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 However, these were reported in a single, as-yet unpublished conference abstract that has not undergone peer review or independent validation.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.

Key Words: 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Core Tip: A single unpublished conference abstract reported an association between ≥ 1 year of melatonin therapy in adults with insomnia and increased new-onset heart failure, heart failure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.

INTRODUCTION

Heart failure (HF) is a chronic and progressive clinical syndrome characterized by significant morbidity and mortality, leading to escalating healthcare costs worldwide[1,2]. Melatonin (N-acetyl-5-methoxytryptamine), is primarily known as a pineal gland secretory product, which regulates circadian rhythms[1,3]; it is also considered to be a novel cardioprotective agent. Melatonin’s recognized anti-oxidant and cardioprotective mechanisms of action can be receptor-mediated and receptor-independent, functioning as a potent anti-oxidant, free radical scavenger, and anti-inflammatory molecule[3-5]. Experimental and initial human studies have supported this beneficial perspective, suggesting melatonin can limit myocardial damage following ischemia-reperfusion injury, reduce cardiac hypertrophy, ameliorate endothelial dysfunction, and improve quality of life in patients with HF[5-7]. Furthermore, reduced nocturnal melatonin secretion has been observed and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with advanced chronic HF (New York Heart Association class III)[1]. This physiological reduction has traditionally been interpreted as the loss of an endogenous cardioprotective mechanism due to neurohormonal activation, such as adrenergic system overactivity[1].

The existing view regarding the cardiotoxicity of melatonin was severely contested by new preliminary evidence presented at the American Heart Association Scientific Sessions 2025[8]. Based on a review of five years of electronic medical records from over 130000 adult insomnia patients, individuals using melatonin supplements for more than a year had a 90% higher risk of developing HF than their peers who did not use melatonin (4.6% vs 2.7%, respectively). The same group of people using melatonin also reportedly faced a threefold greater risk of hospitalization for HF (19.0% vs 6.6%). Although the authors have acknowledged that this observational research established only a correlation but not causation, and its results should be treated as preliminary[8], the significant level of increased risk calls for exploring other possible, yet harmful, modes of action. However, an important methodological issue associated with the above results needs to be noted - confounding by indication: Insomnia, which serves as an indication for using melatonin in this study, is actually a risk factor for developing cardiovascular disease and HF[9]. Therefore, the described relationship may be fully attributed to such a bias, something that cannot be ruled out with the help of the employed retrospective cohort design. The original abstract has not been peer-reviewed, and its results require further verification by another study.

In this review, we will attempt to investigate one possible hormonal pathway connecting the use of exogenous melatonin to negative outcomes on the heart: The melatonin-PRL pathway. We propose that melatonin-mediated hyperprolactinemia caused by continuous consumption at high dosages can be considered a pathophysiological substrate that parallels the development of peripartum cardiomyopathy (PPCM), a rare type of HF[10]. The keywords used in PubMed/MEDLINE and Google Scholar for literature search to develop the narrative review are as follows: Melatonin, PRL, HF, PPCM, hyperprolactinemia, cardioprotective, oxidative stress, dopamine, cathepsin D, vasoinhibin, PRL 16-kDa fragment, and bromocriptine. No date limit was imposed on the database search. No specific pre-determined criteria for inclusion/exclusion of literature was set. This is not a systematic review and there may be a possibility of introducing selection bias while selecting literature for this review.

THE MELATONIN-PRL ENDOCRINE AXIS

Melatonin, which is produced mainly by the pineal gland, acts on circadian rhythms but also works synergistically with pituitary hormones. One neglected role of melatonin, especially with regard to its exogenous supplementation, which has increased significantly in recent years[11,12], is its impact on PRL secretion.

PRL is a peptide hormone largely responsible for lactation and is regulated negatively by dopamine released from tuberoinfundibular dopaminergic neurons in the hypothalamus[13]. Melatonin acts to increase PRL secretion, likely via its action on hypothalamic dopaminergic neurons[12]. Studies dating back to the late 20^th century, and more recently discussed by Venaki et al[12], indicate that acute melatonin administration at doses up to 5 mg could temporarily quadruple PRL levels compared to baseline[12,14,15].

