Growth Hormone Increase Induced by Oral Administration of Melatonin in a Young Woman With Sleep Disturbances

Abstract

Growth hormone (GH) secretion by the pituitary is regulated by stimulatory and inhibitory pathways such as growth hormone releasing hormone (GHRH) and somatostatin, respectively, being also modulated by different neurotransmitters acting at the hypothalamic/pituitary level. The pineal gland hormone melatonin regulates GH secretion in many mammals, including humans, although its role in modulating GH secretion has been debated. We describe the case of a young woman chronically taking melatonin for sleep disturbances, referring to her general practitioner for flushing that appeared just after starting melatonin intake. Laboratory findings showed elevated plasma levels of GH and insulin-like growth factor-1 (IGF-1). She did not show clinical features resembling acromegaly. The evaluation of pituitary and pituitary end organ hormones showed normal plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), estradiol, free thyroid hormones, cortisol, and prolactin. Urinary 5-hydroxyindoleacetic acid levels were normal. One month after melatonin withdrawal, her plasma levels of GH, together with IGF-1, completely normalized. An oral glucose suppression test showed a normal response of GH secretion, further excluding an autonomous secretion. Physicians should be aware of the possible interference of melatonin on GH secretion to prevent misleading diagnosis of autonomous secretion thus avoiding valueless and costly clinical investigations.

Introduction

Growth hormone (GH) secretion by anterior pituitary gland is finely regulated by a stimulatory pathway led by growth hormone releasing hormone (GHRH) and by an inhibitory pathway led by somatostatin [1]. In addition, these main control pathways of GH secretion are modulated by different neurotransmitters acting at the hypothalamic or pituitary level, influencing GHRH and somatostatin secretion [1]. Furthermore, it has been demonstrated, first in animal models and then also in humans, that melatonin plays a role in the regulation of GH secretion [2, 3].

In their studies in the late 1980s to 1990s, Valcavi et al showed that oral administration of melatonin to normal human subjects increases basal GH release and GH responses to GHRH by acting at the hypothalamic and not pituitary level [4, 5].

Nonetheless, the role of melatonin in the modulation of GH secretion in human has been debated over time, with authors reporting both an anti-somatotrophic activity of melatonin [2, 3, 6] or a neutral activity [7, 8], probably depending on the dose of melatonin used in the different experimental settings [5].

Here we describe a patient taking melatonin for sleep disturbances, showing elevated GH and insulin-like growth factor 1 (IGF-1) plasma levels that normalized after melatonin withdrawal.

Case Presentation

A 34-year-old female patient was referred to our endocrinological clinic for the appearance of flushing. Her medical history was unremarkable. Her menstrual cycles were regular, and she had not been taking any medication until 3 months prior, when she started taking melatonin due to sleep disturbances (2 mg/day at bedtime). Soon after starting melatonin intake she complained of the appearance of flushing without any other associated symptoms (headache, weight loss, diarrhea, tachycardia, sweating, tremors, or fever).

Diagnostic Assessment

The patient's general practitioner performed an evaluation of pituitary and pituitary end organ hormones, showing normal plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), estradiol, free thyroid hormones, cortisol, and prolactin. Although GH measurement is not customary in the workup of flushing, GH plasma levels were also determined, showing elevated results (10.9 ng/mL; 10.9 μg/L) (reference range [ref.], 0.01-3.6 ng/mL; 0.01-3.6 μg/L) together with IGF-1 plasma levels (294 μg/L; 38.4 nmol/L) (age corrected ref. 19-51 μg/L; 1.4-32.8 nmol). Urinary levels of 5-hydroxyindoleacetic acid, used as a proxy for serotonin measurement through a 24-hour urine test, showed normal results, excluding a carcinoid syndrome.

The patient was then referred to our outpatient endocrine clinic for further evaluation.

At evaluation, the patient did not show any clinical feature characteristic of acromegaly and physical examination was quite unremarkable. In particular, she did not report headache, heart pounding, sweating, or tremors. Her blood pressure and heart rate were normal.

Treatment

To verify the hypothesis of a possible influence of melatonin on basal GH secretion, the patient was asked to stop melatonin intake for 1 month without taking any other medication.

