FDA committees withhold approval of oral testosterone therapy

Abraham Morgentaler, MD, FACS

The FDA Advisory meeting on testosterone was a step backwards for men’s health and for medical science. By voting to add further restrictions to the label of testosterone products, the FDA will de facto create additional challenges and costs for men currently being treated successfully and appropriately, as insurance companies are sure to follow the FDA’s lead and will use this as an excuse to deny coverage.

The insurance picture is already a major hassle for physicians and patients, and this will only make it worse. The result will be that many men receiving testosterone treatment for legitimate medical reasons will need to pay for treatment out-of-pocket, or not at all. This creates an unfair, two-tiered medical system where men of means will be able to afford treatment and those without will not.

There was no consideration of the impact of hypogonadism on men. Symptoms such as sexual dysfunction, depression and chronic fatigue were minimized and dismissed. This is a shame. This is a condition that affects men profoundly and often responds well to treatment. The FDA committee members fell prey to unsupported, unscientific assertions of overuse and inappropriate use of testosterone. For those of us in the field, it is clear that the rise in testosterone prescriptions is due to increased awareness of the benefits and reduced fear of prostate cancer.

Abdul Traish, PhD

The FDA was concerned about two critical issues. One was is testosterone related to cardiovascular risk and for whom is testosterone indicated?

I thought that argument was already clear there was no evidence whatsoever to link testosterone to increase risked of cardiovascular events. When you look at their vote at the end, they all said that the safety signal was weak or poor, and there just was not enough evidence. This is understandable.

It is a little frustrating, however, that the FDA took this issue and linked it to the indication. That’s a totally different issue. You cannot link them together. To me, the question of whether testosterone is related to cardiovascular risk has two answers: Yes or No. In my view, it’s a no.

Testosterone is indicated for clinical hypogonadism. How do you define clinical hypergonadism? They went through and through, talking about primary, secondary and mixed. But to include a term that has no place in clinical science — age-related hypogonadism — there is no such thing. There is no age-related hyperthyroid. There is no age-related blood pressure. There is no age-related cancer. The word age-related is nonsense.

Neither the panel nor the sponsor have the guts to come and say if you have low testosterone and you suffer from real symptoms, you have clinical hypogonadism. That’s true whether you’re 36 years old, 46 years old or 56 years old. What does it have to do with age? Either you have hypogonadism or you don’t.

Consensus is not evidence. Where’s the evidence here? Consensus is just gathering people in a room and they say “we think so.” That’s the problem with the guidelines, which were quoted over and over. The guidelines came from a group of people sitting in a room for 10 days, discussing and deciding. That’s not evidence-based; that’s consensus.

Frederick Wu (University of Manchester) presented a 3-minute discussion on hypogonadism during the public portion, he had beautiful data on primary hypogonadism, secondary hypogonadism, mixed hypogonadism and went into the idea of co-morbidities or lack thereof.

The presenters for the sponsors were disappointing, they could not make the case — either, or. The panel is a diverse group of clinicians and scientists; they come from various backgrounds; some are OBGYNs, some are men’s health, some are urologists. Their different views are understandable.

But the level of discussion was not what I would imagine among a group of scientists, coming in to inform and be informed. It was not what I would expect, but maybe I’m setting a high standard.

This is a critical issue in men’s health. We cannot deny that. Testosterone has been used since 1940; that means we have 7 decades of testosterone use. Someone should tell us what happened in these last 7 decades.

Is there any census data, scientific data, epidemiological data, anything that tells us that people are dropping dead on the street every now and then from using testosterone? I don’t see that. Every 25 to 33 year-old-male has more testosterone than five of us combined. They’re not dropping dead left and right.

There was no good, scientific discussion. The FDA has a responsibility to engage in a more vigorous and more evidence-based type of discussion, rather than consensus-based. During the discussion, after the voting, the panel shared their reasoning; it seemed no different than tossing a coin.

Consensus is in politics; you compromise. In science, you don’t compromise. You get the evidence.

Frederick Wu, MD

The majority of men in the general population with “low T” have secondary hypogonadism associated with obesity, but independent of age, as described in the European Male Aging Study (Tajar et al. JCEM, 2010). These men have functional suppression of gonadotropins but under-stimulated testes. The use of the term “age-related hypogonadism” in these men is not only a misnomer which overlooks the major aetiological factor but also pathophysiological incorrect, and fails to catch important clinical management implications.

Although testosterone replacement is a well-accepted indication for the treatment of patients with classical (pathological and irreversible) primary or secondary hypogonadism, there is currently no approved therapy for the much more common (functional and potentially reversible) secondary hypogonadism associated with obesity. Exogenous testosterone treatment in these men is not only inappropriate (because of further suppression of gonadotropins) but indeed may be counterproductive, particularly in those still seeking fertility.

Restoring normal function in the hypothalamic-pituitary-testes axis through weight loss (Camacho et al. European J Endocrinol, 2013; Grossmann et al. JCEM, 2011) is a logical first-line management in obesity-related secondary hypogonadism. The use of anti-oestrogens (without the current concerns of exogenous testosterone) to reverse the gonadotropin suppression and raising endogenous testosterone may also be beneficial, although the efficacy should be confirmed in larger randomised studies.