THYROID HORMONES AND ANTITHYROID DRUGS
D.M. RAVICHAND, V. SHESHAYAMMA, V. LAKSHMI KAMESHWARI, T. CHAKRADHAR

Osmania Medical College.
Correspnsence: drravichand21@yahoo.co.in

ABSTRACT
The highly conserved nature of the thyroid gland and the thyroid system among
mammalian species suggests it is critical to species survival. Despite its highly
conserved nature, the thyroid system can have widely different effects on different
tissues in the body. The thyroid hormones (THs) play critical roles in the differentiation,
growth, metabolism and physiological function of virtually all tissues. TH binds to
receptors that are ligand regulatable transcription factors belonging to the nuclear
hormone receptor super family. Antithryroid drugs, which have been in use for more
than half a century, remain cornerstones in the management of hyperthyroidism,
especially for patients with Grave’s disease. The present review considers recent
knowledge of thyroid hormones actions and pharmacologic and clinical data related to
the use of antithyroid compounds.
Key Words: Thyroid Hormones, Thyroid Receptors, Triidothyronine, Thyroxine

INTRODUCTION

Thyroid hormones (THs) play critical roles in differentiation, growth and
metabolism. Indeed, TH is required for the normal function of nearly all tissues,
with a major effect on oxygen consumption and metabolic rate [1]. Disorders of
the thyroid gland are among the most common endocrine maladies. Further
more endemic cretinism due to iodine deficiency remains a public health problem
in developing countries at the advent of the third millennium. The incidence of
reported prevalence of hypothyroidism in adult population is about 2% and that of
hyperthyroidism is 0.2%. Thus the study of TH action has important biological
and medical implications.

Contributions from clinical medicine, physiology, biochemistry and
molecular genetics have had major impacts on our understanding of TH action.
[2,3] In 1914 Kendall [4] isolated 3, 5, 31, 51 – tetraiodo-L-thyronine (T4) from
thyroid extracts and almost 40 years later, Gross and Pitt-Rivers [5] synthesized
3, 5, 31 – tri iodo-L-thyronine (T3) and demonstrated its presence in human
plasma and its ability to prevent goiter in thiouracil treated rats [6]. In the 1960s,
Tata and co-workers first suggested that THs might be involved in the
transcriptional regulation of target genes [7, 8]. Thyroid hormones act on thyroid receptors (TRs). These TRs behave similar to steroid hormone receptors with
respect to nuclear site of action, recognition of specific DNA sequences and
ligand – dependent regulation of transcription. The power of molecular genetics
has greatly aided our understanding of the roles of unliganded and liganded TRs
in regulating target genes.

Normal Thyroid Gland Function:
Thyroid gland, located in the neck, just below the larynx, the thyroid gland
in humans is a brownish – red organ having two lobes connected by an isthmus
and consists of low cuboidal epithelial cells arranged to form small sacs known
as follicles. The two principle thyroid hormones are thyroxin (T4 or L-3, 5, 31, 51
– tetraiododthyronine) and triiodothyronine (T3 or L-3, 5, 31 – triiodothyronine).
These hormones are composed of two tyrosyl residues linked through an
ether linkage and substituted with four or three iodine residues, respectively. T3
is the biologically active hormone and T4, the major thyroid hormone that is
secreted from the thyroid gland, is considered a precursor or prohormone.
Deiodination of T4 in peripheral tissues like liver leads to production of T3 and
reverse T3 (rT3) which has no known biological activity [9].
Fig. 1 Structural formula of thyroid hormones and related compounds.

Background of Thyroid Hormone Synthesis:

Thyroid gland follicles play a critical role in compartmentalizing the
necessary components for thyroid hormone synthesis. Thyroglobulin, a
glycoprotein that comprises of 13H thyrosine residues, and is one of the starting
molecules for thyroid hormone synthesis, fills the follicles. Epithelial cells of the
thyroid gland have a sodium-iodide symporter on the basement membranes that
concentrates circulating iodide from the blood. Once inside the cell, iodide is
transported to the follicle lumen. Thyroid peroxidase (TPO), an integral
membrane protein present in the apical plasma membrane of thyroid epithelial
cells, catalyzes sequential reactions in the formation of thyroid hormones. TPO
first oxidizes iodide to iodine, then iodinates tyrosines on thyroglobulin to produce
monoiodthyrosine and diiodotyrosine. TPO finally links two tyrosines to produce
T3 and / or T4.

