Medicine must be based upon facts and evidence-based findings, observation and monitoring; performed with the best interests of the patient and society central to decisions and policies. What should not influence medical decision-making or informed consent of the patient are prejudiced opinions, media sensationalism, positions taken for political or financial gain, as well as fraudulent or misleading conclusions.
Human health is not an absolute matter of "hard science," dictated by objective and measurable responses that can be categorized by mathematical formulas into defined states. It would be wonderful and simple if that were the case. Even in accepted examples, identifying a threshold value for a diagnosis generally results in treating the consequences of the disease, rather than the cause(s). Type 2 diabetes mellitus may be defined by fasting glucose, OGTT response or HbAIC values—all lab values from blood samples. However, it has now been determined that pre-diabetes has metabolic and health consequences. Similarly, the definition of hypertension (high blood pressure) now recognizes a window of opportunity in treating pre-hypertension. Imagine if the effort and support in lowering LDL cholesterol (long considered a minor risk factor in cardiovascular disease) was applied toward addressing these conditions.
Men's Health Neglected
The field of men's health (for lack of a better term, though "andrology" is used by some) has been neglected and discredited for decades, as is evident in reading the seminal book, The Male Hormone by Paul de Kruif. There are numerous issues with the early introduction of androgen therapy during the 1930s and 1940s, but the objectionable stance held by American Medical Association (AMA) was that older men should not desire "rejuvenation" or sexual restoration. It was the opinion of AMA leaders that aging men should accept senescence (declining function due to aging), and that restoring sexual function and desire in aging men was neither natural or beneficial to the individual or society.
Testosterone and other anabolic-androgenic steroids (AAS) had little demand as medical therapy well into the 1990s. Instead, attention and interest related to the ability to increase muscle mass and strength, predominantly used by athletes and bodybuilders. During this time, the campaign to fund anti-doping efforts painted AAS as dangerous and unethical drugs. This tied in nicely with the need to define AAS as addictive and harmful drugs to justify their scheduling as Controlled Substances by the U.S. Food and Drug Administration (FDA). To this day, AAS are not generally recognized as being classically addictive drugs— despite the efforts of certain researchers.
Unfortunately, there remains an evident but ignored bias against "quality of life" therapies; particularly as they relate to men. Some may point to the emergence of erectile dysfunction drugs (e.g., Viagra) as proof that men have benefited from recent drug development. In fairness, one might concede that point, or use it as evidence of the gender bias against men. PDE5 inhibitors, Viagra-class drugs, were approved with little understanding of their effects beyond the obvious and immediate. Erectile dysfunction is a sign of a broader disease state (e.g., vascular disease, hypogonadism, depression, etc.).
Viagra And Safety Concerns
Shortly after the approval of Viagra, a rash of deaths occurred in men with coronary artery disease. Yet, there was no clamor for the drug to be removed or more stringent monitoring to be in place. Instead, major competitors raced for quickly granted approval of their own PDE5-inhibitor drug. There has never been a call for a long-term clinical trial to assess the "safety" of this class of drug (or most others, including statins). The major advantage of competitor entries was a longer-lasting effect, and these drugs were among the most marketed via direct-to-consumer advertising.
Regulatory agencies and the pharmaceutical industry served primarily older men by providing a potentially deadly drug to provide a quality-of-life benefit (potentially masking the progression of serious underlying pathology). The pharmaceutical industry benefited to the tune of billions of dollars. Certainly, many men benefited from PDE5-inhibitor drugs. Frankly, the development of this class is a welcome addition to the treatment options for "men's health." Since then, little advance has been made in new drugs for men. It would be interesting to know what the AMA leadership of the 1940s would have to say about PDE5 inhibitors. Seemingly, the priority for the regulatory agencies and the pharmaceutical industry now is to give men a "boner in a bottle" and expect them to be placated. Compare this to women's health.
Women's Health and Female HRT
The "change" known as menopause is fairly rapid, and the effects are noticeable. From "hot flashes," to facial hair, to bone loss and cardiovascular disease, the loss of sex hormone production from the ovaries is considered a treatable condition. This was essentially unchallenged until a study, the Women's Health Initiative, called the safety of hormone replacement into question. Overnight, many women stopped taking estrogen and/or progesterone due to the fear created. The study has been challenged by many, and it appears that HRT for women is relatively safe if begun during or shortly after the onset of menopausal symptoms.
There are risks with female HRT (e.g., stroke, acceleration of certain cancers), and women should be advised of such prior to making an informed consent to receiving HRT. Menopause treatment is based upon symptoms, how the lady feels, rather than lab values. The early benefits often impact quality of life (e.g., skin and hair texture, mood, sexual function), rather than treat a specific pathology (e.g., bone loss, cardiovascular risk). Women's health clinics are found in nearly every town and city, yet there is a dearth of men's health clinics-- other than those aimed at treating prostate- and impotence-related issues.
In contrast, there is no urgency in addressing the common decline in sexual desire experienced by many women, including menopausal women.' A variety of agents have been developed or studied, including PDE5 inhibitors, testosterone, etc. However, the FDA has struck down each application, stating a lack of long term safety data or questionable efficacy. It has been suggested that the market for a drug or hormone that can restore or enhance female sexual desire would rival that of the erectile dysfunction drugs for men.
