Steroid and Thyroid Hormones

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Introduction to the Steroid Hormones

The steroid hormones are all derived from cholesterol. Moreover, with the exception of vitamin D, they all
contain the same cyclopentanophenanthrene ring and atomic numbering system as cholesterol. The
conversion of C27 cholesterol to the 18-, 19-, and 21-carbon steroid hormones (designated by the
nomenclature C with a subscript number indicating the number of carbon atoms, e.g. C 19 for androstanes)
involves the rate-limiting, irreversible cleavage of a 6-carbon residue from cholesterol, producing
pregnenolone (C21) plus isocaproaldehyde. Common names of the steroid hormones are widely
recognized, but systematic nomenclature is gaining acceptance and familiarity with both nomenclatures is
increasingly important. Steroids with 21 carbon atoms are known systematically as pregnanes, whereas
those containing 19 and 18 carbon atoms are known as androstanes and estranes, respectively. The
important mammalian steroid hormones are shown below along with the structure of the precursor,
pregneolone. Retinoic acid and vitamin D are not derived from pregnenolone, but from vitamin A and
cholesterol respectively.
Pregnenolone: produced directly from cholesterol, the precursor molecule for all C18, C19
and C21 steroids

Progesterone: a progestagen, produced directly from pregnenolone and secreted from the
corpus luteum, responsible for changes associated with luteal phase of the menstrual cycle,
differentiation factor for mammary glands

Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona

glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na + uptake

Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for
secondary male sex characteristics, produced from progesterone

Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for
secondary female sex characteristics

Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona

fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and
Na+ uptake, numerous effects on the immune system

All the steroid hormones exert their action by passing through the plasma membrane and binding to
intracellular receptors. The mechanism of action of the thyroid hormones is similar; they interact with
intracellular receptors. Both the steroid and thyroid hormone-receptor complexes exert their action by
binding to specific nucleotide sequences in the DNA of responsive genes. These DNA sequences are
identified as hormone response elements, HREs. The interaction of steroid-receptor complexes with DNA
leads to altered rates of transcription of the associated genes.
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Introduction to the Thyroid Hormones

The thyroid hormones (called thyronines) are all derived from the amino acid tyrosine within specific
follicle cells of the thyroid gland. The primary hormone secreted from the thyroid gland is thyroxine (T4:
3,5,3'5'-tetraiodothyronine). Another hormone secreted from the thyroid, but at much lower levels, is
triiodothyronine (T3).
The primary site of T 3 generation is in peripheral tissues via the deiodination of thyroxine. T3 is the most
biologically active form of thyroid hormone and exerts its effects by binding to the thyroid hormone receptor
(TR). TR is a member of the steroid hormone/thyroid hormone superfamily of nuclear receptors. There are
two known TR genes, one encoding TR and the other encoding TR. Synthesis of the thyroid hormones
is controlled by the actions of the anterior pituitary hormone, thyroid stimulating hormone (TSH). The
actions of the thyroid hormones maintain optimal lipid and carbohydrate metabolic homeostasis. Although
the thyroid gland is not essential for life, hypothyroidism in fetal life and in early childhood results in
reduced growth (dwarfism) as well as severe mental retardation. Hypothyroidism in adulthood is
associated with reduced resistance to cold as well as mental and physical impairment. At the other end of
the spectrum, hyperthyroidism in adults is associated with excessive heat generation, metabolic wasting,
cardiac dysfunction (tachycardia), tremors and anxiety.
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Steroid Hormone Biosynthesis Reactions

The particular steroid hormone class synthesized by a given cell type depends upon its complement of
peptide hormone receptors, its response to peptide hormone stimulation and its genetically expressed
complement of enzymes. The following indicates which peptide hormone is responsible for stimulating the
synthesis of which steroid hormone:
Luteinizing Hormone (LH): progesterone and testosterone
Adrenocorticotropic hormone (ACTH): cortisol
Follicle Stimulating Hormone (FSH): estradiol
Angiotensin II/III: aldosterone
The first reaction in converting cholesterol to C 18, C19 and C21 steroids involves the cleavage of a 6carbon group from cholesterol and is the principal committing, regulated, and rate-limiting step in steroid
biosynthesis. The enzyme system that catalyzes the cleavage reaction is known as P450-linked side chain
cleaving enzyme (P450ssc) or 20,22-desmolase, or cholesterol desmolase, and is found in the
mitochondria of steroid-producing cells, but not in significant quantities in other cells.

Mitochondrial desmolase is a complex enzyme system consisting of cytochrome P450, and adrenadoxin (a
P450 reductant). The activity of each of these components is increased by two principal cAMP- and PKAdependent processes. First, cAMP stimulates PKA, leading to the phosphorylation of a cholesteryl-ester
esterase and generating increased concentrations of cholesterol, the substrate for desmolase. Second,
long-term regulation is effected at the level the gene for desmolase. This gene contains a cAMP regulatory
element (CRE) that binds cAMP and increases the level of desmolase RNA transcription, thereby leading
to increased levels of the enzyme. Finally, cholesterol is a negative feedback regulator of HMG CoA
reductase (HMGR) activity (see regulation of cholesterol synthesis). Thus, when cytosolic cholesterol is
depleted, de novo cholesterol synthesis is stimulated by freeing HMGR of its feedback constraints.
Subsequent to desmolase activity, pregnenolone moves to the cytosol, where further processing depends
on the cell (tissue) under consideration.
The various hydroxylases involved in the synthesis of the steroid hormones have a nomenclature that
indicates the site of hydroxylation (e.g. 17-hydroxylase introduces a hydroxyl group to carbon 17). These
hydroxylase enzymes are members of the cytochrome P450 class of enzymes and as such also have a
nomenclature indicative of the site of hydroxylation in addition to being identified as P450 class enzymes
(e.g. the 17-hydroxylase is also identified as P450c17). The officially preferred nomenclature for the
cytochrome P450 class of enzymes is to use the prefix CYP. Thus, 17-hydroxylase should be identified
as CYP17A1. There are currently 57 identified CYP genes in the human genome.