Outcome and Follow-Up

One month after melatonin withdrawal, laboratory results for plasma levels of GH and IGF-1 were completely normalized, together with the disappearance of flushing. To further exclude the presence of an autonomous GH secretion, we also performed an oral glucose suppression test with GH plasma levels evaluation at −15, 0, 30, 60, 90, and 120 minutes after glucose administration (75 g), as described in recent guidelines for the diagnosis of acromegaly [9]. As shown in Fig. 1, the response of GH secretion to oral glucose was completely normal (Fig. 1). Six months after melatonin suspension, the patient's GH and IGF-1 plasma levels remained constantly normal.

Figure 1.

Plasma levels of glucose and growth hormone (GH) before and after the oral glucose suppression test (75 g).

Discussion

Here we describe the case of a young woman showing elevated GH and IGF-1 plasma levels due to melatonin intake for sleep disturbances.

Previous studies in the late 1980s showed that melatonin influences hypothalamic-pituitary end organ axes related to prolactin, GH, thyroid, adrenal, and gonadal function regulation [8, 10, 11]. In this regard, the physiology of melatonin appears to be well established in animals, being related to the transduction of environmental day length information into neurohormonal output, especially in terms of activation or deactivation of the hypothalamic-pituitary-gonadal axis in seasonal breeders [11].

In humans, the physiological role of melatonin in the regulation of GH secretion remains somehow uncertain [10]. Previous studies reported conflicting results reporting both stimulatory and inhibitory effects of pharmacological doses of melatonin on stimulated GH secretion [2, 7, 12‐17], although generally indicating no significant effects of acute melatonin administration on GH secretion. These data apparently debunked a role of melatonin as an acute neuroendocrine modulator of pituitary hormones [10].

However, we do not have any strong evidence on the possible role of the chronic intake of melatonin on GH secretion, above all considering that it is assumed at bedtime when GH secretion begins to be progressively higher, with GH plasma levels that are evaluated early in the next morning. There is only one previous published study reporting a stimulatory effect on GH secretion by chronic treatment with melatonin in a man without a pineal gland [18].

The present case report seems to indicate that chronic melatonin administration can induce a stimulation of GH (and then of IGF-1) secretion that is rapidly reversed by melatonin withdrawal. As previously reported, it is highly probable that melatonin exerts its effects on GH secretion at the central level [4]. Interestingly, no other hypothalamus-regulated pituitary hormone was altered in our patient other than GH.

These observations on melatonin effects on GH secretion could be of interest in view of its wide distribution and when considering its potential clinical use. Melatonin supplementation is in fact largely used to treat sleep-related alterations, such as insomnia, disrupted sleep phase syndrome, jet lag, restlessness, and so on [19].

The growing problem of insomnia in developed countries is the major reason for the growth of demand for melatonin in the United States and will continue to drive the melatonin market growth [19].

The market size of melatonin supplements was valued at approximately USD 2.15 billion in 2022 and is estimated to expand with a compound annual growth rate of about 14% from 2023 to 2032, driven by increasing awareness of the importance of sleep and the growing prevalence of sleep disorders worldwide [20].

Synthetic melatonin is inspected by the Food and Drug Administration (FDA) and by other national drug regulatory agencies as a food supplement, not as a pharmaceutical. Thus, melatonin can be obtained without a prescription at medical stores and natural food stores [20]. Although melatonin is generally considered safe for short-term use [21, 22], its long-term effects and potential side effects are still being studied. Misuse and over-reliance on melatonin supplements without proper medical guidance could lead to adverse effects and potential health risks [21, 22].

Thus, the knowledge of the possible interferences of melatonin with endogenous hypothalamic/pituitary hormones should be considered in these subjects to avoid valueless and costly investigations.

Learning Points

• Chronic melatonin administration might be a potential cause of increased GH plasma levels.

• Suspension of melatonin treatment returns GH plasma levels to normal values.

• Melatonin intake could lead to misleading diagnosis of autonomous GH secretion.

• Physicians should be aware of this possible hormonal interference of melatonin on GH secretion.

Contributors

M.R. and A.D.V. were involved in the diagnosis and management of the patient and manuscript submission. E.Z. and C.P. were involved in the follow-up of the patient. All authors reviewed and approved the final draft.

Abbreviations

FSH

follicle stimulating hormone

GH

growth hormone

GHRH

growth hormone releasing hormone

IGF-1

insulin-like growth factor 1

LH

luteinizing hormone

TSH

thyroid stimulating hormone

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.