Thyroid hormone – containing colloid then is internalized at the apical surface of
the thyroid epithelial cells by endocytosis, lysosomes, which contain hydrolytic
enzymes, fuse with endosomes and release the hormones. Free thyroid
hormones diffuse into blood where they reversibly complex with liver – derived
binding proteins for transport to other tissues. Thyroid stimulating hormone
(TSH) which is secreted by the anterior pituitary gland regulates thyroid hormone
synthesis and secretion in humans. Thyrotrophin releasing hormone (TRH) is
secreted by the hypothalamus, regulates pituitary TSH secretion. Control of
circulating concentrations of thyroid hormone is regulated by negative feedback
loops within the hypothalamic – pituitary thyroid axis (H-P-T) [10].

Physiological Effects of Thyroid Hormones:
Thyroid hormones produce their effect by acting on thyroid receptors
(TRs). They belong to a large super family of nuclear hormone receptors that
include the steroid, vitamin D and retinoic acid receptors as well as orphan
receptors for which there are no known ligand or function [11, 12]. TRs share a
similar domain organization with other family members as they have a central
DNA bending domain containing two zinc fingers and a carboxy – terminal LBD.
(L-Binding Domain)

Thyroid Hormone effects on target tissues:
TRS are expressed in virtually all tissues, although the relative expression
of TR isoforms may vary among tissues [13, 14, 15]. There are two major TR
isoforms encoded on human chromosomes 17 and 3, respectively. They are
represented as TRα and TRβ. These are further sub classified TRα-1 and TRβ-1,
TRβ-2, and TRβ-3. The TRβ-1 mRNA is highly expressed in liver but also
expressed in almost all other tissues, whereas TRβ-2 mRNA is most highly
expressed in the anterior pituitary. TRα-1 is expressed in almost all tissues. In
addition to this variable expression of TR isoforms in different tissues, the role of
TH can vary in different tissues.

Bone:
TH is critical for normal bone growth and development. In children,
hypothyroidism can cause short stature and delayed closure of the epiphyses.
Biochemical studies have shown that TH can effect the expression of various
bone markers in serum, reflecting changes in both bone formation and resorption
[16, 17, 18]. TH increases alkaline phosphatase and osteocalcin in osteoblasts.
Additionally, osteocalcin markers such as urinary hydroxyproline, urinary
pyridinium, and deoxypyridinium cross-links are increased in hyperthyroid
patients. These observations suggest that both osteoblast and osteoclast
activities are stimulated by TH. Indeed, there is enhanced calcification and bone
formation coupled to increased bone resorption in hyperthyroid patients [17, 19].
Additionally, the time interval between formation and subsequent mineralization
of osteoid is shortened. The net effect on these bone cells is bone resorption
and loss of trabecular bone thickness in hyperthyroidism. There also is marked
increase in porosity and decreased cortical thickness in cortical bone in
hyperthyroid patients [18, 19, 20, 21]. These effects can lead to osteoporosis and
increased fractures.

TH may act on bone via TH stimulation of growth hormone and insulin –
like growth factor I (IGF-I) or by direct effects on target genes. Recent studies
have shown that T3 also can directly stimulate IGF-1 production in osteoblasts,
and enhance T3 stimulation of proline incorporation, alkaline phosphatase, and
osteocalcin [22]. TRs recently have been demonstrated in osteoblast cell lines,
osteoclasts derived from an ostoclastoma, as well as in rat and human bones
samples [23, 24, 25, 26, 27]. A little is known about the direct role of T3 on osteoclasts.
Thus far, no T3 regulated target genes have been described in osteoclasts.

Heart:
TH powers systemic vascular resistance, increases blood volume, and
has inotropic and chronotropic effects on cardiac function [28]. The combination of
these effects on both the circulation and the heart itself results in increased
cardiac output. Hyperthyroid patients have a high output circulation state,
whereas hypothyroid patients have low cardiac output, decreased stroke volume
and increased systemic vascular resistance [28]. These changes in cardiac
function by TH ultimately depend on the regulation of target genes within the
heart and indirect effects due to hemodynamic changes by TH. TH enhances
overall total protein synthesis in the heart [29, 30].
A novel and potentially exciting therapeutic use of T3 as an inotropic agent
has been in cardiac surgery. Novitsky [31] showed improved cardiac function and
haemodynamics when brain-dead organ donors were pretreated with T3 and
cardiac transplant recipients treated with T3 postoperatively. A small group of
patients that underwent cardiac bypass surgery and were treated postoperatively
with T3 also showed some benefit [32]. However, a large randomized study
showed no drastic or major in the outcome although T3 increased cardiac output
and decreased systemic vascular resistance in patient, who underwent coronary
artery bypass surgery, there was no improvement in outcome or changes in
postoperative therapy [33].

