome, Social Phobia, Binge Eating Disorder, Adult ADHD, and Dry Eye Syndrome. Each ready to be treated with a billion dollar drug.
Successful medicalization involves 3 steps: widen the fuzzy definition of an already existing diagnosis, create a self-diagnosis questionnaire, and spread awareness of the new disease to a large audience with direct-to-consumer advertising. To see how this is done, we can examine the "low T" campaign, the most successful medicalization campaign of all time.
Step 1 - Widen the fuzzy definition of an already existing diagnosis
A small number of men actually have low Testosterone as a result of real disease. For example, a man with a pituitary tumor in his brain can‘t produce any Testosterone at all. He becomes fatigued, weak, depressed, and loses his libido (sex drive). Testosterone replacement will bring him back to normal. This is why Testosterone got FDA approval in the first place. These real indications for Testosterone replacement only account for a few thousand prescriptions per year in the entire country. The goal of medicalization is to expand this definition. Find a much larger group of men that may have "lowish" Testosterone levels and are complaining of vague symptoms. That is easy. You need not look any further than to men over the age of fifty. Most will slowly develop a mildly low Testosterone level, and most will complain of the same non-specific symptoms as the men with the real disease - fatigue, weakness, depressed mood, and low sex drive. Voila - now we have "Low T". A diagnosis for millions instead of thousands.
Step 2 - Create a self-diagnosis questionnairre
The diagnosis of "low T" hinges on subjective symptoms that overlap with the experience of normal aging. Consequently, no one knows where to draw the line in the sand. This turns out to be the greatest strength of the "low T" diagnosis; no scientist is going to challenge another scientist's proposal for a diagnostic strategy. They could literally just make it up. One of the companies, Organon Pharmaceuticals, did just that. They asked an academic endocrinologist, John Morley MD, to create a questionnaire for patients to diagnose themselves. He developed the ADAM (Androgen Deficiency in Aging Men) questionnaire. According to Dr Morley, it took 20 minutes while in the toilet; he wrote it down on a piece of toilet paper and gave it to his secretary the next day. For this, $40,000 was awarded to his university research fund. “I have no problem calling it a crappy questionnaire” he said. This sounds so ludicrous it could be made up; sadly, it's all too real.
The questionnaire was perfect. So vague and inclusive that almost any aging man taking the questionnaire would test positive for “low T”. See the ADAM test below. Take it for yourself. If you answer Yes to question 1 or 7 or if you answer Yes to 4 or more questions you have "low T". I'll bet if you are over 40 you have it:
In reality, the above symptoms do not correlate with testosterone levels at all. If you are an aging man and have symptoms of fatigue or depression, you are just as likely to have high Testosterone levels as you are to have low Testosterone levels. In this highly cited 2010 study, 3,400 aging men had their Testosterone levels measured and were questioned for symptoms. Testosterone levels did not correlate with any symptoms except for a slight correlation with sexual symptoms.
Step 3 - Spread disease awareness with direct-to-consumer advertising
Direct-to-consumer ads for Pharmaceutical products became legal in the US in the 1990's. They included disease awareness campaigns - an advertisement where the Pharmaceutical company educates the public about a disease instead of promoting the drug that treats the disease. At the time, lawmakers perceived these campaigns as a public service announcement. A force for good. Little did they know.
Armed with the ADAM test, the pharmaceutical company AbbVie launched its brilliant and immensely successful “low T” disease awareness campaign in 2007. “Do you suffer from fatigue, depression, or low sex drive?”, “Well you may have low T”, "Take the following questionnaire", “Ask your doctor". The questionnaire was all over the internet and disseminated to doctors offices by an army of pharmaceutical reps. Patients came to their doctor's visit self-diagnosed with a disease the doctor was unfamiliar with. Since their doctors did not want to sound ignorant, it was an awkward situation. Nor did doctors want to disappoint patients filled with the hopes of feeling young again. Thousands of prescriptions a year turned into millions of prescriptions a year. Testosterone sales in the US skyrocketed from $18 million in 1989 to $1.9 billion by 2012.
