Modulating Thyroid Hormones: Advances in TRb-Selective Ligands, Enzyme Inhibitors, and Deiodinase Mimetics for Endocrine Regulation

Hyperthyroidism is a common thyroid disorder characterized by increased synthesis and secretion of thyroid hormones by the thyroid gland. The most common causes include Graves’ disease (GD), toxic multinodular goiter, and toxic adenoma. Treatment options for hyperthyroidism include thyroid surgery (the oldest method), radioactive iodine (RAI), and antithyroid drugs (ATDs).

As people age, thyroid disease becomes more common.  Overt thyroid illness affects 0.8–7.5% of individuals, while subclinical thyroid disease affects 5–9%.  The only physiologically active chemical that contains iodine is thyroid hormone, which has two crucial roles.  In both humans and animals, it is an essential factor in determining appropriate development, especially in the central nervous system (CNS).  Thyroid hormones impact the operation of almost every organ in humans and control metabolism and homeostasis. Although local metabolism also occurs in tissues like the brain, the liver is the primary site of thyroid hormone metabolism.  The pituitary hormone thyrotropin (TSH) regulates the amount of thyroid hormone in traditional negative feedback regulation. Binding to thyroid hormone receptors (TRs), which control the transcription of particular genes, is how thyroid hormones primarily affect the body.  The nuclear receptor superfamily includes these receptors. Thyroxine (T4), triiodothyronine (T3), and calcitonin are the three hormones secreted by the thyroid gland.  An elevated thyroid-stimulating hormone (TSH) level but normal T4 and T3 levels are the hallmarks of subclinical thyroid illness, which usually doesn't need therapy.  On the other hand, TSH, T4, and T3 levels in people with overt thyroid illness are abnormal and need to be adjusted. Autoimmunity, external head and neck radiation, iodine biosynthesis abnormalities, tumor-related thyroid gland replacement, and the use of specific drugs are known risk factors for thyroid illness such as Age, sex, and iodine deficiency are other risk factors. TRα and TRβ, the two main TR isoforms, are encoded by distinct genes. TRs control the transcription of target genes by binding to thyroid hormone response elements in their promoters.  TSHα and TSHβ are the two subunits that make up the heterodimer TSH.  Human chorionic gonadotropin, FSH, LH, and other glycoprotein hormones share TSHα, a subunit of glycoprotein hormones. The TSHβ is unique to TSH.  By reducing the transcription of the thyrotropin-releasing hormone (TRH) gene and the expression of the TSHα and TSHβ genes, T3 adversely controls the synthesis of TSH. Local brain deiodinases D2 and D3 mainly produce 3,5,3′-triiodothyronine (T3), the main thyroid hormone in the brain, by 5′-deiodinating parent thyroxine (T4). The blood-brain barrier allows maternal T4 and T3 to pass from the mother's circulation to the developing fetus' brain.

Hypothyroidism, in its severe form called myxedema, is the most common thyroid disorder. It is characterized by high levels of antibodies to thyroid peroxidase and, to a lesser extent, to thyroglobulin. Additionally, blocking antibodies to TSH receptors may also be present, leading to further adverse effects. The most common cause of thyroid hormone deficiency is the thyroid gland's failure to produce enough hormone, known as primary hypothyroidism. Central hypothyroidism is rare and results from decreased TSH levels due to dysfunction of the pituitary gland (secondary hypothyroidism) or the hypothalamus (tertiary hypothyroidism). Congenital hypothyroidism, present at birth, is the most common preventable cause of intellectual disability worldwide. There are several treatment options for hyperthyroidism, including the use of antithyroid drugs (ATDs) to reduce hormone synthesis and secretion, radioactive iodine therapy, or surgical removal of the thyroid gland. In general, treatment outcomes for thyroid disease are quite satisfactory, and most patients can be cured or effectively managed. Thyroid peroxidase is an enzyme that catalyzes the oxidation of iodide, the iodination of tyrosine residues in thyroglobulin, and the synthesis of iodotyrosines—monoiodotyrosine (MIT) and diiodotyrosine (DIT)—to produce triiodothyronine (T3) and thyroxine (T4). Antithyroid drugs also possess anti-inflammatory properties, which may contribute to their effectiveness in treating Graves' disease. The term "thyrotoxicosis" refers to a condition characterized by excessive thyroid hormone activity and includes not only hyperthyroidism but also conditions involving thyroid gland destruction or the administration of exogenous thyroid hormones.

