Age-Related Hypogonadism Merits Testosterone Treatment

April 2021

Clinical practice guidelines recommend that men with hypogonadism receive treatment with testosterone therapy, regardless of the underlying causes.1-5 In contrast, the US Food and Drug Administration (FDA) acknowledges that hypogonadism merits treatment, but made an artificial distinction between hypogonadism due to classical causes and hypogonadism due to age-related or obesity-related causes, and proclaiming that only the former merits testosterone treatment. This led to debate among scientists and confusion among physicians. However, the FDA has been unable to demonstrate differences in benefits or risks among men with different forms of hypogonadism, and hence there is no basis for this distinction, as explained in this article.6

KEY POINTS

  • Symptoms and signs of hypogonadism occur as a result of low testosterone levels and may benefit from treatment regardless of whether there is an identified underlying cause.
  • Historically recognized causes of hypogonadism (such as testicular failure, Klinefelter syndrome, pituitary tumor, radiation etc.) are rare. Only a tiny fraction of men has this form of hypogonadism, also known as classical hypogonadism.
  • Age-related hypogonadism, or hypogonadism caused by obesity or type 2 diabetes, is far more common.
  • All forms of hypogonadism, regardless of cause, merit testosterone therapy.

Primary & Secondary hypogonadism vs. Age-related hypogonadism

Hypogonadism, also known as “testosterone deficiency”, is a clinical syndrome characterized by low serum testosterone combined with characteristic signs/symptoms.7 Testosterone deficiency occurs as a result of impaired testicular function (primary hypogonadism) or suppression of the pituitary/hypothalamus (secondary hypogonadism).

There are many causes of primary and secondary hypogonadism. When underlying pathologies have been identified, such as testicular failure due to bilateral torsion, orchitis, Klinefelter syndrome or chemotherapy (primary hypogonadism), and traumatic brain injury, pituitary gland tumor or radiation (secondary hypogonadism), the condition is called classical hypogonadism. Only a minority of men are affected by classical hypogonadism.

More recently, additional causes of hypogonadism have been identified, such as aging, which can impair testicular function (primary hypogonadism), and obesity or type 2 diabetes, which can suppress the pituitary/hypothalamus (secondary hypogonadism), resulting in inadequate secretion of LH and FSH, and consequently reduced testosterone production. Some medications, especially opioids and glucocorticoids, can also cause hypogonadism. For more information, see “Risk factors for hypogonadism

Hypogonadism resulting from these non-classical causes is called functional hypogonadism, age-related hypogonadism, or late-onset hypogonadism.8,9 With the alarmingly high prevalence of obesity and type 2 diabetes, combined with the aging demography, the prevalence of functional hypogonadism is high.

Does hypogonadism that is caused by obesity, type 2 diabetes and/or aging merit testosterone treatment?

In contrast to the European Medicines Agency (EMA), the United States FDA has taken the position – despite data to the contrary - that only classical hypogonadism merits treatment with testosterone therapy.10 This has ignited a debate among scientists and confusion among physicians. Below is a summary of the rationale as to why age-related hypogonadism should be treated as any other clinical condition.

Evidence for benefits of testosterone treatment in men with hypogonadism

The wide range of health consequences of hypogonadism are well documented, and include sexual dysfunction, impaired general health, reduced wellbeing, lack of energy and enthusiasm, obesity, type 2 diabetes, osteoporosis, anemia, as well as increased risk of premature death.11-15 These health consequences have been observed in all men with hypogonadism, regardless of what caused the hypogonadism.