Primary Enzyme Activities of Steroid Hormone Biosynthesis

steroidogenic acute
regulatory protein

StAR

mediates mitochondrial
import of cholesterol

all steroidogenic tissues except

placenta and brain

desmolase, P450ssc

CYP11A1

cholesterol-20,23desmolase

steroidogenic tissues

3-hydroxysteroid
dehydrogenase type 1

HSD3B2

3-hydroxysteroid
dehydrogenase

steroidogenic tissues

P450c11

CYP11B1

11-hydroxylase

only in zona fasciculata and zona

reticularis of adrenal cortex

P450c17

CYP17A1

two activities: 17hydroxylase and 17,20lyase

steroidogenic tissues

P450c21

CYP21A2

21-hydroxylase

not expressed in the zona

reticularis

aldosterone synthase

CYP11B2

18-hydroxylase

exclusive to zona glomerulosa of

adrenal cortex

estrogen synthetase

CYP19A1

aromatase

gonads, brain, adrenals, adipose

tissue, bone

17-hydroxysteroid
dehydrogenase type 3

HSD17B3 17-ketoreductase

steroidogenic tissues

sulfotransferase

SULT2A1

sulfotransferase

liver, adrenals

5-reductase type 2

SRD5A2

5-reductase

steroidogenic tissues

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Steroids of the Adrenal Cortex

The adrenal cortex is responsible for production of three major classes of steroid hormones:
glucocorticoids, which regulate carbohydrate metabolism; mineralocorticoids, which regulate the body
levels of sodium and potassium; and androgens, whose actions are similar to that of steroids produced by
the male gonads. Cholesterol, acquired from the diet or from LDL, or produced de novo in adrenal cortical
cells, serves as the precursor for all of the adrenal steroid hormones. Cholesterol uptake from the blood
occurs through the binding of LDL to the LDL receptor. Chronic stimulation of the adrenal cortex by ACTH
leads to increased LDL receptor gene expression resulting in increased receptor density.
The adrenal cortex is composed of three main tissue regions: zona glomerulosa, zona fasciculata, and
zona reticularis. Although the pathway to pregnenolone synthesis is the same in all zones of the cortex, the
zones are histologically and enzymatically distinct, with the exact steroid hormone product dependent on
the enzymes present in the cells of each zone. Many of the enzymes of adrenal steroid hormone synthesis
are of the class called cytochrome P450 enzymes. These enzymes all have a common nomenclature and
a standardized nomenclature. The standardized nomenclature for the P450 class of enzymes is to use the
abbreviation CYP. For example the P450ssc enzyme (also called 20,22-desmolase or cholesterol
desmolase) is identified as CYP11A1. In order for cholesterol to be converted to pregnenolone in the
adrenal cortex it must be transported into the mitochondria where CYP11A1 resides. This transport
process is mediated by steroidogenic acute regulatory protein (StAR). This transport process is the ratelimiting step in steroidogenesis.

Synthesis of the various adrenal steroid hormones from cholesterol. Only the terminal hormone structures
are included. 3-DH and 4,5-isomerase are the two activities of 3-hydroxysteroid dehydrogenase type 1
(gene symbol HSD3B2), P450c11 is 11-hydroxylase (CYP11B1), P450c17 is CYP17A1. CYP17A1 is a
single microsomal enzyme that has two steroid biosynthetic activities: 17-hydroxylase which converts
pregnenolone to 17-hydroxypregnenolone (17-OH pregnenolone) and 17,20-lyase which converts 17-OH
pregnenolone to DHEA. P450c21 is 21-hydroxylase (CYP21A2, also identified as CYP21 or CYP21B).
Aldosterone synthase is also known as 18-hydroxylase (CYP11B2). The gene symbol for
sulfotransferase is SULT2A1. Place your mouse over structure names to see chemical structures. Click
here for a larger format picture.
Conversion of prenenolone to progesterone requires the two enzyme activities of HSD3B2: the 3hydroxysteroid dehydrogenase and 4,5-isomerase activities. Zona glomerulosa cells lack the P450c17
that converts pregnenolone and progesterone to their C 17 hydroxylated analogs. Thus, the pathways to the
glucocorticoids (deoxycortisol and cortisol) and the androgens [dehydroepiandosterone (DHEA) and
androstenedione] are blocked in these cells. Zona glomerulosa cells are unique in the adrenal cortex in
containing the enzyme responsible for converting corticosterone to aldosterone, the principal and most
potent mineralocorticoid. This enzyme is P450c18 (or 18-hydroxylase, CYP11B2), also called aldosterone
synthase. The result is that the zona glomerulosa is mainly responsible for the conversion of cholesterol to
the weak mineralocorticoid, corticosterone and the principal mineralocorticoid, aldosterone.

