Melatonin supplementation, hyperprolactinemia, and incident heart failure: A proposed prolactin-mediated pathway for cardiovascular risk

Abstract

The problem of heart failure (HF) is complicated and is continuously growing, making the need for novel solutions critical. The role of melatonin, widely used as an over-the-counter medication for sleep disorders, has been historically researched for its cardioprotective actions based on its established antioxidant properties. Recent preliminary evidence, however, points to a possibly alarming association: A statistically significant increased risk of new onset HF, HF requiring hospitalization, and all-cause mortality was observed in association with long-term melatonin therapy (one year or longer in duration), in adult patients suffering from insomnia. However, these were reported in a single, as-yet unpublished conference abstract that has not undergone peer review or independent validation. This hypothesis-generating observation warrants careful investigation of possible mechanisms. In this article we speculatively propose a plausible - but as yet unconfirmed - mechanistic pathway mediated through prolactin (PRL). Melatonin may increase the release of PRL through its modulation of hypothalamic dopaminergic neurons, though whether this effect is sustained with long-term use remains an unresolved critical knowledge gap. This is particularly relevant given that peripartum cardiomyopathy, a dangerous, pregnancy-related variant of HF, has as its central mechanism the cardiotoxic effect of a cytotoxic 16-kDa fragment of PRL. We hypothesize that chronic exogenous melatonin use might - if it were shown to sustain hyperprolactinemia - provide excess PRL that could theoretically be cleaved to the cardiotoxic 16-kDa fragment in patients with pre-existing oxidative stress and cardiovascular risk factors, in a manner analogous to peripartum cardiomyopathy. This speculative mechanism should be tested in prospective mechanistic and clinical studies, with appropriate adjustment for confounders including insomnia severity.

Keywords: Melatonin; Prolactin; Heart failure; Peripartum cardiomyopathy; Hyperprolactinemia; Oxidative stress

Core Tip: A single unpublished conference abstract reported an association between ≥ 1 year of melatonin therapy in adults with insomnia and increased new-onset heart failure, heart failure hospitalization, and all-cause mortality. Confounding by indication (insomnia as an independent cardiovascular risk factor) has not been excluded. We propose a speculative, hypothesis-generating mechanistic pathway involving prolactin (PRL): Melatonin may modulate hypothalamic dopaminergic tone, potentially increasing PRL release. Whether chronic melatonin use sustains hyperprolactinemia is an unconfirmed critical knowledge gap. In susceptible cardiovascular milieus with elevated oxidative stress and systemic inflammation, if sustained hyperprolactinemia occurs, it might theoretically favor PRL cleavage to the cardiotoxic 16-kDa fragment implicated in peripartum cardiomyopathy. This hypothesis requires validation in prospective studies before clinical implications can be drawn.