The prevalence of melatonin use has increased in the United States population[11], leading authors to suggest that the clinical finding of hyperprolactinemia may be encountered more frequently, even if often overlooked in medical history inquiries[12]. A key limitation in the literature is the scarcity of data concerning the effects of chronic melatonin supplementation, which is the type of use associated with the recent adverse cardiac findings[8]. While acute administration clearly elevates PRL, whether long-term, daily use, particularly at the high doses often found in supplements (which can exceed labeled content significantly)[16], results in sustained hyperprolactinemia is an open question that merits critical study[12]. One important - yet unverified assumption about the mechanistic pathway described above - needs to be noted: Although acute melatonin treatment increases blood PRL, it is still unknown whether chronic melatonin intake will induce persistent hyperprolactinemia in humans. Relevant studies are lacking. This constitutes an important scientific gap that needs to be addressed in the future, because the whole cardiac risk mechanism hinges upon this unproven idea.

PPCM: A MODEL OF PRL-MEDIATED CARDIOTOXICITY

Transmembrane receptors of PRL are present throughout the cardiovascular system[17,18]. PPCM is a relatively uncommon - yet potentially lethal - cardiac disorder. PPCM is characterized by HF with reduced ejection fraction (HFrEF). It manifests during the last month of gestation or after childbirth[10,19]; it may serve as an important experimental paradigm, as its etiology is closely associated with the biology of PRL[20].

The fundamental pathophysiologic/causative pathway in PPCM entails oxidative stress-induced degradation of the full-length PRL protein (23 kDa) into a toxic 16 kDa N-terminal portion of PRL[10,19,21]. Such degradation is achieved via the action of proteases, for instance, cathepsin D, which are upregulated in response to oxidative stress in cardiac tissue around the period of delivery[10,21,22].

The 16-kDa fragment of PRL (also termed vasoinhibin), negatively affects endothelial cells, causing damage to cardiac microvasculature[10,21,23]. Moreover, this 16-kDa fragment activates the production of miR-146a, which in turn has harmful effects on cardiomyocytes[10,24], developing into HF. This form of HF has potential to be reversed[10]. The pharmacological suppression of PRL secretion is a proven specific approach to the treatment of PPCM[10,19,25]. Drugs acting on dopamine receptors, such as bromocriptine, inhibit the secretion of PRL from the pituitary gland, preventing the transformation of 23-kDa PRL into the harmful 16-kDa fragment[10,22]. Clinical studies - including randomized multicenter clinical trials - have confirmed that the use of bromocriptine in combination with conventional HF treatment leads to complete cardiac rehabilitation among PPCM patients[22,26,27]. Such treatment may be curative even in women with severe manifestations of the disease and right ventricular insufficiency[22,26,27]. Furthermore, other PRL release inhibitors - such as cabergoline - have shown their effectiveness[28,29]. The therapeutic success of PRL suppression solidifies the concept that elevated circulating PRL levels, when combined with localized cardiac triggers, represent a potent driver of myocardial failure.

PROPOSED CAUSAL LINK: MELATONIN-INDUCED HYPERPROLACTINEMIA AS A CARDIAC RISK FACTOR

The juxtaposition of three key observations creates a biologically plausible, but as yet unconfirmed, hypothesis linking long-term melatonin use to incident HF: (1) Melatonin supplementation is newly associated with an increased risk of HF[8]; (2) Melatonin acutely elevates PRL levels[12]; and (3) PRL, under conditions of oxidative stress, causes severe HF (PPCM)[21]. The likelihood that the proposed adverse PRL-mediated pathway predominates over melatonin's well-established antioxidant and cardioprotective effects is not uniform across all patients. We propose that the following subgroups may carry the highest theoretical risk, should the hypothesis be validated: (1) Patients of advanced age with age-related increases in systemic oxidative stress; (2) Individuals with high comorbidity burden (hypertension, diabetes mellitus, metabolic syndrome, obesity); (3) Patients with pre-existing cardiovascular disease or subclinical left ventricular dysfunction; (4) Individuals with chronic systemic inflammation, as evidenced by elevated C-reactive protein, elevated systemic immune-inflammation index, or composite nutritional-inflammatory scores - since a pro-inflammatory milieu may facilitate cathepsin D-mediated PRL cleavage; and (5) Individuals consuming high or unregulated supplement doses for prolonged periods (one year or more). Conversely, in healthy young adults using low-dose, short-term melatonin, the cardioprotective antioxidant effects are likely to predominate, consistent with the existing supportive literature.