Cells of the zona fasciculata and zona reticularis lack aldosterone synthase (P450c18) that converts
corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid
corticosterone. However, both these zones do contain the P450c17 missing in zona glomerulosa and thus
produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain
P450c17, whose 17,20-lyase activity is responsible for producing the androgens, dehydroepiandosterone
(DHEA) and androstenedione. Thus, fasciculata and reticularis cells can make corticosteroids and the
adrenal androgens, but not aldosterone.
As noted earlier, P450ssc is a mitochondrial activity. Its product, pregnenolone, moves to the cytosol,
where it is converted either to androgens or to 11-deoxycortisol and 11-deoxycorticosterone by enzymes of
the endoplasmic reticulum. The latter 2 compounds then re-enter the mitochondrion, where the enzymes
are located for tissue-specific conversion to glucocorticoids or mineralocorticoids, respectively.
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Regulation of Adrenal Steroid Synthesis

Adrenocorticotropic hormone (ACTH), of the hypothalamus, regulates the hormone production of the zona
fasciculata and zona reticularis. ACTH receptors in the plasma membrane of the cells of these tissues
activate adenylate cyclase with production of the second messenger, cAMP. The effect of ACTH on the
production of cortisol is particularly important, with the result that a classic feedback loop is prominent in
regulating the circulating levels of corticotropin releasing hormone (CRH), ACTH, and cortisol.
Mineralocorticoid secretion from the zona glomerulosa is stimulated by an entirely different mechanism.
Angiotensins II and III, derived from the action of the kidney protease renin on liver-derived
angiotensinogen, stimulate zona glomerulosa cells by binding a plasma membrane receptor coupled to
phospholipase C. Thus, angiotensin II and III binding to their receptor leads to the activation of PKC and
elevated intracellular Ca2+ levels. These events lead to increased P450ssc activity and increased
production of aldosterone. In the kidney, aldosterone regulates sodium retention by stimulating gene
expression of mRNA for the Na +/K+ATPase responsible for the reaccumulation of sodium from the urine.
The interplay between renin from the kidney and plasma angiotensinogen is important in regulating
plasma aldosterone levels, sodium and potassium levels, and ultimately blood pressure. Among the drugs
most widely employed used to lower blood pressure are the angiotensin converting enzyme (ACE)
inhibitors. These compounds are potent competitive inhibitors of the enzyme that converts angiotensin I to
the physiologically active angiotensins II and III. This feedback loop is closed by potassium, which is a
potent stimulator of aldosterone secretion. Changes in plasma potassium of as little as 0.1mM can cause
wide fluctuations (50%) in plasma levels of aldosterone. Potassium increases aldosterone secretion by
depolarizing the plasma membrane of zona glomerulosa cells and opening a voltage-gated calcium
channel, with a resultant increase in cytoplasmic calcium and the stimulation of calcium-dependent
processes.
Although fasciculata and reticularis cells each have the capability of synthesizing androgens and
glucocorticoids, the main pathway normally followed is that leading to glucocorticoid production. However,
when genetic defects occur in the 3 enzyme complexes leading to glucocorticoid production, large
amounts of the most important androgen, dehydroepiandrosterone (DHEA), are produced. These lead to
hirsutism and other masculinizing changes in secondary sex characteristics.
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Functions of the Adrenal Steroid Hormones

Glucocorticoids: The glucocorticoids are a class of hormones so called because they are primarily
responsible for modulating the metabolism of carbohydrates. The overall actions of the glucocorticoids is to
increase the production of glucose while simultaneously inhibiting all other metabolic pathways not directly
involved in glucose production. However, it is important to note that most glucocorticoids bind to the
mineralocorticoid receptor and as such exhibit mineralocorticoid-like activities. Cortisol is the most
important naturally occurring glucocorticoid. As indicated in the Figure above, cortisol is synthesized in the
zona fasciculata of the adrenal cortex. When released to the circulation, cortisol is almost entirely bound to
protein. A small portion is bound to albumin with more than 70% being bound by a specific glycosylated globulin called transcortin or corticosteroid-binding globulin (CBG). Between 5% and 10% of circulating
cortisol is free and biologically active. Glucocorticoid function is exerted following cellular uptake and
interaction with intracellular glucocorticoid receptors (GR) as discussed below. Cortisol inhibits uptake and
utilization of glucose resulting in elevations in blood glucose levels. Glucocorticoids act as insulin
antagonists and also suppress the release of insulin both effect leading to reduced glucose uptake and
enhanced hepatic gluconeogenesis. The effect of cortisol on blood glucose levels is further enhanced
through the increased breakdown of skeletal muscle protein and adipose tissue triglycerides which
provides energy and substrates for gluconeogenesis. Glucocorticoids also increase the synthesis of
gluconeogenic enzymes. The increased rate of protein metabolism leads to increased urinary nitrogen
excretion and the induction of urea cycle enzymes.
In addition to the metabolic effects of the glucocorticoids, these hormones are immunosuppressive and
anti-inflammatory. Hence, the use of related drugs such as prednisone, in the acute treatment of
inflammatory disorders. The anti-inflammatory activity of the glucocorticoids is exerted, in part, through
inhibition of phospholipase A2 (PLA2) activity with a consequent reduction in the release of arachidonic
acid from membrane phospholipids. Arachidonic acid serves as the precursor for the synthesis of various
eicosanoids. Glucocorticoids also inhibit vitamin D-mediated intestinal calcium uptake, retard the rate of
wound healing, and interfere with the rate of linear growth.
Mineralocorticoids: The major circulating mineralocorticoid is aldosterone. Deoxycorticosterone (DOC)
exhibits some mineralocorticoid action but only about 3% of that of aldosterone. As the name of this class
of hormones implies, the mineralocorticoids control the excretion of electrolytes. This occurs primarily
through actions on the kidneys but also in the colon and sweat glands. The principle effect of aldosterone
is to enhance sodium reabsorption in the cortical collecting duct of the kidneys. However, the action of
aldosterone is exerted on sweat glands, stomach, and salivary glands to the same effect, i.e. sodium
reabsorption. This action is accompanied by the retention of chloride and water resulting in the expansion
of extracellular volume. Aldosterone also enhances the excretion of potassium and hydrogen ions from the
medullary collecting duct of the kidneys.
Androgens: The androgens, androstenedione and DHEA, circulate bound primarily to sex hormonebinding globulin (SHBG). Although some of the circulating androgen is metabolized in the liver, the majority
of interconversion occurs in the gonads (as described below), skin, and adipose tissue. DHEA is rapidly
converted to the sulfated form, DHEA-S, in the liver and adrenal cortex. The primary biologically active
metabolites of the androgens are testosterone and dihydrotestosterone which function by binding
intracellular receptors, thereby effecting changes in gene expression and thereby, resulting in the
manifestation of the secondary sex characteristics.
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Clinical Significance of Defective Adrenal Steroidogenesis