The FDA clarifies: Testosterone use in aging men is off-label
Unlike Estrogen, there are no large long term trials evaluating the safety and benefit of Testosterone replacement in aging men. By 2015, the FDA started to get concerned with the exponential rise in prescriptions and safety concerns raised by cardiac events in small studies. They decided to send a message to Testosterone manufacturers to remind them that the FDA did not approve of Testosterone for use in aging men and consider it an off-label use. These days the FDA can't catch a break. Either they are accused of being a shill for Big Pharma approving too many drugs, or they are accused of delaying the approval of potentially life-saving drugs. In this case however, they certainly acted as an advocate for the citizens of our country. AbbVie, on the other hand, is paying for its avarice and meteoric rise. Currently, it is settling thousands of lawsuits because of its predatory and irresponsible marketing practices. Particularly for its failure to disclose or downplay any potential side effects such as sleep apnea or heart disease.
What do the clinical trials say?
As mentioned, the lack of clinical trials of Testosterone compared with Estrogen is striking. In fact, the first moderately large trial testing the benefits of Testosterone was only published in 2016, The Testosterone Trials. This NIH funded study followed 790 subjects for one year. All subjects had symptoms of either fatigue, low sex drive, or apathy, and were randomized to Testosterone vs placebo. At the end of the study there was no improvement in symptoms in the Testosterone group versus the placebo group. There was a statistically significant improvement, however, in sex drive, but it was clinically insignificant - it improved sex drive by 0.3 on a scale from 1 to 10. More disturbing however, was an increase in coronary artery soft plaque in the Testosterone treated group. As mentioned, this trial only followed patients for one year, so it was not powered to detect actual events such as heart attacks, strokes, or blood clots. We still can't say anything about its long term safety.
What do your friends say?
The Testosterone Trials provided sobering results. Other than a weak aphrodisiac effect, Testosterone replacement does not improve symptoms. For some of you, this may contradict with the anecdotes from friends or acquaintances - anecdotes of men with dramatic results from Testosterone replacement. Unfortunately, it's quite challenging to know exactly what is happening in an anecdote. There are many reasons why these men start to feel better. In addition to Testosterone, some men start to exercise and diet. Some men may have been prescribed more than Testosterone by their "Longevity Clinic", such as Human Growth Hormone or amphetamines. Some men may be taking very large (supraphysiologic) doses of Testosterone - the kind of doses that a professional athlete would take. Some men came to the clinic because they were in a slump and came out of it naturally. And some men are just prone to expectation and placebo. It's hard to say.
What does the Endocrine Society say?
The Endocrine Society is a non-for-profit organization based in the US, that represents 18,000 endocrinologists around the world. They regularly convene a task force of experts to draft guidelines. Recently they published the updated 2018 guidelines for the use of Testosterone. Essentially, they go against the FDA and the clinical trials, and suggest the use of Testosterone in aging men with symptoms and low levels. I don’t like to sound like a conspiracy theorist, but one can’t help notice that the chair of the task force and six of the ten members have personal financial ties to AbbVie and/or other pharmaceutical companies. This information is not hidden or hard to find - it is printed in black and white in the appendix of the guidelines - see below:
Just because a physician is paid by a Pharmaceutical company, it does not invalidate his opinion; but it is a conflict of interest and a potential for bias. It should raise a red flag. It should also raise a red flag that the Endocrine Society could not find ten experts without links to Pharma from their pool of 18,000 endocrinologists. Unfortunately, this has become a standard practice in many fields of medicine. On average, about 75% of committee members have financial conflicts of interest.
Should you take testosterone?
Despite all of the above, I still prescribe Testosterone to some of my patients. I use an individualized approach. If there are no symptoms there is no reason to check blood levels of Testosterone. If there are symptoms, I will measure levels. If levels are low, I will repeat them and make sure they are drawn in the morning. If levels are repeatedly low in the morning, and my patient is made aware of the risks, benefits, and unknowns, I offer a therapeutic trial. I have never seen any dramatic responses - only weak ones - and often none at all. In fact, most men end up stopping the treatment due to lack of robust response. (My anecdotal observations seem consistent with the outcomes of the clinical trials). If there is no improvement in symptoms, there is no reason to continue treatment. There is no reason to bring the Testosterone levels to "normal" for the sake of numbers alone.
In conclusion, "low T" does not appear to be a real disease in most men. It exploits the fuzzy line between the symptoms of getting older and low Testosterone levels. At best, Testosterone replacement acts as a weak aphrodisiac. At worst, it is a dangerous treatment that is both pro-aging and has long term side-effects. It is a complex issue with conflicts of interest and no clear answers. Please feel free to discuss it with me.