Classification of different forms of thyrotoxicosis

Hyperthyroidism during pregnancy is a serious medical concern, as it significantly increases the risk of complications such as miscarriage, stillbirth, preterm delivery, and restricted fetal growth. Managing this condition is complex and remains a topic of ongoing debate among endocrinologists. Antithyroid drugs (ATDs), in use since the 1940s, are the primary treatment option during pregnancy. Radioactive iodine therapy is strictly contraindicated in pregnant women. Although thyroidectomy is performed more frequently during pregnancy than in nonpregnant women, it carries a risk of causing fetal thyrotoxicosis.

Among the commonly used ATDs are carbimazole (CBZ), its active metabolite methimazole (MMI), and propylthiouracil (PTU)—all of which are considered effective. The decision regarding which drug to use is not based on their therapeutic efficacy, which is comparable, but rather on the potential risks of adverse effects, especially teratogenicity and serious complications such as liver toxicity.

VITAMIN D AND THYROID HEALTH –

Vitamin D plays a crucial role in the proper functioning of many organs, including the thyroid gland. Given its wide-ranging physiological functions, it is not surprising that vitamin D deficiency has been identified as a potential risk factor for several thyroid disorders, including autoimmune thyroid diseases and thyroid cancer. Despite this, the precise nature of the relationship between vitamin D and thyroid function remains not fully understood.

- Vitamin D and Autoimmune Thyroid Diseases-

The immune system attacking the thyroid gland is a hallmark of autoimmune thyroid diseases.  Studies on animals have shown that vitamin D supplements are useful for illnesses including thyroiditis and Graves' disease.  Vitamin D deficiency was shown to be substantially more common in patients with Graves' disease, according to a meta-analysis by Xu et al. that incorporated data from 26 research (including 1,748 patients with the condition and 1,848 healthy controls). One important factor in regulating the immunological response is vitamin D.  By suppressing proinflammatory cytokines like IL-6, IL-8, IL-9, IL-12, IFN-γ, and TNF-α and encouraging the synthesis of anti-inflammatory cytokines like IL-10, IL-5, and IL-4, it aids in immune function regulation.  These behaviors imply that vitamin D might have a protective impact against autoimmune disease.Although vitamin D's role in autoimmune thyroid illnesses has been extensively studied, it is still unknown if vitamin D insufficiency causes these conditions or if it is a side effect of the autoimmune process.

-  Vitamin D and Thyroid Cancer-

The incidence of thyroid cancer has been rising globally. In 2017, approximately 255,490 new cases were reported worldwide, a significant increase from 95,030 cases in 1990. Thyroid cancers originate from different thyroid cell types. Papillary, Hurthle cell, and follicular thyroid cancers—including benign and anaplastic forms are derived from follicular thyroid cells. In contrast, medullary thyroid carcinoma arises from the parafollicular (neuroendocrine) C cells of the thyroid. The most common form of thyroid cancer is differentiated thyroid cancer, with papillary thyroid carcinoma accounting for roughly 85% of all cases. Several in vitro and in vivo studies suggest that vitamin D, particularly in its active form calcitriol, may have anticancer properties. In vitro experiments have demonstrated that calcitriol and its analog MART-10 can inhibit the growth and metastatic behavior of anaplastic thyroid cancer cells. Furthermore, an increased expression of vitamin D receptors (VDR) and related genes has been observed in breast cancer cells, indicating that vitamin D may offer a protective, antitumor effect. In vivo studies also support this view, showing that calcitriol treatment significantly reduces tumor size in mouse models of both follicular thyroid cancer and metastatic follicular thyroid cancer.

HOW VITAMIN D AFFECTS TSH, THYROID HORMONES, AND ANTI-THYROID ANTIBODIES SECRETION-

TSH and 25(OH) D levels have typically been found to be variable or uncorrelated in investigations involving healthy volunteers; similar findings have been noted in studies involving cancer patients.  Thyroid hormones have been shown to have varying impacts on 25(OH)D levels in healthy individuals, either positive or negative.  Research on autoimmune thyroid disease patients is also debatable.  One-third of the studies discovered an interaction between TSH and 25(OH) D levels, whereas the other two-thirds showed no connection at all. However, there was no correlation between thyroid hormones and 25(OH) D levels in the majority of investigations conducted on patients with autoimmune thyroid disease.  Although several research did not evaluate this link, the majority of studies reported a positive correlation between antithyroid antibodies (antithyroid peroxidase antibody [TPOAb], antithyroglobulin antibody [TgAb], or TSH receptor antibody [TSHRAb]) and 25(OH) D levels.

