Thyroid Disease: Understanding The Endocrine System

Of the many organs and glands within the human body, certain systems are regarded as common knowledge: the beating heart that circulates blood throughout the body, the ballooning lungs that oxygenate the blood, or the twin kidneys that filter out toxins. The endocrine system and thyroid, on the other hand, often eludes that same common understanding, resulting in an underrepresentation, underdiagnosis, or unawareness of thyroid diseases and disorders. [1][2][3][4][5]

This curtailment, however, is not surprising. The symptoms of thyroid disease are often mild and unassuming: as a hormone-secreting gland, the thyroid affects every organ in the body. As such, identifying thyroid-specific symptoms can be difficult for providers and patients alike. Additionally, the majority of thyroid disease cases are subclinical, translating to an even milder presentation than standard thyroid disease. The American Thyroid Association estimates 60% of people with a thyroid disorder may not even be aware of their own diagnosis. Therefore, improving awareness around thyroid disease is essential. [1][2][3][4][5]

Normal Thyroid and Endocrine Function

To understand how thyroid disease works, it is imperative to first understand how the thyroid works normally, as well as how the entire endocrine system works alongside the thyroid. Three glands primarily make up the thyroid system: the hypothalamus, anterior pituitary, and thyroid glands all interact with one another to regulate hormones throughout the body in the aptly-named hypothalamus-pituitary-thyroid axis system. [1][2][3][4][5][6]

Diagram demonstrating the Hypothalamus-Pituitary-Thyroid Axis

The Hypothalamus is an almond-sized section within the base of the brain that regulates hormones. The hypothalamus produces Thyrotropin-Releasing Hormone (TRH), which activates the Anterior Pituitary gland—which sits just beneath the brain and below the hypothalamus. The anterior pituitary, upon receiving a signal from TRH via a TRH receptor, begins to release thyrotropin, otherwise known as Thyroid-Stimulating Hormone (TSH), whose primary function is to stimulate the thyroid to produce thyroid hormones. [1][2][3][4][5]

The Thyroid is a small, isolated, butterfly-shaped gland that rests in the front-bottom neck (below where an Adam's apple might be). The TSH from the anterior pituitary travels to the thyroid and interacts with its TSH receptors to activate the thyroid. Upon receiving that signal from TSH, the thyroid releases hormones Thyroxine (T4) and Triiodothyronine (T3). 80-90% of the released hormone is the T4 and is considered the “inactive” hormone. The remaining 10-20% produced by the thyroid is the T3 hormone and is considered the “active” hormone that activates different organs to perform various actions. Both T4 and T3 are made up of iodine atoms attached to a central thyroglobin base, with T4 containing 4 iodine atoms and T3 containing 3 iodine atoms. Inactive T4 travels to tissues which then utilize a nearby enzyme called deiodinase to remove one iodine, converting T4 into an active T3 hormone that can make changes to the adjacent cells. [1][2][3][4][5]

When lots of T4 and T3 molecules are circulating in the bloodstream, they interact with and act upon many organs and can increase heart rate, oxygenation of the blood in the lungs, development of fast-twitch muscle fibers, basal metabolism, or bone growth stimulation. They also act upon the hypothalamus and anterior pituitary glands to curb production of TRH and TSH to create a negative feedback loop. Therefore, low levels of T3 and T4 indicate high levels of TSH, and high levels T4 and T3 signals low levels of TSH, creating an intricate and delicate inverse balance of hormones that, when skewed, leads to thyroid disease. [1][2][3][4][5]

Hypothyroidism: Underproduction of Thyroid Hormone 

As one of the most common endocrine disorders, Hypothyroidism is present within 4.6% of the U.S. population. Simply put, hypothyroidism describes deficient or insufficient thyroid hormones (T4 or T3). Primary hypothyroidism, the most common version, describes the thyroid’s inability to produce the hormones, whether through gland dysfunction or a significant iodine deficiency. Secondary, tertiary, central, or peripheral hypothyroidism, all of which are much rarer, result from a healthy thyroid but unhealthy secondary or peripheral glands, such as dysfunctional anterior pituitary or hypothalamus, with subsequent decreased TSH or TRH production respectively. [7][8]