Defective synthesis of the steroid hormones produced by the adrenal cortex can have profound effects on
human development and homeostasis. In 1855 Thomas Addison identified the significance of the
"suprarenal capsules" when he reported on the case of a patient who presented with chronic adrenal
insufficiency resulting from progressive lesions of the adrenal glands caused by tuberculosis. Adrenal
insufficiency is, therefore, referred to as Addison disease. In the absence of steroid hormone replacement
therapy, Addison disease can rapidly cause death in a little as 12 weeks.
In addition to diseases that result from the total absence of adrenocortical function, there are syndromes
that result from hypersecretion of adrenocortical hormones (hypercortisolemia). In 1932 Harvey Cushing
reported on several cases of adrenocortical hyperplasia that were the result of basophilic adenomas of the
anterior pituitary. Hypercortisolemias that manifest due to adrenocortical hyperplasia are referred to as
Cushing syndrome, whereas, hypercortisolemias due to excessive anterior pituitary secretion of ACTH are
referred to as Cushing disease.
Despite the characterizations of adrenal insufficiency and adrenal hyperplasia, there remained uncertainty
about the relationship between adrenocortical hyperfunction and virilism (premature development of male
secondary sex characteristics). In 1942 this confusion was resolved by Fuller Albright when he delineated
the differences between children with Cushing syndrome and those with adrenogenital syndromes which
are more commonly referred to as congenital adrenal hyperplasias (CAH) . The CAH are a group of
inherited disorders that result from loss-of-function mutations in one of several genes involved in adrenal
steroid hormone synthesis. In the virilizing forms of CAH the mutations result in impairment of cortisol
production and the consequent accumulation of steroid intermediates proximal to the defective enzyme. All
forms of CAH are inherited in an autosomal recessive manner. There are two common and at least three
rare forms of CAH that result in virilization. The common forms are caused by defects in either CYP21A2
(21-hydroxylase, also identified as just CYP21 or CYP21B) or CYP11B1 (11-hydroxylase). The majority of
CAH cases (9095%) are the result of defects in CYP21A2 with a frequency of between 1 in 5,000 and 1
in 15,000. Three rare forms of virilizing CAH result from either defects in 3-hydroxysteroid
dehydrogenase (HSD3B2), placental aromatase or P450-oxidoreductase (POR). An additional CAH is
caused by mutations that affect either the 17-hydroxylase, 17,20-lyase or both activities encoded in the
CYP17A1 gene. In individuals harboring CYP17A1 mutations that result in severe loss of enzyme activity
there is absent sex steroid hormone production accompanied by hypertension resulting from
mineralocorticoid excess.
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Gonadal Steroid Hormones

Although many steroids are produced by the testes and the ovaries, the two most important are
testosterone and estradiol. These compounds are under tight biosynthetic control, with short and long
negative feedback loops that regulate the secretion of follicle stimulating hormone (FSH) and luteinizing
hormone (LH) by the pituitary and gonadotropin releasing hormone (GnRH) by the hypothalamus. Low
levels of circulating sex hormone reduce feedback inhibition on GnRH synthesis (the long loop), leading to
elevated FSH and LH. The latter peptide hormones bind to gonadal tissue and stimulate P450ssc activity,
resulting in sex hormone production via cAMP and PKA mediated pathways. The roles of cAMP and PKA
in gonadal tissue are the same as that described for glucocorticoid production in the adrenals, but in this
case adenylate cyclase activation is coupled to the binding of LH to plasma membrane receptors.
The biosynthetic pathway to sex hormones in male and female gonadal tissue includes the production of
the androgens, androstenedione and dehydroepiandrosterone. Testes and ovaries contain an additional
enzyme, a 17-hydroxysteroid dehydrogenase, that enables androgens to be converted to testosterone.

In males, LH binds to Leydig cells, stimulating production of the principal Leydig cell hormone,
testosterone. Testosterone is secreted to the plasma and also carried to Sertoli cells by androgen binding
protein (ABP). In Sertoli cells the 4 double bond of testosterone is reduced, producing
dihydrotestosterone. Testosterone and dihydrotestosterone are carried in the plasma, and delivered to
target tissue, by a specific gonadal-steroid binding globulin (GBG). In a number of target tissues,
testosterone can be converted to dihydrotestosterone (DHT). DHT is the most potent of the male steroid
hormones, with an activity that is 10 times that of testosterone. Because of its relatively lower potency,
testosterone is sometimes considered to be a prohormone.