Throw The Men A Boner Pill
So, men were quickly given "boner pills" to satisfy the desire for sexual activity in those affected by (but rarely evaluated for) a variety of conditions. Men's quality-of-life issues or proactively responding to a recognized decline in testes function are subjected to stringent laboratory measures with little regard for subjective symptoms, despite the initial awareness being based upon subjective symptoms (e.g., reduced libido, erectile changes, mood, change in strength, body composition, etc.). Women's health practitioners can respond quickly to the patient, and are not constrained by exaggeratedly conservative laboratory definitions of menopause. However, women's health practitioners are forced to resort to off -label use of certain drugs when addressing a complaint of a lack of sexual desire by their patient. Men's HRT involves drugs scheduled as controlled substances, whereas prescriptions for women's HRT can be written by a health care provider without requiring a DEA [United States Drug Enforcement Administration] registry number.
This bias continues, and appears to be firmly entrenched in the FDA, the regulatory agency that decides whether a drug is approved for use in the United States. The approval process is lengthy and expensive, so pharmaceutical companies only apply when they feel there is a substantial demand and the drug is vetted through clinical trials. The recent overwhelming rejection of yet another testosterone formulation by two FDA committees shows that there is a prejudice against allowing any new testosterone-based products on the market. The sources of this prejudice will likely never be known publicly. It has been suggested that this may be due to a combination of: a) the "cover your ass" mentality of federal agencies; b) influence from manufacturers of existing testosterone formulations already approved (and vulnerable to competition from new entries); and c) a lack of support for, or covert antagonism against, male HRT products.
FDA Approval: It Don't Come Easy
Two related testosterone products have presented to the FDA for approval, both being based upon the 17beta-ester, testosterone undecanoate (TU). The first, Aveed, approved after multiple delays (five years), is an injectable depot that allows for steady-state concentration (therapeutic levels) lasting up to 10 weeks between injections.' The second is an oral capsule, Rextoro, that is absorbed via the lymphatic system, allowing the drug to bypass the liver. Nebido (injectable TU) and Andriol (oral TU) have been approved for use and administered in various countries, including many in Europe. Nebido, as prescribed in other countries, actually allows for up to 12 weeks between injections, but requires a higher volume injection. The FDA felt that would lead to patient discomfort and increase the risk of an oil emboli, which happens when the injected oil gets into a vein and travels to the lung— and many have experienced a coughing sensation almost immediately following an AAS shot. The oral capsule has the benefit of stabilizing blood concentration of testosterone without "straining" the liver, usually detected by increased liver enzyme or bilirubin results from blood work.
There are clear benefits to Aveed and Retoro. Aveed allows clinicians (required to be certified by Endo Pharmaceuticals to dispense Aveed) to titrate therapy by increasing/decreasing the duration between injections. Patients have the injections performed in the clinic, allowing for more frequent follow-up of the patient response and any adverse effects. The oral forms would be markedly safer than any other oral AAS (e.g., methyltestosterone, oxandrolone) in regard to liver function, and more convenient than the current topical options. Further, there would be no risk of transfer- testosterone gel rubbing on to a child or intimate partner, resulting in viritization. The dose is easily titrated by altering the number of capsules prescribed according to patient response and labs.
Bias Against Male HRT
The FDA committees involved in recommending approval of Rextoro have overwhelmingly rejected the application, stating that there is insufficient benefit-to-risk profile, and that the product may not even be effective. This is perplexing, as oral TU would offer an alternative to 17alpha-methyltestosterone (MT), an approved drug in use in the United States. Methyltestosterone is associated with liver enzyme elevations, something the TU formulations avoid. It would also avoid the transfer issue with topical formulations, widely prescribed in the United States. The FDA requires topical formulations to carry a "black box" warning about this risk, so presumably an option that avoids this would carry a clinical benefit.
Instead, the committees have succumbed to the furor raised in the media relating to the limited studies indicating an increased risk of cardiovascular disease in men receiving TRT. This is addressed in the sidebar to this article. Bear in mind, the preponderance of evidence clearly indicates an increased risk of cardiovascular disease, and death in general, in men with low or low-normal testosterone concentrations. Delays caused by this academic challenge may be resulting in patients delaying seeking appropriate health care, and physicians becoming wary of prescribing testosterone in all but the most severe cases.
Lastly, as a clear example of the bias against male HRT, is a statement offered as "testimony" in the committee hearing. "There is no solid evidence that age-related hypogonadism exists or that TRTs are helping patients who take them for this purpose, said Public Citizen's Michael Carom, who offered testimony at the meeting." Public Citizen is a political action organization, not a medical association. Among their stated goals is advocating a single-payer, Medicare-like system for all.
Testosterone's past and future is mired in bias, delaying an understanding and utilization of the therapeutic benefits that might be provided with appropriate treatment guidelines, as opposed to the overly conservative and "least offensive" practices endorsed by our nation's experts. Associating the USE of testosterone with illicit abuse and sports doping only serves those opposed to acknowledging the essential and central role the hypothalamic-pituitary-testes axis serves for men, particularly men succumbing to the effects of age and environment.
By: Michael J. Rudolph, Ph.D
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