Natriuretic peptides are hormones produced by the heart that promote vasodilation and salt excretion. They play an important role in the defense against increased myocardial stretch and strain, which are the main triggers for their release.
Genetic variation leading to lower natriuretic peptide levels are associated with a higher risk of hypertension and cardiovascular disease. Notably, men have 40 percent lower levels of circulating natriuretic peptides than women which could also lead to higher risk, said Katherine N. Bachmann, M.D., an endocrinologist at Vanderbilt University Medical Center and Nashville VA Medical Center.
“Lower natriuretic levels in men compared with women could represent a deficiency that contributes to their elevated risk of hypertension and cardiovascular disease,” Bachmann said. “It’s an interesting question to ask why these sex differences occur.”
Understanding the Testosterone Effect
Epidemiologic and animal studies suggest testosterone may play a role in sex-specific differences in natriuretic peptides. However, “whether testosterone has a causative effect on natriuretic peptides has not been established by prior studies, which were often complicated by comorbidities and other hormones. A big challenge is trying to tease out the effects of testosterone versus estrogen, since testosterone is usually converted to estradiol in the body,” said Bachmann.
A randomized, placebo-controlled clinical trial analyzing the roles of testosterone and estradiol on body composition, strength and sexual function in men provided the perfect platform. In the trial, healthy men without heart failure received goserelin acetate to deplete all natural, endogenous testosterone and estradiol, and then were randomly assigned to placebo gel or four different doses of testosterone gel. They also received an aromatase inhibitor (anastrazole) to prevent conversion of testosterone to estradiol.
Said Bachmann, “It provided a way for us to isolate the effects of testosterone from the effects of estradiol. It gave us a clean way to look at testosterone’s effects on natriuretic peptides.”
Connecting Testosterone to Risk
In results published in the Journal of the American College of Cardiology, Bachmann showed that men who did not receive testosterone replacement (placebo gel group) had dramatic decreases in testosterone to extremely low levels—comparable to testosterone levels typically found in women. These men also had significant increases in their natriuretic peptide levels. Higher doses of testosterone replacement were associated with lower final natriuretic peptide levels after adjustment for covariates. Said Bachmann, “Our results support that testosterone actually causes reductions in natriuretic peptide levels in healthy individuals.”
The results are an initial step toward understanding the physiology of sex-specific differences in natriuretic peptides. “Our data suggest that decreases in testosterone levels comparable to the differences between healthy men and women lead to about 25 percent higher natriuretic peptide levels,” Bachmann said. “Thus, testosterone appears to partially explain why natriuretic peptide levels are lower in healthy men than women.” Testosterone could contribute to a relative “deficiency” in natriuretic peptides—and the increased risk of hypertension and cardiovascular risk—in men as compared with women.
Next steps will be to determine whether the lower levels of natriuretic peptides in men compared with women represent a true “deficiency” and whether correcting that deficiency could protect against the development of hypertension and cardiovascular disease.
Developing New Diagnostics
“Natriuretic peptide deficiency isn’t often thought about in the clinic.”
A circulating natriuretic peptide level on its own may not tell you whether a person has natriuretic peptide “deficiency,” Bachmann noted. “A ‘normal’ natriuretic peptide level can vary widely depending on the situation—whether a patient is otherwise healthy or in heart failure, for example.”
Currently, there are no tests to diagnose natriuretic peptide hormone deficiency, like there are to diagnose hypothyroidism or adrenal deficiency. For example, a Cortrosyn Stimulation Test determines whether the adrenal gland can appropriately produce cortisol in response to a stimulus (failure to do so is diagnostic of adrenal insufficiency). A similar test to measure resiliency of natriuretic peptide production could help identify truly “deficient” patients and thus who may benefit from drugs that can upregulate the natriuretic peptide pathway.
“Natriuretic peptide deficiency isn’t often thought about in the clinic; the focus is on elevations in the context of heart failure,” Bachmann said. “It is equally important to consider the opposite situation—what defines a deficiency, and what these hormones mean for people without heart failure.”