SYMPTOMS OF HYPERTHYROIDISM AND HYPOTHYRODISM-

Symptoms of Hypothyroidism (An underactive thyroid)-

Fatigue; exhaustion feeling run down and sluggish depression, moodiness difficulty concentrating; brain fog; unexplained or excessive weight gain; dry, coarse and/or itchy skin; dry, coarse and/or thinning hair; feeling cold, especially in the extremities; constipation; muscle cramps; increased menstrual flow; more frequent periods; infertility/miscarriage; low blood pressure; frequent infections; bloating/puffiness in hands, feet, eye area, face, etc.

Symptoms of Hyperthyroidism (An overactive thyroid)-

Nervousness; irritability; increased perspiration; thinning of your skin; fine brittle hair; muscular weakness especially involving the upper arms and thighs; shaky hands; panic disorder; insomnia; racing heart; more frequent bowel movements; weight loss despite a good appetite; lighter flow, less frequent menstrual periods etc.

ADVERSE EFFECTS OF ANTITHYROID DRUGS-

Thyroid hormones, particularly thyroxine, are commonly used either as replacements to treat hypothyroidism or as suppressors to stop the production of thyrotropin (thyroid-stimulating hormone) in patients with diffuse/nodular nontoxic goiter or differentiated thyroid carcinoma following total thyroidectomy.  The administration of slightly supra-physiological amounts of thyroxine is required to inhibit thyrotropin secretion.  The risk of these side effects can be minimized by closely monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and modifying the dosage accordingly. Potential side effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats, and possibly left ventricular hypertrophy) and bone changes (reduced bone density and bone mass). The most popular antithyroid medications are thionamides, which include carbimazole, propylthiouracil, and thiamazole (methimazole).  Three to five percent of patients experience negative side effects from long-term use.  Adverse effects are typically mild and temporary (e.g. skin rash, itching, mild leukopenia).  Agranulocytosis is the most harmful side effect, occurring in 0.1 to 0.5% of patients.  Granulocyte colony-stimulating factor injection is now an effective treatment for this potentially fatal disease.  Aplastic anemia, thrombocytopenia, lupus erythematous-like syndrome, and vasculitis are extremely uncommon side effects.

ANTITHYROID DRUG USAGE ALGORITHM FOR GRAVE’S DISEASE PATIENTS-

The primary line of treatment for adults with mild to moderate hyperthyroidism or goiter is antithyroid medication.  Additionally, children, teenagers, and women who are pregnant or nursing are treated with them.  In the US, individuals are frequently treated with radioactive iodine as a first-line treatment; in other countries, this is not usually the case.  Some patients may be candidates for subtotal or near-total thyroidectomy after antithyroid medication treatment.  In most cases, the recommended course of treatment for individuals who relapse is radioactive iodine therapy.  Certain patients choose to take antithyroid drugs again, which is a tactic that works especially well for kids and teenagers.

-Dosing and Monitoring of Antithyroid Drugs-

The usual starting dose for methimazole is 15 to 30 mg once daily, while the initial dose for propylthiouracil (PTU) is typically 300 mg per day, divided into three doses. However, in many patients, the disease can be controlled with lower doses of methimazole, suggesting that the commonly accepted 10:1 dosing ratio of methimazole to PTU may be an underestimate. In later assessments, it has been found that even very small doses of methimazole can effectively manage mild hyperthyroidism in certain patients. Monitoring of thyroid function is recommended every six weeks, at least until thyroid levels stabilize or the patient achieves a euthyroid state. Most patients show improved or normalized thyroid function within 4 to 12 weeks, at which point the drug dosage can often be tapered while maintaining thyroid balance. For maintenance therapy, many patients can be managed with low doses such as 5 to 10 mg of methimazole daily or 100 to 200 mg of PTU. If the dose is not appropriately reduced, hypothyroidism or goiter may develop. After the first 3 to 6 months of treatment, follow-up intervals can be extended to every 2 to 3 months, and later to every 4 to 6 months. It is important to note that, despite normalization of thyroid hormone levels, thyrotropin (TSH) levels may remain suppressed for weeks or months. Therefore, TSH is not a reliable early indicator of recovery. Additionally, some patients may present with elevated serum triiodothyronine (T3) levels even when thyroxine (T4) or free thyroxine (FT4) levels are normal or low, in which case antithyroid drug dosages should be increased, not reduced.