Fat:
TH plays important roles in the development and function of brown and
white adipose tissue [34]. TH can induce white adipose tissue (WAT)
differentiation from preadipocytes in young rats as well as in preadipocyte cell
lines such as Ob17 and NIH3T3-F44ZA cells [35, 36, 37, 38]. The mechanism(s) by
which T3 induces WAT differentiation currently is not known but likely involves transcriptional regulation of important target genes by TRs. Several human
studies have shown that chronic hypo and hyperthyroidsm as well as acute T3
treatment did not affect serum leptin levels [39, 40, 41]. However, one study showed
that hypothyroid patients had increased leptin levels, but the increase was corelated
with adiposity [42]. Another study showed that hyperthyroid patients
treated with thiamazole increased their leptin levels [43].

Liver:
TH has multiple effects on liver function including stimulation of enzymes
regulating lipogenesis and lipolysis as well as oxidative processes [1, 2]. Some of
the lipogenic enzymes that are regulated are malic enzyme, glucose-6-
pohosphate dehydrogenase, and fatty acid synthase. There is a biphasic
induction of the malic enzyme mRNA at 4 and 24H, suggesting that there may be
an initial direct stimulation by T3 and a secondary effect due to stimulation by
other gene products that are regulated by T3 [44].
T3 regulation of malic enzyme gene transcription also can be regulated by
carbohydrate intake, insulin and cAMP. It has been appreciated for many years
that hypothyrodism is associated with hypercholesterolemia with elevated serum
intermediate and low-density lipoprotein (LDL) cholesterol concentrations
[45]. The major mechanism for these effects may be lowered cholesterol
clearance resulting from decreased LDL receptors.

Pituitary:
TH regulates the synthesis and secretion of several pituitary hormones.
Absence of GH has been observed in the pituitaries of hypothyroid rats [46]. TH
also negatively regulates thyrotropin (TSH) transcription by direct and indirect
mechanisms [47]. TH negatively regulates TRH at the transcriptional level,
thereby decreases transcription of TSH mRNA [48, 49]. T3 also down regulates
prolactin mRNA by a similar mechanism and also by direct effects on
transcription [50].

Brain:
TH has major effects on the developing brain in utero and during the
neonatal period [51, 52]. Neonatal hypothyroidism due to genetic causes and
iodine deficiency in humans can cause mental retardation and neurological
defects. Studies in hypothyroid neonatal rats have shown that absence of TH
causes diminished axonal growth and dendritic arborization in the cerebral
cortex, visual and auditory cortex, hippocampus and cerebellum [53, 54]. In the
cerebellum, absence of TH delays proliferation and migration of granule cells
from the external to the internal granular layer.

Reproductive Effects in Males:
Normal thyroid hormone levels are important for maturation of the testes in
prenatal, early postnatal and prepubertal boys. Studies indicate that the major
targets of T3-binding in the testis are the sertoli cells. These cells, along with the
gonocytes, comprise the seminiferous epithelium of the testis and are critical for
the normal sperm maturation [55]. In vitro studies suggest that T3 activation of
TRα1 plays a role in testes differentiation and development [56]. T3 has been
shown to increase glucose carrier units, insulin-like growth factor-1(IGF-1), and
inhibin; decreases aromatase protein, and androgen binding proteins, and inhibit
the expression of mullerian-inhibiting substance by sertoli cells [55].

Reproduction Effects in Female:
The molecular mechanisms that affect female reproduction including
estrogen and androgen metabolism, sexual maturation, menstrual function,
ovulation, fertility and ability to deliver full term infants involve T3 induced
modulation of hormone induced transcription pathways and factors that affect
hormonal status [57].

Thyroid Dysfunction:
There are three categories of thyroid dysfunction that have been
characterized in adult humans; subclinical hypothyroidism, overt hypothyroidism,
and hyperthyroidism. Sub clinical hypothyroidism is defined as a slightly
elevated TSH concentration and normal serum free T3 and T4 concentrations
associated with few or no symptoms [58]. Although there can be various causes
for condition like sub clinical hypothyroidism, patients are positive for TPO
antibodies, which may lead to overt hypothyroidism. Overt hypothyroidism
(underactive thyroid gland) is defined as high serum TSH concentration and a
low free T4 serum concentration. Hyperthyroidism (or thyrotoxicosis) is
characterized by an increase in serum T3 and T4 and a decrease in serum TSH.
The most common cause of hyperthyroidism is Grave’s disease.