When T4 or T3 reach low levels (and, consequently, TSH levels go up), above the clinical threshold, it becomes overt hypothyroidism, often requiring medical intervention. Milder cases of hypothyroidism are called subclinical hypothyroidism, when the clinical definitions and parameters for hypothyroidism are not met but still significantly leave an impact on the body. [7][8]

Symptoms for Hypothyroidism

Possible symptoms of hypothyroidism may include, but are not limited to:

• Abnormally slow heart rate

• Low or depressed mood 

• Slowed cognition

• Decreased libido

• Constipation

• Muscle cramps

• Fatigue or lethargy

• Carpal tunnel syndrome

• Cold intolerance

• Sleep disturbance

• Menstrual cycle abnormalities

• Decreased sweating

• Facial or generalized puffiness or swelling

• Dry skin or other skin changes

• Coarse hair or other voice changes

• Hair loss, coarseness, or other hair changes

• Unusual weight gain

• Goiter (visible enlargement of the thyroid gland)

• Galactorrhea (unexpected milk discharge not related to childbirth or nursing)

Given the widespread, nonspecific, and oftentimes discrete symptoms, it is unsurprising that many people may not think to look for hypothyroidism as a pertinent issue within their healthcare. As such, these symptoms must be clinically correlated with laboratory testing or other clinical findings if indicated by a healthcare provider to determine whether or not the thyroid hormones are decreased in order to diagnose hypothyroidism. [7][8]

Potential Causes of Hypothyroidism

The potential causes of hypothyroidism are just as varied as its symptoms. Women and those over 60 years old are at higher risk to develop hypothyroidism, as well as a previous history of pregnancy complications, autoimmune diseases, or thyroid disorders. One of the most prominent diseases that produces hypothyroidism is Hashimoto’s disease (Hashimoto’s thyroiditis), which is an autoimmune disorder where the body’s immune system erroneously attacks the thyroid and disrupts its normal function. The most prominent behavioral cause of worsening or exacerbation of hypothyroidism is an iodine deficiency. Since iodine is a required building block for making T4 or T3 molecules, the body running out of iodine means no more T4 or T3 can be produced, leading to hypothyroidism. [7][8][9]

Treatment of Hypothyroidism

The most common treatment for hypothyroidism is with a drug called levothyroxine (LT4), which acts as an artificial hormone and structural analog to the inactive T4 hormone. Importantly, it can be converted to the active T3 hormone and perform actions on the cells and the body, effectively supplementing the T4 and T3 deficiencies. Alternatively, if the primary source of the thyroid dysfunction comes from an iodine deficiency, another common recourse is increasing dietary or supplemental iodine intake to help reduce symptoms. [5][7][8][9]

Hyperthyroidism: Overproduction of Thyroid Hormone

Hyperthyroidism is another common thyroid disease that affects 1.3% of the U.S. population and is characterized by overabundance of T4 or T3 hormones, presenting as the inverse of hypothyroidism. Hyperthyroidism can be subcategorized into overt hyperthyroidism and subclinical hyperthyroidism denoting the respective high and low intensity of the disease and its symptoms. Hyperthyroidism can also be organized into the similar primary and secondary hyperthyroidism, with thyroid hormone production originating from thyroid gland dysfunction in primary hyperthyroidism and from elsewhere in secondary hyperthyroidism. [10][11][

Symptoms for Hyperthyroidism

Possible symptoms for hyperthyroidism include, but are not limited to:

• Unintentional weight loss or gain

• Heart palpitations

• Tremors in the arms, legs, head, or elsewhere

• Heat intolerance

• Shortness of breath or windedness with physical exertion

• Increased anxiety or irritability

• Fatigue or muscle weakness

• Increased frequency of bowel movements (or diarrhea)

• Hair loss

• Insomnia

• Decreased libido

• Oligomenorrhea (infrequent menstrual periods, going 35 days or more between periods)