ANTITHYROID ACTIVITY OF HERBAL PLANTS-

Isoflavonoids, which are found in certain plants, significantly affect thyroid hormone levels and bodily functions.   the pituitary-adrenal-hypothalamic axis.   Glycine max, or soybeans, contain genistein and daidzein, which inhibit.   Iodination and the production of thyroid hormones are catalyzed by the enzyme thyroperoxidase.   Two further plants that may have a hypothyroid impact are fonio and pearl millet (Pennisetum glaucum).   Millet (digitaria exilis) and brassica plants, such as cabbage, both contain thiocyanate.   Tropical plants like cassava and lima beans, as well as vegetables like cauliflower, kale, rutabaga, and kohlrabi, are considered cruciferous.   Chickpeas, lentils, and beans.   One source of thiocyanate is tobacco smoke. It has long been known that plants in the Brassicae family (Family Cruciferae), including mustard, rapeseed, broccoli, cauliflower, kale, kohlrabi, Brussels sprouts, swede (also known as yellow turnip, Brassica napobrassica), and cabbage (Brassica oleracea), have goitrogenic and antithyroid effects.   SCN prevents iodine from being integrated into thyroglobulin by inhibiting the thyroid's active uptake and concentration of inorganic iodide, as well as the enzyme thyroperoxidase.   Progoitrin, a thiourea-like compound found in turnips and rutaba, is a precursor to goitrin and also inhibits thyroperoxidase. Sea plants are the most effective herbal therapies for both an underactive and hyperactive thyroid. Bladder wrack, a kind of kelp, is utilised in both Western and Chinese herbal therapy. It can be consumed as a supplement or infusion. Steep dried herbs in boiling water for 10 minutes. This therapy helps with iodine deficit in the diet. Bitters can help treat moderate hypothyroidism. These supplements are typically sold as liquids at natural food stores. Bugleweed, a herb, can promote hyperthyroidism. This plant should not be taken without consulting a doctor. Pregnant women should avoid using it, as it may interact with thyroid replacement medication and cause thyroid hypertrophy. Valerian and passion flower can relieve insomnia caused by hyperthyroidism. To use these herbs, drink 15 drops of each tincture in water 30 minutes before bedtime.

The botanical name for gum guggul, a herbal thyroid stimulant, is Commiphora mukul. The extract from the stem of the mukul myrrh tree has high levels of volatile oils and resins. This herb has a pungent scent and an unpleasant flavour. Guggle contains guggulsterone, which can boost thyroid function and alleviate hypothyroidism symptoms. The article 'Phototherapy Research' verifies the role of guggulsterone. Using the plant can reduce dangerous cholesterol levels, which is a common symptom of hypothyroidism. Side effects are infrequent but may include headaches, stomach trouble, skin rash, and hiccups.

SIDE EFFECTS-

Antithyroid medicines can induce modest to severe side effects, including life-threatening conditions. Methimazole has dose-dependent adverse effects, while propylthiouracil does not have any major ones. Patients with moderate hyperthyroidism may benefit from a lower dose of methimazole instead of propylthiouracil. Antithyroid medicines' most serious side effect is agranulocytosis. In the largest series, agranulocytosis (fewer than 500 cells per cubic millimetre) occurred in 0.37% of patients treated with propylthiouracil and 0.35% of patients treated with methimazole.

Other rare side effects of antithyroid drugs are listed i.e,

SKIN REACTIONS

The most common adverse effects include rash, urticaria, and mild allergic skin reactions like hives, which typically appear within the first few weeks of treatment. A meta-analysis of 5,136 patients found that 6% of MMI users and 3% of PTU users experienced rash, while 2% to 3% had pruritus but no rash. In a randomised experiment, cutaneous responses were seen in 22% and 6% of patients treated with 30 mg and 15 mg MMI, respectively. Approximately one-third of patients transferred to another ATD due to mild medication responses and side effects. According to ATA standards, mild skin reactions should be treated with antihistamines without cessation, moderate reactions should be continued or modified, and severe skin disorders should be avoided altogether. The median period from the commencement of skin responses is about 20 days. The time it takes for complications to appear after starting antithyroid medications.

Time to Onset of Complications After the Initiation of Antithyroid Drugs.