Synthesis of the male sex hormones in Leydig cells of the testis. P450SSC, 3-DH, and P450c17 are the
same enzymes as those needed for adrenal steroid hormone synthesis. 17,20-lyase is the same activity of
CYP17A1 described above for adrenal hormone synthesis. Aromatase (also called estrogen synthetase) is
CYP19A1. 17-ketoreductase is also called 17-hydroxysteroid dehydrogenase type 3 (gene symbol
HSD17B3). The full name for 5-reductase is 5-reductase type 2 (gene symbol SRD5A2). Place your
mouse over structure names to see chemical structures.
Testosterone is also produced by Sertoli cells but in these cells it is regulated by FSH, again acting
through a cAMP- and PKA-regulatory pathway. In addition, FSH stimulates Sertoli cells to secrete

androgen-binding protein (ABP), which transports testosterone and DHT from Leydig cells to sites of
spermatogenesis. There, testosterone acts to stimulate protein synthesis and sperm development.
In females, LH binds to thecal cells of the ovary, where it stimulates the synthesis of androstenedione and
testosterone by the usual cAMP- and PKA-regulated pathway. An additional enzyme complex known as
aromatase is responsible for the final conversion of the latter 2 molecules into the estrogens. Aromatase is
a complex endoplasmic reticulum enzyme found in the ovary and in numerous other tissues in both males
and females. Its action involves hydroxylations and dehydrations that culminate in aromatization of the A
ring of the androgens.

Synthesis of the major female sex hormones in the ovary. Synthesis of testosterone and androstenedione
from cholesterol occurs by the same pathways as indicated for synthesis of the male sex hormones.
Aromatase (also called estrogen synthetase) is CYP19A1.
Aromatase activity is also found in granulosa cells, but in these cells the activity is stimulated by FSH.
Normally, thecal cell androgens produced in response to LH diffuse to granulosa cells, where granulosa
cell aromatase converts these androgens to estrogens. As granulosa cells mature they develop competent
large numbers of LH receptors in the plasma membrane and become increasingly responsive to LH,
increasing the quantity of estrogen produced from these cells. Granulosa cell estrogens are largely, if not
all, secreted into follicular fluid. Thecal cell estrogens are secreted largely into the circulation, where they
are delivered to target tissue by the same globulin (GBG) used to transport testosterone.
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Thyroid Hormones
The thyroid hormones, referred to as the thyronines, are synthesized from the amino acid tyrosine within
specialized cells of the thyroid gland. The two major thyroid hormones are triiodothyronine (T3) and
thyroxine (T4). Within the periphery the major actions of thyroid hormone are exerted via T3. Synthesis of

the thyroid hormones is controlled via the action of the anterior pituitary hormone, thyroid stimulating
hormone, TSH. In addition to pituitary control, synthesis of the thyroid hormones requires iodine uptake
into the thyroid gland and incorporation into tyrosine. The primary functions for the thyroid hormones are
fetal and post-natal development, development of the CNS, modulation of cardiac function through
regulation of myocardial contraction and relaxation, renal water clearance, gastrointestinal motility, thermal
regulation, energy expenditure, and regulation of lipid metabolism. The thyroid gland also synthesizes the
peptide hormone, calcitonin, from parafollicular C cells. However, calcitonin has no physiological role in
humans but the protein is an important marker for thyroid medullary carcinomas.

Primary Activities of Thyroid Hormone (T 3)

Adipose tissue

catabolic

activation of lipolysis and triglyceride breakdown; increases adrenergic receptor density

Bone

developmental

promotes bone growth and differentiation

Central
nervous
system

developmental

promotes development of nervous tissue

Gastrointestinal metabolic
system

increases carbohydrate absorption

Heart

both inotropic
and
chronotropic

increases density of -adrenergic receptors; enhances cardiac

responses to catecholamines; enhances ATPase activity of -myosin
heavy chain

Liver

metabolic

increases gluconeogenesis and glycogen breakdown; increases

cholesterol metabolism; enhances production of LDL receptors

Muscle

catabolic

enhances protein breakdown; increases speed of contraction and

relaxation; increases -adrenergic receptor density

Iodine Homeostasis
Iodine is a critical micronutrient due to its role in the generation of functional thyroid hormones. Dietary
intake of iodine is recommended to be 150g/day for adults and 50-200g/day for children. In the US, and
other developed countries, the use of iodized sodium chloride (salt) ensures an adequate daily intake for
most individuals.
The basolateral membrane of thyroid gland cells (thyrocytes) transports iodide into the cell from the
circulation. The transporter is called the Na+/I symporter (NIS) which is encoded by the SLC5A5 gene.
The NIS transporter move two moles of Na+ and one mole of I into the thyrocyte. The transporter is able
to produce intra-thyrocyte iodide concentrations that are 20-40 fold higher than that in the circulation. The
expression of the thyrocyte SLC5A5 gene is controlled via the actions of TSH. In addition to regulated
expression, TSH controls the migration of NIS into and out of the basolateral membranes of the thyrocyte.
Mutations in the SLC5A5 gene result in thyroid dyshormonogenesis type 1 (TDH1).
In order to continue the uptake of iodide, thyrocytes must transport the Na + back into the circulation which
is catalyzed by a Na+/K+-ATPase. The incorporation of iodine into tyrosine occurs in the lumen of thyroid
follicles (the colloid) and it is transported across the thyrocyte apical membrane via the action of a Cl/I

