Unraveling the Ghrelin-Thyroid Axis: How the Hunger Hormone Influences Thyroid Health and Disease

Abstract

The interplay between hormones governing metabolism, appetite, and endocrine function is complex and multifaceted. Among these, ghrelin, often known as the "hunger hormone," has gained attention not only for its role in appetite regulation but also for its potential influence on thyroid function and thyroid disorders. Ghrelin, secreted mainly by the stomach, acts through the growth hormone secretagogue receptor (GHSR) and influences energy balance, body weight, and endocrine homeostasis. Recent research highlights possible associations between ghrelin levels and thyroid hormone disturbances, including hypothyroidism, hyperthyroidism, Hashimoto’s thyroiditis, and Graves’ disease. This review explores the biological pathways linking ghrelin to thyroid function, evaluates how thyroid dysfunction may alter ghrelin secretion, and discusses whether ghrelin modulation could serve as a biomarker or even a therapeutic target in thyroid diseases. By examining existing literature, the article provides a comprehensive overview of the bidirectional relationship between the ghrelin-thyroid axis, shedding light on potential diagnostic and therapeutic innovations.

Introduction

The endocrine system functions as a highly interconnected network, with numerous hormones influencing one another. Among these hormones, ghrelin, the stomach-derived peptide best known for its appetite-stimulating role, has more extensive systemic effects than once thought. Increasing evidence supports a relationship between ghrelin and thyroid hormones, suggesting that ghrelin may have regulatory roles in thyroid physiology and contribute to pathological changes in thyroid diseases.

As thyroid hormones play a crucial role in metabolism, energy expenditure, and growth, it is unsurprising that they might interact with metabolic regulators like ghrelin. The bidirectional relationship between the thyroid and ghrelin may offer new insights into metabolic dysregulation in thyroid disorders and pave the way for novel therapeutic strategies.

Ghrelin: More Than a Hunger Hormone

Ghrelin Synthesis and Secretion

Ghrelin is primarily secreted by enteroendocrine cells in the stomach, but it is also produced in small amounts in the hypothalamus, pituitary, pancreas, and thyroid gland. It acts via the growth hormone secretagogue receptor (GHSR-1a), stimulating appetite, and growth hormone (GH) secretion, and modulating glucose metabolism and energy homeostasis.

Systemic Effects

While its central role is to promote hunger and energy intake, ghrelin also exerts:

• Anti-inflammatory effects

• Cardiovascular modulation

• Glucose and lipid metabolism regulation

• Influence on reproductive and thyroid hormones

Thyroid Hormones and Metabolic Regulation

Thyroid Hormone Synthesis

Thyroid hormones (T3 and T4) are synthesized in the thyroid gland under the regulation of thyroid-stimulating hormone (TSH), which is secreted from the pituitary gland. These hormones play vital roles in:

• Basal metabolic rate (BMR) control

• Thermogenesis

• Lipid and glucose metabolism

• Protein synthesis and cell growth

Thyroid Dysfunctions

• Hypothyroidism: Decreased thyroid hormone production leading to weight gain, fatigue, and slowed metabolism.

• Hyperthyroidism: Excess thyroid hormone causing weight loss, hypermetabolism, and increased appetite.

• Autoimmune Thyroid Diseases (AITDs): Conditions like Hashimoto’s thyroiditis and Graves’ disease involve immune dysregulation targeting the thyroid.

Ghrelin and Thyroid: Potential Mechanisms of Interaction

1. Ghrelin’s Direct Influence on the Hypothalamic-Pituitary-Thyroid (HPT) Axis

Ghrelin receptors are present in the hypothalamus and pituitary, where they influence the secretion of TSH, the master regulator of thyroid function. Studies suggest that ghrelin may inhibit TSH secretion, indicating a direct suppressive effect on the HPT axis. This could link elevated ghrelin levels to subclinical hypothyroidism.

2. Impact of Thyroid Hormones on Ghrelin Secretion

Thyroid hormones also appear to regulate ghrelin production and release. In hyperthyroidism, ghrelin levels are often suppressed, while hypothyroidism is associated with elevated circulating ghrelin. This reciprocal regulation could serve as a compensatory mechanism in conditions of altered metabolic demand.

3. Ghrelin’s Role in Inflammation and Autoimmune Thyroid Disorders

Ghrelin has anti-inflammatory properties, inhibiting pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6. In autoimmune thyroid diseases such as Hashimoto’s and Graves’ disease, ghrelin may modulate immune responses, potentially influencing disease severity and progression.

Ghrelin and Specific Thyroid Disorders

1. Hypothyroidism

Altered Appetite and Weight Gain

Hypothyroidism is often associated with weight gain despite reduced appetite. Elevated ghrelin levels in hypothyroidism might reflect a compensatory response to reduced metabolic rate and energy expenditure.

Ghrelin Resistance

Some studies suggest that hypothyroid patients may experience central ghrelin resistance, meaning increased ghrelin does not sufficiently stimulate appetite, contributing to the mismatch between increased ghrelin and reduced food intake.

2. Hyperthyroidism

Weight Loss and Suppressed Ghrelin

In hyperthyroidism, weight loss occurs despite increased appetite, and circulating ghrelin levels are often reduced. The high metabolic rate seen in hyperthyroidism may suppress ghrelin production, indicating a potential metabolic feedback loop between thyroid hormones and appetite regulation.

3. Hashimoto’s Thyroiditis

Chronic Inflammation and Metabolic Dysregulation

Hashimoto’s thyroiditis, a leading cause of hypothyroidism, involves chronic inflammation. Ghrelin’s anti-inflammatory effects could theoretically counter some inflammatory processes in Hashimoto’s, though direct clinical evidence is limited.

Ghrelin as a Biomarker

Some researchers propose that ghrelin could serve as a biomarker for inflammation severity or disease activity in Hashimoto’s thyroiditis.

4. Graves’ Disease

Excess Thyroid Hormones and Appetite Dysregulation

In Graves’ disease, excess thyroid hormone increases metabolic rate and suppresses ghrelin, potentially contributing to paradoxical hyperphagia despite weight loss. This mismatch reflects complex interactions between thyroid hormones, ghrelin, and appetite regulation centers.

Clinical Implications: Can Ghrelin Serve as a Diagnostic or Therapeutic Target?

Ghrelin as a Biomarker

Monitoring ghrelin levels in thyroid disease could offer insights into metabolic status and disease progression. Elevated ghrelin may signal impaired thyroid function, while suppressed ghrelin could reflect hyperthyroidism.

Ghrelin Modulation Therapy

Therapeutic strategies aimed at modulating ghrelin—either through ghrelin agonists in hypothyroidism or antagonists in hyperthyroidism—might complement hormone replacement therapies, particularly in patients with metabolic complications.

Future Research Directions

1. Mechanistic Studies

Further research is needed to clarify the precise molecular interactions between ghrelin signaling and the HPT axis, particularly in autoimmune thyroid disease.

2. Longitudinal Cohort Studies

Long-term studies tracking ghrelin levels across the spectrum of thyroid disease could clarify causal relationships and evaluate ghrelin’s utility as a prognostic marker.

3. Therapeutic Trials

Clinical trials investigating ghrelin-based interventions in thyroid disease patients, especially those with concurrent metabolic syndrome, could provide novel therapeutic options.

Conclusion

The relationship between ghrelin and thyroid disease exemplifies the intricate crosstalk between metabolic and endocrine systems. Ghrelin not only influences appetite and energy homeostasis but also modulates thyroid function, inflammation, and immune response. Understanding this interplay may open new diagnostic, prognostic, and therapeutic avenues for managing both thyroid disorders and metabolic complications.