Drug Effects on the Thyroid

Introduction

A variety of treatments and medications can impact thyroid function. Drugs can affect thyroid hormone levels, including the anterior hypothalamus, thyrotropes in the pituitary gland, thyroid hormone synthesis and release, and thyroid metabolism through deiodination, sulfation, and glucuronidation. By changing the affinity for concentrations of thyroxine-binding globulin, drugs may impact thyroid hormone levels. In patients dependent on exogenous levothyroxine, medications may interfere with the absorption of thyroid hormone.

What Exactly Is the Thyroid, and What Are the Different Types of Thyroid Disease?

A medical disorder known as thyroid disease interferes with the thyroid gland's ability to operate. The thyroid gland is an endocrine organ since it is situated at the front of the neck and produces thyroid hormones that pass through the blood to assist in regulating numerous other organs. The body often uses these hormones to control how much energy is used during pregnancy, childbirth, and adolescence.

Thyroid disease can be categorized into five categories, each with distinct symptoms. They are as follows:

• Low thyroid function that is hypothyroidism brought on by insufficient levels of free thyroid hormones.

• High-functioning hyperthyroidism brought on by an excess of free thyroid hormones.

• Structural abnormalities, a goiter being the most prevalent (enlargement of the thyroid gland).

• Tumors can either be malignant (cancerous) or benign (not cancerous).

• Thyroid function tests are abnormal without clinical signs (subclinical hypothyroidism or subclinical hyperthyroidism).

What Drugs Affect People With a Healthy Hypothalamic-Pituitary-Thyroid Axis and Their Mode of Action?

1. Drugs like Glucocorticoids, Dopamine agonists, synthetic somatostatins, and Rexinoids affect people with a healthy hypothalamic pituitary thyroid axis by inhibiting the production of T4 (triiodothyronine) and T3 (thyroxine) hormones.

2. Drug like Metyrapone affect people with a healthy hypothalamic pituitary thyroid axis by elevating thyroid stimulating hormone.

3. Drugs like Furosemide, Phenytoin, Probenecid, Heparin, and NSAIDs (non-steroidal anti-inflammatory drugs) affect people with a healthy hypothalamic pituitary thyroid axis by removal of thyroxine-binding globulin.

What Drugs Impact Thyroid Function in People Taking Levothyroxine and Its Mode of Action?

1. Medications like iron supplements, calcium supplements, hydroxide of aluminum, colestyramine, Colestipol, Sucralfate, and Raloxifene impact thyroid function in people taking Levothyroxine preprations by preventing the gastrointestinal absorption of orally administered Levothyroxine.

2. Drugs like Phenytoin, Carbamazepine, Phenobarbital, Rifampin, Tyrosine kinase inhibitor (Imatinib, axitinib, motesanib, vandetanib), and Rexinoids impact thyroid function in people taking Levothyroxine preparations by changing the chemical concentrations that are released in reponse to drug or metabolites that further leads to increase in the hepatic metabolism.

3. Drugs like Propylthiouracil, Methimazole, Propranolol, Glucocorticoids, and Iodide supplementsimpact thyroid function in people taking Levothyroxine preparations by inhibition of 5' deiodinase enzyme which is responsible for the conversion of T4 (triiodothyronine) to T3 (thyroxine).

4. Drugs like Estrogen, Raloxifene, Tamoxifen, Methadone, Mitotane, and Fluorouracilimpact thyroid function in people taking Levothyroxine preparations by increasing the levels of thyroxine-binding globulin, which leads to increase in the level of bounded thyroid hormone levels and decrease the free thyroid hormone in the blood.

5. Drugs like Androgens, Glucocorticoids, and Nicotinic acid (NAC) impact thyroid function in people taking Levothyroxine preparations by decreasing the levels of thyroxine-binding globulin, which leads to a decrease in total thyroid levels and normal free thyroid hormone levels.

Which Medications Suppress Thyroid Stimulating Hormone ?

1. Glucocorticosteroids.

• Human serum TSH (thyroid-stimulating hormone) levels are known to be influenced by glucocorticoids.

• With lower levels in the morning and greater levels at night, physiological levels of hydrocortisone are crucial in the diurnal fluctuation of serum thyroid-stimulating hormone levels.

• It is demonstrated that hypothyroid patients and healthy individuals had serum thyroid-stimulating hormone levels lowered by large glucocorticoids. This impact, which was regulated at the hypothalamic level, appeared to be related to thyroid-stimulating hormone secretion.

• Although other people have confirmed this effect, it does not seem like long-term high-dose glucocorticoids or Cushing's syndrome cortisol excess induce clinically apparent central hypothyroidism that needs thyroid hormone replacement.

• While Prednisone doses of 30 milligrams are probably necessary to meaningfully modify serum thyroid-stimulating hormone levels, Dexamethasone doses of as little as 0.5 milligrams can diminish serum thyroid-stimulating hormone levels.