Chronic exogenous melatonin and PRL reservoir

The prerequisite for generating the cardiotoxic 16-kDa PRL fragment is the presence of high levels of the full-length 23-kDa precursor[10]. Physiological PRL levels peak in the peripartum period[21]. Prolonged consumption (for more than one year), which was assessed in the recently published abstract by the American Heart Association[8], could result in continuous pharmacological hyperprolactinemia[12]. However, the absence of long-term data regarding melatonin's effects on PRL levels due to its continuous usage is a significant gap in existing knowledge. Although it is well-known that PRL levels increase as a consequence of acute melatonin supplementation, there is no direct evidence that such hormonal increases persist in cases when it is used for extended periods of time. This is the core assumption in regard to the presented pathogenesis, but it requires confirmation through further research[12]. Since melatonin supplements are widely accessible on the market, and doses vary considerably, the probability of achieving prolonged and intensive hormonal exposure in patients is quite high[16]. Such hyperprolactinemia may be regarded as a hormonal substrate similar to the one present in the physiological peripartum period.

Oxidative stress as the cleavage trigger in non-peripartum patients

PPCM patients are in an increased oxidation state, which can trigger the cleavage of 23-kDa PRL to 16-kDa PRL in the myocardium[19,21]. There was no mention of including women in the peripartum period among those using melatonin for a prolonged time in the latest study[8], however, oxidation and inflammation are two cardinal characteristics of HF regardless of its cause[2]. Chronic HF patients exhibit increased neurohormonal activation. This activation state includes adrenergic overactivity and increased blood inflammatory factors, such as C-reactive protein[1,30]. All the above conditions increase oxidative stress by default[2]. The patient group considered in the study linking melatonin and HF was composed of people with insomnia, who are prone to have multiple co-morbidities and sleep disturbances, which in themselves increase systemic stress. Also, research on biomarkers done on chronic heart failure patients (Class III New York Heart Association) have shown a negative correlation between the release of melatonin during the night and levels of NT-proBNP. Researchers postulate that in patients with HF, this decrease in the production of melatonin might be attributed to adrenergic overdrive leading to decreased activity in the pineal gland[1]. This systemic environment, marked by the presence of oxidative stress and inflammation, could thus constitute the appropriate milieu for the activity of proteolytic enzymes such as cathepsin D responsible for cleavage of 23-kDa PRL[21]. According to recent meta-analytical findings, blood PRL represents an independent risk factor for cardiovascular mortality in adulthood, irrespective of the presence of prolactinoma[18,31]. This relationship might partially result from this hormone’s chronotropic and arrhythmogenic activity. Animal studies have found that PRL can cause arrhythmia and possesses a bidirectional effect on heart rate. At moderate doses (50 ng/mL) it increases heart rate significantly, while larger amounts (200 ng/mL) produce an inverse effect[32]. Clinically, plasma PRL correlates positively with resting heart rate, mainly in females and people with depression[33]. PRL also influences the cardiac morphology differentially according to gender. In men with prediabetes, PRL, even within physiological range, constitutes an independent predictor of left ventricular mass/hypertrophy[34]. In contrast, pathologic hyperprolactinemia might induce the development of arterial hypertension and structural injury. The latter are attributed to the modulation of endothelial nitric oxide synthase and the promotion of inflammation, via expression of its receptors in macrophages of atherosclerotic plaques[35,36]. This is an important point of difference between PPCM and the rest of the population (exposed to exogenous melatonin). In PPCM the trigger factor is the physiological rise in PRL levels during the peripartum period, combined with pregnancy-associated stress, whereas in the rest of the population (exposed to melatonin), exogenous administration of melatonin may provide the trigger factor for increased PRL reserve. The risk factors that predispose the patient to chronic HF (such as hypertension, diabetes, old age, or preexisting myocardial disease) will provide the oxidative stress required to induce PRL cleavage. Thus, the unanticipated adverse effect of long-term melatonin consumption in HF patients may be attributed to melatonin interrupting the normal feedback loop that regulates PRL production.