Testosterone therapy has been used to successfully treat hypogonadism since the 1940s, and has become the first-line treatment for restoring testosterone levels.16 Long-term real-world evidence studies have shown that men with all forms of hypogonadism experience significant health benefits from testosterone therapy.17-22

The importance of treating hypogonadism has been demonstrated in long-term real-world evidence studies that compared health outcomes among men with hypogonadism who received testosterone therapy, with those of men with hypogonadism who did not receive testosterone therapy.19-22 These studies showed that men with hypogonadism who did not get testosterone therapy experienced a marked increase in body weight and waist size, along with worsening of erectile dysfunction, wellbeing, lipid profile and glucose control. Furthermore, men with untreated hypogonadism had a significantly higher incidence of myocardial infarction, stroke and premature death.19-22 Both of the largest randomized controlled trials of testosterone therapy, the TTrials 23  and the T4DM trial 24, have provided convincing evidence of health benefits in men with age-related (functional) hypogonadism. These studies also provided reassurance regarding the safety of testosterone therapy.

Age-specific analyses have shown that older men over 65 years of age with age-related hypogonadism benefit as much from testosterone therapy as do younger men with hypogonadism, and that testosterone therapy is a safe treatment for men of all ages.25

Is age-related or functional hypogonadism simply secondary hypogonadism?

Emerging data suggest that functional hypogonadism may in fact be secondary hypogonadism. Systemic low-grade inflammation, which is common in men with obesity, the metabolic syndrome and type 2 diabetes,26,27 can also affect the hypothalamus and cause a disruption of gonadotropin-releasing hormone (GnRH) release and reduced gonadotropin secretion from the anterior pituitary, resulting in secondary hypogonadism.28,29

In a genetic analysis of men with classic isolated hypogonadotropic hypogonadism and acquired functional isolated hypogonadotropic hypogonadism, it was found that the prevalence of rare variants in 28 candidate genes was significantly higher in all patients with isolated hypogonadotropic hypogonadism compared to controls, regardless of age at onset, degree of hypogonadism or presence of obesity.30 Interestingly, there was no difference between patients with classic or functional isolated hypogonadotropic hypogonadism. Hence, it appears that the same gene variants that underlie classic isolated hypogonadotropic hypogonadism could predispose a man to functional isolated hypogonadotropic hypogonadism.30 This could explain, at least partly, why not all men with obesity have hypogonadism; development of hypogonadism may happen in men who have low-grade inflammation in combination with a genetic susceptibility.30

Does it matter what the cause of hypogonadism is?

Whether hypogonadism is a result from classical causes or not is mostly an issue of scientific inquiry, with less clinical practice relevance.

In 2015, an international expert consensus panel convened to discuss the negative impact of hypogonadism on men’s health and quality of life, and evaluated the merits of testosterone therapy in men with hypogonadism.7 Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine and basic science researchers, as well as a representative from the European Medicines Agency. It was concluded that:

1. Symptoms and signs of hypogonadism occur as a result of low testosterone, and may benefit from testosterone therapy regardless of whether there is an identified underlying cause.

2. Testosterone therapy confers a wide range of health benefits in men with hypogonadism, regardless of age.

Conclusion

Regulatory agencies such as the EMA and FDA, have the responsibility to ensure the safety of the public by rigorously examining new drugs before they enter the market. However, regulatory agencies do not dictate the practice of medicine, which falls under the responsibility of medical societies and physicians. Yet the medical community and insurance companies pay close attention to the positions taken by regulatory agencies, and insurance companies frequently restrict coverage based on drug labels.31

It should be emphasized that clinical guidelines do not require that patients have classical hypogonadism to be eligible for testosterone therapy. Clinical practice guidelines only require a diagnosis of hypogonadism, which is made in men who have symptoms/signs of testosterone deficiency combined with low testosterone levels.1-5 Depending on the clinical situation, additional testing may be recommended for individual patients. For more information, see “How to diagnose hypogonadism?”

As stated by the FDA itself, “Once the FDA approves a drug, a health care provider may prescribe the drug for an unapproved use when the health care provider judges that it is medically appropriate for the patient. FDA does not regulate this off-label use, which is considered the practice of medicine.” 32

Therefore, physicians do not have to worry about getting charged for malpractice if they prescribe testosterone therapy to men who suffer from symptoms/signs of testosterone deficiency and have low testosterone levels, even if the actual cause of their hypogonadism has not been identified.

For related information, see:
"Benefits of testosterone therapy in men with testosterone deficiency"

References

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