Given its essential role in these various processes, hypo- or hyperproduction of melatonin and impaired melatonin receptor signaling has been linked to multiple clinical syndromes, as described in the review and briefly summarized here.1

· Hypomelatoninemia. Reduced melatonin production can lead to symptoms such as sleep disorders, metabolic syndrome, glucose intolerance and insulin resistance, hypertension, and increased diabetes and cancer risk. Hypomelatoninemia typically occurs secondary to disease, aging, or environmental disruption, and may improve with melatonin replacement therapy.

· Hypermelatoninemia. Rarely, overproduction of melatonin may lead to medical syndromes including anorexia nervosa, spontaneous hypothermia hyperhidrosis, polycystic ovarian syndrome, hypogonadotrophic hypogonadism, and Rabson-Mendenhall syndrome. Symptoms may include daytime sleepiness, low body temperature, hypotonia, and dizziness, which may ameliorate with phototherapy and beta-blockers.

· Circadian displacement. In patients with this putative syndrome, the “magnitude of the daily melatonin peak is usually not altered but the blood melatonin nocturnal curve is displaced in time”; for example, it may extended to the morning or completely displaced to daytime, as observed in the Smith-Magenis syndrome. Treatment should be individualized for the correct timing and dose of melatonin for each patient, taking into consideration the phase-shifting desired effect.

· Inappropriate melatonin receptor-mediated response. These cases are defined by impaired central and peripheral responses of the organs to melatonin, despite adequate melatonin production and timing. This response primarily results from genetic variations of melatonin receptors and leads to chronodisruption and related symptoms, and potentially disorders such as type 2 diabetes, sleep disorders, Graves disease, polycystic ovarian syndrome, and more. Symptoms depend on the affected tissues.

The review authors noted the following points to be considered when administering melatonin replacement therapy: chronic administration should be limited to nighttime, administration should be carefully timed to achieve the desired effect, and dosage and formulation should be carefully tailored to each individual “to build a blood melatonin profile that mimics the physiological one and end by the beginning of the morning.”1

“In summary, given its periodic circadian release driven by the [suprachiasmatic nucleus], the great contrast between night and day circulating concentrations, in addition to the pleiotropic mechanisms of action controlling central and peripheral oscillators, melatonin acts as a powerful chronobiotic hormone and ultimately participates as one of the most important unifying agents that is responsible for the synchrony between the multitude of circadian rhythms at several levels (cell, tissue, organ, and system),” they concluded.

To further discuss the topic of melatonin dysfunction and related treatment implications, Endocrinology Advisor checked in with Jamie Zeitzer, PhD, associate professor of psychiatry and behavioral sciences at Stanford University and sleep specialist at the Stanford Sleep Medicine Center.