The anti-angiogenic and pro-apoptotic mechanisms

The 16 kDa fragment that is produced is highly cardiotoxic and anti-angiogenic[10]. Endothelial dysfunction, according to several researchers, is a well-known trigger of HF, specifically HFrEF[5]. Although there have been research reports about the role played by melatonin in reversing endothelial dysfunction through its antioxidant activity[5], the negative effects brought about by melatonin due to its action as a pro-cardiotoxic hormone via PRL could outweigh the benefits. The 16-kDa PRL fragment produces damage by inducing microRNA-146a expression, causing apoptosis of cardiomyocytes[10,24]. This process is similar to the pathological process observed in cases of severe HF. These processes include oxidative stress, apoptosis, and remodeling of the heart’s ventricles[2,37]. The availability of the apoptotic trigger induced by PRL may lead to rapid development of existing or latent HF, particularly among people with risk factors for cardiovascular disease and chronic sleeplessness, taking melatonin supplements long-term[8].

Contradictory evidence - contextualizing melatonin’s cardioprotection

The adverse mechanism that we expose above presents a conundrum. It contradicts the large body of research from experimental models and some preliminary evidence from clinical trials, which highlight the cardioprotective potential of melatonin. It is widely known that melatonin functions as a direct antioxidant that scavenges reactive oxygen species and antioxidant enzymes molecules, and increases the levels of antioxidant enzymes[37-39]. Several experimental animal studies have documented that melatonin has cardioprotective effects on ischemia-reperfusion, apoptosis, and cardiac remodeling processes[2,37,40]. Preliminary evidence from clinical studies indicates that melatonin supplements at a dose of 10 mg/day for 24 weeks can positively affect quality of life and NT-proBNP serum levels in HFrEF patients[5,7].

Reconciliation of the paradox: Duration and PRL exposure

The contradiction between the known protective responses and the newly discovered long-term hazard can be explained through the perspective of exposure time and the varying impacts of acute and chronic stimulation of the endocrine system.

Acute vs chronic use: The majority of mechanistically positive studies relate to acute usage, preventive treatment (for example, before ischemia/reperfusion injury), or short clinical trials (such as for 24 weeks)[2,5]. The positive antioxidant effects might overshadow any negative impact over short periods of time. However, the new relationship between the two is characterized by chronic use (of at least one year)[8]. The chronic usage could contribute to the accumulation of PRL within the body, ultimately overpowering the antioxidant effects and resulting in negative outcomes[12].

Dosage and formulation variability: The dose of melatonin required to provide cardioprotective effects in animal studies is relatively high[2,41]. Those taking the supplements might be taking a highly variable dose that is sometimes quite high[16]. Pharmacological doses might cause excessive stimulation of PRL secretion, resulting in hyperprolactinemia[12]. The prolonged presence of hyperprolactinemia could result in the cleavage effect being significantly higher due to oxidative stress in the body.

Endogenous vs exogenous timing: In patients of advanced HF, the endogenous levels of melatonin are found to be decreased; hence, there is no cardioprotective effect[1,2]. The exogenous therapy of such individuals, especially for the treatment of the symptom of insomnia[42], aims at restoring the circadian rhythm. However, the exogenous hormone, specifically high-dose chronic use of melatonin supplements, could pose a threat in the form of elevated PRL substrate; an adverse effect apart from its antioxidant property and neurohormonal control[5]. Thus, despite being a strong antioxidant[37], the upstream regulatory effect of melatonin on neurohormones through PRL seems to be an antagonistic mechanism.