Antithyroid Drugs:

Antithyroid drugs are relatively simple molecules known as thionamides,
which contain a sulfhydryl group and a thiourea moiety within a heterocyclic
structure. Propylothiouracil (6-propyl-2-thiouracil), methimazole (1-methyl-2-
mercaptoimidazole, Tapazole) and Carbimazole,( methimazole analogue )are the
antithyroid drugs used. These agents are actively concentrated by the thyroid
gland against a concentration gradient [59]. Their primary effect is to inhibit
thyroid hormone synthesis by interfering with thyroid peroxidase-meditated
iodination of tyrosine residues in thyroglobulin, an important step in the synthesis
of thyroxine and triiodothyronine. Propylthiouracil, but not methimazole or
carbimazole, can block the conversion of thyroxine to triiodothyronine within the
thyroid and in peripheral tissues, but this effect is not clinically important in most
instances. Antithyroid drugs may have clinically important immunosuppressive
effects. In patients taking antithyroid drugs, serum concentrations of
antithyrotropin-receptor antibodies decrease with time [60], as do other
immunologically important molecules, including intracellular adhesion molecule 1
[61] and soluble interleukin – 2 and interleukin-6 receptors [62, 63]. In addition, there
is evidence that anti-thyroid drugs may induce apoptosis of intrathyroidal
lymphocytes, [64] as well as decrease HLA class II expression [65]. Also, most
studies showed an increased number of circulating suppressor Tcells and a
decreased number of helper T cells [66], and natural killer cells [67, 68].
Both proplythiouracil and methimazole are rapidly absorbed from the
gastrointestinal tract, peaking in serum in one to two hours after drug ingestion
[69, 70]. Serum levels have little to do with antithyroid effects, which typically last
from 12 to 24 hours for propylthiouracil [71]. The doses of these drugs do not need
to be altered in children [72], the elderly [73], or persons with renal failure [74, 75]. No
dose adjustment is needed in patients with liver disease, although the clearance
of methimazole [70] (but not propylthiouracil [76]) may be decreased.
In general, antithyroid drugs are used in two ways: as the primary
treatment for hyperthyroidism or as preparative therapy before radiotherapy or
surgery (Fig 5). Antithyroid drugs are most often used as the primary treatment
for persons with Graves’ disease, in whom “remission” which is usually defined
as remaining biochemically euthyroid for one year after cessation of drug
treatment, is possible. Antithyroid drugs are also the preferred primary treatment
in pregnant patients and in most children and adolescents. Antithyroid drugs are
also used to normalize thyroid function before the administration may attenuate
potential exacerbations following ablative radioiodine therapy [77] which are likely
caused by a rise in stimulating antithyrotropin-receptor antibodies following
radioiodine therapy [78].

The usual starting dose of methimazole is 15 to 30 mg per day as a single
daily dose, and the usuall starting dose of propylthiouracil is 300 mg daily in three
divided doses. Once a patient has been started on an antithyroid drug, follow-up
testing of thyroid function every four to six weeks is recommended, at least until
thyroid function is stable or the patient becomes euthyroid. After 4 to 12 weeks,
most patients will improve considerably or achieve normal thyroid function, after
which the drug dose can often be adjusted to maintaining normal thyroid function.
Antithyroid drugs are associated with side effects which vary from minor to
potentially life-threatening to even lethal complications [79, 80]. Side effects of
methimazole are dose-related, whereas those of propylthiouracil are less clearly
related to dose [79].

Use of Antithyroid Drugs during Pregnancy and Lactation:

Thyrotoxicosis occurs in 1 of every 1000 to 2000 pregnancies [85].
Nevertheless, an antithyroid drug should be started at the time of diagnosis,
since thyrotoxicosis itself presents a risk to the mother and fetus.
Propylthiouracil has been preferred as it cross placenta minimally as compared
to methimazole. However recent studies suggest that propylthiouracil does, in
fact, cross the placenta [86, 87] , and clinical data do not show any differences in
thyroid function at birth between fetuses exposed to propylthiouracil as compared
with those exposed to methimazole [88, 89]. The use methimazole is associated
with a very rare teratogenic syndrome termed “methimazole embryopathy,” which
is characterized by choanal or esophageal atresia [90]. In a recent report, these
anomalies occurred in 2 of 241 children of women exposed to methimazole, as
compared with the spontaneous rate of 1 in 2500 to 1 in 10,000 for esophageal
artresia and choanal atresia, respectively [90]. In contrast, another study found no
increase in the frequency of congenital abnormalities, including aplasia cutis,
among 243 infants who were exposed to methimazole in utero [91]. Many
countries use methimazole for the treatment of thyrotoxicosis in pregnancy.
However, pregnant women should be treated with propylthiouracil when the drug
is available. In the event of allergy to propylthiouracil, methimazole can be
substituted. The Food and Drug Administration has categorized both
propylthiouracil and methimazole as clss D agents (i.e. drugs with strong
evidence of risk to the fetus) because of the potential fetal hypothyroidism.
 

Conclusions:
Six decades after introduction, antithyroid drugs continue to be important
in the management of hyperthyroidism. Patients with Graves’ disease, who have
an approximately 40 to 50 percent chance of remission after 12 to 18 months of
therapy, are the best candidates. Thyroid hormones and Antithyroid drugs are
deceptively easy to use, but because of the variability in the response of patients
and the potentially serious side effects, all practitioners who prescribe the drugs
need to have a working knowledge of their complex pharmacology.

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