exchanger identified as pendrin (SLC26A4). Mutations in the SLC26A4 gene are the cause of Pendrin
syndrome (PDS), also known as thyroid dyshormonogenesis type 2B (TDH2B). PDS is associated with
congenital deafness and thyroid dysfunction resulting in goiter.
Although the thyroid gland is the primary tissue requiring iodine for its hormonal functions, salivary glands,
gastric mucosa, choroid plexus, mammary glands, and the ciliary body of the eye express the SLC5A5
gene.
Thyroid Hormone Synthesis
Chronic stimulation of the thyroid gland, via TSH binding to its receptor on thyrocytes, causes an increase
in the synthesis of a major thyroid hormone precursor, thyroglobulin. Thyroglobulin is a large homodimeric
glycoprotein with a molecular weight of 660,000. Although thyroglobulin contains 140 tyrosine residues,
only four in each subunit serve as substrates for iodination. Following thyroglobulin synthesis and
glycosylation the homodimeric protein is incorporated into exocytic vesicles. Thyroglobulin is then
exoctosed through the apical membrane into the closed lumen of thyroid follicles (the colloid), where it
accumulates as the major protein of the thyroid gland and where maturation takes place. Within the colloid
iodide (I) is oxidized to I+ by thyroid peroxidase (TPO; also called thyroperoxidase) found only in thyroid
tissue. The oxidation reaction catalyzed by TPO requires hydrogen peroxide (H2O2) which is produced by
an NADPH oxidase complex often referred to as thyroid oxidase. TPO and the NADPH oxidase complex
are all associated in a large complex at the apical membrane of thyrocytes. The NADPH oxidase is
composed multiple subunits encoded by different genes. These genes include dual oxidase 1 (DUOX1)
and dual oxidase 2 (DUOX2). Another gene required for the function of the NADPH oxidase complex is
DUOXA2 (dual oxidase maturation factor 2) which is involved in the maturation and membrane localization
of DUOX2. The activity of the NADPH oxidase is also regulated via the actions of TSH. The addition of I+
to tyrosine residues of thyroglobulin is catalyzed by TPO at the thyrocyte apical membrane-colloid
interface. The products of this reaction are thyroglobulin complexes containing monoiodotyrosyl (MIT) and
diiodotyrosyl (DIT) residues. Two molecules of DIT condense to form T 4 while a molecule of MIT and one
of DIT condense to form T3. Mutations in the TPO gene are associated with thyroid dyshormonogenesis
type 2A (THD2A)

Structures of the primary thyroid hormones

Mature, iodinated thyroglobulin contains approximately three molecules of T 4 and one molecule of T3.
Following the iodination reactions, thyroglobulin is taken up into vesicles at the colloid-apical membrane
interface via a process referred to as pinocytosis. These vesicles then fuse with lysosomes. Lysosomal
proteases degrade thyroglobulin releasing T3 and T 4, as well as inactive iodotyrosines and amino acids.
T 3 and T 4 are then secreted into the circulation. These compounds are very hydrophobic and require a
carrier protein for delivery to target tissues. In the plasma, T3 and T 4 are primarily (70%) bound to a carrier
glycoprotein known as thyroxin-binding globulin (TBG) and are disseminated throughout the body in this
form. In addition to TBG, T3 and T 4 can be carried in the blood bound to transthyretin (formerly thyroxinebinding prealbumin) or albumin.
The feedback loop that regulates T 3 and T 4 production is a single short negative loop, with the T 3 and T 4
being responsible for down-regulating anterior pituitary TSH secretion. Conversely, continuously secreted
hypothalamic thyrotropin-releasing hormone (TRH) is responsible for up-regulating pituitary TSH
production. Pituitary thyrotrope secretion of TSH is the net result of the negative effects of T3 and T 4 and
the positive effect of TRH.
T 3 is the more biologically active thyroid hormone and T 4 is converted to T 3 within peripheral tissues via
the actions of a 5'-deiodinase (thyroxine deiodinase type 1; DIO1). This deiodinase is also present in the
thyroid gland and plays a critical role in overall regulation of iodide homeostasis in this tissue. Deiodination
of MIT and DIT also takes place within the thyroid gland. These reactions are catalyzed by an NADPHdependent flavoprotein (iodotyrosine deiodinase; IYD) which recognizes MIT and DIT but not T3 nor T 4.
The iodine released from MIT and DIT is reused for hormone biogenesis.
Thyroid Hormone Receptors
Thyroid hormones act by binding to cytosolic receptors of the steroid-thyroid hormone receptor superfamily
(nuclear receptors) identified as thyroid hormone receptors (TR). There are two TR receptors designated
TR and TR encoded by the THRA and THRB genes, respectively. The THRA gene is located on
chromosome 17q21.1. The THRB is located on chromosome 3p24.2. The mRNAs from both genes are
subject to alternative splicing. This results in the TR1, TR2, and TR3 isoforms from the THRA gene and
TR1 and TR2 from the THRB. Each of these thyroid hormone receptors possesses the characteristic
domains of all members of the nuclear receptor family: ligand-binding domain (LBD), DNA-binding domain
(DBD), and activation function domain (AFD).
All of the TR bind to a specific response element in target genes termed the thyroid hormone response
element (TRE). The TRE is composed of repeated DNA sequences with different configurations. Evidence
indicates that TRs can bind to TREs as monomers or homodimers. However, the major form of the TR
bound to a TRE is a heterodimer with retinoid X receptor (RXR). The RXR binding site is upstream of the
two directly repeated half-sites of the TRE. The TRE half-sites each contain the sequence T(A/G)AGGTCA
as direct repeats separated by a 4 bp spacer. This is referred to as the DR4 element. The RXR response
element is GGGGTCA. An important property of TRs is their ability to bind TREs constitutively in the
absence of thyroid hormone. In this unliganded state, TR generally represses basal transcription. Binding
of thyroid hormone to TR triggers a conformational change in the receptor, resulting in activated
transcription of target genes.
Transcriptional activation by TR is mediated not only by ligand binding but by the activity of several
coactivator proteins. Steroid receptor coactivator-1 (SRC-1) was the first nuclear receptor coactivator
characterized and it has been shown to enhance the activity of ligand-bound TR. The significance of the
role of SRC-1 in thyroid hormone function is evident from the fact that loss of this coactivator results in T3