CLINICAL IMPLICATIONS AND FUTURE RESEARCH DIRECTIONS

The relationship identified between melatonin usage and the incidence of HF points to the need for further understanding regarding hormone supplementation safety. Melatonin is widely marketed as a safe sleep aid, yet long-term cardiovascular safety data are lacking[8]. PRL homeostasis is required for cardiometabolic balance, positioning it as a potentially valuable biomarker for risk stratification[43]. If the proposed PRL-mediated causal link is validated, the clinical management and counseling regarding melatonin use, particularly in individuals with existing cardiovascular risk factors (e.g., hypertension, obesity, metabolic syndrome, or known HFrEF), would require immediate revision[8].

Chronic PRL monitoring

Prospective, randomized controlled trials are urgently needed to assess the effect of long-term (e.g., > 1 year) exogenous melatonin supplementation at typical supplemental doses (3 mg to 10 mg or higher) on sustained plasma PRL levels in non-peripartum individuals with chronic disorders[12]. Measurement of the 16-kDa PRL fragment levels in these patients could be implemented.

Oxidative stress interaction

Studies should investigate whether melatonin-induced hyperprolactinemia in the presence of elevated systemic markers of inflammation (e.g., C-reactive protein) or oxidative stress [e.g., myeloperoxidase, caspase-3, or malondialdehyde levels, which are elevated in severe (pediatric) HF and may reflect systemic damage][3] increases the ratio of 16-kDa/23-kDa PRL, independent of pregnancy status.

Animal modeling

The use of animal models of chronic HF (e.g., transverse aortic constriction or post-infarction models) should be employed to study the administration of exogenous melatonin concurrent with PRL inhibition (e.g., bromocriptine)[2]. If melatonin worsens HF outcomes, and this effect is mitigated by PRL inhibition, it would provide strong evidence for the proposed causal pathway.

Pharmacovigilance and registry data

Given the retrospective nature of the initial alarming data[8], cardiovascular endpoints and PRL levels should be systematically tracked in large-scale patient registries utilizing melatonin, particularly focusing on dosage and duration of use, and whether a history of chronic insomnia or other comorbidities exacerbates risk.

Therapeutic reversal potential

In case the link between long-term melatonin supplementation and HF is verified, we can consider a new approach to treatment. More in detail, dopaminergic medications (inhibitors of PRL secretion), which have so far been used only for PPCM[19,22], could be recommended for a selected group of chronic heart failure patients, those with elevated PRL levels and under chronic melatonin treatment. While such a concept is highly speculative and presents potential risks (e.g., the - debated - risk of thrombosis associated with bromocriptine use in the peripartum setting[44]), the ability of PRL inhibitors to successfully reverse cardiotoxicity in PPCM sets a compelling precedent for disease-specific therapy targeting this endocrine axis[10]. In addition, there is evidence that medications that inhibit PRL secretion, such as bromocriptine, exert non-PRL-dependent cytoprotective actions on the myocardium[22]. This facet of drug action, would make interpretation even more difficult, but would broaden the scope of potential therapy.

CONCLUSION

The serendipitous finding associating long-term melatonin therapy with the development of HF[8] demands further study. The hypothesis-generating nature of this review cannot be denied, as the clinical observation underpinning this idea is preliminary, unpublished, unconfirmed, and subject to bias due to indications. We suggest that the melatonin-induced hyperprolactinemia may act as a source of elevated PRL levels required for the cleaving process leading to the toxic 16-kDa fragment in individuals with chronic oxidative and inflammatory reactions characteristic of existing cardiovascular pathology. This hypothetical mechanism mimics the PPCM pathophysiological processes and indicates an additional hormone-dependent cardiotoxic pathway for melatonin (Figure 1) shows the analogies between PRL and PPCM, as well as the proposed axis of melatonin-PRL-oxidative stress, which results in HF, emphasizing PRL proteolysis.

Figure 1 Analogies between prolactin and peripartum cardiomyopathy, as well as the proposed axis of melatonin-prolactin-oxidative stress, which results in heart failure, emphasizing prolactin proteolysis. ROS: Reactive oxygen species; PRL: Prolactin; PPCM: Peripartum cardiomyopathy; HF: Heart failure. Original work, created on Microsoft PowerPoint, additionally using freely available elements from Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/Licenses/by/4.0/).