AGRANULOCYTOSIS-

Agranulocytosis is often characterised as a granulocyte count of less than 500/mm3, yet in most cases of ATD-associated agranulocytosis, this figure is zero. Agranulocytosis occurs in around 0.2%-0.5% of patients, mainly within the first 90 days of treatment, and is dose-dependent. Agranulocytosis may also occur after restarting the medicine, even if it has been used well for a long time. The symptoms include fever, malaise, and the beginning of pharyngitis. A few studies suggest a gradual decrease in granulocyte count; hence, monitoring the white blood count number may also indicate agranulocytosis. Treatment for ATD-induced agranulocytosis typically involves discontinuing the medication, supplementing, administering granulocyte colony-stimulating factor, and using broad-spectrum antibiotics. The general public of agranulocytosis occurs within the first three months of medication.

HEPATOTOXICITY-

ATD can cause hepatotoxicity, from modest transaminase increase to catastrophic hepatic necrosis. From 1990 to 2007, the FDA recorded 1 to 3 liver transplants associated with PTU annually in the US. MMI and PTU were associated with hepatotoxicity in 0.3% and 0.15% of individuals, respectively. The MMI group had a considerably greater rate of non-infectious liver disease compared to the PTU group (0.25% vs 0.08%). Patients with PTU had greater rates of morbidity compared to those with MMI. Both medications resulted in equal rates of cholestasis. In a second study from China (80), 81% of 90 patients with severe hepatotoxicity from ATD experienced it within 12 weeks after PIA. MMI and PTU have similar hepatotoxicity profiles (cholestasis and hepatocellular destruction), with average doses of 20 mg and 200 mg, respectively. The majority of hepatotoxicity occurs within the first three months of medication.

VASCULITIS-

The first description of ATD-induced lupus erythematosus dates back to 1970. Unlike other rare cases of ATD, it typically develops after years of treatment. Surprisingly, patients with GD and those who remain asymptomatic while receiving ATD may test positive for ANCA in the absence of ATD. Routine testing for ANCA positive is not suggested. Symptoms usually include fever, malaise, and joint pain. Patients may have indications of cutaneous, pulmonary, and renal vasculitis involvement. Symptoms often improve with regular medication therapy, although some patients may require antidiarrheal therapy and haemodialysis.

ARTHRALGIAS/ ARTHRITIS-

During ATD treatment, joint soreness may occur. Arthritis affected 1.6% of patients receiving ATD treatment. Patients suffering from joint pain in their hands, shoulders, hips, knees, or ankles required general anaesthesia for 1 to 3 weeks. There were only a few incidences of joint oedema or erythema.

THYROID HORMONES AND THEIR ROLES-

The main function of the thyroid gland is to produce two steroid hormones, triiodothyronine (T3) and thyroxine (T4), as well as one peptide hormone, calcitonin. The key components for the synthesis of thyroid hormones are iodinated tyrosine residues; each T3 molecule has three iodine atoms, whereas T4 molecules have four, which accounts for their names.

Three main physiological processes are regulated by thyroid hormones:

1. Metabolic Functions: Raise the baseline metabolic rate (BMR). Encourage cellular uptake, absorption, and metabolism of glucose.

 increase the amount of free fatty acids by encouraging the breakdown of lipids.  Thyroid hormones, however, reduce blood cholesterol levels, perhaps by hastening the conversion of cholesterol into bile.

2. Cardiovascular Functions: Increase the heart's contraction force and rate. Boost mitochondrial activity to raise oxygen consumption and respiratory rate.  Together, these effects increase body temperature and blood flow.
3. Developmental Functions: Essential for typical development and growth, particularly in kids. Encourage growth in the early years of life are essential for the development of the brain, particularly in the womb and the first several years after birth. T3 and T4, which are necessary for neurological maturation, primarily target brain cells.
4. Moreover, the thyroid hormones also play a role in maintaining normal sexual function, sleep, and thought patterns.

After being released from the gland, just a small portion of thyroid hormone is free to move through the circulation.  The majority are attached to thyroxine-binding globulin (TBG), and to a lesser degree, to albumin and transthyretin.  Just 0.03% of T4 and 0.3% of T3 are moving through the body in unbound form, which is where the hormonal activity is found.  Furthermore, iodothyronine deiodinases in various organs throughout the body convert T4 to T3, producing up to 85% of the T3 in blood.

Following its passage through the cell membrane, the hormone attaches itself to the nuclear thyroid hormone receptors TR-α1, TR-α2, TR-β1, and TR-β2. The hormone receptor complex then connects with transcription factors and hormone response elements to modify the transcription of the particular protein's DNA.  In addition to these functions, thyroid hormones also interact with glucose transporters in the cytoplasm of cells and enzymes such as calcium ATPase and adenylyl cyclase.

The pharmacokinetic data of T4 and T3.