resistance. Several other members of the SRC family of coactivators have been shown to enhance the
functions of TR. Coactivators of the SRC family associate with p300/CBP [CBP: CREB (cAMP response
element-binding protein)-binding protein]. Given that p300/CBP interacts with and mediates the activation
of other transcriptional regulation factors it is clear that this protein is a regulator of multiple signal
transduction pathways in addition to its role in steroid/thyroid hormone receptor functions.
Thyroid Hormone Biogenesis Disorders
Numerous inherited disorders in the biogenesis of the thyroid hormones have been described. All of these
disorders are associated with congenital hypothyroidism. Currently seven distinct gene defects are known
that result in this type of disorder. Three of these disorders were indicated in the discussion above, TDH1,
TDH2A, and TDH2B.
TDH1

Na+/I symporter (NIS):

SLC5A5
chromosome 19p13.2
p12

TDH2A

thyroid peroxidase, TPO

chromosome 2p25

recurrent goiter, complete iodide release

TDH2B

pendrin: SLC26A4
chromosome 7q31

sensorineural hearing loss, goiter, partial iodide release, enlarged

vestibular aqueduct

TDH3

thyroglobulin, TG
chromosome 8q24

large goiters with soft and elastic consistency

TDH4

tyrosine deiodinase, IYD

chromosome 6q25.1

goiter, continuous iodine and tyrosine loss in the urine, delayed

psychomotor development, stunted growth

TDH5

dual oxidase maturation

factor 2: DUOXA2
chromosome 15q15.3

goiter

TDH6

dual oxidase 2 (DUOX2):

thyroid oxidase 2
chromosome 15q15.3

partial or defective iodide organification

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Hypo- and Hyperparathyroidism

Numerous congenital and acquired forms of hypothyroidism and hyperthyroidism are the result of
alterations in the expression, processing, and function of the TSHR. The most common TSHR disorder
resulting in hyperthyroidism (thyrotoxicosis) is Graves disease. Graves disease is caused by thyroidstimulating autoantibodies (TSAb, also called thyroid-stimulating immunoglobulins, TSIs) which bind to and
activate the human TSH receptor, leading to the thyrotoxicosis characteristic of this disease. TSAbs bind to
the TSH receptor and mimic the TSH stimulation of the thyroid gland by increasing intracellular cAMP. The
hyperactivated thyroid then secretes excessive T 3 and T 4. Graves disease is classified as a form of
thyrotoxicosis, the name for the clinical syndrome resulting from tissues exposed to high levels of thyroid
hormones. One theory proposed for the development of the TSAb is that there is a defect in suppressor T
cells that allows helper T cells to stimulate B cells to produce thyroid autoantibodies. The clinical features
of Graves disease are thyrotoxicosis, goiter (enlarged thyroid gland), an ophthalmopathy in the form of

exophthalmos (eyes bulge out), and dermopathy in the form of pretibial myxedema (localized lesions of the
skin, primarily in the lower legs, resulting from the deposition of hyaluronic acid).
At the other end of the spectrum are disorders that lead to hypothyroidism. Deficiency in iodine is the most
common cause of hypothyroidism worldwide. Indeed the practice of producing iodized table salt was to
stem the occurrence of hypothyroidism. When hypothyroidism is evident in conjunction with sufficient
iodine intake it is either autoimmune disease (Hashimoto thyroiditis) or the consequences of treatments for
hyperthyroidism that are the cause. In the embryo, thyroid hormone is necessary for normal development
and hypothyroidism in the embryo is responsible for cretinism, which is characterized by multiple
congenital defects and mental retardation. Because the neurological consequences of congenital
hypothyroidism are severe, neonatal screening for thyroid hormone levels at birth is routine. Most infants
born with congenital hypothyroidism appear normal at birth. However, if left untreated the symptoms will
include a thick protruding tongue, poor feeding, prolonged jaundice (which exacerbates the neurological
impairment), hypotonia (recognized as "floppy baby syndrome"), episodes of choking, and delayed bone
maturation resulting in short stature.
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Steroid and Thyroid Hormone Receptors