• Amenorrhea (loss of a menstrual cycle with no pregnancy)

Similarly to hypothyroidism, hyperthyroidism’s diffuse and nonspecific symptoms need clinical correlation with laboratory testing to confirm whether or not thyroid hormones are abnormally elevated and responsible for the symptoms or not. [10][11]

Causes of Hyperthyroidism

As with hypothyroidism, the potential causes of hyperthyroidism vary. Women and those over 60 years old are also at higher risk to develop hyperthyroidism, as well as a previous history of pregnancy complications, autoimmune diseases, or thyroid disorders. The most common cause of hyperthyroidism in the U.S. is Graves’ disease, an autoimmune process where the thyroid’s TSH receptors are overactivated by antibodies that leads to hyperthyroidism. Children are more likely to manifest Graves’ disease due to its autoimmune process. Antibodies mimicking TSH erroneously stimulate the TSH receptors in the thyroid to therefore produce an excess of T4 and T3. This thyroid overactivation may also cause the thyroid to grow larger than normal. [10][11][12]

Other common pathologies for hyperthyroidism is Toxic Multinodular Goiter (TMNG) or Solitary Toxic Nodules, which are more common in older adult and iodine-deficient populations. While differing in pathology, both processes follow similar general trends. Nodules within the thyroid have their TSH receptors are incrementally activated for longer and longer periods of time. During this gradual increase, symptoms subtly grow and worsen until multiple nodules and thyroid follicular cells swell, causing goiter (visibly enlarged thyroid). Eventually, the their TSH receptors are essentially permanently activated, causing a permanent output of T4 and T3 and resulting in hyperthyroidism. [10][11]

Treatment of Hyperthyroidism

The first considered treatment for hyperthyroidism are usually Anti-Thyroid Drugs (ATDs), which serve to dampen the overactive thyroid, and are considered safe and effective treatments. Some common drugs are methimazole, carbimazole, or propylthiouracil, which are all under the drug classification of Thionamides. By subduing the thyroid’s ability to produce thyroid hormones, hyperthyroidism can be safely reduced and managed in the long-term without major structural damage to the thyroid gland. 

During cases of thionamide drug incompatibilities, another non-drug treatment is Radioactive Iodine (RAI) ablation. By flooding the thyroid with radioactive iodine, the radioactive iodine invades individual thyroid follicular cells and destroys them so they can no longer produce thyroid hormones, thereby reducing thyroid hormone levels. While treatment occurs on a much faster timeline—oftentimes done in a single dose with routine follow up—the potential damages to the thyroid may potentially lead to further complications, especially if considering interactions between other preexisting health conditions.

For cases where the previous treatments are unavailable, either due to drug incompatibility, radiation incompatibility, or both (such as with pregnancy), partial or complete surgical removal of the thyroid is an option. Similarly to RAI, removing the thyroid reduces its total function, thereby bringing thyroid hormone levels back down to normal. [10][11][12]

Conclusion

The poorly understood and grossly overlooked symptoms and consequences of thyroid disease can lead to serious health complications if left unaddressed. These gradual and incremental changes can also be difficult to notice. However, recognizing these aggregate and chronic symptoms with seemingly no cause can help reduce the amount of missed or underdiagnoses of thyroid disease. It is equally important to voice these concerns to a healthcare provider who may not be immediately inclined to suspect thyroid disease and can be relatively easily identified with laboratory testing of thyroid hormone levels. As with many health conditions, many people can live long, healthy, and fruitful lives with overt or subclinical thyroid disease given proper management and treatment. 

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References

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7. Patil N, Rehman, A., Anastasopoulou, C., et al. Hypothyroidism. [Updated 2024 Feb 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519536/. 

8. Zamwar, U. M., Muneshwar, K. N. Epidemiology, Types, Causes, Clinical Presentation, Diagnosis, and Treatment of Hypothyroidism. Cureus. 2023 Sep 30;15(9):e46241. doi: https://doi.org/10.7759/cureus.46241. 

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