• As a result of their direct effects on TRH (thyrotropin-releasing hormone) in the hypothalamus, Glucocorticoids can decrease blood thyroid-stimulating hormone levels and thyroid-stimulating hormone production.

• Clinically significant central hypothyroidism is not caused by chronic high doses of Glucocorticoids or severe Cushing's syndrome.

2. Dopamine or Bromocriptine.

• Serum thyroid-stimulating hormone can be decreased by dopamine, used in critical illness, and Bromocryptine, a Dopamine agonist used to treat conditions including hyperprolactinemia.

• Bromocryptine has been demonstrated to lower serum thyroid-stimulating hormone in people with selective pituitary resistance to thyroid hormone.

• This direct stimulating action on the hypothalamus cannot overcome the inhibitory effect of dopamine on the pituitary since the overall effect of dopamine is to lower serum thyroid-stimulating hormone.

• Many patients receiving Bromocryptine for macroprolactinomas have their adenoma-related central hypothyroidism resolved.

• Prolonged Bromocriptine therapy does not promote central hypothyroidism.

3. Somatostatin Analogues.

• Through adenylate cyclase signaling, calcium flow, and cell polarisation, somatostatin inhibits hormone release by binding to 5 distinct extracellular receptors on pituitary cells.

• When thyroid hormone resistance syndrome or pituitary tumors that secrete TSH cannot be successfully controlled surgically, somatostatin analogs are a helpful medical therapy.

• Somatostatin treatment reduced serum thyroid-stimulating hormone pulse amplitude and frequency during repeated blood collection in healthy participants. This is partially accomplished by directly inhibiting pituitary thyrotropes' thyroid-stimulating hormone release.

• While chronic nocturnal octreotide therapy in children being treated for tall stature lowers nocturnal levels of serum thyroid-stimulating hormone without changing serum thyroxine concentrations.

• Long-acting Somatostatin analogs suppress serum thyroid-stimulating hormone and blunt TRH-stimulated thyroid-stimulating hormone levels in healthy volunteers.

• Somatostatin analogs lower serum thyroid-stimulating hormone through direct impacts on pituitary thyrotropes; however, these effects are mostly temporary and do not result in clinically significant central hypothyroidism.

4. Retinoids.

• A subclass of Retinoids, or medications derived from vitamin A, known as Retinoids, interact with the Retinoid X receptor, a particular nuclear hormone receptor (RXR).

• Along with the thyroid hormone receptor (TR), retinoic acid receptor (RAR), vitamin D receptor (VDR), peroxisome proliferator-activated receptor (PPAR), liver X receptor, and others, RXR forms a protein partner, or heterodimer, with other nuclear transcription factors.

• By activating either RXR or its protein partner with ligands, these heterodimer partners can affect the transcription of a wide range of target genes.

• The only rexinoid that has been given clinical approval to date is Bexarotene (Targretin), which is used largely to treat cutaneous T-cell lymphoma.

• Other advanced cancers, such as those of the thyroid, breast, and lung, are currently being treated with Bexarotene and other "second-generation" Rexinoids.

• Rexinoids may also be effective treatments for several metabolic diseases, such as diabetes and obesity.

5. Other Drugs That Might Influence TSH (Thyroid Stimulating Hormone) Levels.

• Some antiepileptic drugs, such as Carbamazepine, Oxcarbemazepine, and Valproic acid, enhance thyroid hormone metabolism through the hepatic P450 system.

• They may also change the pituitary's receptivity to hormonal feedback, resulting in central hypothyroidism.

• Whether these drugs impact thyrotrope function and serum thyroid-stimulating hormone levels in humans is debatable because other researchers have demonstrated that they do not impact the hypothalamic-pituitary axis, and a specific mechanism has not been discovered.

• There is evidence from recent observational studies that Metformin may reduce serum thyroid-stimulating hormone levels.

• One study found that this impact only occurred in people with type 2 diabetes with hypothyroidism, not in people with normal thyroid function. Although the precise mechanism is unknown, this impact may result from decreased free T4 levels in hypothyroid patients.

Conclusion

Only a tiny fraction of pharmaceuticals (glucocorticoids, dopamine agonists, Somatostatin analogs, and Rexinoids decrease thyroid-stimulating hormone at the hypothalamic or pituitary levels. However, many drugs and therapies have the potential to impact thyroid function. Thankfully, even over extended periods at high doses, the commonly used Glucocorticoids and Somatostatin analogs do not cause clinically apparent central hypothyroidism.

Although Dopamine agonists may not directly produce clinically significant central hypothyroidism, they may have an additive impact that reduces thyroid-stimulating hormone in patients with nonthyroidal illnesses, which could result in an iatrogenic state of central hypothyroidism in this patient population. Most individuals with rexinoids develop clinically substantial central hypothyroidism, necessitating Levothyroxine therapy and regular monitoring of serum-free T4 levels.