The receptors to which steroid and thyroid hormones bind are ligand-activated proteins that regulate
transcription of selected genes. Unlike peptide hormone receptors, that span the plasma membrane and
bind ligand outside the cell, steroid/thyroid hormone receptors are found in the cytosol or the nucleus in the
absence of ligand. All of these receptors belong to the steroid and thyroid hormone receptor super-family of
receptors. This large family of receptors includes the androgen receptor (AR), the progesterone receptor
(PR), the estrogen receptor (ER), the thyroid hormone receptor (TR), the vitamin D receptor (VDR), the
retinoic acid receptors (RARs), the mineralocorticoid receptor (MR), and the glucocorticoid receptor (GR).
This large class of receptors is known as the nuclear receptors.
When these receptors bind ligand they undergo a conformational change that renders them activated to
recognize and bind to specific nucleotide sequences. These specific nucleotide sequences in the DNA are
referred to as hormone-response elements (HREs). When ligand-receptor complexes interact with DNA
they alter the transcriptional level (responses can be either activating or repressing) of the associated
gene. Thus, the steroid-thyroid family of receptors all have three distinct domains: a ligand-binding domain
(LBD), a DNA-binding domain (DBD) and a transcriptional regulatory domain, referred to as the activation
function domain (AFD). Although there is the commonly observed effect of altered transcriptional activity in
response to hormone-receptor interaction, there are family member-specific effects with ligand-receptor
interaction. Binding of thyroid hormone to its receptor results in release of the receptor from DNA. Several
receptors are induced to interact with other transcriptional mediators in response to ligand binding. Binding
of glucocorticoid leads to translocation of the ligand-receptor complex from the cytosol to the nucleus.
The receptors for the retinoids (vitamin A and its derivatives ) are identified as RARs (for retinoic acid, RA
receptors) and exist in at least three subtypes, RAR, RAR and RAR. In addition, there is another family
of nuclear receptors termed the retinoid X receptors (RXRs) that represents a second class of retinoidresponsive transcription factors. The RXRs have been shown to enhance the DNA-binding activity of
RARs and the thyroid hormone receptors (TRs). The RXRs represent a class of receptors that bind the
retinoid 9-cis-retinoic acid. There are three isotypes of the RXRs: RXR, RXR, and RXR and each
isotype is composed of several isoforms. The RXRs serve as obligatory heterodimeric partners for
numerous members of the nuclear receptor family including PPARs, LXRs, and FXRs (see below and the
Signal Transduction page). In the absence of a heterodimeric binding partner the RXRs are bound to

hormone response elements (HREs) in DNA and are complexed with co-repressor proteins that include a
histone deacetylase (HDAC) and silencing mediator of retinoid and thyroid hormone receptor (SMRT) or
nuclear receptor corepressor 1 (NCoR).

Model for NR interactions with corepressors: An example of the transcription corepressor complexes
associated with both the RXR and RAR heterodimeric transcription factor complex at an HRE, and several
basal transcription factors associated with RNA pol II at a target gene transcriptional start site. The
presence of histone deacetylases (e.g. HDAC3) leads to removal of any chromatin activating histone
acetylation sites causing formation of transcriptionally repressed chromatin structure.
RXR is widely expressed with highest levels liver, kidney, spleen, placenta, and skin. The critical role for
RXR in development is demonstrated by the fact that null mice are embryonic lethals. RXR is important
for spermatogenesis and RXR has a restricted expression in the brain and muscle. The major difference
between the RARs and RXRs is that the former exhibit highest affinity for all-trans-retinoic acid (all-transRA) and the latter for 9-cis-RA.
Additional super-family members are the peroxisome proliferator-activated receptors (PPARs). The PPAR
family is composed of three family members: PPAR, PPAR/, and PPAR. Each of these receptors
forms a heterodimer with the RXRs. The first family member identified was PPAR and it was found by
virtue of it binding to the fibrate class of anti-hyperlipidemic drugs or peroxisome proliferators.
Subsequently it was shown that PPAR is the endogenous receptor for polyunsaturated fatty acids.
PPAR is highly expressed in the liver, skeletal muscle, heart, and kidney. Its function in the liver is to
induce hepatic peroxisomal fatty acid oxidation during periods of fasting. Expression of PPAR is also
seen in macrophage foam cells and vascular endothelium. Its role in these cells is thought to be the
activation of anti-inflammatory and anti-atherogenic effects. PPAR is a master regulator of adipogenesis
and is most abundantly expressed in adipose tissue. Low levels of expression are also observed in liver

and skeletal muscle. PPAR was identified as the target of the thiazolidinedione (TZD) class of insulinsensitizing drugs. The mechanism of action of the TZDs is a function of the activation of PPAR activity
and the consequent activation of adipocytes leading to increased fat storage and secretion of insulinsensitizing adipocytokines such as adiponectin. PPAR is expressed in most tissues and is involved in the
promotion of mitochondrial fatty acid oxidation, energy consumption, and thermogenesis. PPAR serves
as the receptor for polyunsaturated fatty acids and VLDLs. Current pharmacologic targeting of PPAR is
aimed at increasing HDL levels in humans since experiments in animals have shown that increased
PPAR levels result in increased HDL and reduced levels of serum triglycerides.
Genome wide association screening (GWAS) has demonstrated a role for polymorphisms in the PPAR
gene in the etiology of type 2 diabetes. As indicated above, pharmacologically, TZDs are useful in the
treatment of the hypoglycemia associated with type 2 diabetes. The TZDs bind to and alter the function of
PPAR resulting in reductions in circulating triglycerides which secondarily leads to reduced serum
glucose levels and subsequently increased insulin sensitivity. It is still not completely clear how impaired
PPAR signaling can affect the sensitivity of the body to insulin or indeed if the observed mutations are a
direct or indirect cause of the symptoms of insulin resistance.
In addition to the nuclear receptors discussed here additional family members (discussed in more detail in
the Signal Transduction page) are the liver X receptors (LXRs), farnesoid X receptors (FXRs), the
pregnane X receptor (PXR), the estrogen related receptors (ERR and ERR), the retinoid-related orphan
receptor (ROR), and the constitutive androstane receptor (CAR).
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Last modified: April 6, 2015